03 - Rapport FR-PB J150

JOINT RAPPORTEURS
Assessment Report on the Applicants responses to the

D150 CHMP LOQ

OVERVIEW

VICTRELIS
Boceprevir

EMEA/H/C/0002332/000

Applicant: Schering-Plough

Rapporteur:
Co-Rapporteur:
EMA PTL:
Start of the procedure: 26 November 2010
Date of this JOINT D150 report: 4 May 2011
Deadline for CHMP comments 9 May 2011

2

TABLE OF CONTENTS
1. RECOMMENDATION ................................................................................. 6
2. EXECUTIVE SUMMARY ............................................................................. 7
2.1. Problem statement ............................................................................................... 7
2.2. About the product ................................................................................................ 8
2.3. The development programme/Compliance with CHMP Guidance/Scientific Advice ......... 9
2.4. General comments on compliance with GMP, GLP, GCP ........................................... 10
2.5. Type of application and other comments on the submitted dossier............................ 10
3. SCIENTIFIC OVERVIEW AND DISCUSSION ............................................ 11
3.1. Introduction....................................................................................................... 11
3.2. Quality aspects .................................................................................................. 11
3.3. Non clinical aspects ............................................................................................ 13
3.4. Clinical aspects .................................................................................................. 20
4. ORPHAN MEDICINAL PRODUCTS ........................................................... 62
5. BENEFIT RISK ASSESSMENT .................................................................. 62
5.1. Conclusions ....................................................................................................... 68
6. LIST OF ISSUES TO BE FURTHER CLARIFIED AND COMMITMENTS ....... 69
6.1 Quality aspects ................................................................................................. 69
6.2 Non clinical aspects ........................................................................................... 71
6.3 Clinical aspects ................................................................................................. 71
7. SUMMARY OF PRODUCT CHARACTERISTICS (SMPC)............................ 73
3
ADMINISTRATIVE INFORMATION
Invented name of the medicinal product: VICTRELIS
INN (or common name) of the active
substance(s):
BOCEPREVIR
Applicant: Schering-Plough
Applied Indication(s): Treatment of chronic hepatitis C genotype 1
infection, in combination with peginterferon alpha
and ribavirin, in adult patients with compensated
liver disease who are previously untreated or who
have failed previous therapy.
Pharmaco-therapeutic group
(ATC Code):
Not yet assigned
Pharmaceutical form(s) and strength(s): 200 mg
Rapporteur contact person:

Co-Rapporteur contact person:

EMA Product Team Leader:

Names of the Rapporteur assessors
(internal and external):

Names of the Co-Rapporteur assessors
(internal and external):

4
LIST OF ABBREVIATIONS
AE adverse event
ALT alanine transaminase
ANC absolute neutrophil count
aPTT Activated Partial Thromboplastin Time
AUC area under the concentration-time curve
BMI body mass index
BND benzphetamine N-demethylase
CHC chronic hepatitis C
CHMP Committee for Medicinal Products for Human Use
CI confidence interval
CL/F apparent clearance
Cmax maximum drug concentration
CSR clinical study report
CV coefficient of variation
CYP cytochrome P450
DMC data monitoring committee
DNA deoxyribonucleic acid
ECOD 7-ethoxycoumarin O-deethylase
ELISA enzyme linked immunosorbent assay
EROD 7-ethoxyresorufin O-deethylase
ESRD end-stage renal disease
ETR end of treatment response
EU European Union
FDA US Food and Drug Administration
GCP Good Clinical Practice
GGT gamma glutamyl transferase
HCV hepatitis C virus
HIV human immunodeficiency virus
IFN interferon
IFN interferon alfa
ITT intention-to-treat
IU international units
IV intravenous(ly)
LOD limit of detection
MedDRA Medical Dictionary for Regulatory Activities
PCR polymerase chain reaction
PD Pharmacodynamics
PEG-IFN pegylated interferon
PEG-IFN2a peginterferon alfa-2a
PEG-IFN2b peginterferon alfa-2b
PR Peginterferon+Ribavirin
PK pharmacokinetics
PT Prothrombin Time
PROD 7-pentoxyresorufin O-dealkylase
RBV ribavirin
RNA ribonucleic acid
SAE serious adverse event
SC subcutaneous(ly)
SOC Standard of Care=Peg-IFN+Ribavirin = Bitherapy
SVR sustained virologic response
t1/2, absorption half-life
5
t1/2,z elimination half-life
TSH thyroid stimulating hormone
ULN upper limit of normal
US United States of America

SCH 18908 Ribavirin
SCH 503034 Boceprevir
SCH 534128 Diastereoisomer of boceprevir with S-configuration at the third carbon atom from the
ketoamide end of the molecule
SCH 534129 Diastereoisomer of boceprevir with R-configuration at the third carbon atom from the
ketoamide end of the molecule
SCH 54031 PEG-Intron, peginterferon alpha
SCH 629144 Major circulating metabolite of boceprevir in monkeys and humans
SCH 783004 Diastereoisomer of SCH 629144, formed from SCH 534129
6
1. RECOMMENDATION
Based on the review of the data on quality, safety and efficacy, the Rapporteurs consider that the
application for VICTRELIS (Boceprevir), in the treatment of genotype 1 chronic hepatitis C infection in
adult patients with compensated liver disease, could be approvable provided the SPC is revised in line
with Rapporteurs comments. Moreover, two main issues should be part of the annex II since it is
considered compulsory to further substantiate the benefit/risk balance:
1- the clinical dossier so far does not allow to fully appreciate to what extent the management of the
substantial incremental anemia induced by boceprevir on top of PR could per se negatively affect the
benefit-risk balance of boceprevir, having in mind that on the one hand ribavirin dose reduction could
potentially alter the benefit and on the other hand the EPO use, through its safety profile (associated with
risk of PRCA and thrombosis events), could alter the risk.
It is therefore considered compulsory that, in order to establish the most rational management of anemia,
additional investigations be performed by the applicant to better understand the causes (and consequently
possible patient characteristics) and potential negative consequences of the management of the high rate
of anemia (as a result of the incremental risk with boceprevir) in patients receiving the tritherapy with
boceprevir+ribavirin+peginterferon.
In particular the MAH is required to present plans and protocols investigating the following:

a. the mechanism underlying the observed increase of anemia (and to a lesser extent neutropenia and
thrombocytopenia) in patients co-administered boceprevir with PR standard of care, which is suggested
being the result of an additional suppressive effect on bone marrow hematopoietic processes.

b. the potential impact on efficacy of lowering the dose of ribavirin in the management of anemia. In
particular the data generated should provide further insight into the impact on the most optimal treatment
regimen and duration and the characterisation of the potential patient population for which ribavirin dose
reduction might be an option to manage the anemia.

c. the anemia management in patients treated for hepatitis C in the EU in the presence of boceprevir
in clinical practice.

2. The applicant should be committed to dispel the current level of uncertainties on whether those
patients with favourable factors (on treatment viral kinetics and/or IL28B) for interferon responsiveness
could still retrieve a significant benefit of adding boceprevir to the bitherapy. The design of the protocol
aimed at addressing this issue and currently under reflexion at the applicant level should mandatorily be
validated by the CHMP before the study starts and the timelines for submission of this draft protocol
should be shortened (beginning of September 2011 instead of December 2011) to avoid a late
implementation of the study.

7

2. EXECUTIVE SUMMARY
2.1. Problem statement
Hepatitis C virus (HCV) infection is one of the most important causes of chronic liver disease and a
growing global health concern.
Worldwide, approximately 3% of the population is infected with HCV, which represents several millions
of people who are at risk of developing serious liver disease, including cirrhosis, liver failure and
hepatocellular carcinoma.
In Europe, the prevalence tends to vary from 0.5% in Northern European countries to 2% and higher in
the Mediterranean countries and in Eastern Europe.

Approximately 70% of newly infected HCV patients become chronic carriers; among them 20% will
develop cirrhosis with a mean of 20 years. In patients with cirrhosis, the 5-year risk of hepatic
decompensation is approximately 15-20% and the risk of hepatocellular carcinoma 10%. End stage liver
disease due to HCV infection currently represents the major indication for liver transplantation in
developed countries.

At least 6 major genotypes of HCV, each including multiple subtypes, have been identified worldwide.
Genotype 1 accounts for most HCV infections globally, as well as in most European regions, with an
overall prevalence that is estimated above 60%. Infection with genotype 2 or 3 generally represents 20 to
30% of all HCV infection.

The current standard of care for CHC consists of the combination of pegylated interferon-alfa (2a
or 2b) and ribavirin. Treatment duration is generally 48 weeks for patients with genotype 1 or 4 and 24
weeks for patients with genotype 2 or 3 but may vary depending on baseline viral load and initial virologic
response to therapy. The primary treatment outcome is sustained viral response (SVR), which is defined as
HCV viral undetectability using a sensitive PCR-based assay 24 weeks following completion of therapy.

There are several pejorative factors (for the disease evolution and) for the response to treatment.
They may be virus related: notably infection by genotype 1 (majority of EU patients) is associated with
very limited response rates (40-50% SVR) as compared to the 80% response rates of genotype 2/3.

Moreover, patients co-infected with HIV-HCV viruses are known as exhibiting a more pejorative course
of the disease and have a lower response rate to the bitherapy.
The degree of fibrosis (cirrhotic patients are known as being difficult-to-treat patients) and the response
to prior course of bitherapy (null responders to a bitherapy are very poor response rate <10% to a
subsequent line of bitherapy) also particularly account for pejorative criteria.
Therefore, there are several of sub-populations of HCV infected patients that need to be covered
within clinical development since difficult to handle in clinical practice.

Currently the SOC is contra-indicated (since associated with particularly severe adverse events, notably
sepsis) in patients with decompensated liver disease, i.e. corresponding to the population of patients for
which the only remaining option is the transplantation. Nevertheless, in clinical practice the bitherapy is
used to achieve HCV RNA negativity in pre-transplant so as to decrease the likelihood of viral
breakthrough in post transplant.

Since viral breakthrough is quasi systematic in post transplant (most candidates to transplant having HCV
RNA positive before transplant), the population of post-transplant patients also accounts for a challenging
population especially as regards the need to also deal with immunosuppressive treatments.

8
Boceprevir belongs to the new class of Direct Acting Antiviral agents (DAA). After decades of
treatment only relying on the bitherapy with (Peg-)IFN+ribavirin, a lot of DAAs are currently in the
pipeline and offer perspectives of therapeutic improvement for the patients infected with a genotype 1, for
which there is a critical room for improvement, as opposed to the genotype 2/3 (good responders to SOC).

It is anticipated that the first generations drugs (including boceprevir) will one day be superseded
by next generations approaching Applications status (with simplified dosing regimen, higher
potency and higher genetic barrier)as in field of HIV infection.

In parallel to the development of these new DAAs, a new significant finding has emerged from the
scientific community as regards the likelihood of response to the SOC with the bitherapy Peg-
IFN+ribavirin. It has recently been identified that a genetic polymorphism near the IL28B gene,
encoding interferon--3, was strongly associated with the likelihood of response to SOC (Ge D, Fellay J,
Thompson JT, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature
2009; 461, 399-401.IL28B genomic-based treatment paradigms for patients with chronic hepatitis C infection: the future of personalized HCV
therapies. Clark PJ, Thompson AJ, McHutchison JG. Am J Gastroenterol. 2011 Jan;106(1):38-45).
Three different genotypes of this polymorphism were identified: CC, TT, and CT. The prevalence of the
favorable CC genotype varied among racial groups, this genotype was seen to provide a stronger baseline
predictor of SVR within each racial group than viral load, HCV genotype, cirrhosis or any other known
predictor of responsiveness to interferon-based therapy.

Still recently, a genetic variant leading to inosine triphosphatase (ITPA) deficiency has been associated
with risk of ribavirin-related anemia during SOC. (Fellay J, Thompson AJ, Ge D, Gumbs CE, Urban TJ, Shianna KV, et al.
ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature 2010;464:405-408.Thompson AJ, Fellay J, Ge D,
Urban T, Shianna K, Sulkowski M, et al. Genome wide analysis of patients from the IDEAL study identifies a causal role for ITPA genetic
variation in ribavirin-induced hemolytic anemia. Poster presented on April 15, 2010 at the Annual Meeting of the European Association for the
Study of the Liver (EASL), April 14-18, 2010; Vienna, Austria).

2.2. About the product
Boceprevir is a new antiviral agent, serine protease inhibitor, specifically designed to inhibit the HCV
nonstructural protein 3 (NS3) protease and, thereby, inhibit viral replication in infected host cells. The
mechanism of inhibition involves formation of a stable reversible covalent bond between the ketoamide of
boceprevir and the NS3 protease active site serine, which is the protease that mediates the cleavage of the
HCV polyprotein to form the functional proteins essential for viral propagation. This mechanism is
distinct from those of currently approved therapies; thus, boceprevir represents a novel class of HCV
inhibitors.

The proposed indication for Victrelis (boceprevir) is the treatment of chronic hepatitis C (HCV)
genotype 1 infection, in combination with peginterferon alpha and ribavirin, in adult patients (18 years and
older) with compensated liver disease who are previously untreated or who have failed previous therapy.

9
The proposed treatment regimen is 800 mg of Boceprevir administered orally three times daily (TID) with
food.
For the patients who are previously untreated, the therapeutic schema proposed is:
peginterferon alpha and ribavirin for 4 weeks (Treatment Weeks 1 4).
and addition of Victrelis 800 mg orally three times daily to peginterferon alpha and ribavirin regimen
at Treatment Week (TW) 5. Based on the patient's HCV-RNA levels at TW 8 and TW 24, the
following Response Guided Therapy (RGT) guidelines must be used to determine the duration of
treatment :

ASSESSMENT
(HCV-RNA Results*)
ACTION
At Treatment
Week 8
At Treatment
Week 24
Undetectable Undetectable Complete three medicines regimen at Treatment Week 28.
Detectable Undetectable
1. Continue all three medications until Treatment Week 28,
and then
2. Administer peginterferon alpha and ribavirin until
Treatment Week 48.
Any Result Detectable Discontinue three medicines regimen.
* In clinical trials, HCV-RNA in plasma was measured with a Roche COBAS TaqMan
assay with a limit of detection of

9.3 IU/ml.

Patients who have failed previous therapy, the therapeutic schema proposed is:
peginterferon alpha and ribavirin for 4 weeks (Treatment Weeks 1 4).
and addition of Victrelis 800 mg orally three times daily to peginterferon alpha and ribavirin regimen
at Treatment Week (TW) 5. Based on the patient's HCV-RNA levels at TW 8 and TW 12, the
following Response Guided Therapy (RGT) must be used to determine the duration of treatment :

ASSESSMENT
(HCV-RNA Results*)
ACTION
At Treatment
Week 8
At Treatment
Week 12
Undetectable Undetectable
Continue three medicines regimen until completion through
Treatment Week 36.
1. Continue all three medications until Treatment Week 36, and
then
2. Administer peginterferon alpha and ribavirin until Treatment
Week 48.
* In clinical trials, HCV-RNA in plasma was measured with a Roche COBAS TaqMan
assay with a limit of detection of

9.3 IU/ml.

2.3. The development programme/Compliance with CHMP Guidance/Scientific Advice
GMP:
All relevant sites of drug product underwent GMP inspections by EEA/MRA authorities with a
satisfactory outcome within the last 3 years.
The manufacturing site of the active substance Boceprevir is covered by relevant declaration from the
Qualified Person of Victrelis batch release site.
Based on review of Quality dossier, no need has been identified for inspection request prior to
authorization. Nevertheless, a routine GMP and product specific inspection has been proposed by the
EMA Compliance and Inspection Sector and endorsed by the CHMP in February 2011 for the
manufacturing facility Schering-Plough Ltd., 50 Tuas West Drive, SG-638413, Singapore.

10
The applicant has made extensive efforts to reduce impurities as suggested by the scientific advice sought
with EMA: the total of 11.5% at the time of scientific advice has been reduced to NMT 6.0%.
Recommendations of the scientific advice have been well followed and implemented.
Regulatory advice on the phase 3 development program was obtained via National Advice from Sweden
and France in 2008.

2.4. General comments on compliance with GMP, GLP, GCP

2.5. Type of application and other comments on the submitted dossier
Legal basis
The application is submitted in accordance with art 8 of directive 2001/83/EC for a new active substance,
i.e. a complete dossier with administrative, quality, pre-clinical and clinical data.

Accelerated procedure
In novembre 2010, the CHMP agreed to the applicants request for an accelerated assessment of the
Marketing Application for boceprevir.

Conditional approval
N/A
Exceptional circumstances
N/A
Biosimilar application
N/A
1 year data exclusivity
N/A
Significance of paediatric studies
N/A
11

3. SCIENTIFIC OVERVIEW AND DISCUSSION
3.1. I ntroduction
3.2. Quality aspects
Drug substance
Boceprevir, the active substance of Victrelis, is a novel serine protease inhibitor specifically inhibiting the
hepatitis C virus non-structural protein 3/4A protease. Boceprevir is a new chemical entity (NCE) not yet
described in any pharmacopoeia.
Boceprevir contains 5 chiral centres, four of them have a fixed stereochemical configuration controlled
during the synthesis and the last one is obtained as a mixture of 2 configurations R and S. Thus,
Boceprevir is manufactured as an equal mixture of two diastereoisomers in an approximate amount of 1:1.
Boceprevir is hygroscopic, poorly soluble in water and a non ionisable substance therefore its solubility is
not pH dependant. In addition, Boceprevir is obtained as an amorphous substance and attempts to obtain it
as a crystalline material have not been successful. This problem, in addition to the fact that a salt form
does not exists, makes that purification of Boceprevir has represented a challenge to the applicant.
Boceprevir powder is consistently obtained with a specific surface area of 3.0 to 9.4 m
2
/g.
Due to the presence of a diketoamide function, Boceprevir can exist in a gem diol form in presence of
water. The gem diol form is in equilibrium with the active substance. Boceprevir is, in addition,
predisposed to tautomerisation leading to an enol form. The enol form co-exists with the 2
diastereoisomers of Boceprevir in plasma and other biological fluids.
The manufacture of Boceprevir is described in details in three steps. The choice of starting materials is
well justified, their specifications and sources are sufficiently described in the dossier. Two intermediates
are isolated and controlled. For each steps, in-process controls are in place and critical control parameters
(CPPs) have been identified. The applicant has performed characterisation studies that have served to
optimisation of the process and led to reproducible production of Boceprevir further supported by a great
number of batch results (44 batches). Proven acceptable ranges (PARs) have been established within the
definition of ICH Q8. It is noted that design space is not claimed. The control strategy in place consists of
a combination of quality of starting materials, intermediates and raw materials together with established
process parameters and IPCs. Few clarifications have been raised on manufacture and controls in place.
Boceprevir has a complex impurity profile, purification by crystallisation or by preparative
chromatography were not possible. In addition, some of related substances exist as diastereoiomers. Thus,
four sets of impurities have been distinguished as group A, group B, dimers and group W related
compounds. Limits proposed for all the specified impurities are supported by levels present in preclinical
batches. Unspecified impurities are in compliance with ICH thresholds for a daily intake exceeding 2g.
The applicant has made efforts to reduce impurities during different phases of development. Thus, the
actual results for total of related substances up to 11.5% in preclinical batches and 6.5% in clinical batches
have been reduced to maximum 3.30 % in the last 23 batches produced by the intended commercial
process. Change in reagents of the third stage of manufacture has led to removal of some of brominated
impurities present. The applicant has explained its limitations for further purification.
Specifications of Boceprevir include the important quality attributes of the drug substance and suitable
methods such as XRD to monitor the amorphous form, diastereoisomers content, specific surface area,
four HPLC methods to monitor different impurities and two headspace GCs for residual solvents.
Justification for lack of specification for few materials and solvents used in the process still remains to be
clarified.

12
Boceprevir is an unstable active substance as it is sensitive to light, heat, humidity in solid and acidic,
basic, oxidative conditions in solution. Stability results provided justify a retest period of 24 months
when Boceprevir is packed in double LDPE bags, in presence of silica gel packs, placed in metal drums
with a precaution storage of store in refrigerator and keep protected from light.

Drug Product
VICTRELIS drug product is a hard capsule for immediate release. Each capsule consists in a yellowish-
brown colored cap with the Merck MSD logo printed in red ink, and an off-white opaque body with
product code ID 314 printed in red ink.
One dosage strength, containing 200 mg of boceprevir as drug substance, is proposed.
The formulation comprises the following excipients: microcrystalline cellulose, lactose monohydrate,
pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, and magnesium stearate.
The drug product is packaged into unit dose blister cells thermoformed from clear Aclar/PVC film and
sealed with a peelable paper faced foil lidding.
The pharmaceutical development of Victrelis was guided by the defined Quality Target Product Profile.
Development and optimization of the formulation is adequately documented. The choice and the level of
the excipients are justified on grounds of solubility, processability and chemical compatibility.
Formulation robustness has been challenged through raw material variability risk assessment and
formulation characterization studies.
Manufacturing process development program consisted in process characterization studies, completed by
scale-up studies, to support robustness of the process. A systematic and risk-based approach was followed
in order to establish linkages between inputs (raw materials, process parameters), intermediate attributes,
and critical quality attributes. Principles of Quality by Design have been applied to some extent and
science-based risk management processes have been used to facilitate risk reduction. Extensive
development studies have been carried out in order to acquire better understanding of the manufacturing
process and to define appropriate control strategy to produce a consistent product quality. Design of
experiments were conducted with the purpose to optimise operating parameters and to test the robustness
of the process, not with the scope of process flexibility. Ranges explored were, indeed, very restricted. The
applicant confirms that the intended commercial manufacturing process will be run at setpoint values and
that a design space is not claimed.
During development, stability studies have been performed to address temperature excursions in
storage/shipping conditions. Data support a cumulative time out of refrigeration (TOR) for drug product,
from manufacture until final dispensing to the patient, of maximum 30 days at temperatures up to 25C,
including excursions of up to 50C for a maximum of 3 days and down to -20C for maximum of 10 days.
Bulk shipping studies have been performed to ensure that drug product remained within the desired
temperature conditions and allowable excursions.
The drug product manufacturing site, in charge of manufacturing only, is Schering-Plough (Singapore)
PTE Ltd.. Packaging is performed by Schering-Plough Labo N.V. (Belgium) or by Merck Sharp & Dohme
B.V. (The Netherlands). Control and batch release are performed by Schering-Plough Labo N.V.
(Belgium).

Manufacturing process is sufficiently described. Operating parameters are set with their target values and
their proven acceptable ranges. Maximum hold time periods have been validated during manufacturing
process development.
Adequate control strategy, comprised of raw material controls, process parameter controls, in-process
controls, and finished product specifications for the critical quality attributes, is proposed.
13
The manufacturing process for Victrelis will be validated at Schering-Plough Singapore PTE Ltd. prior to
commercialization. Validation protocol is enclosed. It has been adequately characterized and scaled to the
proposed commercial batch sizes at the commercial manufacturing site. Data provided is thus considered
sufficient to give confidence in the robustness and consistency of the process at the time of submission.
Excipients used for the formulation of Boceprevir capsules are all of Ph. Eur. quality and classical for the
intended dosage form.

Specifications proposed for drug product include the important quality attributes and suitable methods for
this dosage form while accounting of specific characters of Boceprevir drug substance. Degradants in drug
product, are those of Boceprevir and no new degradant has been identified. The applicant has accepted to
tighten slightly the acceptance criteria for groups of related substances as it appears clearly from batch
results and stability data that the formulation used stabilises Boceprevir drug substance.

Efficiency of the packing blisters made in Aclar/PVC/ Alu has been demonstrated in stability studies.
Victrelis capsules have been shown stable when blisters have been exposed to an ICH photostability
without secondary packaging.

Formal stability studies have been performed at 5 3C as long term storage condition and at 25C/60%
RH as accelerated condition. Limited extrapolation can be accorded due to the long term storage condition
used and number of supportive batches. Based on this extrapolation, Victrelis capsules can be accorded
a shelf life of 24 months-before patient use- with a precaution storage of store in refrigerator. The
patient in-use period up to 3 months after dispensing from the pharmacy for Boceprevir capsules is
supported at temperatures below 30C by the submitted studies and data.
Conclusions on the chemical, pharmaceutical and biological aspects
Based on the review of the data on quality, many of the questions raised have been resolved. However,
few unresolved points remain and need to be addressed before final approval. It is assumed that answer to
questions 1, 7, 8, 12, 13, 14, 15, 16 and 18 does not need performing additional studies and therefore an
immediate response is expected.

3.3. Non clinical aspects
Pharmacology
Primary pharmacodynamics
The Hepatitis C virus (HCV) is a (+)-stranded RNA virus whose genome encodes a single polyprotein of
about 3000 amino acids. The resulting polyprotein undergoes both co- and posttranslational proteolytic
maturation by host- and virally encoded proteases. Boceprevir is a serine protease inhibitor, which inhibits
NS3, a viral protease which is involved in further cleavage of the viral polyprotein into downstream
nonstructural proteins. Boceprevir binds covalently, yet reversibly, to the NS3 protease active site serine
through a ketoamide functional group, thereby inhibiting the cleavage of the viral polyprotein into
functional units, thereby inhibiting HCV replication.
Due to the lack of robust viral cell/culture systems, activity of boceprevir was investigated in replicon
assays and biochemical enzyme assays with recombinant NS3-NS4A (NS4A is a cofactor required by NS3
for viral activity). In a chromogenic assay with recombinant proteases, it was shown that SCH 534128 is
the active diastereomer and SCH 534129 the inactive, and that there is rapid interconversion between the
two diastereomers. In replicon assays with the human hepatoma cell line Huh7 transfected with RNA
based on HCV genotype 1b, IC50 was 200 900 nM and IC90 was 400 1400 nM. In the presence of
human serum, IC50 was 500 nM. In an enzyme assay, Ki was 14 nM for genotype 1a and 1b, and 39 nM
and 25 nM for genotypes 2a and 3a respectively. In vitro studies showed that mutations emerge at
14
concentrations up to 10 M. Mutations are therefore expected to emerge at human exposures if boceprevir
is used as monotherapy.
In replicon assays, boceprevir induced an up to 6-12 fold increase in IC90 after 8-10 passages and an up to
8-48 fold increase after approximately 30 passages. Resistance-associated variants (RAVs) in replicon
cells were observed at positions V36, Q41, F43, T54, Q86, S122, A150, R155, A156, V170, E176. A
second mutation generally increased fold change above that induced by a single mutation. A156T
conferred the highest level of resistance (increase in IC90 80-fold), but also significantly reduced replicon
fitness. In a replicon assay, the combination of boceprevir at 6xIC90 (2.5 M) and interferon alpha at
1xIC90 (1 IU/ml) reduced resistance from 0.14% to 0.005% of the cell population.
In HCV samples from Phase 1 and 2 patients (genotype 1 non-responders), RAVs were observed at
positions V36, T54, V55, R155, A156, V158, V163, V170. Among patients from Phase 3 clinical trials,
the most detected RAVs were V36M, R155K and T54S for genotype 1a and T54A, T54S, V170A, A156S
and V55A for genotype 1b. Overall, post-baseline RAVs were detected in 15% of the subjects. The overall
percentage was similar among treatment failure subjects and treatment nave subjects and for shorter
treatment (response-guided therapy) and standard treatment. 53% of patients who did not achieve
sustained virologic response (SVR) had RAVs. More subjects with poor interferon response had RAVs
(41%) compared to interferon responsive subjects (6%).
HCV replication is rapid and virus production recovers quickly when inhibition of the NS3 enzyme is
removed. Therefore, it is assumed that potent and durable suppression of HCV replication in vivo will
depend on maintaining plasma trough concentrations (Cmin) at levels IC90. The applicant concludes
that the Cmin has to be 200 ng/ml (approximately 400 nM). Based on in vitro studies, this estimate is
rather low. Furthermore, clinical pharmacokinetic data show that in a large part of the patient population
Cmin of 200 ng/ml was not even achieved. Moreover, this value represents the total fraction, as a result of
which the freely available, non-protein-bound fraction is even lower. However, based on clinical
pharmacokinetic data, higher dosing would not seem to increase Cmin substantially, and therefore a higher
Cmin seems not likely achieved. Ultimately, the clinical response is the most important and clinical data
point towards a significant effect of boceprevir in combination with peginterferon alpha and ribavirin
compared to peginterferon alpha and ribavirin alone. Likely, the combination with peginterferon alpha and
ribavirin contributes significantly to the efficacy.
The activity of boceprevir was not investigated in animal studies. This is endorsed; robust in vitro cell
culture systems are lacking and animal models for hepatitis C are not readily available, except
chimpanzees, and activity measurements in chimpanzees are not expected to add significantly to clinical
data.
Boceprevir showed minimal cytotoxicity in several human cell lines (CC50 was 80 - >100 M).
Secondary pharmacology
Cross reactivity of boceprevir with an extensive panel of proteases, other enzymes and receptors was
investigated in vitro. Only cathepsin L was inhibited by boceprevir to a substantial extent. This is
considered not likely to have a relevant impact. Cathepsin L is only one of a large family of proteases, it is
involved in nonspecific protein breakdown and most likely there will still be sufficient proteolytic
pathways.
Safety pharmacology
The main criticism regarding the cardiovascular safety pharmacology programme is that the
concentrations tested in vitro were too low with regard to the clinical plasma levels. Nonetheless, a
prolongation of the Purkinje action potential reaching 40 ms was observed at 0.5 Hz. In that context, it is
difficult to accept that boceprevir is unlikely to prolong QT interval since no significant effect on hERG
potassium channel has been observed in a study performed at concentrations in the range of the clinical
Cmax.
The in vivo model was Cynomolgus monkey. At the top dose, an increase in heart rate was observed
without any effect on QT interval. However, the Cynomolgus model is not a good model, as compared to
dog for example, to investigate the potential effects of a drug on the ECG pattern, due in particular to the
high and rapidly changing heart rate of these animals. Therefore it is not surprising that no effect could be
detected during the in vivo studies. In addition, the monkey-to-human Cmax ratio ranged actually from 0.5
to 4.1 in the aforementioned study.
15
The major human metabolite SCH 629144 was not tested. The applicant considers that due to the presence
of the main metabolite in monkeys, its potential cardiotoxicity was evaluated during the in vivo studies.
For the same reasons as above, this is not convincing at all.
A thorough QT/QTc study performed according to ICH E14 in human volunteers was negative, but the
data show a tendency to QT interval prolongation within acceptable limits with increasing boceprevir
doses. Taking into account that the pharmacokinetics of boceprevir is highly variable and complex, and
that the patients may present some pathophysiological conditions (e.g. electrolytic disturbances) that may
potentate a potential drug-related effect on cardiac physiology, there are some concerns regarding the
results obtained in in vitro and in vivo cardiovascular safety pharmacology studies.
Overall, there is some doubt concerning the potential effects of boceprevir on QT prolongation, in
particular in subjects presenting with low heart rates. Therefore, the positive findings observed in vitro are
reported in SPC 5.3 to give adequate information to the prescriber, and a warning is included in SPC 4.4.
In addition, it is still considered necessary to amend the RMP to monitor events possibly related to effects
on the cardiovascular system.
Pharmacodynamic drug interactions
IFN and boceprevir showed additivity of effect in a replicon system. It was shown in vitro that IFN
decreased emergence of resistance to boceprevir. The interaction with ribavirin was not investigated
preclinically. However, the combination of boceprevir with peginterferon- and ribavirin is investigated
clinically. No relevant pharmacodynamic interactions were observed with HIV protease inhibitors
atazanavir, lopinavir and ritonavir.
Pharmacokinetics
Both non-validated and validated LC-MS/MS methods have been used for the detection of boceprevir, its
individual diastereomers SCH 534128 and SCH 534129, and its major metabolite SCH 629144 (collective
designation for SCH 783007, SCH 783005, SCH 783006, and SCH 783004) in plasma. Regarding the
total recovery of the analytical methods in plasma (and serum), no explanation is provided with regard to
the greatly varying recoveries (between QCL, QCM and QCH) within the studies. This should be clarified
further.
Absorption was generally rapid in all species. After oral administration, the bioavailability of boceprevir
was moderate in male mice, rats, and dogs (34%, 26%, and 30%, respectively) but was low in fasted male
monkeys (4%). Subsequent studies in rats and male monkeys showed that the bioavailability of both SCH
534128 and SCH 534129 was similar. In monkeys, the bioavailability increased under fed conditions (10-
13%). The half-life of boceprevir is short, ranging from 1 to 5 h in the pre-clinical species and humans. In
addition, the half life of the active diastereomer SCH 534128 ranged from 1 to 4 h in rat and monkey and
~2 h in humans. No information was provided on the half-life in other pre-clinical species.
From TK data obtained after a single dose, gender-related differences in systemic exposure were evident
in rodents with females more exposed than males given the same boceprevir dose (up to 3-fold in mice
and rats). In addition, there was some inter-study variability regarding the exposure levels measured for a
given dose and in a given sex, particularly at high dose levels. A time-related effect on the kinetics of
boceprevir was observed in mice only, with a decrease in exposure levels probably related to the induction
of cytochrome P450 enzymes.
Animals were treated once daily in the pre-clinical repeated dose studies and humans were treated two or
three times a day (every 8 to 12 hours) in the clinical studies. In addition, the ratio of the two
diastereomers is species dependent. In mice, the steady state SCH 534128:SCH 534129 ratio was 1.2:1
and the ratio in male mice was greater than the ratio in female mice. The steady state SCH 534128:SCH
534129 ratio was 1:1 in rat plasma. In monkey, the SCH 534128:SCH 534129 ratio was approximately
1:5.9 in plasma at steady state. The ratio of diastereomer concentrations in humans at steady-state was
2.2:1 (SCH 534128:SCH 534129).Therefore, the comparison of the kinetic parameters is hampered.
Exposure values in juvenile rats were higher than exposure values in adult rats on a restricted diet; but
lower than exposure values in adult rats fed ad libitum. However, based on the comparison of exposure
data obtained in adult and juvenile male rats under fed conditions, it cannot be excluded that the
pharmacokinetics in juveniles are different than that in adults and may be caused by not fully expressed
16
liver metabolic enzymes in the juvenile. It is expected that off-label use will take place in juveniles.
Therefore, the applicant should state in the SPC that contradicting findings were observed in juvenile rats
compared to adult rats, in a perspective of a future use in paediatric patients.
Boceprevir is moderately bound to plasma proteins in all species, and was shown to cross the placenta in
pregnant rats. In rats administered radiolabeled boceprevir, the highest radioactivity levels were measured
in the liver, bladder, kidneys, prostate gland, other endocrine tissues (adrenal, harderian, and salivary
glands), and bone marrow. The results did not indicate a specific binding of drug-related radioactivity to
melanin-containing tissues, and there was no gender-related difference in the tissular distribution profile.
Only bladder, liver, kidney, bone marrow, endocrine glands and reproductive organs contained
quantifiable levels of radioactivity at 8 h post-dose. All tissues, except bone marrow, were below
quantifiable limits after 24 h. Based on the provided distribution data, the fact that patients are treated
every 8 h hours and similar half-lives in rat and humans, accumulation in humans can be expected in bone
marrow and endocrine glands. Effects on bone marrow were not specifically investigated in the pre-
clinical toxicity studies. However, no toxicity was observed in bone marrow and blood after 6 months
repeated dosing in rat.
Boceprevir undergoes extensive metabolism in all tested species. In vitro, human liver microsomes
converted approximately 99% of boceprevir to metabolites, and at least 31 metabolites were produced. In
vivo, the percentage of drug excreted unchanged was weak and the number of produced metabolites was
of the same order. The metabolism of boceprevir involves mainly oxidation and/or reduction, and
hydrolysis reactions. Two main pathways can be described. The first involves the reduction of boceprevir
to SCH 629144 (4 stereoisomers SCH783005, SCH783007, SCH783006, SCH783004) and is catalysed by
the cytosolic aldo-keto reductase (AKR) family of enzymes, more precisely AKR1C2 and 1C3 isoforms.
AKR1C3 preferentially metabolised SCH 534128 to SCH 783007 and AKR1C2 preferentially
metabolised SCH 534129 to SCH 783004. Metabolising data indicate that the formation of the different
SCH 629144 diastereomers is different between the different species with more SCH 783006 in rat
compared to the other pre-clinical species and humans. Exposure to SCH 629144 increased as the dose of
boceprevir was increased. AKR1C2 and 1C3 are expressed in the liver and in hormone-associated tissues
(prostate, uterus, mammary gland, testes). Therefore, this metabolic pathway would take place in both
hepatic and extra-hepatic tissues, which could explain why PK parameters are not modified in patients
with hepatic insufficiency. Regarding the potential auto-inhibition of this pathway, only data showing that
boceprevir has no inhibitory potential for AKR1C3 were provided. Therefore, the applicant is requested to
provide boceprevir inhibition data for AKR1C2 or clinical data showing the absence of effects on the
endocrine hormone metabolism.
The second pathway involves the CYP3A4 and CYP3A5 isoenzymes, mainly responsible for the
formation of oxidized metabolites. Another metabolite, SCH 503034-K (M0BA), is a hydrolytic cleavage
product and also a low-level impurity in the drug substance whose formation depends on the presence of
SLS (sodium lauryl sulphate) in the formulation. In humans dosed with boceprevir as capsule, the
circulating levels of SCH 503034-K relative to parent drug were lower than levels that may raise a safety
concern. Therefore, this metabolite was clinically not relevant.
Qualitatively, the metabolites detected in humans were also detected in mice, rats, and monkeys.
However, quantitatively, significant inter-species variability was noted. This is notably the case of the
major human metabolite SCH 629144, whose AUC represented 2-7%, 47-93% and 620-760% of the AUC
of boceprevir in rats, mice and monkeys, respectively in toxicity studies. In humans, this figure amounted
to 440% at the recommended dose. Therefore, SCH 629144 is a minor metabolite in the rat. This species
is thus to be considered as not fully relevant for humans.

In all species, the main route of excretion was via the faeces, as a combination of biliary excretion of
metabolites and excretion of unabsorbed drug. In rats, a limited fraction of an oral dose (3%) underwent
enterohepatic circulation. In lactating rats, boceprevir-related radioactivity was rapidly excreted into
maternal milk. No information was provided concerning the precise composition of radioactivity as found
in rat milk samples. Consequently, the SPC mentions that a risk to the newborn/infant cannot be excluded
and that breast-feeding must be discontinued prior to initiation of therapy in patients who will be
administered boceprevir

17
Boceprevir is an inducer of CYP2B and 3A in mice, but not in other species including humans. A study on
human liver microsomes showed that it is rather a competitive inhibitor of CYP3A4/5 at concentrations in
the range of that reached in patients.
Boceprevir was shown to be both a P-glycoprotein and a weak BCRP substrate, therefore this should be
reported in SPC 5.2 and a warning about a likely interaction with inhibitors of these transporters should be
included in SPC 4.5. Regarding the inhibitory potential for transporters, it can be concluded that
boceprevir is not expected to significantly inhibit MRP2 and BCRP at therapeutic concentrations.
Nevertheless, it was shown to be a P-glycoprotein inhibitor in vitro and the applicant committed to
perform a clinical drug-drug interaction study with digoxin to determine the clinical relevance. In addition,
it was also shown to be an OATP1B1 inhibitor, but additional data is requested since a positive control
was not used to warrant the reliability of the in vitro model used.
In an enzyme induction study with three batches of human hepatocytes, boceprevir did not cause
significant induction of CYP1A2, CYP3A4 and CYP2B6. As these enzymes are sensitive indicators for
activation of the AhR, PXR and CAR receptors, and activation of these receptors can also result in the
induction of some of the UGT enzymes, the potential that boceprevir will cause significant induction of
UGT enzymes is low.

Toxicology
The observed max. non-lethal oral acute doses in rat, dog and monkey were resp. 2000, 300 and 1000
mg/kg.

Repeat-dose toxicity and carcinogenicity studies have identified the liver as a target organ in mice and
rats. In mice treated for up to 3 months, uncorrelated minimal to mild increases in transaminases (ALAT,
ASAT) and focal neutrophilic infiltrates were noted. The safety margins for the occurrence of focal
neutrophilic infiltrates in the liver, seen only after 3-month dosing, reach 1.4 in males and 4.8 in females
based on NOAELs of 500 and 600 mg/kg/day, respectively. In the mouse carcinogenicity study, there was
an increased incidence of hepatocellular adenomas at the high-dose level (650 mg/kg/day, corresponding
to a mouse-to-human exposure ratio of 5.8). Based on the fact that the incidence of hepatocellular
adenomas was increased in only one tissue, one gender, and one species, without findings suggesting
increased malignancy, without any impact on mortality, and considering also the negative results obtained
in genotoxicity studies (notably the mouse bone marrow micronucleus assay), the applicants position that
this poses no clinical concern is shared. Non-neoplastic liver findings reported in the carcinogenicity study
consisted in accumulation of pigment staining positive for lipofuscin in liver macrophages at 250
mg/kg/day, and single cell necrosis of hepatocytes at high dose levels (500 mg/kg/day in males, 650
mg/kg/day in females). In rats, uncorrelated minimal to mild increases in ALAT and ASAT in both sexes
and multinucleated hepatocytes in males were observed. The latter effect was noted in 3-month and 6-
month studies without any safety margin based on a NOAEL of 15 mg/kg/day. It is described as species-
and gender-specific by the applicant, which is not fully endorsed. In fact, it may be viewed as species- but
not gender-specific because multinucleated hepatocytes were also reported in a dose-related manner in
female rats included in the carcinogenicity study. There was no safety margin for this finding, however no
physiological consequences was noted in the affected animals. The occurrence of multinucleated
hepatocytes has been characterized as an adaptative response in rats.

Repeat-dose toxicity and carcinogenicity studies also highlighted the male reproductive tract as a target
organ in male rats.
In 3- and 6-month studies, the histopathological findings consisted in Sertoli cell vacuolation, spermatid
degeneration, atrophy of seminiferous tubules in the testes, presence of cellular debris in the epididymides,
hypospermia in the epididymides. It correlated with decreased weights of the epididymides and testes, and
with macroscopic findings of small epididymides and testes. In the 6-month study, the NOAEL for these
findings reached 15 mg/kg/day meaning that there is no safety margin for these effects. The applicant
suggests that these findings may be reversible based on the results of a 3-month study (no.04124) showing
a trend towards functional recovery in the testes that was observed during a 2-month post-dose interval. Of
18
note, this is the only repeat-dose toxicity study performed in adult animals where a recovery period was
included. Similar effects were reported in the juvenile rat toxicity study, and they were not reversible. In
the carcinogenicity study, non-neoplastic lesions were also noted on the male reproductive tract, and were
qualitatively similar to that reported in the aforementioned studies.
The applicant performed a 1-month study in adult rats showing that the occurrence of these findings is
dose- and time-dependent, and suggesting initiation of testicular toxicity on the first dose and continual
progression of boceprevir-induced changes following daily dosing. There was no impact on serum LH,
FSH and testosterone levels, and an additional study showed that boceprevir is devoid of agonistic and
antagonistic activity the estrogen receptor alpha and androgen receptors, respectively, thus discarding a
hormonal mechanism. The applicant concludes that the Sertoli cell is probably the primary target and that
thus inhibin B is a valid marker for this effect in clinical studies. The overall non-clinical and clinical data
suggest that the testicular toxicity observed in rats only is not likely to be relevant for humans. However,
no definitive mechanism is proposed to support the assumption that the testicular findings are rat-specific.

In monkeys treated for up to 12 months, no target organ could be identified. A dose-dependent increase in
aPTT was observed, but it was not associated with clinical observations, changes in other clinical
pathology parameters suggestive of haemorrhage, and gross pathology or histopathology evidence of
haemorrhage. It is agreed that the effect on APTT of boceprevir seen in monkeys is probably not an
important risk factor for humans. In fact, such a prolongation in aPTT was not reported in clinical studies.

Boceprevir was not genotoxic in an ICH-compliant battery of in vitro and in vivo tests.
Two-year carcinogenicity studies were conducted in mice and rats. In addition to the liver and testicular/
epididymidal lesions described above, gall bladder discolouration occurred in mice without
histopathologic correlate, inflammation, tumor formation, evidence of concretions, or long-term impact to
gall bladder integrity. No gall bladder finding was reported in monkeys, therefore this effect is considered
likely specific to mice. Overall, boceprevir was shown to be devoid of carcinogenic potential in male
mice, and in male and female rats. Hepatocellular adenomas were noted in female mice, but are not
considered clinically relevant (see above).

Boceprevir altered the fertility of female rats (mated to untreated males), that was related to increased pre-
and post-implantation losses. This effect was shown to be reproducible and reversible. The underlying
mechanism remains unknown, but is not hormone-related as shown in an investigative study. Boceprevir
also altered the fertility of male rats (mated to untreated males), and this can be reasonably attributed its
toxic effects on the male reproductive organs. In both male and female rats, the NOAEL for the effects on
fertility amounted to 75 mg/kg/day, thus corresponding to a lack of safety margin for males and a weak
one (1.0 to 1.9) for females.
Embryo-fetal toxicity studies showed that boceprevir is devoid of embryotoxic or teratogenic potential in
both rats and rabbits at maternotoxic dose levels.
The peri-post-natal toxicity study showed decreased body weight of F1 rat offsprings that was limited to
the pre-weaning period in the group dosed at 150 mg/kg. No other treatment-related effect on the
development of F1 pups/ offsprings was reported. It should also be considered that boceprevir is to be co-
administered with ribavirin, whose SPC states that lactation is contra-indicated because of the potential for
adverse reactions in breast-fed infants.
The main target organs identified in juvenile rats were the testes / epididymides and the thyroid. Whereas
testicular/ epididymidal toxicity was expected based on the data previously available in more mature rats,
this is not the case for the occurrence of reversible and reproducible follicular thyroid hyperplasia. The
phenobarbital-like mechanism proposed by the applicant to explain the thyroid effects is not clearly
established. At the present time, MAA is sought for use of boceprevir in adults. Regarding the thyroid
findings, more data may be requested at a later time in case of an application to extend the indication to
paediatric patients.

All boceprevir-related impurities are considered qualified at the proposed acceptance criteria level based
on the level of impurity tested in the qualification repeat-dose and genotoxicity tests, the level of impurity
19
tested when normalized for human dose on an mg/kg basis, and/or by virtue of the impurity also being a
metabolite present in non-clinical species.

Standard immunotoxicity endpoints including white blood cell counts, differentials lymphoid organ
weights, lymphoid tissue histopathology and bone marrow cellularity were assessed in general toxicity
studies and did not indicate a need for specific inmmunotoxicity or antigenicity studies to be conducted.

Boceprevir showed no effect on red blood cell osmotic fragility in human blood and no effect on APTT
(activated partial thromboplastin time) in cynomolgus monkey blood.

In rats, the combination of ribavirin with boceprevir did not increase the toxicity of boceprevir in a 3-
month study. Administration of diflunisal, ritonavir and ribavirin caused more toxicity in a 3-month study
in rats with thymus, adrenal gland, kidneys and thyroid glands as targets. Co-administration of boceprevir,
ribavirin and ritonavir increased dose normalized exposure to boceprevir at steady state approximately 2 to
6-fold (in females) or 4 to 9-fold (in males). This increase is considered to be due to the net boost effect of
ritonavir. The combination of PEG-Intron and ribavirin with boceprevir showed mild effects which were
only attributable to PEG-Intron and ribavirin.

Ecotoxicity/environmental risk assessment
The PECSURFACEWATER value determined in the phase I risk assessment exceeds the action limit value by a
1200-fold factor. Therefore, it is agreed that boceprevir should enter into phase II Tier A risk assessment.
However, the environmental risk assessment could not be finalised because most studies are not
completed at this stage. Therefore, the study report on log Kow and the study reports related to the phase
II assessment should be provided as soon as available.

Discussion on non-clinical aspects
Boceprevir is expected to be effective in combination with interferon alpha and ribavirin. However,
mutations causing decreased susceptibility are expected to emerge at human exposures.

The analysis of the results obtained in pharmacokinetic and toxicokinetic studies highlights considerable
inter-species variability, and even inter-study variability within the same species, at various levels of the
kinetics of boceprevir (e.g., diastereoisomers ratios, absorption, systemic exposure, metabolism, hepatic
enzymatic induction/inhibition). Therefore, significant inter- and intra-individual variability is to be
expected in patients. Attention will thus have to be paid to the conditions of administration, to patients
with enzymatic deficiencies, and to potential drug-drug interactions.

Anaemia was frequently reported as a treatment-related effect in humans. An in vitro assay in human
blood did not provide any evidence of a haemolytic potential for boceprevir. In spite of the lack of
investigations for such a potential with metabolites, further studies in non-clinical species are not
considered necessary since i) anaemia was not reported in mice, rats and monkeys, and ii) bone marrow
smears performed in the 6- and 12-month monkey studies did not show any treatment-related effect.

Overall, the toxicological profile of boceprevir could be acceptable.

Conclusion on non-clinical aspects
There are no major objections against a marketing authorisation from a non-clinical point of view. Some
questions still remain to be addressed.

20
3.4. Clinical aspects

Tabular overview of clinical studies

Phase Study ID
study centres
Study Posology Design

Treatment Population Primary Endpoint Major findings
II P03523
SPRINT 1

67 sites

800 mg TID Randomized
placebo-
controlled
dose-ranging
multi-site
double blind
Peg/Rvb -48W
Peg/Rvb/Boc -28W
LI+Peg/Rvb/Boc -28W
Peg/Rvb/Boc -48W
LI+Peg/Rvb/Boc -48W
---
Peg/Rvb/Boc -48W
Peg/Rvb low/Boc -48W
Nave patients

598 subjects
Efficacy (SVR)

- SVR :
Peg/Rvb :37.5%
Peg/Rvb/Boc28: 54.2% (=16.7)
LI+Peg/Rvb/Boc28: 56.3% (=18.8)
Peg/Rvb/Boc48: 67% (=29.5)
LI+Peg/Rvb/Boc48:74.8% (=37.3)

- EPO use :
Peg/Rvb :33%
Peg/Rvb/Boc28: 56%
LI+Peg/Rvb/Boc28: 66%
Peg/Rvb/Boc48: 80%
LI+Peg/Rvb/Boc48:87%

II P03659
RESPOND 1

30 sites
100 mg TID
200 mg TID
400 mg TID
800 mg TID
Randomized
placebo-
controlled
dose-ranging
multi-site
double blind
Peg/Rbv/Boc 400/800
Peg/Boc 100
Peg/Boc 200
Peg/Boc 400
Peg/Rbv/Boc 400
Peg/Boc 800
Non-responders

357 subjects
Safety and effective
dose range
As recognized by the applicant in the
summary of clinical efficacy, results are
difficult to interpret due to significant
changes in the study design.
Long
Term
phase II
P05063

800 mg TID ongoing,
multicenter,
long-term
follow-up
study
None Subjects who
participated in a
Phase 1, 2, or 3
clinical study in
which
boceprevir was
administered.

604 subjects
from P03523,
P03659,
P04487 and
P04531 studies
Durability of the SVR
Long term Safety
Natural history of HCV
- High percent of RAVs returns to Wild
type within 2 years
III P05216
SPRINT 2

placebo-
controlled
Two cohorts with 3
arms (1 with white
subjects and 1 with
Nave patients

1099 subjects
Efficacy (SVR) - SVR :
LI+Peg/Rbv : 37.7%
LI+RGT : 63.3% (=25.6)
22
149 sites multi-site
double blind
black subjects) :
LI+Peg/Rbv -44W
LI+RGT
1

LI+Peg/Rbv/Boc -44W
LI+Peg/Rbv/Boc : 66.1% (=28.4)

- EPO use :
LI+Peg/Rbv : 24%
LI+RGT : 43%
LI+Peg/Rbv/Boc : 43%

III P05101
RESPOND 2

78 sites
placebo-
controlled
multi-site
double blind
LI+Peg/Rbv -44W
LI+RGT
2

LI+Peg/Rbv/Boc -44W
Non-responders

404 subjects
Efficacy (SVR) - SVR :
LI+Peg/Rbv : 21.3%
LI+RGT: 58.6% (=37.4)
LI+Peg/Rbv/Boc : 66.5% (=45.2)

- EPO use:
LI+Peg/Rbv : 21%
LI+RGT : 41%
LI+Peg/Rbv/Boc : 46%
LI: lead in phase Peg+Rbv during 4 weeks
1
RGT : response guided therapy (Peg/Rbv/Boc during 24 weeks, patients with undetectable HCV-RNA at TW 8 completed therapy at TW 28 and entered follow-up, while those with detectable
HCV-RNA at TW 8 received an additional 20 weeks of placebo plus PR, for a total treatment duration of 48 weeks.)
2
RGT : response guided therapy (Peg/Rbv/Boc during 32 weeks, patients with undetectable HCV-RNA at TW 8 completed therapy at TW 32 and entered follow-up, while those with detectable
HCV-RNA at TW 8 received an additional 12 weeks of placebo plus PR, for a total treatment duration of 48 weeks.)

Pharmacokinetics
Boceprevir is administered as an equal mixture of two diastereoisomers i.e SCH 534128 an active
diastereoisomer and SCH 534129 an inactive diasteroisomer. Because of the low solubility in water and
low permeability, boceprevir is considered as a class 4 compound according to the Biopharmaceutic
Classification System.

Absolute bioavailability has not been determined since no IV formulation was available. The data
supported that the bioavailability of a capsule formulation containing 3% SLS was substantially improved.
The bioavalaibility of boceprevir is increased by 40-60% when administered with food. The meal type i.e
high fat or low-fat and the timing of meal administration did not seem to notably affect this increase in
bioavailability. The recommendation in the SPC to take the drug with food is supported.

The apparent volume of distribution was not determined since no IV formulation was available. The
plasma protein binding was approximately 80%. Over the range of concentrations resulting from the doses
investigated in the clinical studies i.e 0-5000 ng/ml, the decrease in plasma protein binding was 8%.

A study with
14
C boceprevir showed that a mean total of 88.2% (range 85%-91.6%) of the radioactive
dose was recovered in the urine (mean 9.3%) in feces (mean 78.9%) over 168 hrs after a single
administration dose of 800mg. Approximately 3% and 8% of the dosed radiocarbon were eliminated as
unchanged boceprevir in urine and feces respectively.

Plasma boceprevir concentrations declined in a biphasic manner. The mean terminal half-life boceprevir
across the studies seems to be variable. In most studies the mean half-life was short ~2-4 hr whereas in
some studies it was much longer ~10 hr. The mean half-life of the active diastereoisomer was found to be
ranging from 1.5 to 5 hrs across doses and studies.

The AUC values across the clinical studies and doses suggest that the plasma clearance of the inactive
diastereoisomer SCH 534129 was greater than that of the active diastreoisomer SCH 534128. The ratio of
diastereoisomer concentrations in humans varies with time approaching a steady-state ratio of about 2:1
(active:inactive diastereoisomer).

Based on in vitro data studies, the metabolism in humans appears to be primarily via isoforms of AKR
(AKR1C2 and AKR1C3) and to a minor extent via CYP3A4/5-mediated oxidation. The metabolism of the
2 diastereoisomers by both AKR1C3 and AKR1C2 leads to the formation of ketone reduced metabolites
in the form of stereoisomers quantifiable in the plasma: the active diastereoisomer SCH 534128 is
metabolized into SCH 783007 (M28) and SCH 783005 and the inactive diastereoisomer SCH 534129 is
metabolized into SCH 783004 (M31) and SCH 738006 (M30). All these 4 ketone-reduced metabolites are
inactive as protease inhibitor. The minor pathway of metabolism via CYP3A4/5 was responsible for the
production of a large variety of hydroxylated and oxidized metabolites.

Another minor metabolite (MOBA) is a hydrolytic cleavage product resulting from the hydrolysis of
boceprevir in the presence of SLS and acidic medium in the stomach.

In plasma (pooled 2 hrs and 6 hrs), the metabolic profiling following a single 800 mg dose of
14
C
boceprevir showed that SCH 783007 (M28), SCH 783004 (M31) and SCH 783006 (M30) are the main 3
major ketone reduced metabolites quantifiable in plasma. The exposure to the sum of these 3 metabolites
was approximately 2.5-fold greater than that of boceprevir. MOBA was 4 % of the circulating
radiocarbon. After a 800 mg tid dosing the plasma exposure to SCH 629144 was 4 to 5.4 fold higher than
that of boceprevir.

Following a tid 800 mg dosing, the mean Cmax of SCH 629144 i.e the sum of M28, M30 and M31 was
approximately 5100 ng/ml. The median Tmax ranged between 3 to 4 hrs and the mean half-life was 2.7
hours.

24
For boceprevir and the active diastereoisomer SCH 534128 steady-state exposure increases in a less than
dose-proportional manner from 200 mg to 800 mg. At doses greater than 800 mg, the exposure does not
increase notably.

After multiple dose administration, accumulation is minimal for both boceprevir and the active
diastereoisomer SCH 534128 and steady-state is reached after approximately 1 day of t.i.d dosing.

The range of interindividual variability measured at steady-state (800 mg tid for 14 days) expressed as
CV was 11-32% for AUC, 21-35% for Cmax and 27-57% for Cmin in Caucasian and Japanese subjects.
The intraindividual variability was not determined.

HCV-infected subjects were found to have similar PK profiles to healthy subjects.

The PK of boceprevir was investigated in subjects with end stage renal disease undergoing dialysis. The
mean PK parameters indicated that ESRD and dialysis did not affect the PK of boceprevir.

In subjects with various degrees of stable chronic hepatic impairment, there was a trend toward an
increase in the mean boceprevir Cmax and AUC with the decrease in liver function, especially in the
severe group. The boceprevir ratio estimates for mild, moderate and severe hepatic impaired subjects
compared with healthy subjects were 91%, 114% and 149% for AUC0-t and 100%, 107% and 161% for
Cmax respectively.
The applicant has proposed that BOC be contraindicated in patients with a Child-Pugh score > 6 i.e with
moderate and severe hepatic impairment. However, this contra-indication seems rather justified by the
need to co-administer BOC to pegylated IFN-Ribavirin for which moderate and severe hepatic
impairments are currently part of the contra-indication than justified by the impact of hepatic impairment
on the BOC PK parameters. A specific contra-indication to boceprevir could appear excessive especially
in view of the limited impact of the moderate hepatic impairment on the BOC PK parameters.
This issue deserves some attention insofar as patients with decompensated liver disease are currently being
treated off label with Pegylated IFN+Ribavirin despite the contra-indication to obtain HCV RNA
undetectability before transplant. Physicians might be inclined to increase the likelihood of achieving
HCV RNA undetectability by adding BOC to the tritherapy.
Awaiting for other approaches, notably DAA combinations, physicians have to face with very challenging
situations in clinical practice and formal contra-indication might amount denying the difficulties of their
daily life practice.

Race and weight were not shown to affect the PK of boceprevir. Gender slightly affected the clearance
(19% decrease in females) and the absorption rate (16% increase in males). These effects were not
considered to be clinically significant.

Drug-drug interaction studies

The interaction programme was rather limited.

All clinical studies were conducted in healthy volunteers, with multiple doses study design when
appropriate. As a limitation of these interaction studies, most of them were performed with a boceprevir
dose not corresponding to the recommended 800 mg TID.

- Effect of AKR inhibitors (AINS diflunisal or ibuprofen) seems moderate on boceprevir concentrations.
However, with ibuprofen, boceprevir plasma exposure is not altered in a significant manner whereas with
diflunisal, boceprevir plasma exposures tend to increase. As part of the CHMP D120 LOQ, the Applicant
was asked to discuss these conflicting results and their clinical relevance. The limitations of the
investigations were acknowledged and overall given the limited use of AKR inhibitor in clinical practice,
no mention was to be made in the SPC.

25
- The combination of boceprevir 400 mg TID with ritonavir 100 mg BID has been studied compared to
boceprevir 400 mg TID. Ritonavir affects the elimination of SCH629144 (110% increase in AUC). Given
that an increased exposure was expected by the applicant when boceprevir was combined with ritonavir
(as reflected in their tested dose reduction adjustment), the findings of study P04624 can be regarded as
somewhat conflicting with such an assumption insofar as a significant decrease in boceprevir plasma
exposure and notably Cmin, which decreases about 48 %, was observed. As part of the D120 LOQ, the
applicant was asked to clarify and further discuss the potential consequence of the co-administration of
ritonavir and boceprevir.

This issue is of importance since new therapeutic options are particularly awaited for treating HIV-HCV
co-infected patients well admitted as being a more pejorative population (in terms of natural course of the
disease and response to the biotherapy) as compared to mono-infected patients. Reassurance should be
obtained as regards the use of the drug with boosted Protease Inhibitors. Co-administration with boosted
Protease Inhibitors should be performed to check the applicants assumption of a lack of significant effect
with ritonavir, which is currently regarded as disputable in view on the impact on BOC Cmin. The
applicant is asked to complete the interaction programme with exploration of drug-drug interaction with
widely used boosted PIs, notably darunavir/rtv and atazanavir/rtv. In response to the D120, the Applicant
has committed to perform clinical studies with boosted protease inhibitors i.e. atazanavir/ritonavir,
darunavir/ritonavir and lopinavir /ritonavir. Results from theses studies will allow clarifying the net effect
of ritonavir on boceprevir plasma exposure.

- Ketoconazole leads to a two-fold increase in boceprevir AUC. Therefore, the proposed recommendation
in the SPC, that no dosage adjustment is required with ketoconazole, is not endorsed. The Applicant was
asked to discuss at the D120 the clinical relevance of such PK variations and halving the dose of
boceprevir was to be considered. In its response the applicant discuss the lack of clear relationship
between Cmin and boceprevir adverse events.

Furthermore, since the CYP3A4 pathway is marginally involved in boceprevir metabolism, the
mechanism behind this increase should be discussed and the respective role of P-gp and CYP3A4
inhibition should be precisely assessed. This may be of importance so as to define which inhibitors may be
of concern: CYP3A4 or P-gp inhibitors. Finally, At D120 the Applicant was asked to discuss to what
extent the results observed with ketoconazole should apply to other azol antifungals, i.e. itraconazole,
voriconazole and posaconazole.
Overall, the Rapporteurs have considered that attention should be alerted on a potential alteration of the
boceprevir safety profile in case of co-administration with ketoconazole and azoles in general.

- Tenofovir was not found to have a significant effect on boceprevir concentrations, and vice versa.

- Efavirenz having drug-metabolizing enzyme inducing properties decreased AUC of boceprevir by 19%
and Cmin by 44%. These results together with the absence of complete elucidation of elimination
pathways should lead to contra-indicated combination with potent inducers. This refers also to P-gp
inducers. The applicant was asked to discuss at the D120.It was admitted that efavirenz is a moderate
rather than a potent CYP3A4 inducer as compared to rifampicin, phenobarbital or carbamazepine and the
SPC statement was revised accordingly.

- As expected, midazolam AUC is increased by 5-fold after addition of boceprevir. Therefore, in the
proposed SPC, the Applicant contra-indicates the combination of boceprevir with midazolam per os and
recommends a caution with midazolam IV.

- Effect of boceprevir on oral contraceptive drugs is rather complex: boceprevir increased drospirenone
exposure substantially. Drospirenone metabolism only involves CYP3A4 to a minor extent. Therefore, the
observed interaction with boceprevir is unexpected. As indicated in the study report, boceprevir may affect
other metabolic pathways, however it remains unclear which one. As part of the D120, the applicant stated
that a study was being conducted with boceprevir and a combination oral contraceptive containing
norethindrone and ethinylestradiol to identify if the effect on drosperinone is likely to be unique.

26
- No significant effect on PEG interferon was observed with boceprevir.

- With clarithromycin, the design of the study cannot allow drawing any conclusion.

Overall to further substantiate interaction profile of boceprevir and in particular its inhibitory potency on
CYP3A4 and P-gp, additional studies are required which are of particular relevance for the future use of
the drug in clinical practice notably with:
- Methadone
- immunosuppressive drugs administered in transplants patient which are CYP3A substrate (ciclosporin
and tacrolimus),
- and drugs which are P-gp substrate

As part of the D120 the applicant provided clarification on the PK and DDI that may help finalising the
recommendation for physicians in sections 5.2 and 4.5. Furthermore the applicant commits to perform
additional relevant interaction studies (anti-HIV drugs, contraceptive drugs).

Pharmacodynamics
Boceprevir is the first representative of protease inhibitor in the HCV treatment. Boceprevir inhibits NS3
protease at low nanomolar concentrations. The inhibitory concentration (IC50 and IC90) values for
boceprevir were approximately 200 nM (n=25) and 400 nM (n=25), respectively, in a 72-hour assay. In
50% human serum, the replicon IC50 value for boceprevir was 500 nM.
Boceprevir had minimal cytotoxic effects.
In a phase 1 study (P03516) in which boceprevir was administered as monotherapy, a concentration-
response analysis was performed. The results indicated that the maximal decrease in HCV-RNA
concentrations correlated best with Cmin.
Based on the results of the PK-PD results, the in vitro IC50 and IC90 and the Cmin concentrations
obtained with the different studied dosing regimens, the selection of 800 mg tid dosing appears
reasonable.

Evaluation of varying combinations of boceprevir and interferon alfa-2b that produced 90% suppression
of replicon RNA showed additivity of effect; no evidence of synergy or antagonism was detected.

The replicon assay highlighted 6 major resistance mutation to Boceprevir: V36M, T54A, R155K, V170A,
A156T and A156V.
A selection pressure-based method employed to analyze sequence data from the Phase 2 boceprevir trial in
nonresponders identified two other mutations: V55A and V158I.

Resistance-associated amino acid variants (RAVs) at baseline were detected in 6% of the patients in
longterm (34/556) and update (66/1020) studies. RAVs at baseline were observed in the same way in SVR
patients (6% in longterm study, 6% in update study) and non-SVR patients (6% in longterm study and 7%
in update study) which suggests a low impact of baseline RAVs on SVR.
Baseline RAVs were observed more frequently in patients with genotype 1a (32/352, 9% in longterm
study and 53/656, 8% in update) than genotype 1b (1/196, 1% in longterm and 13/359, 4% in update).
SAVs were detected at baseline in 186/556 (33%) patients in the longterm study.
Among the subjects treated with Boceprevir, post baseline RAVs were observed in 42% in the longterm
study (236/556) and 15% in the update analysis (156/1020). The majority of the resistances were
observed in Non-SVR patients (234/296, 79% in longterm study and 155/343, 45% in update
analysis) and less than 1% of the patient who achieved SVR presented a resistance.
27
RAVs emergence were similar in RGT arm and no RGT treatment arm (52%, 82/158 in RGT arm and
52%, 74/142 in BOC/PR48 weeks) which casts doubt on the hypothesis that RGT would minimize the
presuure of selection.

In the longterm study, the prevalence of baseline mutation were similar in patients previously non
responder (4%) and in naive patients (8%) but post baseline mutations were more observed in patients
who previously failed to treatment by SOC (79% RAVs) than in naive patients (18% RAVs).
In both study, the most frequently detected post-baseline RAVs were V36M (52% in longterm study and
46% in update), T54S (67% in longterm study and 24% in update) and R155K (64% in longterm study
and 51% in update).
In the update analysis, poor interferon responders had a higher proportion of RAVs (68%) compared to the
overall subjects (52%) and Black subjects presended more detectable RAVs (64%) than non black patients
(53%).
The 2 years of follow up data of the longterm study suggest that post baseline RAVs may return to wild
type over time (88.7% of the V36M mutation, 63.7% of the T54S, 69.7% of the R155K return to wild type
within 2 years).
As part of the D120 the applicant was asked to further substantiate the impact on SVR of baseline RAV.

The data although limited were reassuring on the lack of significant impact.
Finally, as a particular limitation of the resistance analysis, clonal analysis was only performed in phase 1
study of boceprevir. Based on these limited data and as expected when referring to the data from other
ketoamide NS3 inhibitors, linked RAV combinations were observed at V36M+T54S, V36A+R155K,
T54S+R155K or T54S+A165S. In his response to D120, the applicant was committed to compensate for
the limitation of its original analysis by assessing linkage of multiple RAVs in phase 3.

28
Clinical efficacy

The Boceprevir clinical development program mainly comprised 5 clinical studies:
- Phase II dose-controlled trials (P03523/SPRINT 1 in treatment nave patients and
P03659/RESPOND 1 in treatment experienced patients,)
- Phase III trials (P05216/SPRINT 2 in treatment nave patients and P05101/RESPOND 2 in treatment
experienced patients).
- A long term follow up trial (P05063) including all the subjects who participated in a Phase 1, 2, or 3
clinical study in which boceprevir was administered is on-going at this time. The goals of this study are to
examine the durability of SVR, the long-term safety after boceprevir treatment and the natural history of
resistance-associated variants over time. Patients were off treatment in this long term study.

Phase II dose selection development programme:

The first phase 2 study (P03659) was initiated in September 2005 in previous treatment experienced
subjects (including relapse, partial responder and null responder subjects).
This phase II dose ranging study had a complex 7-arms design to meet the multiple objectives of:
- determining the most effective dose and treatment duration of BOC (100 mg TID, 200 mg TID, 400
mg TOD or 800 mg TOD) in non responders patients,
- determining whether ribavirin is mandatory to enhance the efficacy of pegIFN and BOC, and
- evaluating the safety of BOC.
In view of the poor anti-HCV activity due to the low dose of Boceprevir and the important development of
resistance in the group without ribavirin, the Data review Advisory Board took the decision to switch all
continuing subjects to tritherapy with boceprevir 800mg TID.

The multiple amendments of this study made its results difficult to interpret. Nevertheless lessons
were used to design the subsequent phase II in treatment nave patients:
- notably that ribavirin was compulsory to protect the antiviral agents
- study P03659 also demonstrated a dose-related antiviral activity of boceprevir. It was observed that
800 mg TID of boceprevir in combination with PegIntron resulted in the most rapid time to the first HCV-
RNA negative samples. The mean time in weeks to achieve the first negative HCV-RNA sample during
treatment with 800 mg TID boceprevir was the shortest (4.9 weeks) when compared with the lower
doses of 100 mg, 200 mg, and 400 mg TID (16.3, 8.4, 7.8 weeks, respectively).
Predicted Cmin of boceprevir were observed to exceed the IC90 of the compound for the virus (200
ng/mL) at a dose of 400 mg TID, with the greatest number of predicted concentrations exceeding this
target in the 800 mg TID dose group. In addition, preliminary pharmacokinetic data in healthy volunteers
who received 800 mg TID and 1200 mg TID suggest that further dose escalation to 1200 mg TID will
not increase trough concentrations.
29

Preliminary Scatter Plot of Individual Predicted Boceprevir Cmin vs Dose

Overall, the support of the dose selection is limited (derived from one phase I I study the interpretation
of which being jeopardized by several amendments). The adequacy of the dose is ultimately to be judged
on the basis of the efficacy/safety data derived from the phase I I I studies.

The second phase 2 study (P03523) was initiated in January 2007 in treatment nave HCV infected
subjects with a genotype 1. The BOC 800 mg TID dose was directly selected for this phase II study.
The study compared standard-of-care PEG2b (1.5 g/kg) plus ribavirin (800 to 1400 mg/day) for 48
weeks to five treatment arms containing boceprevir 800 mg TID. The five treatments included standard of
care plus boceprevir for 28 or 48 weeks, with and without a 4-week lead-in with P/R (Part 1), and
exploration of PEG2b plus low-dose ribavirin (400 to 1000 mg/day) plus boceprevir for 48 weeks (Part
2).

Again, this phase II had a complex design with the ambitious multi-objectives of exploring:
- different treatment durations of the tritherapy (28 vs 48 weeks),
- interest of the Lead in (LI) phase (4 weeks with the bitherapy Pegylated IFN+ribavirin before the
addition of the boceprevir). The LI phase presents the theoretical advantage of allowing the introduction of
the antiviral agent once the steady state of ribavirin has been reached, i.e. under the optimal condition for
the DAA (to best protect the DAA against functional monotherapy and to reduce the pre-existing variants
for limiting the pressure of selection).
Whether or not the lead in phase was compulsory for this DAA, was specifically assessed in this
phase II study with comparative arms with or without lead in phase.
Of note, it is thought that some drugs might afford achieving maximal viral suppression without the LI and
despite pre-existing variants
- a lower dose of ribavirin to minimize the risk of anemia due to the tritherapy with boceprevir

30

As regards the primary efficacy analysis derived from this phase II study in treatment nave patients, the
Sustained virologic response (SVR) and relapse rate are described below:

All BOC arms showed statistically significant increased in SVR rate as compared to SOC. A considerable
30-37% increase in SVR rate was observed in patients adding BOC to SOC for 48 weeks as compared to
SOC therapy (as a reminder, a 20% increase was targeted by the Applicant). SVR rate was increased by
17-19% when BOC is added to SOC for 28 weeks.
As a matter of fact, the higher SVR rate observed in BOC arms was driven by a higher EOT in all BOC
arms and by a lower relapse rate for the 48 weeks BOC arms only.

As regards the treatment duration:
These data suggest that 28 weeks tritherapy may not be sufficient enough to eliminate variants in a
substantial proportion of patients.
Nevertheless, rapid virological response might help discriminate patients that can benefit from shorter
treatment duration without maximizing relapse, as highlighted in the table below:

c: Undetectable HCV-RNA at or before 4 weeks of P/R for Arm 1; undetectable HCV-RNA at or before 4 weeks of
boceprevir (TW 4 for Arms 2, 4, 6, and 7 and TW 8 for Arms 3 and 5).

It appears from these data that 48 weeks treatment regimen would be the most protective approach even in
patients with RVR. Relapse rates for the 48-week boceprevir arms in Part 1 were significantly lower
compared to P/R control (Arm 4 vs P/R control: P=0.008; Arm 5 vs P/R control: P=0.0002).

Emergence of the concept of Response Guided Therapy
When the response rates in these two arms were examined looking at subsets of subjects based on the
time each subject first achieved undetectable HCV-RNA, it was identified that subjects who attained
undetectable HCV-RNA by TW 8 had relatively similar SVR rates in both arms. For late responders,
subjects with detectable HCV-RNA at TW 8, the SVR rates in the 48-week arm were superior to that in
the 28-week arm.
Based on these data, the concept of a treatment duration tailored to the early kinetics of virologic
response has emerged (i.e. the Response Guided Therapy/RGT). This concept was then formally
tested in the two phase III studies.
31

As regards the comparative data with lead in vs no lead in phase
The data derived from this study speak in favour of a lead in phase. As illustrated in the above tables,
the lead in phase was indeed associated with higher SVR and lower relapses as compared to the
corresponding no lead in phase arms.

Finally, results from the low dose ribavirin arm argue in disfavour of this strategy. Full dose
ribavirin appears to be critically needed to reduce relapse rate and to achieve SVR also in the setting of
tritherapy with BOC.

Phase III development programme:

The two pivotal phase 3 study [in treatment nave patients (P05216/SPRINT 2) and in treatment
experienced patients (P05101/RESPOND 2] initiated in August 2008 were designed taking into
account the findings from the phase II studies.
Of note, although the phase III study in treatment nave patients can be regarded as being further
consolidated by the phase II study in the same population (and with the 800 mg TID dose), the same does
not apply to the phase III study in treatment experienced patients since the corresponding phase II could
not be interpreted due to several amendments.

1. As regards their designs:

For both phase III studies, the main following aspects of their design can be underlined:

- double blind (although the significant rate of dysgueusia with boceprevir (see safety assessment) might
have to some extent given some insight to the boceprevir containing arms).

- multi-centers studies with centers from US, EU, Canada and South Africa [P05101 : 78 sites: USA (44),
Europe (27), Canada (8), South America (1) / P05216 : 149 sites: USA (82), Europe (49), Canada (11),
South America (7)]

- the control arm was the current established standard-of-care (SOC), Pegylated Interferon
+Ribavirin for 48 weeks

In both phase III studies (as well as in phase II studies) pegylated interferon alfa 2b was used. This is
important to note when considering that the applicant claimed indication does not qualify the type of
pegylated interferon. However, based on the the IDEAL study where, although similar SVR, different
EOT results were observed with the bitherapy of ribavirin and pegylated IFN, depending on the type of
pegylated IFN (alfa 2a and alfa 2b), it cannot be excluded that the difference in the viral kinetics under
alfa 2a or 2b might have a potential translation as regards the antiviral activity of boceprevir. At the D120,
it was admitted that Peg-IFN alfa 2b could be regarded as a worse case scenario in terms of DAAs
protection against virological breakthrough.At the D120 it was concluded that the indication (although
not to be restricted with alfa 2b) should underline that the clinical experience has only been gained
boceprevir with pegylated interferon alfa 2b, at least until the availability of the results of an ongoing
study with alfa 2a (P05685).

- in both studies the tested hypothesis was superiority. In the P05216 study in treatment nave patients,
the targeted improvement was 13% over the SOC (assuming a control SVR of 45%).
In the P05101 study in treatment experienced patients, the targeted improvement was 21.4% over the SOC
(assuming a control SVR of 22%).
- boceprevir treatment arms comprise a lead in phase
32
- a response guided therapy (RGT): based on the phase II study in nave patients (P03523) where
different treatment duration were explored (28 weeks and 48 weeks), treatment duration tailored to the
patient early virologic response to boceprevir (TW8=4W LI+ 4W tritherapy with boceprevir) was
specifically assessed in the phase III studies as compared to fixed treatment duration of 48 weeks
(including 4 weeks of lead in phase with the bitherapy).

Response Guided
Therapy (RGT)
TREATMENT NAVE
(P05216/SPRINT 2)
TREATMENT EXPERIENCED
(P05101/RESPOND 2)
Early responders
UndetectableHCV
1

4W LI + 24W BPR = 28 W 4W LI + 32W BPR = 36W
Late responders
DetectableHCV RNA l
2

4W LI + 24W BPR + 20 PR = 48 W 4W LI + 32W BPR + 12W PR = 48W
FIXED TREATMENT
DURATION
4 W LI+ 44W BPR = 48W 4 W LI+ 44W BPR = 48W
1
in treatment naive patients : Undetectable HCV RNA at all assays from TW8 through TW24
and in patients who have failed previous therapy : Undetectable HCV RNA at all assays from TW8 through TW12.

2
in treatment naive patients: Detectable HCV RNA at all assays from TW8 through TW24
and in patients who have failed previous therapy : Detectable HCV RNA at all assays from TW8 through TW12.

Although the interest of the RGT (potentially allowing shortening the tritherapy period) can be
acknowledged (in terms of adverse events and pressure of selection), the data will have to be scrutinized
so as to ensure that it is ultimately conservative enough in terms of efficacy.
As illustrated the time duration of the tritherapy (BPR) period and bitherapy (PR) consolidation phase is
different for both populations. This is based on extrapolation, from the Phase 2 trial in previous
nonresponders (P03659) the minimum length of therapy selected was 36 weeks, instead of 28 weeks.

- The primary efficacy endpoint of the study was the sustained virologic response defined as plasma
HCV-RNA level below the lower limit of detection at Followup Week 24 in the FAS population; witch is
the established endpoint of all current study performed in HCV population. The FAS population includes
all randomized subjects who received at least one dose of any study medication.

- Missing data, LOCF approach
Replacement of a missing FW24 data by the value at FW12 (LOCF imputation) might be agreed
however, given that the applicant did not provide the number of patients who relapse between FW12 and
FW24, it is difficult to evaluate the impact of such approach. Results without imputation of missing data
were not provided in the report.

- Among the secondary analyses:
In line with the above table
In early responders: comparison of 28 weeks (in treatment nave)/36 weeks (in treatment experienced) vs
48 weeks
In late responders: comparison of 48 weeks treatment with RGT (i.e. 4W LI + 24W BPR + 20 PR in
nave / 4W LI + 32W BPR + 12W PR in treatment experienced) vs 48 weeks treatment without RGT (4LI
+ 44 W BPR)

- Patient populations:
Subjects co-infected with HIV were excluded from both studies. A dedicated study (P05411) is on
going in this population. This indication is not claimed by the applicant. However, an off label use can
be anticipated since this population is characterized by a more pejorative evolution (in terms of natural
course and response to the SOC) and consequently a particular medical need. The SPC should not be silent
on this population.
Null responders to the SOC: it is noteworthy that whereas this population is particularly challenging in
clinical practice, this population was excluded from the P05101/RESPOND 2 phase III study, likely out of
33
fear of functional monotherapy. Currently the only option for those patients is the re-treatment with
particularly low response rates (<10%) and then the transplantation once decompensation occurred.
The applicant requalified patients on the basis of their W4 response at the end of the lead in period. As
such, the applicant claimed that a substantial proportion of patients requalified as null responders (i.e, with
< 1log10 decrease at treatment W4 in the study) have actually been included in the study. The applicant
relies on this argument to encompass the null responder population in the claimed indication but
studies were not built to evaluate the impact of Boceprevir in this population.
In clinical practice, categorization of patients relies on their historical response to the bitherapy at week
12. The possibility to give the indication to prior null responders as defined by the week 12 response
during previous treatment on the sole basis of data obtained in patients categorized as null responders by
their on treatment week 4 response during current PEG/rbv treatment cannot be foreseen. Some data
illustrate an important level of mismatch between historical 12 weeks and 4 weeks on treatment.
Black patients: these patients are known as being poor responders to the SOC and as such represent a
difficult to treat population. Of interest, the applicant specifically addressed the question of the added
benefit of boceprevir to the SOC in this population through a dedicated cohort (cohort 2) in the Phase III
study in nave patients.

-Stratification
In the study P05216 (nave), the randomization occurred separately for Cohort 1 and Cohort 2. Within
Cohort 1 and Cohort 2, randomized treatment assignment was stratified according to baseline viral load:
high viral load (>400,000 IU/mL) versus low viral load (400,000 IU/mL) and to HCV G1 subtype (G1a
vs G1b).
In the study P05101 (experienced), the randomization was stratified according to prior response (non
responders vs relapser) and to HCV G1 subtype (G1a vs G1b).

Genotype 1a is associated with lower response rate to SOC and higher viral failure rates than genotype
1b.

- The futility rule: it is noteworthy that the futility rules were different for nave and treatment
experienced patients which do not match with the current clinical practice with the PEG/RBV. A
disputable non conservative 24 weeks futility rule was predefined in the phase III study in nave patients
whereas it was set at 12 weeks (as for the SOC) for treatment experienced patients. As part of the D120
CHMP LOQ, the applicant was asked to justify that conservative measures are not equally
proposed for both nave and treatment experienced patients, especially as regards the risk of
resistance in non responders (see further).

- Use of Erythropoietin
Erythropoietin (epoetin alfa) was allowed during the study by clinical decision and was permitted anytime
after initiation of study medications. If the serum hemoglobin is 10 g/dL, corrective action should occur:
reduction of ribavirin, or initiation of erythropoietin therapy, or a combination of both may be used. Initial
dose of erythropoietin was 40,000 units SC, QW. Due to limited experience in this setting long-acting
formulations (eg, darbepoetin alfa) were not allowed.

Pharmacogenetic aspects: IL28B and inosine triphosphatase (ITPA) deficiency
It was recently identified that a genetic polymorphism near the IL28B gene, encoding interferon--3, was
strongly associated with the likelihood of response to SOC. Recent US and EU guidelines recommend
stratification according to IL28B genotype, but the phase III study was initiated far before the release of
these recommendations. However, the applicant added a specific site amendment in the 2 phase III studies
to perform IL28 genotype assay.
In both phase III studies, blood samples were collected for exploratory PGx analyses, including IL-28b
and ITPA, to identify whether a similar association exists with boceprevir combination therapy, and to
investigate the role of mRNA expression as a predictor of treatment response.
34

Pharmacogenetics analysis on IL28B are provided for the ~60% of subjects who specifically
consented to these procedures.
More recently, a genetic variant leading to inosine triphosphatase (ITPA) deficiency has been associated
with risk of ribavirin-related anemia during PR therapy. No data have been submitted on ITPA. As part
of the D120 CHMP LOQ, the applicant was asked to provide results of this pharmacogenetic
analysis and the potential clinical utility of ITPA. However, based on the analysis provided the
clinical utility was unlikely.

2.Main Efficacy Results

2.a from study in treatment nave patients (P05216/SPRI NT 2) :

- Population
A significant number of European patients were included (24%). The population mainly consisted of male
(657/1099, 60%), white (940/1099, 82%) patients with mean age of 49 years old (range 18-76 years) and a
mean BMI of 28.
A large majority of patients had high viral load >400 000 UI/ml (92%) with a mean value of 6.53 log10
UI/ml; 50% were classified as G1a and 36% as G1b with TRUGENE method.
Overall, in the BOC arms only 40 patients had cirrhosis which hampers formal conclusion on the
efficacy/safety of the drug in this difficult to treat population.

It is important to note that overall 43% (138/734) were receiving EPO in the BOC arms as compared to
24% (87/363) in the Control PEG/RBV arm. The use of EPO is associated with a lower level of treatment
failure and does not markedly influence the discontinuation for adverse events as illustrated in the table
below

Subject Disposition by Erythropoietin Use

b Includes all AEs that caused discontinuation (eg, vomiting, neutropenia).
c Includes subjects with virologic breakthrough
d Includes the following categories on the eCRF: lost to follow-up, subject did not wish to continue for reasons unrelated to assigned study
treatment; subject did not wish to continue for reasons related to assigned study treatment; subject withdrew consent; and noncompliance with
protocol.
35

- Main efficacy results (P05216/SPRI NT 2) :

As illustrated in the table below the addition of boceprevir to the SOC provides a significant ~30%
improvement of SVR (correlated to cure), the high significance (p<0.0001) provides robustness in the
demonstration.
(Of note this goes beyond the applicants expectation of 13% targeted improvement)

COHORT 1 : White COHORT 2: Black
Groups PR48 RGT BOC/PR48 PR48 RGT BOC/PR48
FAS N=311 % N=316 % N=311 % N=52 % N=52 % N=55 %
SVR
a
125 40.2 211 66.8 213 68.5 12 23.1 22 42.3 29 52.7
- SVR 26,6 28,3 19,2 29,7
- P value <0.0001 <0.0001 0.0440 0.0035
RR
c
37 22.8 21 9.1 18 7.8 2 14.3 3 12.0 6 17.1
EOT
b
176 56.6 235 74.4 241 77.5 15 29 26 50 36 66

a SVR: The last available value in the period at or after Follow-up (FW) 24. If there is no such value, the FW 12 value is carried forward. SVR24
rates (SVRwith missing=failure approach) were nearly identical. Subjects who were missing FW 24 results and had undetectable HCV-RNA at
FW 12 included 3, 4, and 3 subjects in the PR48 control, RGT, and BOC/PR48 arms, respectively, in Cohort 1 and 1, 0, and 1 subject,
respectively, in Cohort 2. Using the Cochran-Mantel Haenszel Chi-square test adjusted for baseline stratification factors: viral load (>400,000
vs. 400,000 IU/mL) and Genotype (1a vs 1b). In addition, cohort (race: Black vs. Non-Black) was also adjusted in the test for combined cohorts.
b Undetectable HCV-RNA at End of Treatment (EOT) regardless of treatment duration.
c Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA at End of
Follow-up (EOF) among subjects who were undetectable at EOT and not missing EOF data.
COHORT 1 + 2
Groups PR48 RGT BOC/PR48
FAS N=363 % N=368 % N=366 %
SVR
a
137 37.7 233 63.3 242 66.1
- SVR 25,6 28,4
- P value <0.0001 <0.0001
RR
c
39 22.2 24 9.3 24 9.1
EOT
b
191 52.6 261 70.9 277 75.7
36

- Predictability (P05216/SPRI NT 2): SVR based on the early virological response

As part of the D120 CHMP LOQ, the applicant was requested to discuss the added value of boceprevir
on top of PR in patients wih good virologic prognostic factors for interferon responsiveness, having in
mind the burden of the incremental anemia..

- SVR based on I L 28 genotye (CC, CT, TT) :

It was admitted that the benefit of boceprevir was not only to be considered in terms of percentages of
patients achieving SVR but also in terms of percentages of candidates for shortened treatment duration. To
this purpose it was noted that 69% of treatment nave C/C genotypes had an early response allowing for 28
weeks of therapy (rather than 48 weeks as per peginterferon/ribavirin label) in the SPRINT-2 study

37
- Comparison of SVR I N RGT vs NO RGT ARMS (P05216/SPRI NT 2)

Eventhough overall, both RGT and fixed treatment duration provides similar SVR, when focusing on the
more difficult-to-treat population of black patients (poor response to SOC), the fixed treatment duration
of 48 weeks (4W LI+ 44 W tritherapy including BOC) appear more conservative.
This is further illustrated when scrutinizing other sub-set of patients with pejorative factors for response
(fibrosis F3/F4).

Treatment naive subjects
P05216 COHORT 1 + 2
PR48 RGT BOC/PR48
N=137 % N=233 % N=242 %

Fibrosis
- F0/1/2 123 38 213 67 211 67
- F3/4 9 38 14 41 22 52

2.b from study in previous treatment experienced patients (P05101/RESPOND 2)

- Population

A significant number of European patients were included (29%).
The study population mainly consisted of male (268/403, 67%), white (344/403, 85%) patients with mean
age of 53 years old (range 26-74 years) and a mean BMI of 28. Twelve percent of the study population
was of Black race and patients with cirrhosis accounted for 12% of the overall study population. The
number of cirrhosis remains overall limited (n=49, 39 of whom being exposed to BOC).
A large majority of patients had high viral load >800 000 UI/ml (88%) with a mean value of 6.63 log10
UI/ml; 47% were classified as G1a and 44% as G1b with TRUGENE method.

The use of EPO tends to be associated with a lower level of treatment failure, but the data are limited to
enable firm conclusion

38
Disposition of Subjects by Erythropoietin Use

b Includes subjects with virologic breakthrough.
c Includes the following categories on the eCRF: subject did not wish to continue for reasons unrelated to assigned study treatment (n=9 [Control
no EPO, n=4; RGT no EPO, n=1, BOC/PR48 EPO, n=2; BOC/PR48 no EPO, n=2]); subject withdrew consent (n=5 [RGT no EPO, n=4;
BOC/PR48 EPO, n=1]); subject did not wish to continue for reasons related to assigned study treatment (n=4 [Control EPO, n=1; Control no
EPO, n=1; RGT no EPO, n=1; BOC/PR48 EPO, n=1]); non-compliance with protocol (n=2 [RGT no EPO, n=1; BOC/PR48 no EPO, n=1]);
lost to follow-up (n=1 [RGT no EPO]), and administrative reasons (n=1 [RGT no EPO]).

- Main efficacy results (P05101/RESPOND 2)

Addition of BOC to SOC allow for a significant improvement of SVR in both the prior relapser patients
(=40-46%) and the prior partial responders patients (=33-45%). Such results translate into a SVR
reaching 75% in relapser patients (a rate close to the response rate reported in nave patients) and a SVR
reaching 52% in prior partial responders. The high significance (p<0.0001) provides robustness in the
efficacy demonstration.

FAS N=80 % N=162 % N=161 %
SVR
a
17 21.3 95 58.6 107 66.5
- SVR 37.4 45.2
- P value <0.0001 <0.0001
- Previous Non-responder 2 6.9 23 40.4 30 51.7
- Previous Responder 15 29.4 72 68.6 77 74.8

EOT
b
25 31.3 114 70.4 124 77.0

RR
c
8 32.0 17 15.3 14 11.6

VB
d
0 - 2 1.2 3 1.9

IVR
e
1 1.3 7 4.3 4 2.5

a SVR: The last available value in the period at or after FW 24. If there is no such value, the FW 12 value was carried forward. P values were
calculated using the two-sided Cochran-Mantel Haenszel (CMH) Chi-square test adjusted for the baseline stratification factors: previous
treatment response (nonresponder vs relapser) and genotype (1a vs 1b).
b Undetectable HCV-RNA at End of Treatment (EOT) regardless of treatment duration.
c Relapse rate Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment (EOT) and detectable HCV-RNA at
End of Follow-up (EOF) among subjects with undetectable HCV-RNA at EOT and not missing EOF data.
d Viral breakthrough (BT): Any subject who achieved undetectable HCV-RNA and subsequently had HCV-RNA >1,000 IU/mL.
e Incomplete Virologic Response (IVR): Any subject who had a 1.0 log10 increase in HCV-RNA from their lowest result (or a 2.0 log10
increase if the time interval from PEG2b injection to HCV-RNA sampling was different for the two samples) with an HCVRNA >1,000 IU/mL.

39

- Predictability (P05101/RESPOND 2) SVR based on the early virological response

The data reflect the important predictability of W4 response at the end of the lead-in phase as already
observed for the bitherapy.

FAS N=80 % N=162 % N=161 %
SVR by TW4 response
-<1.0 log decline
f
0 - 15 32.6 15 34.1
-1.0 log decline
g
17 25.4 80 72.7 90 78.9
- undetectable 2 100 0 - 2 100

SVR by TW8 response
- Undetectable RNA 7 100 64 86.5 74 88.1
- Detectable RNA 8 12.3 29 40.3 30 42.9

f Poorly interferon responsive: <1.0 log10 decline in HCV-RNA at TW 4 from baseline.
g Interferon responsive: 1.0 log10 decline in HCV-RNA at TW 4 from baseline. Subjects with undetectable HCV-RNA at TW 4 are also included.

- SVR based on I L 28 genotye (CC, CT, TT):

Overall, it was concluded at D120 that the limited number of patients with undetectable HCV RNA at
week 4 and in the PR/CC (n=13) did not allow to reliably interpret the worthiness of adding BOC to PR
in these good responders to PEG/RBV and further investigation were requested.
40

- Comparison of SVR RGT vs NO RGT ARMS (P05101/RESPOND 2)

Eventhough overall, both RGT and fixed treatment duration provides similar SVR, the question still
remains whether RGT will be conservative enough for difficult-to-treat populations, given the limited
number of patients involved in the subgroup analyses. Notably, the number of black patients and F3/F4
were too limited to enable reliable scrutinizing the subgroups.

Previous treatment failures
P05101
PR48 RGT BOC/PR48
N=17 % N=95 % N=107 %
Fibrosis
- F0/1/2 14 23 77 66 81 68
- F3/4 2 13 14 44 21 68

Discussion on clinical efficacy
Based on the significant improvement of SVR over the PEG/RBV, the CHMP concluded at D120
that boceprevir represented a therapeutic advance that justified the principle of an accelerated
review as decided by the CHMP in November 2010.
As illustrated below, improvement of ~30% in treatment nave patients and ~40% in treatment
experienced patients, with a high significance (p<0.0001) providing robustness in the results.
41

However, several limitations were identified at the D120 by the CHMP that required to be
further substantiated by the applicant:

1. Added value of boceprevir in patients with good prognostic factors of response to PR
Given the safety profile of boceprevir (and notably the incremental anemia), the applicant was requested
to thoroughly identify, based on predictability factors (early on treatment viral kinetics notably +/- host
IL28B*), for which treatment nave and treatment experienced (excluding null responders) patients there
are uncertainties on the added value (discussed both in terms of SVR rates and in terms of shortened
duration of therapy) of boceprevir on top of the bitherapy and should propose measures to resolve such
uncertainties.
*In his response, the applicant was to discuss to what extent the retrospective data available (taking into
account potential biases) on host IL28B would suggest that IL28B genotype CC could have an
independent clinical utility beyond on-treatment viral kinetics for this purpose.

Overall, considering the applicants response, it is concluded that:
- there are limitation of the retrospective analysis (60% of subjects and potential biases) to draw
formal conclusion
- there are uncertainties on the clinical utility of IL28B genotyping in clinical practice:
o Already in the context of the current bitherapy (April 2011 EASL guidelines, may be
useful to identify a patients likelihood of response to treatment with pegylated interferon
alpha and ribavirin; however, the predictive value is low)
o All the more in the forthcoming era of DAAs: it is uncertain whether it could have
significant additional value beyond on treatment early viral kinetics

Therefore, in agreement with the applicant, only a prospective study will help to draw formal
conclusion on the clinical utility of IL28B genotyping.

To this purpose, the applicant specifies that the following testable hypotheses are generated:
1. among treatment-nave patients with large declines in HCV-RNA levels at the end of the 4-week lead-
in, administration of short-course boceprevir + PR (SCBPR) regimens results in SVR rates that are non-
inferior to those achieved with the boceprevir+PR regimens defined by the Phase 3 studies (Standard
BPR);
42

2. among treatment-nave patients with an IL28B CC genotype, administration of SCBPR regimens
induces SVR rates that are non-inferior to those achieved with Standard BPR;
and
3. HCV-RNA levels at the end of the 4-week lead-in identify patients whose genotype is not IL28CC but
who nevertheless achieve high SVR rates following SCBPR.

The design of a study to evaluate some or all of these hypotheses is under discussion at the Applicant;
consultation with external advisors is planned. An applicants given example of SCBPR that is being
considered by the applicant is: PR for 4 weeks then BPR for 12 weeks then PR for 8 weeks administered
to patients who:
(1) have IL-28 C/C genotype
(2) AND (2) have >1-log10 reduction in HCV-RNA at TW4.
The applicant proposes to submit the final protocol to the EMA with its rational by the end of December
2011 to allow study start in early 2012.

Therefore, for patients cumulating factors of good response to PR, the whole treatment duration could be
24 weeks including 12 weeks of tritherapy (whereas currently a short course is being proposed for early
responders at week 8 (after 4 weeks of bitherapy and 4 weeks of tritherapy) and is of 28 weeks overall
including 24 weeks of tritherapy.

The burden of the tritherapy would thus indeed be substantially reduced. However, it may only concern a
limited number of patients.
Considering the potency and genetic barrier of the drug, the applicant is obviously considering the 12
weeks short duration of the tritherapy in only those patients cumulating the favourable predictive factors.

Overall, the fact that boceprevir has currently and in the best case scenario (nave early responders at 8
weeks) to be used for as long 24 weeks with the bitherapy is regarded as a particular burden especially
in view of the incremental anemia the management of which will require either the resort to EPO (raising
safety issues) or ribavirin dose reduction (potentially negatively altering the efficacy of the drug).

Therefore it is critical that the applicant be committed to dispel the current level of uncertainties on
whether those patients with favourable factors (on treatment viral kinetics and/or IL28B) for
interferon responsiveness could still retrieve a significant benefit of adding boceprevir to the
bitherapy.

Given the importance of such matter, the design of the protocol should mandatorily be validated by the
CHMP before the study starts and the timelines for submission of this draft protocol should be
shortened (beginning of September 2011 instead of December 2011) to avoid a late implementation of
the study.

Of note, the applicant states that the conduct of such study will require the use of a validated IL28B
assay, however, the IL28B genotyping will have be proceeded in line with what has been done so far
through the retrospective analysis to avoid any delay. It is noteworthy that the commercial use of IL28B
might even depend on the outcome of such study.

Finally, the SPC should factually describe the data on IL28B (60% of patients and biases for IL28B) with
a concluding statement that
The degree of added value of boceprevir on top of the bitherapy will depend on the likelihood of
achieving SVR with the bitherapy only. There are uncertainties concerning the added value of boceprevir
on top of the bitherapy with pegylated Interferon+ribavirin in patients who might have good predictive
factors for achieving SVR with the bitherapy only. Whether on treatment early viral response and/or
IL28B genotype could reliably identify those patients who are unlikely to retrieve significant benefit of
boceprevir (higher SVR rates or short course treatment duration) on top of the bitherapy is currently
under investigation
43

2. Candidates for Response Guided Therapy/RGT:

Having in mind that a RGT might not be considered appropriate if this results in a net loss of efficacy, the
applicant was requested at D120 to thoroughly delineate in the most conservative approach (given the
potential limitations of subgroup analyses in patients with pejorative criteria for treatment responses such
as black patients, patients with advanced fibrosis F3/F4,..) the appropriate candidates for Response guided
therapy [short (28w for treatment nave/36w for treatment experienced patients) as well as long (48
including (4+24+20 weeks / 4+32+12 weeks)].

The main applicants argument has consisted of acknowledging the limitations of the subgroup analyses
notably for the difficult-to-treat population (black patients, cirrhotic) for the comparison of RGT vs no
RGT while claiming a consistency in subgroups as compared to the results in all patients.

However, when considering the following:

.Treatment nave/ Early responders (undetectable at week 8 through week 24): overall 323 patients are
devoted to the comparison of 28 w vs 48 w as follows:

TREATMENT NAVE
(P05216/SPRINT 2)
N=323
Response Guided Therapy
(RGT)/Early responders

4W LI + 24W BPR = 28 W n=161
FIXED TREATMENT
DURATION
4 W LI+ 44W BPR = 48W n=162

Sustained Virologic Response in Early Responders by Race and Fibrosis (IVRS), P05216
Subgroup Category SVR, % (n/N)
RGT BOC/PR48
All Subjects All Subjects 96.3 (156 /162 ) 96.3 (155 /161 )
Race Blacks 86.7 (13 /15 )
Relapse rate:
13.3 (2/15)
94.7 (18 /19 )
Relapse rate:
5.3 (1/19)
Non-Blacks 97.3 (143 /147 ) 96.5 (137 /142 )
Fibrosis F0/1/2 98.0 (144 /147 ) 96.4 (135 /140 )
F3/4 75.0 (9 /12 )
Relapse rate:
18.2 (2/11)
92.3 (12 /13 )
Relapse rate:
0(0/12)
Missing 100 (3 /3 ) 100 (8 /8 )

Overall, the data are reassuring in early responders that shortened treatment duration,
substantially reducing the burden of the treatment, could suffice to achieve adequate SVR: 96.3% in
both RGT and no RGT arms.

However, the limited difficult-to-treat population of black (only 34 patients devoted to the
comparison) and F3/F4 (only 25 patients devoted to the comparison) mandate caution, all the more that
the data give some insight towards a lower level of response.

.Treatment nave/Late responders (Detectable HCV RNA at all assays from TW8 through TW24)
overall 155 patients are devoted to the comparison of 48 weeks total treatment duration with different
duration of the tritherapy (24 weeks vs 44 weeks) as follows:
44

TREATMENT NAVE
(P05216/SPRINT 2)
N= 155
(RGT)/ Late responders
4W LI + 24W BPR + 20 W PR = 48 W n=82
FIXED TREATMENT
DURATION
4 W LI+ 44W BPR = 48 W N=73

Sustained Virologic Response in Late Responders by Race and Fibrosis Subgroups (IVRS), P05216

RGT BOC/PR48
All Subjects All Subjects

72.0 (59 /82 )

*66% (45/68)

75.3 (55 /73 )

Race Blacks 58.3 (7 /12 ) 87.5 (7 /8 )
Non-Blacks 74.3 (52 /70 ) 73.8 (48 /65 )
Fibrosis F0/1/2 74.3 (52 /70) 78.3 (47 /60 )
F3/4 50.0 (4 /8 ) 58.3 (7 /12 )
Missing 75.0 (3 /4 ) 100 (1 /1 )
*14 patients with a false positive HCV RNA result between W8 and W24 are excluded from the analysis

In late responders (indicative of difficulties in achieving virologic suppression), the revised analysis
(excluding false positive) is in favour of the no RGT arm.
Again, the limited difficult-to-treat population of black (only 20 patients devoted to the comparison)
and F3/F4 (only 20 patients devoted to the comparison) mandate further caution in the recommendation.

Treatment experienced /early responders (undetectable at week 8 through week 12) overall 144 patients
are devoted to the comparison of 36 w vs 48 w as follows:

TREATMENT
EXPERIENCED
(P05101/RESPOND 2)
N=144
Response Guided
Therapy (RGT)/Early
responders
4W LI + 32W BPR =
36W
n=71
FIXED TREATMENT
DURATION
4 W LI+ 44W BPR =
48W
N=73

45

Sustained Virologic Response in Early Responders by Previous Response, Race, Fibrosis (IVRS),
P05101

RGT BOC/PR48
All Subjects All Subjects 88.7(63 /71 ) 97.3 (71 /73 )
Previous Response Non-Responder 87.5 (14 /16 ) 100 (20 /20 )
Relapser 89.1 (49 /55 ) 96.2 (51 /53 )
Race Blacks 75.0 (3 /4 ) 100 (5 /5 )
Non-Blacks 89.6 (60 /67 ) 97.1 (66 /68 )
Fibrosis F0/1/2 89.7 (52 /58 ) 96.0 (48 /50 )
F3/4 87.5 (7 /8 )
Relapse rate:
14.3 (1/7)
100 (18 /18 )
Relapse rate:
0 (0/18)
Missing 80.0 (4 /5 ) 100 (5 /5 )

Overall, the data favour the no RGT arm with a delta of about 10%: 88.7% vs 97.3% in RGT vs no
RGT. It is noteworthy that this trend in favour is also observed in the relapsers known as being easier
to treat than partial responders (and even more than null responders) and it is unlikely to be driven by
the proportion of relapser -black or -F3/F4 given their small proportion and even the imbalance in
disfavour of the no RGT arm for F3/F4.

Again, the data mandate all the more cautious in the difficult-to-treat population of black (only 9
patients devoted to the comparison) and F3/F4 (only 26 patients devoted to the comparison, with an
imbalance even favouring the RGT arm).

.Treatment experienced /late responders (detectable from week 8 through week 12) overall the data
devoted to the comparison of RGT vs no RGT with 48 weeks total treatment duration but different
duration of the tritherapy (32 weeks vs 44 weeks) are too limited since only 75 patients are devoted to
this comparison as follows. This all the more applies to difficult-to-treat population of black (only
13 patients devoted to the comparison) and F3/F4 (only 15 patients devoted to the comparison)

TREATMENT
EXPERIENCED
(P05101/RESPOND 2)
N=75
Response Guided
Therapy (RGT)/
Late responders
4W LI + 32W BPR +12W PR = 48W N=35
FIXED TREATMENT
DURATION
4 W LI+ 44W BPR = 48W N=40

46
Sustained Virologic Response in Late Responders by Race, Fibrosis, and Previous
Response (IVRS), P05101

Subgroup Category
SVR, % (n/N)
RGT BOC/PR48
All Subjects All Subjects 80.0 (28 /35 ) 72.5 (29 /40 )
Previous Response Non-Responder 66.7 (8 /12 ) 66.7 (10 /15)
Relapser 87.0 (20 /23 ) 76.0 (19 /25)
Race Blacks 100 (7 /7 ) 66.7 (4 /6 )
Non-Blacks 75.0 (21 /28 ) 73.5 (25/34)
Fibrosis F0/1/2 91.7 (22 /24 ) 81.8(27 /33 )
F3/4 60.0 (6 /10 ) 40.0(2 /5 )
Missing 0.0 (0 /1 ) 0.0 (0 /2 )

Overall:

- the RGT needs to be further substantiated in the difficult to treat populations of black and
cirrhotic patients whatever the population of treatment nave and experienced be there early or
late responders. Awaiting for these further data (commitment to be requested to the applicant), the
RGT would have to be discouraged in these populations (it is nevertheless acknowledged that the
attitude might have to differ for cirrhotic and black patients and will need to be further debated, a
teleconference is planned with the FDA where this issue will be notably discussed).

- As regards treatment nave/early responders, considering that:
o being an early virologic responder is already indicative of a higher likelihood of achieving
a SVR as compared to being a late responder
o for the whole comparison (excluding the subgroup analyses in the difficult to treat
populations as above discussed) the data can be regarded as adequate with more than 300
patients devoted to the comparison of RGT vs no RGT and quite similar SVR results in
RGT vs no RGT.
The RGT (28 weeks total treatment duration, including 4 weeks lead in and 24 weeks
tritherapy) could be recommended in treatment nave/early responders

- As regards treatment nave/late responders, considering that:
o being a late virologic responder is already indicative of difficulties in achieving virologic
suppression
o the overall data devoted to the comparison of RGT no RGT can be regarded as substantial
(at the exclusion of the difficult to treat populations as above discussed) but the
comparative SVR (with exclusion of false positive in RGT) raises some source of
concern with results favouring the No RGT arm. Whether due to chance of truly
indicative of a loss of efficacy remains to be established by further data substantiating the
RGT in this population.

- As regards treatment experienced/early responders. There are reservations as regards the RGT in
since the data are more limited and the comparative SVR are indicative of a potential loss of
efficacy with RGT (89 % vs 97%). Again, whether due to chance of truly indicative of a loss of
efficacy remains to be established by further data substantiating the RGT in treatment experienced
patients.

- As regards treatment experienced/late responders, the limited number of patients devoted to the
comparison in this a priori more difficult to treat population, mandates adopting a conservative
attitude of not recommending RGT.

47
Finally, outside the best case scenario of (non black and non cirrhotic patients) early responders -
treatment nave patients there are reservations against the RGT. These reservations could be
ranked from a discouragement to a not recommended use (treatment experienced), having in mind
the burden of anemia and the fact that even if somewhat downgraded with RGT as compared to no RGT,
the benefit could remain substantial in terms of increased rates of SVR as compared to the control group.
Of note, Interaction with FDA is planned to attempt drawing harmonised recommendation since
divergences on treatment duration might be source of confusion.
It is important to note that it is quite unfortunate that the RGT was not tested in the study performed in
treatment experienced patients with pegylated interferon alfa 2 that the applicant has newly submitted
(P05685, see below).

3. Adequacy of the futility rules in treatment nave patients:

In the pivotal Phase 3 study in treatment-nave patients, patients who failed to achieve undetectable HCV-
RNA after 24 weeks of therapy were to discontinue therapy.
To evaluate whether the implementation of an early futility rule (eg, at TW12) would suffice or whether a
futility rule at TW24 would also need to be maintained, the number of boceprevir-treated patients who had
at least a 2-log10 decline from baseline at TW12 but had detectable HCV-RNA at TW 24 (ie, met the per
protocol TW24 stopping rule) was determined. Approximately 10% (68/646) of the boceprevir-treated
patients who had 2-log10 decline in HCV-RNA at TW12 had detectable HCV-RNA at TW24. It was
therefore concluded that if a futility rule at TW12 were introduced, the TW24 futility rule would
also need to be maintained.
According to the Applicant the futility rule implemented in the Phase 3 treatment-nave study
appropriately discontinues therapy in patients unlikely to benefit from continued treatment (thereby
reducing the potential for adverse experiences and resistance development), while not stopping therapy
early in patients who may with continued therapy achieve undetectable HCV-RNA levels (and sustained
virologic response). Furthermore, the futility rule of undetectable HCV-RNA at TW24 is clear and simple
to implement in the clinical practice setting. Any futility rule involves trade-offs of maximizing SVR,
minimizing number treated who will not respond, minimizing number of times HCV-RNA is measured,
and having a regimen that is practical enough to actually implement without excessive confusion. An
additional futility rule could be implemented based on response at TW8 or TW12 but would further
increase the complexity of the regimen.
Overall, the question is, should physician do something between week 12 and week 24, to avoid unduly
keeping a treatment nave patient under unchanged treatment whereas no benefit can be anticipated (and
only risk).
Since it is unlikely that an early responder (undetectable at week 8 would become detectable at week 12
and then undetectable at week 24), the question is what is the proportion of patients with detectable HCV
RNA at week 8 (potentially late responder) who would have detectable HCV RNA level and <2 log
decrease from baseline that would ultimately achieve undetectability at week 24. If marginal, this speaks
in favour of stopping at week 12 under those conditions.
However, it is also acknowledged that even though treatment nave patients would achieve a significant
decrease in HCV RNA level at week 12 as compared to baseline (>2 log copies/ml) they might still remain
with detectable HCV RNA level at week 24 (10% of patients), therefore the 24 week stopping might
further prevent from unduly pursuing the treatment in patients ultimately unlikely to achieve SVR.
Of note, Interaction with FDA is also planned on this issue.
48

4. Null responders

At D120 the CHMP has considered that the applicants claimed indication should not encompass the
population of null responders among treatment experienced since this population was an exclusion criteria
from the pivotal study SPRINT 2/P05101 in treatment experienced. Despite this exclusion criteria, the
applicant claimed that a clinical experience was gained in null responders by using the lead in phase to
re-qualify patients (<1 log copies/ml at week 4).

In its response to D120 CHMP LOQ the applicant insists upon encompassing the null responders in the
indication based on several considerations:
- there is a close correlation between the historical week 12 response to prior treatment (<2 log
copies/ml) and the week 4 on treatment (<1 log copies/ml)
- when applying the week 4 definition of null responders, a significant benefit of the tritherapy is
shown in RESPOND 2/P05101 over the PR in this challenging population (RGT 33%, no RGT
34%, PR 0%)
- based on interim results (EOT) from 42 patients in the control arm of SPRINT 2/P05216 in
treatment nave patients and RESPOND 2/P05101 treated with boceprevir (P05514/PROVIDE
Study, pooling respectively a second course of treatment, i.e. PR- Retreatment by BPR in
treatment nave; and a third course of treatment in treatment experienced, i.e. PR-Retreatment
with PR and then rescue with BPR ), it is estimated that SVR with the tritherapy would be
substantial in patients with <1 log copies/ml decrease at week 4 as compared to baseline.

Although it can be acknowledged that the addition of boceprevir might indeed increase the likelihood of
achieving SVR in null responders, it remains disputable to formally promote the use in null responders
through the indication of boceprevir given that:
- the null responders as defined through the EU guidelines, i.e. <2 log10 copies/ml decrease as
compared to baseline and still detectable at EOT were an exclusion criteria of the
P05101/RESPOND 2 phase III study (of note as opposed to the telaprevir development
programme),
- the applicant has retrospectively reassess the data using the lead in period to re-qualify patients
with a revised definition of null responders (<1 log10 copies/ml at week 4)
- in general, it is anticipated that null responders would require antiviral combination to achieve
adequate SVR, therefore although some patients could not afford (due to their disease
evolution) waiting for these combinations, it would be misleading to equally promote the use of
the tritherapy in null responders as compared to partial responders and even relapsers.
- Based on the prospective analysis from the pivotal study of telaprevir REALIZE/C216 where null
responders defined on the basis of their 12 week HCV RNA on prior PR, the benefit of the
tritherapy over the bitherapy is shown as being limited (around 25%). This is all the more true in
the challenging cirrhotic null responders corresponding to a particular medical need in clinical
practice.
Overall, only a statement in section 4.4 (the section 4.1 will cross-refer to this statement, see SPC
comments) could be accepted such as:
Null responders to prior bitherapy were excluded from the RESPOND 2/P05101 study. However, based
on a retrospective analysis performed with requalifying the patients on the basis of their on treatment
virologic response at week 4 (using the lead in period) as compared to baseline, null responders might
retrieve some benefit in adding boceprevir to the tritherapy. However, this cannot be reliably quantified
from the retrospective analysis. Moreover the optimal management of null responders remains to be
established and might in the future require antiviral combination.

49
5. Co-administration with pegylated interferon alfa 2a
As part of the D120 the applicant was asked to discuss the co-administration with alfa 2a in terms of
efficacy/safety, since the clinical experience was only gained with peginterferon alfa 2b (although
admitted as being regarded as a worse case scenario in terms of DAA protection based on the IDEAL
study results).
It is appreciated that the applicant has substantiated his response to the D120 CHMP LOQ with a newly
submitted double blind multi center study (P05685) with boceprevir combined with Peg-IFN alfa
2a+ribavirin vs Peg-IFN alfa 2a+ribavirin in subjects with HCV genotype 1 who failed prior treatment
with PEG/RBV (overall approx 200 patients were included with a ratio 2:1).
To be underlined as regards the study design:
In relation to the issue on Response Guided Therapy (RGT), it is noteworthy that this study in treatment
experienced started in February 2009 and the RGT was not tested.
Moreover, in line with the pivotal phase III study P05101 in treatment experienced (started in Aug 2008),
this study also excluded null responders.
In this study as well, EPO was allowed and very consistently with was shown in study P05101, the
use of EPO was overall in 27% of the PR arm and 49% in the BPR arm.

Overall the efficacy results are consistent with the clinical data derived from the study P05101 and
adequately substantiate that boceprevir could be used either with Peg-IFN alfa 2b (main data) or Peg-IFN
2a. This can overall be accepted that on the theoretical point of view the alfa 2b would be regarded as a
worse case scenario in terms of degree of protection of the DAA.

Cross-Study Comparison of Sustained Virologic Response and Relapse Rates:
P05101 (RESPOND-2) and P05685

P05685 P05101
Arm 1
PEG-2a/R48
a

n=67
Arm 2
BOC/PEG-2a/R48
a

n=134
Arm 1
PR48
b

n=80
Arm 3
BOC/PR48
b

n=161
SVR
c
, n (%) 14 (20.9) 86 (64.2) 17 (21.3) 107 (66.5)
95% CI (11, 31) (56, 72) (12, 30) (59, 74)
P value
d
-- <0.0001 -- <0.0001
Relapse
e
, n/N (%) 7/21 (33.3) 11/95 (11.6) 8/25 (32.0) 14/121 (11.6)
95% CI (13, 54) (5, 18) (14, 50) (6, 17)
P value
f
-- 0.013 -- 0.009
a
Arm 1 (PEG-2a/R48) = PEG-2a + RBV for 48 weeks.
Arm 2 (BOC/PEG-2a/R48) = PEG-2a/R lead-in for 4 weeks, then BOC/PEG2a/R for 32 weeks.
b
Arm 1 (PR48) = PEG-2b + RBV for 48 weeks.
Arm 3 (BOC/PR48) = PR lead-in for 4 weeks, then BOC/PR for 44 weeks.
c
SVR (Sustained Virologic Response): The last available value in the period at or after FW 24. If there is no
such value, the FW 12 value was carried forward. SVR24 rates (SVR with missing=failure approach)
were nearly identical (P05685: 11/67 [16.4%] Control, 84/134 [62.7%] BOC/PEG2a/R; P05101: 17/80
[21.3%] PR Control, 106/161 [65.8%] BOC/PR48.)
d
Versus PR control arm. P values were calculated using the two-sided Cochran-Mantel Haenszel (CMH) Chi-
square test adjusted for the baseline stratification factors: previous treatment response (nonresponder vs
relapser) and genotype (1a vs 1b).
e
Relapse rate was the proportion of patients with undetectable HCV-RNA at End of Treatment (EOT) and
detectable HCV-RNA at End of Follow-up (EOF) among patients with undetectable HCV-RNA at EOT and
not missing EOF data.
f
Versus PR control arm. P values were calculated using the two-sided Chi-square test.

50
It is nevertheless to be underlined, as regards the safety data derived from this study, that the risk of
neutropenia (including grade ) is markedly increased when boceprevir is combined to alfa 2a. This
is all the more concerning in view of the increased grade 4 neutropenia.

Study P05685 Study P05101
PegIFN
alfa2a/RBV
PegIFN alfa
2a/RBV/BOC
PegIFN
alfa2b/RBV
PegIFN
alfa2b/RBV/BOC
N=67 N=334 N= 80 N= 161
Treatment duration (mean) 105 days 334 days 104 days 336 days
AE 100% 100% 96% 100%
SAE 10% 13% 5% 14%
Death 0 2 (1%) 0 0
Drug discontinuation 4% 17% 3% 12%
Dose modification 22% 43% 14% 33%

Anaemia as AE 33% 50% 20% 47%
Hb<10g/dl 22% 37% 24% 35%
Hb<8.5g/dl 4% 13% 1% 14%
Use of EPO 30% 47% 21% 46%

Dysgueusia 25% 39% 11% 45%

Neutropenia as AE 18% 31% 10% 14%
Neutrophils<750/mm3
Grade3-4
18% 28% 9% 20%
Neutrophils<500/mm3
Grade4
3% 14% 4% 7%

Thrombocytopenia as AE 6% 7% 0% 6%
Platelets < 50 (Grade3) 7% 10% 0 5%
Platelets <25 (Grade 4) 0 1% 0 0

In conclusion it can therefore be accepted that the 4.1 section does not put emphasis on the type of Peg-
IFN. In section 5.1, a statement should be added that a study with alfa 2a in treatment experienced
patients gave consistent results as compared to the study P05101. However, in section 4.8 a statement
will have to be added that the risk of neutropenia (including grade 4 neutropenia) could be
markedly increased when boceprevir is combined with pegylated alfa 2a as compared to alfa 2b

Conclusion on clinical efficacy
The benefit of boceprevir over the bitherapy with Peginterferon ribavirin is critical. However, SPC
revisions are requested to ensure optimal therapeutic management of patients (candidates for RGT,
stopping rules, null responders) as well as additional studies to further substantiate the added value of
boceprevir on top of the bitherapy in those patients having good predictive factors to interferon
responsiveness.
Clinical safety
The safety profile of Boceprevir was investigated in over 2800 subjects. At the proposed dose for
marketing, 800 mg three times daily, 1900 subjects have been exposed in Boceprevir including 66% of
them for at least 24 weeks.
The Key Studies Integrated for Safety Assessment included one Phase 2 study performed in nave
population (SPRINT1) and two Phase 3 studies, respectively conducted in nave patients (SPRINT-2) and
in patients who had failed previous therapy (RESPOND 2).
51
Safety data from these three studies were presented pooled and separated according to the analysed
population (nave and pretreated). Overall, 1548 subjects were exposed to boceprevir in these studies.

Globally, the addition of boceprevir to standard of care led to a slight increase in the rate of serious
adverse events and the rate of adverse events leading to study drug discontinuation or dose modification
compared with the control arm. The difference was more marked in pre-treated patients than in nave
patients.

The most frequently reported adverse reactions in boceprevir treatment arms were comparable to those
reported in the control arm, i.e flu-like syndrome (fatigue, chills, headache), hematologic disorders and
(anaemia) and gastrointestinal disorders. However, compared with the control arm, the addition of
boceprevir increased significantly the risk of developing anaemia, neutropenia and gastrointestinal
disorders such as diarrhoea, nausea but also in a higher extent dygsueusia.
There was by contrast no apparent increase of the risk of having other IFN related adverse reactions, such
as psychiatric disorders, cardiovascular disorders or endocrine disorders.

The main safety data raised from the clinical development program of boceprevir are summarized in the
table below:

Naive patients

Non naive patients Total patients (non naive
and naive patients)
PR
n=467
BOC/PR
N=1225
PR
N=80
BOC/PR
n=323
PR
n=547
BOC/PR
n=1548
Treatment-emergent AE 99% 99% 96% 99% 98% 99%
Serious AE 8% 10% 5% 12% 8% 11%
Death N=4 N=3 0 N=1 N=4 N=4
Study drug discontinuation due to AE 14% 14% 3% 10% 12% 13%
Dose modification due to AE 26% 41% 14% 31% 24% 39%
Anaemia 30% 50% 20% 45% 29% 49%
Neutropenia 19% 25% 10% 14% 18% 23%
Thrombocytopenia 1% 4% 1% 2% 1% 4%
Dysgueusia 16% 35% 11% 44% 15% 37%
Diarrhoea 19% 23% 15% 23% 18% 23%

The most salient aspect of the safety profile of the drug is marked by the high rate of anaemia and
dysgueusia that occurred in 49% and 37% of boceprevir-treated subjects respectively.

Regarding dysgueusia, this event generally did not lead to study drug discontinuation (only in 2 patients in
the clinical develpment program) and few events were judged serious by the investigator.

More problematic is the occurrence of anaemia since decrease in Hb < 10g/dl was reported twice as often
in boceprevir-treated subject compared with placebo-treated subjects (49% versus 29% respectively). In
summary, the addition of boceprevir to SOC was reflected by an additional decrease of Hb of
approximately 1g/dl versus -2.5 to 3.5g/dl with peginterferon and ribavirin only. Consequently, the
proportion of subjects who required dose reduction of antiviral therapy and/or the use of
erythropoietin was much higher in boceprevir treatment arms, whatever the studied population
(nave or pre-treated). More boceprevir-treated patients also required transfusion. The main safety
information related to the management of anaemia is summarized in the table below:

Management of anaemia in the boceprevir
clinical development program
Naive patients

Non nave patients Total patients (non
naive and naive
patients)
PR
n=467
BOC/PR
N=1225
PR
N=80
BOC/PR
n=323
PR
N=547
BOC/PR
n=1548
Dose modification (any drug) due to anaemia 13% 25% 6% 19% 12% 24%
Use of EPO 25% 43% 21% 43% 24% 43%
Transfusion 0.4% 1.8% 0 5% 0.4% 3%
52

Regarding the mechanism of boceprevir-induced anaemia, the MAH failed to demonstrate the impact of
boceprevir alone on the red blood cells as part of the Phase 1 study P05351. However, it is important that
the MAH makes further efforts to better investigate the mechanism behind the higher rate of anaemia
reported in patients treated with the tritherapy BOC/P/R.

The benefit /risk ratio of EPO in the management of HCV therapy-induced anaemia has not been validated
yet even though a scientific rational is admitted to support its use in this context. Globally, as part of the
assessment of the MAA of boceprevir, it is important to ensure that the need of using EPO due to
anaemia in more of 40% of boceprevir-treated subjects does not induce additional safety concerns
that could counterbalance the potential advantage brought by this drug in terms of virological
response and efficacy parameters.
Regarding this issue, the MAH has explored the safety data in patients who received EPO in the clinical
development program. One case of PRCA with anti-EPO antibodies was reported. The
immunomodulatory effects of IFN in the occurrence of such event cannot be ruled out. There was no
apparent increase in the rate of thrombo-embolic events in patient who received EPO. However, the MAH
was requested at D120 to go more in depth in this analysis by performing a research using SMQ
terminology.
Interim results from the ongoing long term safety study conducted in patients who were previously treated
with boceprevir did not raise concern regarding pro-tumoral risk in patients who also receive EPO in
previous treatment study. However, this issue should continue to be explored.

The addition of boceprevir to standard of care was also associated to an increased risk of developing
neutropenia and Grade3/4 neutropenia and, in a lesser extent, to an increased risk of developing
thrombocytopenia.
Due to the potential increased risk of Grade3/4 neutropenia-related infections, it is important that
physicians are alerted on this concern and the need of monitoring this potential adverse reaction by a
warning in section 4.4 of Victrelis SmPC. As part of the D120, the risk of neutropenia was identified as
being further increased when boceprevir was combined with pegylated interferon alfa 2a as compared to
alfa 2b. This will have to be reflected in section 4.8 and further discussed by the applicant.

Safety with Response Guided Therapy in the key studies P05216 and P05101

Two of the key safety studies included a response guided therapy (RGT) arm in which subjects were
assigned to either a 28- or a 48-week treatment duration (study P05216 in treatment-nave subjects) or a
36- or 48-week treatment duration (study P05101 in previous PEG/R treatment failures ) based upon their
on-treatment virologic response at week 8.
This offers the opportunity to shorten the treatment duration for a proportion of patients achieving
undetectable HCV-RNA at week 8 (early virologic responders).

53

The overview of adverse events, SAEs, study drug discontinuation and dose modification due to AEs, by
treatment arm in studies P05216 and P05101 is presented below:

The benefit of the RGT in terms of reduction of adverse events is not striking although it may offer the
advantage to reduce the occurrence of such late-occurring events in patient who had undetectable HCV
RNA at week 8.

In terms of laboratory findings, excluding hematology disorders that are presented above, the MAH has
presented an analysis of liver function tests across studies that did not reveal safety concern. However, an
analysis of other blood chemistry values (such as but not limited to cholesterol, glycemia, CK, urea, etc..)
is missing. The MAH should therefore provide an overview of these parameters to complete this
deficiency.

Regarding the impact on QT/QTc prolongation, the assessment of the thorough QT/QTc study performed
according to ICH E14 guideline was overall reassuring with negative results. However, due to some
concerns raised in preclinical studies regarding this issue, it is strongly recommended that the cardiac
safety profile continue to be assessed when boceprevir will be prescribed in normal condition of use.
Specific attention should be paid on this area in future PSURs.

The safety profile of boceprevir should be more investigated in sensitive populations, such as HIV-HCV
co-infected patients and patients with cirrhosis or advanced liver fibrosis. At this stage, although the safety
data appear globally comparable in these populations compared with the general population, it is
important to get more information from the ongoing clinical studies to formally conclude on this issue.
Long term safety in previously-treated patients with boceprevir should also continue to be more
investigated.

Overall, at the D120 several issues were identified that require to be further substantiated by the applicant:

54
1. Incremental risk of anemia with boceprevir

The applicant was asked to discuss to what extent the anemia of boceprevir + pegIFN/ribavirin could be
managed without the resort of EPO (considering the need for sufficient ribavirin exposure), having in
mind that the use of EPO raises safety concerns (risk of PRCA notably) and could impact the benefit risk
balance.

In its response to the D120, the applicant underlined that as mentioned in the recently (April 2011)
European Association for the Study of Liver Disease (EASL) Clinical Practice Guidelines on the
management of hepatitis C virus infection in clinical practice, erythropoietin is broadly used worldwide
to manage the anemia associated with peginterferon and ribavirin (PR) therapy in patients with chronic
hepatitis C.
The applicant also underlined the considerable variation in the use of erythropoietin within Europe as
reflected in the table below:
Anemia Management Strategies By Region and Country in the Key Studies: BOC/PR
Protocol Nos. P03523, P05216, and P05101
BOC/PR
Region
Country
Number of
Subjects EPO Only
RBV Dose
Modification Only Both Neither
Europe 341 57 (17) 24 (7) 51 (15) 209 (61)
Belgium 23 0 2 (9) 3 (13) 18 (78)
France 141 38 (27) 1 (1) 19 (13) 83 (59)
Germany 66 9 (14) 11 (17) 9 (14) 37 (56)
Italy 61 8 (13) 7 (11) 13 (21) 33 (54)
Netherlands 10 0 0 0 10 (100)
Spain 39 2 (5) 3 (8) 6 (15) 28 (72)
Switzerland 1 0 0 1 (100) 0
North America 1187 247 (21) 35 (3) 303 (26) 602 (51)
Canada 131 31 (24) 1 (1) 10 (8) 89 (68)
Puerto Rico 3 0 0 0 3 (100)
United States 1053 216 (21) 34 (3) 293 (28) 510 (48)
Latin America 20 5 (25) 1 (5) 4 (20) 10 (50)
Argentina 20 5 (25) 1 (5) 4 (20) 10 (50)
Note: Percentage is based on the number of subjects for each category.
BOC=boceprevir 800 mg PO TID; EPO=erythropoietin; P=peginterferon alfa-2b; PO=orally; PR=peginterferon alfa-2b+ribavirin;
R=ribavirin; TID=three times daily.

Moreover, the applicant pointed out that,
- No new safety issues associated with the use of erythropoietin were identified in the key boceprevir
studies. Overall, erythropoietin use was well tolerated and enabled patients to complete treatment.
Comparing BOC/PR-treated patients who did and did not use erythropoietin, the incidence of
discontinuations for adverse events was similar (12% in erythropoietin users vs 14% in non-erythropoietin
users). Erythropoietin users had a lower incidence of discontinuations for treatment failure compared with
non-erythropoietin users (10% vs 17%) and a higher overall study completion rate (73% vs 56%). Similar
results were seen comparing erythropoietin users and non-users in the PR arm.
-There were no apparent increases in cardiovascular or thromboembolic events, malignancies, or
hypertension associated with use of erythropoietin
55
Embolic and thrombotic events (standardized MedDRA query) occurred in 1% of patients receiving
erythropoietin and 1% of patients who did not receive erythropoietin overall.
- Although 1 serious case of PRCA was observed in a 56-year-old patient receiving boceprevir,
peginterferon, ribavirin, and erythropoietin, PRCA is also known to occur with use of peginterferon and
ribavirin alone ald also with EPO in the context of other indications. The patient was treated with
rituximab, methylprednisolone, and intravenous immunoglobulin, and has had a full recovery of erythroid
series and is no longer transfusion dependent.
The PRCA rate observed in the key boceprevir studies of 1.5 per 1000 patients (1 out of 667 patients in
the BOC/PR arms who received erythropoietin) is consistent with the rate of 3.4 per 1000 patients (2 out
of 581) observed in a retrospective survey study in chronic hepatitis C patients in France conducted in
2005 (Thvenot et al, 2007). It is, however, not established whether the rate of PRCA with erythropoietin
use in patients with chronic hepatitis C infection is higher than in patients with other disease states for
which erythropoietin is indicated (eg, chronic renal failure, cancer).
- SVR rates seen in patients with anemia were high and were independent of the intervention used for the
management of anemia (ribavirin dose reduction and/or erythropoietin)
Sustained Virologic Response By Anemia Management in the Pivotal Studies
Protocol Nos. P05216 and P05101
Treatment-Nave
P05216
PR Treatment Failures
P05101
BOC/PR BOC/PR
Anemia Management Strategy % n/N % n/N
Ribavirin Dose Reduction Only 78 29/37 83 5/6
Erythropoietin Only 74 95/129 80 47/59
Both Ribavirin Dose Reduction and Erythropoietin 71 109/153 72 48/67
Neither 68 30/44 76 19/25
BOC=boceprevir 800 mg PO TID; EPO=erythropoietin; P=peginterferon alfa-2b; PO=orally; PR=peginterferon alfa-2b+ribavirin;
R=ribavirin; TID=three times daily.

A study (P06086) of ribavirin dose reduction compared to erythropoietin use in the management of
anemia in chronic hepatitis C patients is ongoing to further substantiate these findings.
Overall, it is acknowledged that the use of EPO for the management of RBV-induced anaemia is relatively
common in clinical practice in particular in North America and some European countries such as France.
This practice, although off label, has been acknowledged as a widely applied practice by the recent
EASL Guideline in April 2011 (with recommendations of use) and in some countries, as France, in order
to avoid RBV dose reduction potentially compromising the chance of eradicating the virus.
However, due to the known safety profile of EPO, it is important to ensure that the addition of EPO to
antiviral tritherapy to manage the increased risk of anaemia in boceprevir-treated patients does not
deteriorate further the global safety profile of BOC/PegIFN/RBV.
In this context, the MAH was requested to discuss the safety profile of EPO in the boceprevir clinical
development program and to discuss whether anaemia can be managed without using EPO.
In terms of safety, tables 3 and 4 provided by the Applicant show that there was no apparent increased risk
of developing adverse events commonly associated with erythropoietin in EPO users versus non EPO
users in the Boceprevir development program. A slight increase of thrombo-embolic events is however
observed in boceprevir treated subjects who receive EPO (1.2%) versus those who did not receive EPO
(0.7%). This slight increase is mainly driven by a slight higher percentage of deep vein thrombosis (0.6%
vs 0.2%) and pulmonary embolism (0.3% vs 0.1%). Globally, these differences were not unexpected due
to the known safety profile of EPO, it is reassuring to observe that they remain somewhat limited.
56
More problematic is the occurrence of one serious of PRCA with anti-EPO antibodies in the boceprevir
clinical development program (with an incidence of 1.5 per 1000 patients). Of note, the Applicant has
provided a new information regarding the outcome of this case. Reassuringly, the patient fully recovered
and was not transfusion dependant anymore. In agreement with the Applicant, the occurrence of PRCA
cannot be attributed to boceprevir only but rather to tritherapy and use of EPO. It is likely that the
immunomodulatory effect of IFN and the impact of the underlying disease itself may increase the risk of
developing PRCA in patients co-receiving EPO. That is why, it is particularly important to supervise the
use of EPO in the context of hepatitis C, in particular by restricting its use only when Hb<10g/dl, which
has not been done in the above case of PRCA.
Regarding the possibility of managing tritherapy-induced anaemia without using EPO, the Applicant has
provided table 5 displaying the rates of sustained virologic response by anemia management in the pivotal
studies.It should be noted that these patients conserved a high sustained virologic response (78% and 83%
in studies P05216 and P05101 respectively) which remain comparable or higher than those whom anaemia
was managed by erythropoietin only (74% and 80% respectively).The Applicants response is however
somewhat difficult to interpret since very few patients had only ribavirin dose reduction in both studies
P05216 and P05101.
It is important to underline that the efficacy and safety results with and without EPO could only
have been reliably interpreted if a randomization would have been performed according to EPO.
Overall, it is difficult to conclude based on the available data whether anaemia can be adequately managed
with only RBV dose reduction without impacting on the efficacy results of the tritherapy. It might be true
in some situations where the anaemia was not very pronounced and easily manageable with low ribavirin
dose reduction; However, when high dose reduction of RBV was required for severe Hb level decrease,
one can not exclude an impact on efficacy and other measures are considered in practice in order to
maintain RBV concentrations and achieve better response rates. Results of the ongoing P06086 comparing
RBV dose reduction and EPO use for the management of anaemia might help answering this question
(having also in mind the need to be reassured on the adequate protection of the DAA despite not full dose
of ribavirin). However, the results of this study are expected by November 2012 (no interim analysis
planned).
In conclusion, although the data provide some degree of reassurance, the clinical dossier so far does not
allow to fully appreciate to what extent the management of the substantial incremental anemia induced by
boceprevir on top of PR could per se negatively affect the benefit-risk balance of boceprevir, having in
mind that on the one hand ribavirin dose reduction could potentially alter the benefit and on the other hand
the EPO use, through its safety profile (associated with risk of PRCA and thrombosis events), could alter
the risk.
possible patient characteristics) and potential negative consequences of the management of the high rate of
anemia (as a result of the incremental risk with boceprevir) in patients receiving the tritherapy with




c. the anemia management in patients treated for hepatitis C in the EU in the presence of boceprevir in
clinical practice.
57

Besides the main issue of the substantial incremental risk of anemia associated with boceprevir on top of
Peginterferon + ribavirin, other issues were identified as requiring further data/discussion by the applicant:

2. Potential proarrhtymic effects
In relation to the electrophysiological signal, the applicant was asked to make a thorough review any
signal of potential proarrhythmic effect of boceprevir.

In his response the applicant underlined that no patient in either treatment group experienced torsades de
pointes, QT prolongation, a ventricular arrhythmia, or sudden death and provided the following summary
of the clinical events as potential signal towards proarrhytmic effects.

Treatment-Emergent Adverse Events in the Torsades de Pointes/QT Prolongation Standardised MedDRA Query (SMQ) in
the Key Studies, Including Exposure-Adjusted Rates
Protocol Nos. P03523, P05216 and P05101
Number (%) of Subjects

PR Total
n=547
BOC/PR Total
n=1548
Adverse Event n (%) Rate N (%) Rate
Subjects with Any Adverse Event 7 (1) 2.0 31 (2) 3.2
Cardiac Arrest 1 (<1) 0.3 0 0.0
Cardio-Respiratory Arrest 1 (<1) 0.3 0 0.0
Loss of Consciousness 1 (<1) 0.3 3 (<1) 0.3
Syncope 5 (1) 1.5 28 (2) 2.9
Note: Rate is incidence per 100 person-years.
BOC=boceprevir 800 mg PO TID; P=peginterferon alfa-2b; PO=orally; PR=peginterferon alfa-2b+ribavirin; R=ribavirin; TID=three
times daily

Serious Adverse Events in the Cardiac Arrhythmias Standardized MedDRA Query (SMQ) in the Key Studies, Including
Exposure-Adjusted Rates
Protocol Nos. P03523, P05216 and P05101

PR Total
n=547
BOC/PR Total
n=1548
Adverse Event n (%) Rate n (%) Rate
Subjects with Any Adverse Event 2 (<1) 0.3 12 (1) 0.6
Atrial Fibrillation 0 0.0 2 (<1) 0.2
Atrial Flutter 0 0.0 1 (<1) 0.1
Cardiac Arrest 1 (<1) 0.3 1 (<1)
a
0.1
Cardio-Respiratory Arrest 1 (<1) 0.3 0 0.0
Loss of Consciousness 1 (<1) 0.3 0 0.0
Supraventricular Tachycardia 0 0.0 1 (<1) 0.1
58

PR Total
n=547
BOC/PR Total
n=1548
Adverse Event n (%) Rate n (%) Rate
Syncope 0 0.0 6 (<1) 0.3
Tachycardia 0 0.0 1 (<1) 0.1
Note: Rate is incidence per 100 person-years. A subject may have more than one adverse event.
BOC=boceprevir 800 mg PO TID; P=peginterferon alfa-2b; PO=orally; PR=peginterferon alfa-2b+ribavirin; R=ribavirin; TID=three
times daily
a: The cardiac arrest SAE in the BOC/PR group was not treatment-emergent (occurred during Follow-up Week 24).

Overall although it can be concurred with the applicant that the clinical data are reassuring so far, it
remains that boceprevir has a proarrhytmic potential based on electrophysiological findings and the trend
observed toward a prolongation of the QT interval in the dedicated ICHE14 study.

Therefore, it is considered that attention of physicians should be alerted:

Section 4.4 Although a dedicated study in healthy volunteers (ICHE14 QT/QTc study) was deemed
negative, some dose dependent trend toward a prolongation of the QT interval (see also 5.3) warrants
caution in patients at risk for QT prolongation (congenital long QT, hypokaliemia,...).

Section 5.3
In safety pharmacology, boceprevir prolongs the action potential duration with reverse-use dependency,
which clinical relevance remains uncertain (en 4.4)

Conclusions on clinical safety

Overall the main burden associated with the use of boceprevir relies on the marked increase of
anemia as compared to the already significant rate of anemia with the SOC.
Although the available data provide some degree of reassurance, the clinical dossier so far does not
allow to fully appreciate to what extent the management of the substantial incremental anemia
induced by boceprevir on top of PR could per se negatively affect the benefit-risk balance of
boceprevir, having in mind that on the one hand ribavirin dose reduction could potentially alter the
benefit and on the other hand the EPO use, through its safety profile (associated with risk of PRCA and
thrombosis events), could alter the risk.
It is therefore considered compulsory that, in order to establish the most rational management of
anemia, additional investigations be performed by the applicant to better understand the causes (and
consequently possible patient characteristics) and potential negative consequences of the management of
the high rate of anemia (as a result of the incremental risk with boceprevir) in patients receiving the
tritherapy with boceprevir+ribavirin+peginterferon.

Pharmacovigilance system
The Pharmacovigilance system as described by the Applicant (and further to clarification provided in
response to the D120 CHMP LOQ) fulfils the requirements and provides adequate evidence that the
Applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary
means for the notification of any adverse reaction suspected of occurring either in the Community or in a
third country.

59
Risk Management plan
The Applicant submitted an updated Risk Management Plan version 1.1 dated 20 April 2011.
The Applicant agrees to update the list of risks with some safety concerns raised (highlighted in green in
the summarized table below).
However, the Applicant disagrees to add some concerns (highlighted in red in the summarize table below)
and should commit to revise it as proposed.

Proposed pharmacovigilance activities
Proposed Risk
minimisation
activities
Routine
PASS
study
Pregnancy
Registry
Ongoing
clinical
studies
Routine Additional
Important identified risks
Anemia
X
Additional
Pharmacovigilance
to Routine
Activities : anemia
questionnaire to
enhance collection
of postmarketing
reports.

P06086
P05514
P05411

X
X
PEM *
CYP3A4/5 inhibition X
P06086
P05514
P05411
X
Neutropenia X
P06086
P05514
P05411
X
Thrombocytopenia X
P06086
P05514
P05411
X

Important potential risks

Resistance-associated
amino acid variants
X
P05063
P06086
P05514
P05411
X
Impact of dysgeusia on
quality of life or treatment
discontinuation
X
Thyroid neoplasm X
QT prolongation X
Medication errors X

60
Important missing information

Potential exposure during
pregnancy
X
X
(Ribavirin
Pregnancy)
- X
Exposure during lactation X - X
HCV/HIV coinfection X P05411 X
Exposure in the paediatric
population
X
P07614
P08034
X
Exposure in elderly patient X
P06086
P05514
P05063
X

Exposure in patients with
severe cirrhosis (Child-
Pugh > 6, Class B&C)

X - X

HBV/HCV coinfection

X - X

Exposure in organ
transplant patients

X - X
HCV genotype 2/3/4 X P03648 X

Patients with previous
tritherapy boceprevir -
PR treatment failure

X - X
Haemoglobin < 13g/dL
(male) or < 12 g/dL
(female)
X
Psychiatric disorders X
Long term therapy X
* PEM : Physician Educationnal Material : Erythropoietin alfa therapy for HCPs for treatment of
anemia. The Sponsor will provide guidelines for administration of erythropoietin alfa to HCPs for
treatment of anemia during boceprevir therapy.

Anaemia/EPO use
The main safety concern is the increase risk of anaemia in patient treated with boceprevir-PR
compared to PR alone. The Rapporteurs agree that an additionnal pharmacovigilance is required
with the implementation of a specific questionnaire to ensure complete post marketing reporting on
anaemia.
The pharmacovigilance plan includes an ongoing phase 3 clinical study (P06086) to evaluate dose
reduction of ribavirin versus use of erythropoietin for management of anemia in patients receiving
boceprevir. Results of this study are expected in November 2012.
61
As previously discussed in the safety part the anemia management in clinical practice will have to be
investigated through a dedicated study to be proposed by the applicant.
As requested, the applicant provides also risk minimization actions with a prescribers guide, focused on
management of anemia. The format and main items focused on the proposed guide seem to be appropriate.
However, the content should be revised according to the requested modifications on the SmPC. Moreover,
the final version of this document should be submitted for validation to each national competent authority
before distribution.

Other safety concerns:

- There is still some doubt concerning the potential effects of boceprevir on QT prolongation, in particular
in subjects presenting with low heart rates. QT prolongation must be kept as an important potential
risk in the RMP. The Applicant should follow cardiac adverse effects such as syncopes, palpitations and
QT prolonged during routine pharmacovigilance activities with a specific focus on these cardiac concerns
in every PSUR. Moreover sections 4.4 and 5.3 of the SmPC should be modified as proposed.

- Taking together the pre-clinical findings which cannot exclude an effect on the thyroid hormone levels
and the thyroid gland, the 2 cases in clinical studies where the contribution of boceprevir could not be
excluded and was assessed as probable (thyroid neoplasm is included in section 4.8 of the SmPC), and
the reported AEs goitre, hypo- and hyperthyroidisms (included in 4.8), thyroid neoplasm has to be
included in the RMP as important potential risk.
- The Rapporteurs agree with the Applicant that dysgeusia should not be added as an Important identified
Risk. However, outside clinical trials supervision, study drug discontinuation will certainly be higher and
consequences for the patients disease progression not negligible. Therefore, the Applicant is requested
to add Impact of dysgeusia on quality of life or treatment discontinuation as an important potential
risk. At this stage routine pharmacovigilance seems sufficient. The impact of dysgeusia on treatment
discontinuation needs to be carefully monitored in each PSUR.
The Applicant proposal to list concerns related to off label use in HIV co-infected patients, pre/post
transplant patients, patients with other HCV genotypes than 1 as important missing information instead of
important potential risk is endorsed. Data on off label use will be thoroughly monitored in PSUR.
Moreover, other important missing concerns should be added in the RMP (as reported in table above).

The Applicant committed to submit study results as soon as they are available and provided a planned
calendar for submission. The Applicant is requested to specify in table 62 of the RMP, as done for studies
P05411 and P06086, that interim results of study P05063 are expected in December 2012.
- Routine risk minimisation activities are deemed sufficient for other identified and potential risks listed
and no additional measures for patient information are warranted.
In table 65 of the RMP, the MAA should precise, for each concern, product labeling especially section
amended in the SmPC (as it was done in the previous version of the RMP).
An impact study to measure efficacy and understanding of educational material by HCP is proposed. The
survey could be conduct around 6 months after the launch. The applicant should pay attention to involve
representative HCP in selected EU countries and will have to conclude on this point during survey report.
In this way, the post-implementation assessment of minimization activities should be conducted within 1
year after licensure of boceprevir.

A further revised RMP will have to be submitted taking into account the Rapporteurs comments.
Moreover, it should adequately reflect
- the need to investigate shortened treatment duration having in mind the burden of the incremental
anemia induced by boceprevir and the potential negative impact of its management on efficacy (ribavirin
dose reduction) and safety (EPO use).
62
- the need to further substantiate the resistance pattern and the clinical consequence of resistance.
To these purposes long term data from ongoing studies should be submitted and results of ongoing clonal
analyses from phase III. Treatment of patients failing boceprevir regimen should be part of these
investigations.

4. ORPHAN MEDICINAL PRODUCTS
N/A

5. BENEFIT RISK ASSESSMENT
HCV is a major public health matter as stated by the WHO (cirrhosis, liver transplantation,
hepatocarcinoma).
The current standard of care (SOC) relies on the bitherapy with ribavirin and pegylated interferon.
This bitherapy has the ability to cure patients.
However, there are several pejorative factors in the response to treatment.
Notably infection by genotype 1 (majority of the EU population) is associated with very limited response
rates (around 40%) as compared to the 80% response rates for infection with genotype 2/3 (leaving few
room for improvement with additional therapeutic options).

After decades with the bitherapy only and its limited response rate in the majority of the EU population,
boceprevir is the first representative of the Direct Acting Antiviral Agent (DAA) that has emerged from
the pipeline (currently containing a lot of new entities).
Boceprevir is a new antiviral agent, serine protease inhibitor, specifically designed to inhibit the HCV
nonstructural protein 3 (NS3) protease.

This new antiviral agent has been recognized by the CHMP, through the accelerated assessment (in
November 2010), as carrying important perspective of therapeutic advance in this area [it is nevertheless
anticipated that new drugs in the pipeline will one day supersede this option (with simplified dosing
regimen, higher potency and higher genetic barrier)]

The Boceprevir clinical development program mainly comprised 5 clinical studies focused on HCV
genotype 1 chronically infected patients.
- Phase II dose-controlled trials (P03523/SPRINT 1 in treatment nave patients and
P03659/RESPOND 1 in treatment experienced patients,)
- Phase III trials (P05216/SPRINT 2 in treatment nave patients and P05101/RESPOND 2 in treatment
- A long term follow up trial (P05063) including all the subjects who participated in a Phase 1, 2, or 3
clinical study in which boceprevir was administered (on-going at this time). The goals of this study are to
examine the durability of SVR, the long-term safety after boceprevir treatment and the natural history of
resistance-associated variants over time. Patients were off treatment in this long term study.

Through the phase II clinical development programme the applicant has explored several questions of
scientific interest, unfortunately rendering the design of the phase II studies too complex and then
ultimately hampering the reliability of the interpretation of their results.

Nevertheless, these phase II explorations were useful in determining that boceprevir could not do without
being protected with ribavirin (full dose) in addition to pegylated IFN. Moreover, there were useful to
substantiate the contribution of the lead in (LI) period (4 weeks period with pegylated
interferon+ribavirin prior to the addition of boceprevir). As compared to the no LI arms, the LI arms being
63
associated with higher SVR and lower relapse rates, the lead in period was then kept in the phase III
study.
Finally the phase II in treatment experienced patients has to some extent substantiated the concept of a
tailored treatment duration based on the early kinetics of virological response, i.e. the Response Guided
Therapy (RGT) that was finally tested in the phase III study.

The support of the dose selection is limited (mainly derived from the phase II study in treatment
experienced patients, the interpretation of which being jeopardized by several amendments). The
adequacy of the dose is ultimately judged on the basis of the efficacy/safety data derived from the
phase II study in nave and the two phase III studies.

The clinical benefit is mainly to be judged on the two double blind multi-centers phase III clinical studies.
As regards the population of both multi-centers phase III, a significant number of European patients were
included: 24% in treatment nave patients and 29% in treatment experienced patients.

The results of both studies show a significant improvement of SVR over the PEG/RBV, i.e. ~30% in
treatment nave patients and ~40% in treatment experienced patients, thus to some extent upgrading the
response rates in the genotype 1 CHC to the level of response rates in the genotype 2/3 good responders to
the bitherapy.
Based on these results boceprevir is regarded as representing a significant therapeutic advance that
justifies the principle of an accelerated review as decided by the CHMP in November 2010.
The robustness of the efficacy demonstration is supported by the high statistical significance (p<0.0001)
of the difference in terms of SVR between the tritherapy (BPR) versus the bitherapy (PR) for both
populations in these two blinded studies. Moreover, approx 45% of (nave and pretreated) patients will
achieving undetectability at week 8 and therefore could be candidates for a shortened treatment duration
(28 weeks instead of 48 weeks for treatment nave patients and 36 weeks instead 48 weeks for treatment

When focusing to the subgroup analyses based on predictability criteria (early virological response
notably), the high response rate to the PEG/RBV leaves few room for improvement and raises the question
of the worthiness of adding boceprevir to PEG/RBV, especially in treatment nave patients. There are
currently some uncertainties on the (independent) value of IL28B to help identifying adequate candidate to
the tritherapy (retrospective analysis with disputable representativeness of the sub-population).
As part of the D120 LOQ, the added value of boceprevir on top of Peg-IFN+Ribavirin was to be
thoroughly discussed by the applicant in view of the safety profile of the drug.
In response to the D120, given the limitations of the data available so far, the applicant could not formally
delineate the patients who are unlikely to retrieve significant benefit of adding boceprevir to the
biotherapy (either increasing the rate of SVR or shortening the whole treatment duration). The applicant
informed that the protocol to address the issue was currently being designed.
Given the importance of such matter, the design of the protocol should mandatorily be validated by the
CHMP before the study starts and the timelines for submission of this draft protocol should be
shortened (beginning of September 2011 instead of December 2011) to avoid a late implementation of
the study.

Waiting this issue to be fully resolved physicians should be alerted by statement in section 4.4 that The
degree of added value of boceprevir on top of the bitherapy will depend on the likelihood of achieving
SVR with the bitherapy only. There are some degree of uncertainties on the added value of boceprevir on
top of the bitherapy with pegylated Interferon+ribavirin in patients who might have good predictive
under investigation
64

Moreover, as regards the optimal regimen for achieving high SVR, there are some degrees of uncertainties
on whether the Response Guided Therapy/RGT (depending on the TW8 early virological response) would
be conservative enough as compared to the fixed 48 weeks treatment duration in some subgroup of
patients with pejorative criteria of response (black patients, with advanced fibrosis F3/F4). The
limitations of the subgroups mandate caution and the recommendation should be made in the most
conservative approach. This was a significant issue to be addressed as part of the D120 LOQ.

The applicants response due to the current limitations of the data did not provide sufficient reassurance on
the adequacy of the RGT in some patients. Outside the best case scenario of (non black and non
cirrhotic patients) early responders -treatment nave patients there are reservations against the RGT.
Physicians should be alerted on these reservations could be ranked from a strong discouragement (to a not
recommended use (black patients and cirrhotic patients), having in mind the burden of anemia and the fact
that even if somewhat downgraded with RGT as compared to no RGT, the benefit remains substantial in
terms of increased rates of SVR as compared to the control group. The SPC should express these
reservations against the RGT.
It is quite unfortunate that the RGT was not tested in the study performed in treatment experienced
patients with pegylated interferon alfa 2 that the applicant has newly submitted (P05685).

When now considering the potential risks, the risk of resistance is a new issue that will have to be dealt
with for this new antiviral as for any other DAAs. Although long term data available (from P05063) are
reassuring in terms of reversibility to the wild type (The rate of return to wild type within 2 years is 88.7%
for V36M mutation, 100% for T54A, 63.7% for T54S and 69.7% for R155K), the clinical consequence of
emerging mutations remains to be substantiated (notably in terms of impact on response to subsequent
lines of therapy with other DAAs, with potential cross resistance). It has nevertheless to be underlined that
HCV being a RNA virus without DNA intermediate, contrarily to HIV, the archiving of resistant variant
will not occur, but still minor populations could influence treatment response depending on the pressure of
selection.

The salient issue of its safety profile is the worsening of the already significant risk of anemia with the
bitherapy (49% of boceprevir-treated patients experienced anaemia < 10g/dl during treatment versus 29%
in placebo-treated subjects. The addition of boceprevir to SOC was reflected by an additional decrease of
Hb of approximately 1g/dl versus -2.5 to 3.5g/dl with peginterferon and ribavirin only. This differences
are seen whatever the population [nave or pretreated patients].).

The Erythropoetin (EPO) was allowed in the clinical studies. The widespread use of EPO in the current
clinical practice with PEG/RBV (supported by the literature: Afdhal N.H., Dieterich D.T., Pockros P.J., Schiff E.R.,
Shiffman M.L., Sulkowski M.S., et al. Epoetin Alfa Maintains Ribavirin Dose in HCV-Infected Patients: A Prospective, Double-
Blind, Randomized Controlled Study) is to some extent reflected by the significant proportion of patients
receiving EPO in the clinical trials (37 % in Nave patient and 39% in pretreated subjects) and by
the recent EASL guidelines (April 2011).
This issue has necessarily introduced the EPO use into the debate of the benefit/risk assessment of
boceprevir. The incremental risk of anemia with boceprevir puts further emphasis on discussion regarding
the need and desirability to resort to EPO to manage anemia and notably avoiding ribavirin dose reduction
(potentially altering the likelihood of the virological response). However, EPO is associated with specific
risks (Pure Red cell Aplasia and Thrombosis notably) raising concerns about the benefit-risk balance for
boceprevir when co-administration is extensive.

Other issues on the safety profile rely on the risk of fertility impairment based on a signal from the non
clinical development. However, the clinical data with measurement of inhibin B in a large male sample
(n=355) can be regarded as reassuring on the lack of significant clinical relevance of this animal finding.

As regards the cardiotoxicity of the drug, some disturbing electrophysiological data are observed although
the ICHE14 QT study can be concluded as negative and the clinical data are reassuring so far. This will
have to be further monitored through forthcoming PSUR once the drug will be used in real life and
notably co-administered with drugs potentially increasing its exposure.
65

Overall,

Benefits

Beneficial effects
The results of both phase III studies show a significant improvement of SVR over the PEG/RBV, i.e.
~30% in treatment nave patients (P05216/SPRINT 2) and ~40% in treatment experienced patients
(P05101/RESPOND 2).
The benefit of the drug is also to be regarded (in line with the EU guidelines on anti-HCV development
programme) in terms of candidates for a shortened treatment duration With boceprevir, approx 45% of
patients will achieve 8 weeks undectability that could qualify them for a 28 weeks (treatment nave) or 36
weeks (treatment experienced) instead of 48 weeks. When considering the burden of treatment, this
benefit is worth taken into consideration.
Based on these results boceprevir is regarded as representing a significant therapeutic advance that
justifies the principle of an accelerated review as decided by the CHMP in November 2010.

Given that SVR is correlated with cure, the addition of boceprevir to the current SOC will significantly
increase the individual likelihood of being cured (avoiding progression to cirrhosis and hepatocarcinoma).
Uncertainty in the knowledge about the beneficial effects
Recently the importance of patient genotype IL28B as strongest predictor of SVR in HCV genotype 1
infected patients became known. This was after the start of the phase III studies, thus patients were not
stratified for this baseline characteristic. This information was only available for approx 60% of treatment
nave and pretreated patients (patients who gave their informed consent), which significantly compromise
the interpretation of the data, all the more that the representativeness of these populations is questioned
(based on comparative SVR of this subgroup vs the overall population).
Although overall addition of BOC to PR resulted in significant higher SVR rates, pharmacogenomic
analysis in which SVR rates were evaluated according to patients IL28B genotype, indicate that (nave)
patients with genotype IL28B CC might not substantially benefit from additional BOC to PR, contrary to
patients with IL28B genotype CT or TT. SVR rates in nave patients with IL28B CC treated with BOC/PR
were 82% and 80%, for shorter and longer BOC/PR treatment duration and in nave patients treated with
PR 78%. Thus SVR rate for nave patients with genotype CC treated with standard of care (PR) are
considerably higher than overall SVR rates in nave patients (40-45%). Based upon the currently available
data it appears that for pretreated patients with genotype IL28B CC the addition of BOC to PR might have
additional value, contrary to nave patients with genotype CC. However, as the numbers of pretreated
patients is small and the pharmacogenomic analysis was done in a subset of patients and baseline
characteristics between the subset included in the pharmacogenomic analysis was not completely balanced
with that of the not included subset, all these findings are uncertain. It is also admitted that the
introduction of IL28 into clinical practice is uncertain in the perspective of the tritherapies, since IL28B
might not have added value beyond early virological response to treatment.
To this purpose and having in mind the particular burden of anemia, the applicant should commit to
resolve the uncertainties of the added value of boceprevir to the bitherapy in those patients having good
predictive factors for interferon responsiveness.

Having in mind that a Response Guided Therapy might not be considered appropriate if this results in a
net loss of efficacy, the applicant should commit to further substantiate the RGT outside the best case
scenario of (non black patients and non cirrhotic patients) early responders treatment nave patients.

The clinical development will have to be completed, with additional data from populations not currently
covered or not adequately covered in the clinical dossier submitted.

66
The treatment experienced population in the phase III study, excluded the challenging population of Null
Responders (currently the unique therapeutic option is the re-treatment with the bitherapy with less than
10% response rates, when entering into the decompensated liver disease the remaining option is the
transplantation) qualified as such based on their prior response to pegylated IFN and interferon at week 12
(exclusion criteria). The applicant has used the lead in period to requalify the patients and finally claiming
a clinical experience in the Null responders as defined on the basis of the 4 weeks on treatment. A
mismatch is nevertheless observed between the 12 weeks historical definition and the 4 weeks on
treatment definition is reported. Therefore, including null responders in the indication was regarded as
disputable by the CHMP at the D120 and the applicant was asked to further susbtantitate this issue.
In his response to the the CHMP D120 LOQ, the applicant has provided prediction of the SVR and the
interim results on only approximately 40 patients on a roll over study (PROVIDE) of the control arm from
the phase III SPRINT 2 and RESPOND 2 studies. Overall, although it can be acknowledged that the
addition of boceprevir might indeed increase the likelihood of achieving SVR in null responders, it
remains disputable to formally promote the use in null responders through the indication of boceprevir
given the limitations of the data available so far and all the more that in this very pejorative population
other strategies (quadritherapy, SOC sparing strategies) will probably be mandatory to substantially
improve response rate. Nevertheless, it is admitted that depending on their evolution some patients could
not afford waiting for these combination. Physicians will be aware through a statement in section 4.4 that
null responders might retrieve some benefit in adding boceprevir to the tritherapy. However, this cannot
be reliably quantified (retrospective analysis).

The HIV-HCV co-infected population was excluded from these studies despite corresponding to a critical
medical need (as regards their more pejorative outcome in terms of natural history of the disease and
lower response rates as compared to the HCV mono-infected population). However, a study is ongoing
(P05411). In line with the above, it is noteworthy that RGT was not used in this difficult to treat
population of HIV co-infected patients. Given that off label is highly anticipated in this population given
the particular medical need this should covered through the RMP and SPC statement.

The proportion of patients with cirrhosis is limited, with only 100/1097 (9%) in the phase III in nave
patients and 49/403 (12%) in the phase III in treatment experienced patients. This will have to be reflected
in the SPC.

The possibility to co-administer boceprevir with pegylated interferon alfa 2 a (+ribavirin) will need to be
substantiated. A study is ongoing P05685 with pegylated alfa 2a.
Although based on PK characteristics (half life) and on the IDEAL study (although similar SVR between
alfa 2a and alfa 2b, EOT was lower for alfa 2b), the pegylated alfa 2b might be considered as a worse
case scenario in terms of protection of the DAA. The fact that the clinical data so far only pertain to the
co-administration with alfa 2b will have to be underlined in the SPC (section 4.1).
Risks
Unfavourable effects
The salient issue of its safety profile is the worsening of the already significant risk of anemia with the
bitherapy (49% of boceprevir-treated patients experienced anaemia < 10g/dl during treatment versus 29%
in placebo-treated subjects.

67
Uncertainty in the knowledge about the unfavourable effects
As part of the D120, the applicant was asked to thoroughly discuss to what extent the anemia of
boceprevir + pegIFN/ribavirin could be managed without the resort of EPO (considering the need for
sufficient ribavirin exposure), having in mind that the use of EPO raises safety concerns (risk of PRCA
notably) and could impact the benefit risk balance.

Overall eventhough the data provide some degree of reassurance, the clinical dossier so far does not
allow to fully appreciate to what extent the management of the substantial incremental anemia
induced by boceprevir on top of PR could per se negatively affect the benefit-risk balance of
boceprevir, having in mind that on the one hand ribavirin dose reduction could potentially alter the
benefit and on the other hand the EPO use, through its safety profile (associated with risk of PRCA and
thrombosis events), could alter the risk.
It is therefore considered compulsory that, in order to establish the most rational management of
anemia, additional investigations be performed by the applicant to better understand the causes (and
consequently possible patient characteristics) and potential negative consequences of the management of
the high rate of anemia (as a result of the incremental risk with boceprevir) in patients receiving the
tritherapy with boceprevir+ribavirin+peginterferon.

Moreover, additional issues will have to be addressed through the ongoing development programme,
notably:

- In the current analysis of resistance, the limited frequency of baseline RAVs could not allow to
appreciate to what extent baseline levels (higher or other types of RAVs) might jeopardize future
treatment of treatment failures.
The clinical consequence of the emerging mutations (in terms of response to boceprevir and impact to
subsequent lines of therapies) need to be further substantiated through ongoing development.

- Electrophysiological data carries some concerns as regards the cardiotoxicity of the drug in real life (co-
administration, electrophysiological disturbances). This is all the more to be followed that although the
ICH E14 Thorough QT study (P04489) was categorized as negative it remains that a dose dependency is
observed and a borderline result 11 msec was recorded.
- Interaction profile will need to be better characterized especially in the perspective of use in HIV-HCV
co-infected patients, that is likely to start as soon as the drug will be marketed, the same applies for
pre/post transplant patients given the high medical need. As part of the D120 the applicant has committed
to perform relevant additional interaction studies (including boosted Protease Inhibitors).
Balance
Boceprevir has been shown to significantly increase the percentage of treatment nave and treatment
experienced (excluding null responders) patients chronically infected by HCV genotype 1 achieving
Sustained Virologic Response (correlated with cure) and will reduce the treatment duration for some
patients.
Considering the limited response rate achieved so far with the Peg-IFN+ ribavirin in patients chronically
infected with HCV genotype 1 and given the burden of such a treatment, this represents a significant
therapeutic advance.
This benefit is regarded as overweighing the safety issues associated with this drug, eventhough the
incremental anemia is anticipated as being a particular burden in clinical practice.

68
5.1. Conclusions
The Benefit/Risk ratio of boceprevir is overall considered positive.
However, two main issues should be part of the annex II since compulsory for further substantiating the
benefit/risk assessment:
1- the clinical dossier so far does not allow to fully appreciate to what extent the management of the
substantial incremental anemia induced by boceprevir on top of PR could per se negatively affect the
benefit-risk balance of boceprevir, having in mind that on the one hand ribavirin dose reduction could
potentially alter the benefit and on the other hand the EPO use, through its safety profile (associated with
risk of PRCA and thrombosis events), could alter the risk.
possible patient characteristics) and potential negative consequences of the management of the high rate of
anemia (as a result of the incremental risk with boceprevir) in patients receiving the tritherapy with



c. the anemia management in patients treated for hepatitis C in the EU in the presence of boceprevir in
clinical practice

2. The applicant should be committed to dispel the current level of uncertainties on whether those patients
with favourable factors (on treatment viral kinetics and/or IL28B) for interferon responsiveness could still
retrieve a significant benefit of adding boceprevir to the bitherapy. The design of the protocol aimed at
addressing this issue and currently under reflexion at the applicant level should mandatorily be validated
by the CHMP before the study starts and the timelines for submission of this draft protocol should be
shortened (beginning of September 2011 instead of December 2011) to avoid a late implementation of the
study.

Please note that interaction is planned with the FDA before the CHMP opinion that might impact on
commitments and SPC.

69
6. LIST OF ISSUES TO BE FURTHER CLARIFIED AND
COMMITMENTS
6.1 Quality aspects
Other concerns

Drug substance

1. Irrespective of the amount of data submitted to support process development studies, all
process parameters (CPP and non CPP) should be described in 3.2.S.2.2 section along with
their NOR and PAR. In addition, the ICH Q8 definition of PARs is to be adhered to. Indeed, a
PAR is defined as A characterized range of a process parameter for which operation within this
range, while keeping other parameters constant, will result in producing a material meeting
relevant quality criteria. Consequently the applicant should confirm that, in case of excursion
of one process parameter out of its normal operating range, but within the proven acceptable
range, the other process parameters will be maintained at their target/ normal operating value
(as per ICH Q8 definition of proven acceptable ranges). This applies to each stage referred to
as reaction block of the process. (previous Q2)

2. Regarding previous Q4, Compound I
a. The information provided from Kaneka and Evonik is too brief and does not permit to
judge of the elimination of impurities raised from biological steps.
b. Given that typical batches of Compound I from both vendors have mass balances
greater than 99%, therefore the applicant can make an effort to tighten the
specification. In addition, if the mass imbalance is partly explained by potential
presence of residual solvents the specifications can be updated to include them unless
otherwise justified.
c. Regarding the information provided by Kaneka, TSE and viral safety issues are still not
addressed.

3. Regarding previous Q5c, the control of residual solvents by LOD in compounds I, II and VI can
be acceptable for class III solvents but not for the others. The discussion on removal of
residues of these solvents during work up including distillation and drying steps is not based on
demonstrated data.
In addition, starting material specifications should include adequate limits for the solvents used
in their synthesis as these may affect the quality of the final substance. If necessary, it may be
indicated that a specific solvent applies to a specific supplier or is not controlled on routine
basis due to proven elimination during the process (batch analysis data to be provided) or
because the solvent is controlled in a later intermediate or in the final substance. The Applicant
should update the specifications of the starting materials accordingly.

4. Regarding previous Q6a and d, the applicant should still discuss the carry over of
impurities/solvents/reagents that may remain from the routes of synthesis of compound VI as
the intermediates previous to this compound are not part of its specifications. See also
question 5c.

5. The applicant is recommended to tighten the chemical assay of compound II and compound VI
together with the limit of DTTA and total of impurities in compound II as these acceptance
criteria do not reflect batch results. In addition, the data may be extended with results for
residual solvents as referred to by the applicant in question 5c. (previous Q7)

6. The absolute configuration of boceprevir is assessed by comparison to another compound for
which the scheme of synthesis and operation conditions are unknown. The applicant states that
the compound II is used as starting material for both boceprevir and SCH 900518. Actually
because this compound is a key starting material clarification has been asked on the absolute
configuration. The HPLC methods mentioned are capable of distinguishing the enantiomers but
they do not give the absolute configuration. The applicant is requested to bring an unequivocal
proof of configuration of chiral centres present by performing either an in depth NMR analysis
(COESY, NOESY) or an X-ray of a single crystal or any other method of choice on one of the
isolated intermediates V or VII or on compound II as a minimum. (previous Q8)
70
7. It appears logical that the identification test should cover the characteristic of boceprevir as
being a mixture of two diastereoisomers. The ICH Q6A decision tree 5 for establishing identity,
assay and enantiomeric impurity procedures for chiral new drug substances prescribes that
when a substance is chiral but even racemic, the need for verifying the chiral identity should be
considered. Therefore, the applicant is requested to propose such test and to this regard the
distereoisomer content in HPLC B can be an option. (previous Q12)
8. Regarding distereoisomer content, the question on the lower limit of SCH 4128 and the upper
limit of SCH 4129 is not answered. As responded by the applicant for previous question 14, the
limit of diastereisomer content should be set based on manufacturing capability and batch
history. Therefore the question is maintained as that there is no lot with 49% content of SCH
534128 and either no lot with 51% SCH 534129. (previous Q13)
9. Demonstration of absence of acetonitrile, isopropyl acetate and N-methylmorpholine is not
brought on actual data therefore the question is maintained i.e. lack of specification for these
solvents remains to be justified. Regarding methylcyclohexane and NMP, though the content
observed is less than ICH limits however this is not sufficiently low in order to justify absence
of routine control according to the nfg CPMP/QWP/450/03. Therefore, a routine control of
methylcyclohexane and NMP is awaited along with revision of specifications to include
appropriate test and limit. (previous Q15)
10. Lack of specification for some impurities/reagents such as lutidine, N,N-dimethylcyclohexyl-
amine, EDCP HCl and compounds II and VI remains to be justified and demonstration on
absence of carry over into the final substance should be done. The response of the applicant is
not based on actual data (previous Q17)

11. Regarding content of hydrate/diol, the applicant is requested to clarify if the response will be
applicable in case of higher content of diol e.g. up to 23% as observed in batch analysis and in
such case as to whether the dissolution criterion would be respected. (previous Q 21)

Drug product

12. The previous specification (Q=75% at 45 min) appears more stringent in terms of specification
time point, and more adequate for routine testing. Q=75% at 45 min should be maintained at
release and at shelf-life. (previous Q27)

13. In accordance with ICH Q8 definition of proven acceptable ranges, the applicant should confirm
that, in case of excursion of one process parameter out of its normal operating range, but
within the proven acceptable range, the other process parameters will be maintained at their
target/ normal operating value. (previous Q29)

14. Since sampling and frequency of the in-process tests is part of the information which has to be
described in the Quality documentation to ensure that manufacturing process is adequately
controlled in routine, the proposed testing frequencies for the filling step should be added to
the updated module 3.2.P.3.3. (previous Q31)

15. Regarding identification of the active in drug product, it is noted that no validation for
specificity of IR towards other substances (unless the mixture of placebo) is presented and
therefore it is recommended to implement a test that characterise the mixture of boceprevir
diastereoisomers. This can be an identification at the same time that assay with HPLC method
B and even better the diastereoisomer content. (previous Q36)

16. Diastereoisomers content and microbial contamination are to be included in drug product
specifications as non routine tests. The drug product should be compliant, if tested. (previous
Q41)

17. Regarding the specifications at the end of shelf life and end of the patient in-use period, the
justification for limits of individual and total degradation products for groups A and B seems
appropriate. With respect to the dimers, the proposed limits should be re-evaluated when
worst-case in-use stability data at 30C/75% RH are available on several lots (with product
tested at the end of its shelf-life). (previous Q42)

71
18. For further clarity, final approved process validation scheme containing additional details
provided (final dissolution acceptance criterion and reference batches used to perform the f2
comparison) should be enclosed in updated module 3.2.R. (previous Q48)

6.2 Non clinical aspects
1. Regarding the validation of LC-MS/MS methods used for detection of boceprevir and its
diastereoisomers, the applicant mentions that in case of initial plasma levels above the upper limit of
the calibration range, the sample was re-assayed following dilution as per Standard Operation
Procedures (SOPs). However, these SOPs were not available to the assessors and should be
provided by the applicant.
2. Regarding the total recovery of the analytical methods in plasma (and serum), the applicant should
clarify the greatly varying recoveries (within the QCL, QCM and QCH samples within one run) within
the studies.
3. Study no.PK005 was performed to assess the inhibitory potential of boceprevir for OATP1B1. Results
show that boceprevir inhibited the known probe substrate pitavastatin (IC50: 18 2.4 M).
However, a known potent inhibitor as a positive control (e.g. ciclosporin) was not used to warrant
the reliability of the model. Indeed, the effect of boceprevir on pitavastatin uptake into MDCKII-
OATP1B1 cells was compared to MDCKII cells in the absence of boceprevir. Therefore, a further
handling should be added in this study i.e. ciclosporin use in both transfected MDCKII and non
transfected MDCKII, with and without boceprevir.
4. The applicant is requested to provide boceprevir inhibition data for AKR1C2 or clinical data showing
the absence of effects on the endocrine hormone metabolism.
5. The ERA and supporting studies should be submitted as soon as available.
6. Some other issues were not considered (fully) resolved, and so it is proposed to amend the SPC
and/or the RMP as follows:
- Cardiovascular safety pharmacology: there is still some doubt concerning the potential effects
of boceprevir on QT prolongation, in particular in subjects presenting with low heart rates.
Therefore, it is considered that the positive findings observed in vitro should be mentioned in
SPC 5.3 to give adequate information to the prescriber (with cross-reference to SPC 4.4). In
addition, it is still considered necessary to amend the RMP to monitor events possibly related
to effects on the cardiovascular system (such as syncopes, unexplained deaths, and QT
prolongation).
- Drug-drug interactions: SPC 5.2 should indicate that boceprevir is both a P-gp and a weak
BCRP substrate, and a warning about a likely interaction with inhibitors of these transporters
should be included in SPC 4.5.
- Potential off-label use in children: the applicant should state in SPC 5.3 that contradicting
findings were observed in juvenile rats compared to adults, indicating deviating kinetics
leading to higher exposure to the active compound at similar dosages and deviating metabolic
profiles. A cross reference to SPC 4.2 will be included

6.3 Clinical aspects
Point to be addressed before the CHMP opinion
1. On the basis of table 13, 0.7% of subjects in the PR arms versus 0.9% of subjects in the BOC/PR arms
were reported with an adverse event in the Suicide/Self-injury SMQ . However, it is of note that this table
refers only to events reported up to 30 days after the last dose of medication. The Applicant discusses in
the second paragraph of its response the occurrence of two additional cases suicidal attempt and two
additional cases of completed suicide in BOC/PR arms that occurred after the 30-day period. As
psychiatric disorders with peginterferon/RBV may occur at least six months after discontinuation of
antiviral therapy, it is important to compare the incidence of suicidal events by including events reported
after the 30 day period.
72
The Applicant should therefore confirm that the incidence of suicidal events (including those
reported after the 30 day period) was similar in both treatment groups.
2. The applicant should discuss the marked difference in neutropenia and notably in grade 4 neutropenia
when boceprevir is combined with alfa 2 a as compared to alfa 2b as observed in the newly submitteed
P05685 (with one death reported with severe neutropenia and Staphylococcal infection, although other
risk factors were noted including history of IV drug abuse) and discuss the potential clinical impact
(scrutinizing comparative degree and length of the neutropenia)

3. The applicant should further discuss on whether physician should do something between week 12 and
week 24, to avoid unduly keeping a treatment nave patient under unchanged treatment whereas no benefit
can be anticipated (and only risk).
4. A further revised RMP will have to be submitted taking into account the Rapporteurs comments, and
adequately reflecting
- the need to investigate shortened treatment duration having in mind the burden of the incremental
anemia induced by boceprevir and the potential negative impact of its management on efficacy (ribavirin
dose reduction) and safety (EPO use).
- the need to further substantiate the resistance pattern and the clinical consequence of resistance.
To these purposes long term data from ongoing studies should be submitted and results of ongoing clonal
analyses from phase III. Treatment of patients failing boceprevir regimen should be part of these
investigations.
73

7. Summary of Product Characteristics (SmPC)

1. NAME OF THE MEDICINAL PRODUCT

Victrelis 200 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each hard capsule contains 200 mg of boceprevir.

Excipient: each capsule contains mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

Each capsule has a yellowish-brown, opaque cap with an "MSD" logo imprinted in red ink and off-
white, opaque body with the code "314" imprinted in red ink.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Victrelis is indicated for the treatment of chronic hepatitis C (HCV) genotype 1 infection, in combination
with peginterferon alpha (see section 4.4) and ribavirin, in adult patients with compensated liver
disease who are previously untreated or who have failed previous therapy (see section 4.4 for null
responders).
(see also section 5.1)

Assessors comments:
Only a statement in section 4.4 could be accepted for covering null responders such as:
Null responders to prior bitherapy were excluded from the RESPOND 2/P05101 study. However, based
on a retrospective analysis performed with requalifying the patients on the basis of their on treatment
virologic response at week 4 (using the lead in period) as compared to baseline, null responders might
retrieve some benefit in adding boceprevir to the tritherapy. However, this cannot be reliably quantified
from the retrospective analysis. Moreover the optimal management of null responders remains to be
established and might in the future require antiviral combination.
In line with the JAR, it can be accepted on an efficacy point of view that the 4.1 section does not put
emphasis on the type of Peg-IFN. In section 5.1, a statement should be added that a study with alfa 2a in
treatment experienced patients gave consistent results as compared to the study P05101. However, in
section 4.8 a statement will have to be added that the risk of neutropenia (including grade 4
neutropenia) could be markedly increased when boceprevir is combined with pegylated alfa 2a as
compared to alfa 2b. This might have to be strengthened depending on the applicants response to
clarification

74

4.2 Posology and method of administration

Posology
Victrelis must be administered in combination with peginterferon alpha and ribavirin. The Summary of
Product Characteristics of peginterferon alpha and ribavirin must be consulted prior to initiation of
therapy with Victrelis.

The recommended dose of Victrelis is 800 mg administered orally three times daily (TID) with food.
Maximum daily dose of Victrelis is 2,400 mg. Administration without food could be associated
with a net loss of efficacy due to sub-optimal exposure.

Patients who are previously untreated

Initiate therapy with peginterferon alpha and ribavirin for 4 weeks (Treatment Weeks 1 4).
Add Victrelis 800 mg orally three times daily to peginterferon alpha and ribavirin regimen at
Treatment Week (TW) 5. Based on the patient's HCV-RNA (hepatitis C ribonucleic acid) levels at
TW 8 and TW 24, use the following Response Guided Therapy (RGT) guidelines to determine
duration of treatment (see Table 1).

Table 1.
Duration of therapy using Response Guided Therapy (RGT) in patients who are previously
untreated

ASSESSMENT
(HCV-RNA Results*)
ACTION
At Treatment Week 8
At Treatment
Week 24
Complete three medicines regimen and finish
through Treatment Week 28.
3. Continue all three medicines and finish
through Treatment Week 28, and then
4. Administer peginterferon alpha and
ribavirin and finish through Treatment
Week 48.
* In clinical trials, HCV-RNA in plasma was measured with a quantitative polymerase chain reaction (PCR) assay with a limit of detection of
9.3 IU/ml and a limit of quantification of 25 IU/ml.

Patients who have failed previous therapy
Initiate therapy with peginterferon alpha and ribavirin for 4 weeks (Treatment Weeks 1 4).
Add Victrelis 800 mg orally three times daily to peginterferon alpha and ribavirin regimen at
Treatment Week (TW) 5. Based on the patient's HCV-RNA levels at TW 8 and TW 12, use the
following Response Guided Therapy (RGT) guidelines to determine duration of treatment (see
Table 2).

Table 2.
Duration of therapy using Response Guided Therapy (RGT) in patients who have failed
previous therapy

ASSESSMENT
(HCV-RNA Results*)
ACTION
At Treatment Week 8
At Treatment Week
12
75
Continue three medicines regimen and finish
through Treatment Week 36.
1. Continue all three medicines and finish
through Treatment Week 36, and then
2. Administer peginterferon alpha and
ribavirin and finish through Treatment
Week 48.
* In clinical trials, HCV-RNA in plasma was measured with a quantitative PCR assay with a limit of detection of 9.3 IU/ml and a limit of
quantification of 25 IU/ml.

In line with the JAR,
- the RGT needs to be further substantiated in the difficult to treat populations of black and
cirrhotic patients whatever the population of treatment nave and experienced be there early or
late responders. Awaiting for these further data (commitment to be requested to the applicant),
the RGT would have to be discouraged in these populations (it is nevertheless acknowledged that
the attitude might have to differ for cirrhotic and black patients and will need to be further
debated, a teleconference is planned with the FDA where this issue will be notably discussed).

- As regards treatment nave/early responders, considering that:
o being an early virologic responder is already indicative of a higher likelihood of
achieving a SVR as compared to being a late responder
o for the whole comparison (excluding the subgroup analyses in the difficult to treat
populations as above discussed) the data can be regarded as adequate with more than 300
patients devoted to the comparison of RGT vs no RGT and quite similar SVR results in
RGT vs no RGT.
The RGT (28 weeks total treatment duration, including 4 weeks lead in and 24 weeks
tritherapy) could be recommended in treatment nave/early responders

- As regards treatment nave/late responders, considering that:
o being a late virologic responder is already indicative of difficulties in achieving virologic
suppression
o the overall data devoted to the comparison of RGT no RGT can be regarded as
substantial (at the exclusion of the difficult to treat populations as above discussed) but
the comparative SVR (with exclusion of false positive in RGT) raises some source of
concern with results favouring the No RGT arm. Whether due to chance of truly
indicative of a loss of efficacy remains to be established by further data substantiating the
RGT in this population.

- As regards treatment experienced/early responders. There are reservations as regards the RGT in
since the data are more limited and the comparative SVR are indicative of a potential loss of
efficacy with RGT (89 % vs 97%). Again, whether due to chance of truly indicative of a loss of
efficacy remains to be established by further data substantiating the RGT in treatment
experienced patients.

- As regards treatment experienced/late responders, the limited number of patients devoted to the
comparison in this a priori more difficult to treat population, mandates adopting a conservative
attitude of not recommending RGT.

Finally, outside the best case scenario of (non black and non cirrhotic patients) early responders
-treatment nave patients there are reservations against the RGT. These reservations could be
ranked from a discouragement to a not recommended use (treatment experienced), having in mind
the burden of anemia and the fact that even if somewhat downgraded with RGT as compared to no RGT,
the benefit could remain substantial in terms of increased rates of SVR as compared to the control group.
76
Of note, Interaction with FDA is planned to attempt drawing harmonised recommendation since
divergences on treatment duration might be source of confusion.
It is important to note that it is quite unfortunate that the RGT was not tested in the study performed in
treatment experienced patients with pegylated interferon alfa 2 that the applicant has newly submitted
(P05685).

The Section 4.2 should be re-visited to better acknowledge these limitations in the RGT, in the following
spirit:

Section 4.2

During the phase III development programme, different regimens were tested:
- a fixed treatment duration, i.e. 4 weeks lead in phase with Pegylated IFN+Ribavirin before the
initiation of the tritherapy with boceprevir during the subsequent 44 weeks
- a Response Guided Therapy (RGT) depending on the HCV RNA detectability at week 8 through
week 24 in treatment nave patients and at week 8 through week 12 in treatment experienced
patients.

Due to limited data available in black patients and cirrhotic patients, the RGT cannot be currently
recommended in these patients. Boceprevir should be administered on the basis of the fixed treatment
duration i.e. 4 weeks lead in phase with Pegylated IFN+Ribavirin before the initiation of the tritherapy
with boceprevir during the subsequent 44 weeks.

Treatment nave

. Early responders (undetectable at week 8 through week 24)

The RGT can be recommended due to adequate reassurance on the comparison with the fixed treatment
duration.

(RGT)
4W LI + 24W BPR = 28 W

. Late responders (detectable HCV RNA at all assays from TW8 through TW24)

(RGT)
4W LI + 24W BPR + 20 W PR = 48 W
FIXED TREATMENT
DURATION
4 W LI+ 44W BPR = 48W

Lower SVR might be associated with the RGT as compared to fixed treatment duration in
treatment nave patients/late responders.

Treatment experienced

The data are currently too limited (especially in treatment experienced/late responders) to
recommend the RGT, the RGT could be associated with net loss of efficacy.

77
. Early responders (undetectable at week 8 through week 12)

Response Guided
Therapy (RGT)
4W LI + 32W BPR = 36W
FIXED
TREATMENT
DURATION
4 W LI+ 44W BPR = 48W

. Late responders (detectable from week 8 through week 12)

Response Guided
Therapy (RGT)
4W LI + 32W BPR +12W PR = 48W
FIXED
TREATMENT
DURATION
4 W LI+ 44W BPR = 48W

Stopping rules criteria:

Will have to be further considered in light of clarification.

If a patient misses a dose and it is less than 2 hours before the next dose is due, the missed dose
should be skipped.

If a patient misses a dose and it is 2 or more hours before the next dose is due, the patient should
take the missed dose with food and resume the normal dosing schedule.

Dose reduction
Dose reduction of Victrelis is not recommended.

If a patient has a serious adverse reaction potentially related to peginterferon alpha and/or ribavirin,
the peginterferon alpha and/or ribavirin dose should be reduced. Refer to the Summary of Product
Characteristics for peginterferon alpha and ribavirin for additional information about how to reduce
and/or discontinue the peginterferon alpha and/or ribavirin dose. Victrelis must not be administered in
the absence of peginterferon alpha and ribavirin.

Renal impairment
No dose adjustment of Victrelis is required in patients with any degree of renal impairment (see section
5.2).

Hepatic impairment
No dose adjustment of Victrelis is required for patients with mild, moderate or severe hepatic
impairment. Ribavirin or peginterferon alfa-2b are contraindicated in patients with severe hepatic
impairment or decompensated cirrhosis of the liver. Victrelis, in combination with peginterferon alpha
and ribavirin, is contraindicated in cirrhotic patients with a Child-Pugh score > 6 (class B and C) (see
sections 4.3 and 5.2).

Paediatric population
The safety and efficacy in children below 18 years of age have not yet been established.

Elderly
Clinical studies of Victrelis did not include sufficient numbers of subjects aged 65 and over to
determine whether they respond differently from younger subjects. Other clinical experience has not
identified differences in responses between the elderly and younger patients (see section 5.2).
78

HIV co-infection
The safety and efficacy of Victrelis alone or in combination with peginterferon alpha and ribavirin for
the treatment of chronic hepatitis C genotype 1 infection have not been established in patients co-
infected with Human Immunodeficiency Virus (HIV) and HCV. A clinical study is ongoing.

HBV co-infection
the treatment of chronic hepatitis C genotype 1 infection in patients co-infected with hepatitis B Virus
(HBV) and HCV have not been studied.

Organ transplant recipients
the treatment of chronic hepatitis C genotype 1 infection in liver or other organ transplant recipients
have not been studied.

HCV genotypes other than genotype 1
the treatment of chronic hepatitis C genotypes other than genotype 1 have not been established.

Patient who have previously failed treatment with an HCV protease inhibitor
the treatment of chronic hepatitis C genotype 1 infection has not been studied in patients who have
failed previous therapy with Victrelis or other HCV protease inhibitors.

Method of administration

Take orally with food.

4.3 Contraindications

Victrelis, in combination with peginterferon alpha and ribavirin, is contraindicated in:
Patients with hypersensitivity to the active substance or any of its excipients.
Patients with autoimmune hepatitis.
Patients with hepatic decompensation [Child-Pugh score > 6 (class B and C)] (see sections 4.2
and 5.2).
Co-administration with medicines that are highly dependent on CYP3A4/5 for clearance, and for
which elevated plasma concentrations are associated with serious and/or life-threatening
events such as orally administered midazolam and triazolam, amiodarone, bepridil, pimozide,
propafenone, quinidine, lumefantrine, halofantrine, tyrosine kinase inhibitors, and ergot
derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine) (see section 4.5).
Pregnancy (see section 4.6).

Refer to the Summary of Product Characteristics for peginterferon alpha and ribavirin for additional
information.

Co-administration with medicines that are highly dependent on CYP3A4/5 for clearance, and for which
elevated plasma concentrations are associated with serious and/or life-threatening events such as orally
administered midazolam and triazolam, bepridil, pimozide, lumefantrine, halofantrine, tyrosine kinase
inhibitors, and ergot derivatives (dihydroergotamine, ergotamine) (see section 4.5).

79
4.4 Special warnings and precautions for use

Assessors comments:
Proarrhytmic effects:
Although it can be concurred with the applicant that the clinical data are reassuring so far, it remains that
boceprevir has a proarrhytmic potential based on electrophysiological findings and the trend observed
toward a prolongation of the QT interval in the dedicated ICHE14 study.

Therefore, it considered that attention of physicians should be alerted:

Section 4.4 Although a dedicated study in healthy volunteers (ICHE14 QT/QTc study) was deemed
negative, some dose dependent trend toward a prolongation of the QT interval (see also 5.3) warrants
caution in patients at risk for QT prolongation (congenital long QT, hypokaliemia,...).

Section 5.3
In safety pharmacology, boceprevir prolongs the action potential duration with reverse-use dependency,
which clinical relevance remains uncertain (en 4.4)

Anaemia
The onset of anaemia has been reported with peginterferon alpha/ribavirin therapy by Treatment
Week 4. The addition of Victrelis to peginterferon alpha and ribavirin is associated with an additional
decrease in serum haemoglobin concentrations of approximately 1 g/dl by Treatment Week 8
compared to standard of care (see section 4.8). Complete blood counts should be obtained
pretreatment, Treatment Week 4, Treatment Week 8, and thereafter, as clinically appropriate. If serum
haemoglobin is < 10 g/dl, a decrease in dose or interruption of ribavirin and/or administration of
erythropoietin (epoetin alfa) may be warranted (see sections 4.8 and 5.1).

Please also refer to the Summary of Product Characteristics for ribavirin for statements regarding dose
reduction and/or interruption.

Drospirenone-containing medicines
Caution should be exercised in patients taking drospirenone-containing medicines with conditions that
predispose them to hyperkalaemia or patients taking potassium-sparing diuretics. Alternative
contraceptives should be considered (see section 4.5).

HCV protease monotherapy
Based on results of clinical studies, Victrelis must not be used alone due to the high probability of
increased resistance without combination anti-HCV therapies (see section 5.1).

It is unknown what effect therapy with Victrelis will have on the activity of subsequently administered
HCV protease inhibitors, including re-treatment with Victrelis.

Use in patients with rare hereditary disorders
Victrelis contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp
lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Potent CYP3A4 inducers ( rifampicin, carbamazepin, phenobarbital, phenytoin)
The concomitant use of boceprevir with potent CYP3A4 inducers is not recommended (see section 4.5).

80

4.5 Interaction with other medicinal products and other forms of interaction

Victrelis is a strong inhibitor of CYP3A4/5. Medicines metabolized primarily by CYP3A4/5 may have
increased exposure when administered with Victrelis, which could increase or prolong their therapeutic
and adverse effects (see Table 3). Victrelis does not inhibit or induce the other enzymes of the CYP450.

Victrelis is partly metabolized by CYP3A4/5. Co-administration of Victrelis with medicines that induce or
inhibit CYP3A4/5 could increase or decrease exposure to Victrelis.

The concomitant use of Victrelis with rifampicin or anticonvulsants (such as phenytoin, phenobarbital or
carbamazepine) may significantly reduce the plasma exposure of Victrelis. No data are available,
therefore, the combination of boceprevir with these drugs is not-recommended (see 4.4 section).

Victrelis is a P-gp substrate. Since no data are available with a potent P-gp inhibitor ( e.g.ciclosporine,
ketoconazole, verapamil), a clinically relevant interaction cannot be ruled out. Therefore, a close clinical
monitoring should be exercised.

Victrelis, in combination with peginterferon alpha and ribavirin, is contraindicated when co-administered
with medicines that are highly dependent on CYP3A4/5 for clearance, and for which elevated plasma
concentrations are associated with serious and/or life-threatening events such as orally administered
midazolam, bepridil, pimozide, lumefantrine, halofantrine, and tyrosine kinase inhibitors, and ergot
derivatives (dihydroergotamine, ergotamine) (see section 4.3).

Assessors comment
The Applicant persists to mention amiodarone, quinidine, propafenone, ergonovine and methylergonovine
in the list of at risk CYP3A4 substrates whilst no strong scientific data are provided. Therefore, the need
to delete these drugs remains.

Caution should be exercised with drugs known to prolonge QT interval such as amiodarone, quinidine,
methadone ( see also table 3), pentamidine and some neuroleptics (see section 4.4).

Assessors comment
According to the warning raised about the risk of QT prolongation, this statement is proposed.

81
Table 3.
Pharmacokinetic interactions data

Medicinal products by therapeutic
areas
Interaction*
(postulated mechanism of
action, if known)
Recommendations
concerning co-
administration

Assessors comment regarding the coadministration with Peginterferon alfa-2b
Considering the indication of boceprevir and the clinical experience the Rapporteurs propose to delete
interaction data with pegylated interferon.

Antifungals
Ketoconazole
(ketoconazole 400 mg two times daily
+
Victrelis 400 mg single dose)

Itraconazole
Posaconazole
Voriconazole

boceprevir AUC 131%
boceprevir Cmax 41%
boceprevir Cmin N/A

Not studied.

Caution should be exercised
when boceprevir is
combined with
ketoconazole or azole
antifungals (itraconazole,
posaconazole,
voriconazole). A Clinical
monitoring should be
considered during the
combination.

Antiretroviral
Nucleoside Reverse Transcriptase Inhibitor (NRTI)
Tenofovir
(tenofovir 300 mg daily + Victrelis
800 mg three times daily)
boceprevir AUC 8%
**

boceprevir Cmax 5%
boceprevir Cmin 8%

tenofovir AUC 5%
tenofovir Cmax 32%
No dose adjustment
required for Victrelis or
tenofovir.
Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Efavirenz
(efavirenz 600 mg daily + Victrelis
boceprevir AUC 19%
**

boceprevir Cmax 8%
boceprevir Cmin 44%

efavirenz AUC 20%
efavirenz Cmax 11%

Plasma trough
concentrations of Victrelis
were decreased when
administered with
efavirenz. The clinical
outcome of this observed
reduction of Victrelis
trough concentrations has
not been directly assessed.
82
areas
Interaction*
action, if known)
Recommendations
concerning co-
administration
HIV Protease Inhibitor (PI)
Ritonavir
(ritonavir 100 mg daily + Victrelis
boceprevir AUC 19%
boceprevir Cmax 27%
boceprevir Cmin 4%

No data are currently
available with ritonavir as a
booster in combination with
protease inhibitors.
Theoretically, the
combination of boceprevir
with PIs /ritonavir is not
expected to be clinically
significant. However, a
clinical monitoring should
be made if boceprevir is
coadministered with
PIs/ritonavir.
Integrase inhibitor
Raltegravir Not studied.

Based on theoretical data,
the combination of
boceprevir and raltegravir
is not expected to be
clinically significant.
However a clinical
monitoring should be
made during the
combination.

Assessors comment regarding the coadministration with non-steriodal anti-inflammatories (NSAI Ds)
According to the Rapporteurs comment following the Applicants response to the clinical PK question 1,
these statements should be removed.

ORAL CONTRACEPTIVES
Drospirenone/Ethinyl estradiol:
(drospirenone
3 mg daily + ethinyl estradiol
0.02 mg daily + Victrelis 800 mg three
times daily)
drospirenone AUC 99%
drospirenone Cmax 57%

ethinyl estradiol AUC 24%
ethinyl estradiol Cmax

(drospirenone - CYP3A4/5
inhibition)
Caution should be exercised
in patients with conditions
that predispose them to
hyperkalaemia or patients
taking potassium-sparing
diuretics (see section 4.4).
Alternative contraceptives
should be considered for
these patients.
83
areas
Interaction*
action, if known)
Recommendations
concerning co-
administration
SEDATIVES
Midazolam (oral administration)
(4 mg single oral dose + Victrelis

Triazolam
(oral administration)
midazolam AUC 430%
midazolam Cmax 177%
(CYP3A4/5 inhibition)

Interaction not studied
Co-administration of oral
midazolam and oral
triazolam with Victrelis is
contraindicated (see
section 4.3).
Alprazolam, midazolam, triazolam
(intravenous administration)

Interaction not studied

Close clinical monitoring
for respiratory depression
and/or prolonged sedation
should be exercised during
co-administration of
Victrelis with intravenous
benzodiazepines
(alprazolam, midazolam,
triazolam). Dose adjustment
of the benzodiazepine
should be considered.
Immunosuppressants Not studied Therapeutic drug
monitoring is recommended
when administering
Victrelis with tacrolimus or
cyclosporine. Individual
patients may require
additional titration of their
immunosuppressant dosage
when Victrelis is started or
stopped to ensure clinically
effective blood levels.
Statins (e.g., simvastatin and
atorvastatin.)
Not studied A close clinical and
biological monitoring is
recommended when
administering Victrelis with
simvastatin or atorvastatin.
Methadone Not studied A close clinical and
biological monitoring is
recommended when
administering Victrelis with
methadone.
Assessors comment
Of note, methadone is not a probe CYP3A4 substrate but is mainly metabolised by CYP2B6.
*
Interaction of Victrelis with other medicinal products (change in mean ratio estimate of Victrelis in
combination with co-administered medicine/Victrelis alone): equals a decrease in mean ratio estimate
> 20%; equals an increase in mean ratio estimate > 25%; no effect () equals a decrease in mean ratio
estimate of 20% or increase in mean ratio estimate 25%.
**
0-8 hours

0-168 hours

Reported AUC is 200 mg and 400 mg cohorts combined.

84

4.6 Fertility, pregnancy and lactation

Pregnancy

Victrelis in combination with ribavirin and peginterferon alpha is contraindicated.in women who are
pregnant (see section 4.3).

No effects on foetal development have been observed in rats and rabbits (see section 5.3). There are no
data on the use of Victrelis in pregnant women.

Treated patients and their partners must use two effective forms of contraceptive methods when
boceprevir is used in combination with peginterferon alpha and ribavirin. Refer to Summary of Product
Characteristics for ribavirin and peginterferon alpha for additional information.

Breastfeeding
Boceprevir/metabolites are excreted in rat milk (see section 5.3). It is not known whether boceprevir is
excreted in human breast milk.
A risk to the newborns/infants cannot be excluded.

A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from therapy with
Victrelis taking into account the benefit of breastfeeding for the child and the benefit of therapy for the
woman.

Fertility
No human data on the effect of Victrelis on fertility are available. Effects on fertility and Sertoli cells have
been observed in rats but not in mice and monkeys. Clinical data (semen analyses and inhibin B levels [a
glycoprotein produced by Sertoli cells- used as a surrogate marker of testicular function]) showed no
evidence of altered testicular function. Available pharmacodynamic/toxicological data in rats have shown
effects of boceprevir/metabolites on fertility, which in females have been shown to be reversible (see
section 5.3).

4.7 Effects on ability to drive and use machines

Combination therapy of Victrelis, peginterferon alfa-2b and ribavirin may influence some patients ability
to drive and use machines. Patients should be informed that fatigue, dizziness, syncope, blood pressure
fluctuations and blurred vision have been reported (see section 4.8).

4.8 Undesirable effects

The safety profile represented by approximately 1,500 patients for the combination of Victrelis with
peginterferon alfa-2b and ribavirin was based on pooled safety data in two clinical trials in patients who
were previously untreated [SPRINT-1 (P03523) and SPRINT-2 (P05216)] and one clinical trial in patients
who had failed prior therapy [RESPOND-2 (P5101)]. Patients with chronic hepatitis C received
Victrelis 800 mg three times daily in combination with peginterferon alfa-2b and ribavirin in each study.
The population studied had a mean age of 49 years (2% of patients were > 65 years of age), 39% were
female, and were 82% white and 15% black. Subjects received Victrelis 800 mg three times daily in each
study. Patients with chronic hepatitis C were randomized to receive Victrelis in the three studies for a
median exposure of 201 days (see section 5.1).

The most frequently reported adverse reactions were similar across all study arms. The most frequently
reported adverse reactions considered by investigators to be causally related to the combination of
85
Victrelis with peginterferon alfa-2b and ribavirin in adult subjects in clinical studies were: fatigue,
anaemia (see section 4.4), nausea, headache, and dysgeusia.

During the four-week lead-in period with peginterferon alfa-2b and ribavirin, 28/1,263 (2%) subjects in
the Victrelis-containing arms experienced adverse reactions leading to discontinuation of treatment.
During the entire course of treatment, the proportion of subjects who discontinued treatment due to
adverse reactions was 13% for subjects receiving the combination of Victrelis with peginterferon alfa-2b
and ribavirin and 12% for subjects receiving peginterferon alfa-2b and ribavirin alone. Events resulting in
discontinuation were similar to those seen in previous studies with peginterferon alfa-2b and ribavirin.
Only anaemia and fatigue were reported as events that led to discontinuation in > 1% of subjects in any
arm.

Adverse reactions that led to dose modifications of any medicine occurred in 39% of subjects receiving
the combination of Victrelis with peginterferon alfa-2b and ribavirin compared to 24% of subjects
receiving peginterferon alfa-2b and ribavirin alone. The most common reason for dose reduction was
anaemia, which occurred more frequently in subjects receiving the combination of Victrelis with
peginterferon alfa-2b and ribavirin than in subjects receiving peginterferon alfa-2b and ribavirin alone.

Adverse reactions considered by investigator to be causally related to the combination of Victrelis with
peginterferon alfa-2b and ribavirin are listed by System Organ Class (see Table 4). Within each system
organ class, adverse reactions are listed under headings of frequency using the categories: very common
( 1/10); common ( 1/100 to < 1/10); uncommon ( 1/1,000 to < 1/100); rare ( 1/10,000 to < 1/1,000).

Table 4.
Adverse reactions in combination with Victrelis with peginterferon alfa-2b and ribavirin reported
during clinical trials
and

System Organ Class Adverse Reactions
Infections and infestations
Common: Bronchitis*, cellulitis*, herpes simplex, influenza, oral
fungal infection, sinusitis
Uncommon: Gastroenteritis*, pneumonia*, staphylococcal
infection*, candidiasis, ear infection, fungal skin
infection, nasopharyngitis, onychomycosis,
pharyngitis, respiratory tract infection, rhinitis, skin
infection, urinary tract infection
Rare: Epiglottitis*, otitis media, sepsis
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Rare: Thyroid neoplasm
Blood and lymphatic system disorders
Very common: Anaemia*, neutropenia*
Common: Leukopenia*, thrombocytopenia*
Uncommon: Haemorrhagic diathesis, lymphadenopathy,
lymphopenia
Rare: Haemolysis
Immune system disorders
Rare: Sarcoidosis*, porphyria non-acute
Endocrine disorders
Common: Goitre, hypothyroidism
Uncommon: Hyperthyroidism
Metabolism and nutrition disorders
Very common: Decreased appetite*
Common: Dehydration*, hyperglycaemia*,
hypertriglyceridaemia, hyperuricaemia
Uncommon: Hypokalaemia* appetite disorder, diabetes mellitus,
86
gout, hypercalcaemia
Psychiatric disorders
Very common: Anxiety*, depression*, insomnia, irritability
Common: Affect lability, agitation, libido disorder, mood altered,
sleep disorder
Uncommon: Aggression*, homicidal ideation*, panic attack*,
paranoia*, substance abuse*, suicidal ideation*,
abnormal behaviour, anger, apathy, confusional state,
mental status changes, paranoia*, restlessness
Rare: Bipolar disorder*, completed suicide*, suicide
attempt*, hallucination auditory, hallucination visual,
psychiatric decompensation
Nervous system disorders
Very common: Dizziness*, headache*
Common: Hypoaesthesia*, paraesthesia*, syncope*, amnesia,
disturbance in attention, memory impairment,
migraine, parosmia, tremour, vertigo
Uncommon: Neuropathy peripheral*, cognitive disorder,
hyperaesthesia, lethargy, loss of consciousness, mental
impairment, neuralgia, presyncope
Rare: Cerebral ischaemia*, encephalopathy
Eye disorders
Common: Dry eye, retinal exudates, vision blurred, visual
impairment
Uncommon: Retinal ischaemia*, retinopathy*, abnormal sensation
in eye, conjunctival haemorrhage, conjunctivitis, eye
pain, eye pruritus, eye swelling, eyelid oedema,
lacrimation increased, ocular hyperaemia, photophobia
Rare: Papilloedema
Ear and labyrinth disorders
Common: Tinnitus
Uncommon: Deafness*, ear discomfort, hearing impaired
Cardiac disorders
Common: Palpitations
Uncommon: Tachycardia*, arrhythmia, cardiovascular disorder
Rare: Acute myocardial infarction*, atrial fibrillation*,
coronary artery disease*, pericarditis*, pericardial
effusion
Vascular disorders
Common: Hypotension*, hypertension
Uncommon: Deep vein thrombosis*, flushing, pallor, peripheral
coldness
Rare: Venous thrombosis
Respiratory, thoracic and mediastinal disorders
Very common: Cough*, dyspnoea*
Common: Epistaxis, nasal congestion, oropharyngeal pain,
respiratory tract congestion, sinus congestion,
wheezing
Uncommon: Pleuritic pain*, pulmonary embolism*, dry throat,
dysphonia, increased upper airway secretion,
oropharyngeal blistering
Rare: Pleural fibrosis*, orthopnoea, respiratory failure
Gastro-intestinal disorders
87
Very common: Diarrhoea*, nausea*, vomiting* dry mouth, dysgeusia
Common: Abdominal pain*, abdominal pain upper*,
constipation*, gastrooesophageal reflux disease*,
haemorrhoids*, abdominal discomfort, abdominal
distention, anorectal discomfort, aphthous stomatitis,
cheilitis, dyspepsia, flatulence, glossodynia, mouth
ulceration, oral pain, stomatitis, tooth disorder
Uncommon: Abdominal pain lower*, gastritis*, pancreatitis*, anal
pruritus, colitis, dysphagia, faeces discoloured,
frequent bowl movements, gingival bleeding, gingival
pain, gingivitis, glossitis, lip dry, odynophagia,
proctalgia, rectal haemorrhage, salivary hypersecretion,
sensitivity of teeth, tongue discolouration, tongue
ulceration
Rare: Pancreatic insufficiency
Hepatobiliary disorders
Uncommon: Hyperbilirubinaemia
Rare: Cholecystitis*
Skin and subcutaneous tissue disorders
Very common: Alopecia, dry skin, pruritus, rash
Common: Dermatitis, eczema, erythema, hyperhidrosis, night
sweats, oedema peripheral, psoriasis, rash
erythematous, rash macular, rash maculo-papular, rash
papular, rash pruritic, skin lesion
Uncommon: Photosensitivity reaction, skin ulcer, urticaria
Musculoskeletal and connective tissue disorders
Very common: Arthralgia, myalgia
Common: Back pain*, pain in extremity*, muscle spasms,
muscular weakness, neck pain
Uncommon: Musculoskeletal chest pain*, arthritis, bone pain, joint
swelling, musculoskeletal pain
Renal and urinary disorders
Common: Pollakiuria
Uncommon: Dysuria, nocturia
Reproductive system and breast disorders
Common: Erectile dysfunction
Uncommon: Amenorrhoea, menorrhagia, metrorrhagia
Rare: Aspermia
General disorders and administration site conditions
Very common: Asthenia*, chills, fatigue*, pyrexia*, influenza-like
illness
Common: Chest discomfort*, chest pain*, malaise*, feeling of
body temperature change, mucosal dryness, pain
Uncommon: Feeling abnormal, impaired healing, non-cardiac chest
pain
Investigations
Very common: Weight decreased
Uncommon: Cardiac murmur, heart rate increased
* Includes adverse reactions which may be serious as assessed by the investigator in clinical trial
subjects.
Since Victrelis is prescribed with peginterferon alpha and ribavirin, please also refer to the
respective Summary of Product Characteristics of peginterferon alpha and ribavirin.
Injection-site reactions have not been included since Victrelis is administered orally.
88
Description of selected adverse reactions
Assessors comment
These paragraphs should be revisited to avoid diluting the concern and to avoid falsely reassuring
statements, such as Boceprevir did not appear to exacerbate this difference.
Anaemia
Anaemia was observed in 49% of subjects treated with the combination of Victrelis with peginterferon
alfa-2b and ribavirin compared with 29% of subjects treated with peginterferon alfa-2b and ribavirin
alone. Victrelis was associated with an additional decrease of approximately 1 g/dl in haemoglobin
concentration. The mean decreases in haemoglobin values from baseline were larger in previously treated
patients compared to patients who had never received prior therapy. Dose modifications due to
anaemia/hemolytic anaemia occurred twice as often in patients treated with the combination of Victrelis
with peginterferon alfa-2b and ribavirin (26%) compared to peginterferon alfa-2b and ribavirin alone
(13%). In these clinical trials, proper management of anaemia was associated with continued treatment
and higher sustained virologic response, with the majority of the anaemic subjects having received
erythropoietin when haemoglobin levels were 10 g/dl (see section 5.1). The proportion of subjects who
received erythropoietin for the management of anaemia was 43% (667/1,548) of subjects in the Victrelis-
containing arms compared to 24% (131/547) of subjects receiving peginterferon alfa-2b and ribavirin
alone. The proportion of subjects who received a transfusion for the management of anaemia was 3% of
subjects in the Victrelis-containing arms compared to < 1% of subjects receiving peginterferon alfa-2b and
ribavirin alone.

Neutrophils and platelets
The proportion of subjects with decreased neutrophil and platelet counts was higher in the Victrelis-
containing arms compared to subjects receiving only peginterferon alfa-2b and ribavirin. Seven percent of
subjects receiving the combination of Victrelis with peginterferon alfa-2b and ribavirin had neutrophil
counts of < 0.5 x 10
9
/l compared to 4% of subjects receiving only peginterferon alfa-2b and ribavirin. The
percentage of patients with Grades 3-4 neutropenia was higher in boceprevir-treated patients (29%) than in
placebo-treated patients (17%), in combination with peginterferon alfa-2b and ribavirin.

Three percent of subjects receiving the combination of Victrelis with peginterferon alfa-2b and ribavirin
had platelet counts of < 50 x 10
9
/l compared to 1% of subjects receiving only peginterferon alfa-2b and
ribavirin. As with the other blood cells, platelet counts were decreased for subjects in the Victrelis
containing-arms compared to those receiving only peginterferon alfa-2b and ribavirin. The proportion of
subjects who experienced Grade 3-4 thrombocytopenia was higher in the Victrelis-containing arms
compared to subjects receiving peginterferon alfa-2b and ribavirin alone. Mean platelet counts remained
above 100 x 10
9
/l. There was only one case of significant bleeding (hematemesis) in a subject with Grade
3 thrombocytopenia and a history of pre-existing portal hypertension and portal gastropathy. For subjects
in the Victrelis-containing arms, 14% of subjects with cirrhosis experienced WHO Grade 3
thrombocytopenia on treatment compared to 2% of subjects without cirrhosis. For subjects who received
only peginterferon alfa-2b and ribavirin, 7% of subjects with cirrhosis experienced WHO Grade 3
thrombocytopenia on treatment compared to 1% of subjects without cirrhosis. No subjects with cirrhosis
in the Victrelis-containing arm experienced Grade 4 thrombocytopenia, compared to three (3/1,386, <1%)
subjects in the Victrelis-containing arm without cirrhosis. No subjects who received only peginterferon
alfa-2b and ribavirin only developed Grade 4 thrombocytopenia. While thrombocytopenia and anaemia
were more common in subjects with cirrhosis (n=112) compared to those without cirrhosis in the
Victrelis-containing arms, these adverse events were also more common in cirrhotic subjects (n=31) than
non-cirrhotic subjects in subjects receiving peginterferon alfa-2b and ribavirin alone. Boceprevir did not
appear to exacerbate this difference.

89

4.9 Overdose

Daily doses of 3,600 mg have been taken by healthy volunteers for 5 days without untoward symptomatic
effects.
There is no specific antidote for overdose with Victrelis. Treatment of overdose with Victrelis should
consist of general supportive measures, including monitoring of vital signs, and observation of the
patients clinical status.

5. PHARMACOLOGICAL PROPERTIES

Assessors comments:
This section should be re-visited to avoid falsely reassuring message on RGT. The results should be
displayed with RGT no RGT for relevant subgroups in line with what has been done in the corresponding
response to the D120.
The SPC should factually describe the data on IL28B (60% of patients and statement on potential biases)
with a concluding statement that
The degree of added value of boceprevir on top of the bitherapy will depend on the likelihood of
achieving SVR with the bitherapy only. There are uncertainties concerning the added value of boceprevir
on top of the bitherapy with pegylated Interferon+ribavirin in patients who might have good predictive
under investigation

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Not yet assigned ATC code: Not yet assigned

Mechanism of action
Victrelis is an inhibitor of the HCV NS3 protease. Victrelis covalently, yet reversibly, binds to the NS3
protease active site serine (Ser139) through a (alpha)-ketoamide functional group to inhibit viral
replication in HCV-infected host cells.

Antiviral activity in cell culture
The antiviral activity of boceprevir was evaluated in a biochemical assay for slow binding inhibitors of
NS3 protease and in the genotype 1a and 1b HCV replicon system. The IC50 and IC90 values for
boceprevir against different genotype 1b replicons ranged from 200 to 600 nM and 400 to 900 nM,
respectively, in a 72-hour cell culture assay. Loss of replicon RNA appears to be first-order with respect to
time of treatment. Treatment at IC90 for 72 hours resulted in a 1-log drop in replicon RNA. Prolonged
exposure resulted in a 2-log decrease in RNA levels by Day 15. In a genotype 1a replicon, the IC50 and
IC90 values for boceprevir were 900 nM and 1,400 nM, respectively.

Evaluation of varying combinations of boceprevir and interferon alfa-2b that produced 90% suppression
of replicon RNA showed additivity of effect; no evidence of synergy or antagonism was detected.

Resistance
Resistance to Victrelis was characterized in biochemical and replicon assays. In replicon assays, the
potency of Victrelis was reduced (2 16 fold) by the following major resistance resistant-associated
amino acid variants (RAVs): V36M, T54A, R155K, A156S, and V170A. A loss of potency (> 50 fold)
was observed with resistant-associated amino acid variants: A156T. Of note, replicons carrying the A156T
variant are less fit than replicons carrying other RAVs. Similar results were obtained with Victrelis in in
vitro NS3 enzymatic studies, where potency was reduced (2 to 17 fold) by RAVs V36M, T54A, T54S,
90
V55A, R155K, A156S and V170A. The loss of potency associated with A156T was >50 fold. The fold
increase in resistance for double RAVs was approximately equal to the product of fold resistances for the
individual RAVs.

In a pooled analysis of subjects who were previously untreated and subjects who have failed previous
therapy who received four weeks of peginterferon alfa-2b and ribavirin followed by Victrelis 800 mg three
times daily in combination with peginterferon alfa-2b and ribavirin in two Phase III studies, post-baseline
RAVs were detected in 15% of all subjects. In Victrelis-treated subjects who did not attain sustained
virologic response (SVR) for whom samples were analyzed, 53% had post-baseline RAVs detected. The
most frequently detected post-baseline RAVs in these subjects were amino acid substitutions V36M
(46%), T54A (15%), R155K (52%), and T54S (23%). In subjects treated with Victrelis, interferon
responsiveness (as defined by 1-log10 decline in viral load at Treatment Week 4) was associated with
detection of fewer RAVs, with 6% of these subjects having RAVs compared to 41% of subjects with < 1-
log10 decline in viral load at Treatment Week 4 (poorly interferon responsive). In subjects treated with
Victrelis with post-baseline samples analyzed for RAVs, interferon responsiveness was associated with
detection of fewer RAVs, with 31% of these subjects having post-baseline RAVs compared to 68% of
subjects with < 1-log10 decline in viral load at Treatment Week 4. The presence of baseline RAVs did not
appear to have a notable association with treatment response in subjects receiving the combination of
Victrelis with peginterferon alfa-2b and ribavirin.

An analysis of data from an ongoing, long-term follow-up study in subjects from these Phase III studies
who did not achieve SVR examined the persistence of RAVs. During the 6-14 month post-therapy period,
the majority of subjects (68%-94%) had RAVs that became undetectable by population sequencing.

Efficacy

The efficacy of Victrelis as a treatment for chronic hepatitis C (genotype 1) infection was assessed in
approximately 1,500 adult subjects who were previously untreated (SPRINT-2) or who had failed previous
therapy (RESPOND-2) in Phase III clinical studies. In both studies, the addition of Victrelis to the current
standard of care (peginterferon alpha and ribavirin) significantly increased sustained virologic response
(SVR) rates compared to the current standard of care alone.

Patients who are previously untreated
SPRINT-2 (P05216) was a randomized, double blinded, placebo-controlled study comparing two
therapeutic regimens of Victrelis 800 mg orally three times daily in combination with PR [peginterferon
alfa-2b 1.5 g/kg/week subcutaneously and weight-based dosing with ribavirin (600-1,400 mg/day orally
divided twice daily)] to PR alone in adult subjects who had chronic hepatitis C (HCV genotype 1)
infection with detectable levels of HCV-RNA and were not previously treated with interferon alfa therapy.
Subjects were randomized in a 1:1:1 ratio in two cohorts (Cohort 1/non-Black and Cohort 2/Black) and
stratified by HCV genotype (1a or 1b) and by HCV-RNA viral load ( 400,000 IU/ml vs.
> 400,000 IU/ml) to one of the following three treatment arms:
Peginterferon alfa-2b + ribavirin for 48 weeks (PR48).
Peginterferon alfa-2b + ribavirin for 4 weeks followed by Victrelis 800 mg three times daily +
peginterferon alfa-2b + ribavirin for 24 weeks. The subjects were then continued on different
regimens based on Treatment Week (TW) 8 response-guided therapy (Victrelis-RGT). All patients
in this treatment arm were limited to 24 weeks of therapy with Victrelis.
o Subjects with undetectable HCV-RNA at TW 8 (early responders) and who were also
negative through TW 24 discontinued therapy and entered follow-up at the TW 28 visit.
o Subjects with detectable HCV-RNA at TW 8 or any subsequent treatment week but
subsequently and negative at TW 24 (late responders) were changed in a blinded fashion
to placebo at the TW 28 visit and continued therapy with peginterferon alfa-2b + ribavirin
for an additional 20 weeks, for a total treatment duration of 48 weeks.
Peginterferon alfa-2b + ribavirin for four weeks followed by Victrelis 800 mg three times daily +
peginterferon alfa-2b + ribavirin for 44 weeks (Victrelis-PR48).

91
All subjects with detectable HCV-RNA in plasma at TW 24 were discontinued from treatment. Sustained
Virologic Response (SVR) to treatment was defined as undetectable
1
plasma HCV-RNA at follow-up
week 24.
The addition of Victrelis to peginterferon alfa-2b and ribavirin significantly increased the SVR rates
compared to peginterferon alfa-2b and ribavirin alone in the combined cohort (63% to 66% Victrelis-
containing arms vs. 38% PR48 control) for randomized subjects who received at least one dose of any
study medicine (Full-analysis -Set population) and decreased the length of therapy to 28 weeks for early
responders (see Table 5). SVR rates for Blacks who received the combination of Victrelis with
peginterferon alfa-2b and ribavirin were 42% to 53%; these rates are approximately two-fold higher than
the SVR rate for the PR48 control (23%) (see Table 5). A secondary analysis of subjects who received at
least one dose of Victrelis or placebo after the four-week lead-in with peginterferon alfa-2b and ribavirin
(Modified-Intent-to-Treat population) demonstrated SVR rates in the combined cohort of 67% to 68%
Victrelis-containing arms vs. 40% PR48 control.

Table 5.
Sustained Virologic Response (SVR)
*
, End of Treatment (EOT) and Relapse
Rates for patients who

are previously untreated

Study Cohorts Victrelis-RGT Victrelis-PR48 PR48
Cohort 1 Plus Cohort 2 n=368 n=366 n=363
SVR
% (n/N)
95% CI
63 (233/368)
(58.4, 68.2)
66 (242/366)
(61.3, 71.0)
38 (137/363)
(32.8, 42.7)
EOT(Undetectable HCV-RNA) % (n/N)
95% CI
71 (261/368)
(66.3, 75.6)
76 (277/366)
(71.3, 80.1)
53 (191/363)
(47.5, 57.8)
Relapse
%(n/N)
95% CI
9 (24/257)
(5.8, 12.9)
9 (24/265)
(5.6, 12.5)
22 (39/176)
(16.0, 28.3)
Cohort 1 (non-Black) n=316 n=311 n=311
SVR
% (n/N)
95% CI
67 (211/316)
(61.6, 72.0)
68 (213/311)
(63.3, 73.7)
40 (125/311)
(34.7, 45.6)
EOT(Undetectable HCV-RNA) % (n/N)
95% CI
74 (235/316)
(69.6, 79.2)
77 (241/311)
(72.9, 82.1)
57 (176/311)
(51.1, 62.1)
Relapse
%(n/N)
95% CI
9 (21/232)
(5.4, 12.7)
8 (18/230)
(4.4, 11.3)
23 (37/162)
(16.4, 29.3)
Cohort 2 (Black) n=52 n=55 n=52
SVR
% (n/N)
95% CI
42 (22/52)
(28.9, 55.7)
53 (29/55)
(39.5, 65.9)
23 (12/52)
(11.6, 34.5)
EOT (Undetectable HCV-RNA) % (n/N)
95% CI
50 (26/52)
(36.4, 63.6)
65 (36/55)
(52.9, 78.0)
29 (15/52)
(16.5, 41.2)
Relapse
% (n/N)
95% CI
12 (3/25)
(0, 24.7)
17 (6/35)
(4.7, 29.6)
14 (2/14)
(0, 32.6)
*
The Full Analysis Set (FAS) consisted of all randomized subjects (N=1,097) who received at least
one dose of any study medicine (peginterferon alfa-2b, ribavirin, or Victrelis). Mean age of
subjects randomized was 49.1 years. The race distribution of subjects was as follows: 82% White,
14% Black, 2% Asian, 1% multiracial, 1% American Indian or Alaskan Native. The distribution of
subjects by gender was 60% men and 40% women.

Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of Treatment
(EOT) and detectable HCV-RNA at End of Follow-up (EOF) among subjects who were
undetectable at EOT and not missing End of Follow-up (EOF) data.

SVR: The last available value in the period at or after Follow-up Week (FW) 24. If there is no
such value, the FW 12 value is carried forward. SVR24 rates (SVR with "missing=failure"
approach) were nearly identical. Cohort 1: 39% PR48; 66% Victrelis-RGT, 68% Victrelis-PR48.
Cohort 2: 21% PR48, 42% Victrelis-RGT, 51% Victrelis-PR48. Cohort 1+ Cohort 2: 37% Control;
62% Victrelis-RGT, 65% Victrelis-PR48.

1
In clinical trials, HCV-RNA in plasma was measured with a quantitative PCR assay with a limit of detection of 9.3 IU/ml and a limit of
quantification of 25 IU/ml..
92

Interferon-responsiveness (as defined by 1-log
10
decline in viral load at TW 4) was predictive of SVR.
Victrelis-treated subjects who demonstrated interferon responsiveness by TW 4 achieved SVR rates of 79-
81%. In subjects with < 1-log10 decline in viral load at TW 4 (poor interferon-responsiveness), treatment
with the combination of Victrelis with peginterferon alfa-2b and ribavirin resulted in SVR rates of
2838%, respectively, compared to 4% in patients treated with standard of care.

Response-guided therapy based on TW 8 response is equally effective as adding Victrelis to the 48-week
standard of care regimen. Fifty-seven percent (208/368) of subjects in the Victrelis-RGT arm had
undetectable HCV-RNA at TW 8 (early responders). After accounting for treatment discontinuations, 44%
(162/368) of subjects reached TW 24 and were assigned a short (28 weeks) treatment with Victrelis in
combination with peginterferon alfa-2b and ribavirin in the Victrelis-RGT arm. These Victrelis-RGT early
responders demonstrated similar SVR rates (156/162 or 96%) after 28 weeks of treatment compared with
the matched population in the Victrelis-PR48 arm (e.g., those subjects in the Victrelis-PR48 arm who also
had undetectable HCV-RNA at TW 8 through TW 24) (155/161 or 96%) (see Table 6).

Similarly, subjects in the Victrelis-RGT arm with detectable HCV-RNA at any assay from TW 8 up to
TW 24, but achieving undetectable HCV-RNA at TW 24 (82/368, 22%), were considered late responders
and received an initial 4 weeks of peginterferon alfa-2b and ribavirin, then 24 weeks of Victrelis with
peginterferon alfa-2b and ribavirin followed by 20 weeks of peginterferon alfa-2b and ribavirin alone in
the Victrelis-RGT arm. These Victrelis-RGT late responders who were assigned to the Victrelis-RGT arm
that received 48 weeks of treatment also had SVR rates (72%, 59/82) that were similar to those in the
matched subjects in the Victrelis-PR48 arm (75%, 55/73) (see Table 6). Subjects in the Victrelis-RGT arm
received a total of 48 weeks of therapy with peginterferon alfa-2b and ribavirin, but only 24 weeks of
Victrelis (TW 4 to TW 28). While these late responders in the Victrelis-RGT arm continued on
peginterferon alfa-2b and ribavirin alone (plus placebo) for the last 20 weeks of therapy, subjects in the
Victrelis-PR48 arm received Victrelis plus peginterferon alfa-2b and ribavirin for 44 weeks. These data
support the concept that continued therapy with Victrelis in addition to peginterferon alfa-2b and ribavirin
standard of care after TW 28 (as executed in the Victrelis-PR48 arm) does not improve SVR rates in late
responders who receive a total of 48 weeks of peginterferon alfa-2b and ribavirin treatment.

Table 6.
Sustained Virologic Response (SVR), End of Treatment (EOT) and Relapse Rates in experimental
arms with undetectable or detectable HCV-RNA at TW 8 through TW 24 in patients who
are previously untreated in the combined cohort

Undetectable HCV-RNA
at TW 8
*

Detectable HCV-RNA
at TW 8
*

Victrelis-RGT
Victrelis-PR48 Victrelis-RGT
Victrelis-PR48
SVR
%
(n/N)
96
(156/162)
96
(155/161)
72
(59/82)
75
(55/73)
EOT (Undetectable HCV-
RNA), % (n/N)
100
(162/162)
99
(159/161)
80
(66/82)
90
(66/73)
Relapse

%
(n/N)
3
(5/161)
1
(2/157)
11
(7/66)
14
(9/64)
*
Per the study design, subjects with undetectable HCV-RNA at TW 8 and all subsequent assays
through TW 24 ended treatment at TW 28 (treatment duration assigned by Interactive Voice
Response System (IVRS).
Victrelis-RGT Subjects received peginterferon alfa-2b and ribavirin for 4 weeks, then Victrelis
800 mg three times daily + peginterferon alfa-2b and ribavirin as follows: Victrelis 800 mg three
times daily + peginterferon alfa-2b and ribavirin for 24 weeks (subjects with undetectable HCV-
RNA at TW 8 (early responders) and all subsequent assays through TW 24) or Victrelis 800 mg
three times daily + peginterferon alfa-2b and ribavirin for 24 weeks followed by placebo +
peginterferon alfa-2b and ribavirin for 20 weeks (subjects with detectable HCV-RNA at TW 8 up to
TW 24; but achieving undetectable HCV-RNA at TW 24).
93

Sustained Virologic Response (SVR): The last available value in the period at and after Follow-up
Week (FW) 24. If there is no such value, the FW 12 value was carried forward.


SVR rates in subjects in the Victrelis-RGT and Victrelis-PR48 compared to subjects receiving PR alone
with the following baseline factors were as follows: Baseline HCV-RNA > 400,000 IU/ml (62 and 65%
vs. 34%), advanced liver disease (F3/4) (41 and 52% vs. 38%), genotype 1a (59 and 62% vs. 34%), and
genotype 1b (71 and 73% vs. 40%).

Patients who have failed previous therapy
RESPOND-2 (P05101) was a randomized, parallel-group, double-blinded study comparing two
therapeutic regimens of Victrelis 800 mg orally three times daily in combination with PR [peginterferon
alfa-2b 1.5 g/kg/week subcutaneously and weight-based ribavirin (600 1,400 mg BID) orally divided
twice daily] compared to PR alone in adult subjects with chronic hepatitis C (HCV) genotype 1 infection
with demonstrated interferon responsiveness (as defined historically by a decrease in HCV-RNA viral
load 2 log10 by Week 12 or undetectable HCV-RNA at end of prior treatment with a subsequent
detectable HCV-RNA in plasma) and who failed prior treatment with peginterferon alpha and ribavirin.
Null responders (as defined historically by a decrease in HCV-RNA viral load < 2 log10 by Week 12 to
prior therapy) were excluded. Subjects were randomized in a 1:2:2 ratio and stratified based on response
to their previous qualifying regimen (relapsers vs. non-responders) and by HCV subtype (1a vs. 1b) to one
of the following treatment arms:
Peginterferon alfa-2b + ribavirin for 48 weeks (PR48).
peginterferon alfa-2b + ribavirin for 32 weeks. The subjects were then continued on different
treatment regimens based on TW 8 response-guide therapy (Victrelis-RGT). All patients in this
treatment arm were limited to 32 weeks of Victrelis.
o Subjects with undetectable HCV-RNA at TW 8 (early responders) and TW 12 completed
therapy at TW 36 visit.
o Subjects with a detectable HCV-RNA at TW 8 but subsequently undetectable at TW 12
(late responders) were changed in a blinded fashion to placebo at the TW 36 visit and
continued treatment with peginterferon alfa-2b + ribavirin for an additional 12 weeks, for
a total treatment duration of 48 weeks.
peginterferon alfa-2b + ribavirin for 44 weeks (Victrelis-PR48).

All subjects with detectable HCV-RNA in plasma at TW 12 were discontinued from treatment. Sustained
Virologic Response (SVR) to treatment was defined as undetectable
2
plasma HCV-RNA at FW 24.

The addition of Victrelis to the peginterferon alfa-2b and ribavirin therapy significantly increased the SVR
rates compared to peginterferon alfa-2b and ribavirin therapy alone (59% to 66% Victrelis-containing
arms vs. 21% PR48 control) for randomized subjects who received at least one dose of any study medicine
(Full Analysis Set population) and decreased the length of therapy to 36 weeks for many previous
treatment failures (see Table 7). A secondary analysis of subjects who received at least one dose of
Victrelis or placebo after the four week lead-in with peginterferon alfa-2b and ribavirin (Modified Intent
to Treat population) demonstrated SVR rates of 61% to 67% in the Victrelis-containing arms compared to
22% PR48 control.

Achievement of SVR was associated with the subject's response to peginterferon alfa-2b and ribavirin
therapy, whether defined by classification of response to previous treatment, or by a decrease in HCV-
RNA at TW 4 (see Table 7). The TW 4 response was a stronger predictor of SVR compared to response to
previous treatment and allowed the determination of the subject's on-treatment interferon responsiveness.

2
In clinical trials, HCV-RNA in plasma was measured with a quantitative PCR assay with a limit of detection of 9.3 IU/ml and a limit of
quantification of 25 IU/ml.

94

Table 7.
Sustained Virologic Response (SVR)
*
, End of Treatment (EOT), and Relapse
**
Rates for patients
who have failed previous therapy

Overall
Previous Treatment
Response
Lead-In Response

(Viral Load Reduction)
Previous
Non-
Responders
***

Previous
Relapsers

< 1-log10
decline
1-log10
decline
PR48 (N=80)
SVR

%
(n/N)
95% CI
21
(17/80)
(12.3, 30.2)
7
(2/29)
29
(15/51)
0
(0/12)
25
(17/67)
EOT %
(n/N)
95% CI
31
(25/80)
(21.1, 41.4)
10
(3/29)
43
(22/51)
0
(0/12)
37
(25/67)
Relapse
**
%
(n/N)
95% CI
32
(8/25)
(17.3, 50.3)
33
(1/3)
32
(7/22)
0
(0/0)
32
(8/25)
Victrelis-RGT (N=162)
SVR

%
(n/N)
95% CI
59
(95/162)
(51.5, 66.2)
40
(23/57)
69
(72/105)
33
(15/46)
73
(80/110)
EOT %
(n/N)
95% CI
70
(114/162)
(63.3, 77.4)
54
(31/57)
79
(83/105)
41
(19/46)
86
(95/110)
Relapse
**
%
(n/N)
95% CI
15
(17/111)
(8.6, 22.0)
18
(5/28)
14
(12/83)
12
(2/17)
16
(15/94)
Victrelis-PR48 (N=161)
SVR

%
(n/N)
95% CI
66
(107/161)
(59.2, 73.8)
52
(30/58)
75
(77/103)
34
(15/44)
79
(90/114)
EOT %
(n/N)
95% CI
77
(124/161)
(70.5, 83.5)
60
(35/58)
86
(89/103)
48
(21/44)
89
(101/114)
Relapse
**
%
(n/N)
95% CI
12
(14/121)
(5.9, 17.3)
14
(5/35)
10
(9/86)
25
(5/20)
9
(9/99)
*
The Full Analysis Set (FAS) consisted of all randomized subjects (N=403) who received at least
one dose of any study medicine (peginterferon alfa-2b, ribavirin, or Victrelis). Mean age of
subjects randomized was 52.7 years. The race distribution of subjects was as follows: 85%
White, 12% Black, 1% Asian, < 1% multiracial, < 1% Native Hawaiian or Other Pacific Islander.
The distribution of subjects by gender was 67% men and 33% women.
**
***
Previous Non-Responder = subject who failed to achieve SVR after at least 12 weeks of
previous treatment with peginterferon alfa-2b and ribavirin, but demonstrated a 2 log10
reduction in HCV-RNA by Week 12.

Previous Relapser = subject who failed to achieve SVR after at least 12 weeks of previous
treatment with peginterferon alfa-2b and ribavirin, but had undetectable HCV-RNA at the end of
treatment.

Eleven subjects were missing TW 4 assessment (HCV-RNA) and were not included in the Lead-
95
In response results.

Sustained Virologic Response (SVR): The last available value in the period at and after Follow-
up Week (FW) 24. If there is no such value, the FW 12 value was carried forward. SVR rates
(SVR with missing=failure approach) 17/80 [21.3%] PR48, 94/162 [58.0] Victrelis-RGT,
106/161 [65.8%] Victrelis-PR48.

Response-guided therapy based on TW 8 response is equally effective as adding Victrelis to the 48-week
standard of care regimen. Forty-six percent (74/162) of subjects in the Victrelis-RGT arm and 52%
(84/161) of subjects in the Victrelis-PR48 arm were early responders (subjects with undetectable HCV-
RNA at TW 8). Of the subjects that were early responders, 71 subjects were undetectable at TW12 in the
Victrelis-RGT arm and 81 subjects were undetectable at TW 12 in Victrelis-PR48 arm. Victrelis-RGT
early responders, who received 36 weeks of therapy (an initial 4 weeks of peginterferon alfa-2b and
ribavirin followed by 32 weeks of Victrelis with peginterferon alfa-2b and ribavirin), had an SVR rate of
86% (64/74) compared with an SVR rate of 88% (74/84) in the matched population in the Victrelis-PR48
arm who received 48 weeks of therapy (an initial 4 weeks of peginterferon alfa-2b and ribavirin followed
by 44 weeks of Victrelis with peginterferon alfa-2b and ribavirin) (see Table 8).

In subjects who were not early responders (subjects with detectable HCV-RNA at TW 8), the SVR rate in
the Victrelis-RGT arm was 40% (29/72) compared with an SVR rate of 43% (30/70) in the matched
population in the Victrelis-PR48 arm (see Table 8). Thirty-eight subjects in the Victrelis-RGT arm and
37 subjects in the Victrelis-PR48 arm had detectable HCV-RNA at TW 8 but were subsequently
undetectable at TW 12 (late responders). Victrelis-RGT late responders, who received an initial 4 weeks
of peginterferon alfa-2b and ribavirin then 32 weeks of Victrelis with peginterferon alfa-2b and ribavirin
followed by 12 weeks of peginterferon alfa-2b and ribavirin alone, had an SVR rate of 76% (29/38)
compared with an SVR rate of 62% (23/37) in the matched population in the Victrelis-PR48 arm, who
received 4 weeks of peginterferon alfa-2b and ribavirin followed by 44 weeks of Victrelis in addition to
peginterferon alfa-2b and ribavirin. These data support that, in late responders, 36 weeks of Victrelis with
peginterferon alfa-2b and ribavirin followed by 12 weeks of peginterferon alfa-2b and ribavirin is
adequate and that treatment with Victrelis may be shortened to 32 weeks in patients who have received
previous therapy.

Table 8.
Sustained Virologic Response (SVR), End of Treatment (EOT), and Relapse Rates in the
experimental arms with undetectable or detectable HCV-RNA at TW 8 in patients who
have failed previous therapy

Undetectable HCV-RNA
at TW 8
Detectable HCV-RNA
at TW 8
Victrelis-RGT
Victrelis-PR48 Victrelis-RGT
and
Victrelis-PR48
SVR
*
%,
(n/N)
86
(64/74)
88
(74/84)
40
(29/72)
43
(30/70)
EOT (Undetectable
HCV-RNA) % (n/N)
97
(72/74)
96
(81/84)
56
(40/72)
57
(40/70)
Relapse

%

(n/N)
11
(8/71)
8
(6/80)
24
(9/38)
21
(8/38)
*
Sustained Virologic Response (SVR): The last available value in the period at and
after Follow-up Week (FW) 24. If there is no such value, the FW 12 value was carried
forward.
Victrelis-RGT Subjects received peginterferon alfa-2b and ribavirin for 4 weeks,

then Victrelis 800 mg three times daily + peginterferon alfa-2b and ribavirin as
follows: Victrelis 800 mg three times daily + peginterferon alfa-2b and ribavirin for 32
weeks (subjects with undetectable HCV-RNA at TW 8 (early responders) and TW 12)
or Victrelis 800 mg three times daily + peginterferon alfa-2b and ribavirin for 32
weeks followed by placebo + peginterferon alfa-2b and ribavirin for 12 weeks
96
(subjects detectable HCV-RNA at TW 8 but subsequently negative by TW 12).

Relapse rate was the proportion of subjects with undetectable HCV-RNA at End of
Treatment (EOT) and detectable HCV-RNA at End of Follow-up (EOF) among
subjects who were undetectable at EOT and not missing End of Follow-up (EOF) data.

Includes all subjects with detectable HCV-RNA at TW 8. Late responders represent a
subset of this group, subjects with a detectable HCV-RNA at TW 8 but subsequently
undetectable at TW 12. In late responders, the SVR rate was 76% (29/38) in
Victrelis-RGT arm and 62% (23/37) in the Victrelis-PR48.

The difference in the number of subjects who achieved SVR between the Victrelis-RGT arm and the
Victrelis-PR48 arm is explained by imbalances in treatment response observed while subjects in each arm
were receiving identical therapy prior to TW 36.

SVR rates of subjects in the Victrelis-RGT and Victrelis-PR48 compared to subjects receiving
peginterferon alfa-2b and ribavirin alone with the following baseline factors were as follows: Baseline
HCV-RNA > 400,000 IU/ml (57% and 66% vs. 19%), advanced liver disease (F3/4) (44% and 68% vs.
13%), genotype 1a (53% and 64% vs. 24%), and genotype 1b (67% and 70% vs. 18%).

Use with erythropoietin in Phase III trials

Assessors comment:
This paragraph should be kept as minimal only describing the percentage of patients having received
EPO in clinical trials in both treatment arms. The guidance on how to use EPO depends on national
policies.

The use of erythropoietin was permitted with or without ribavirin dose reduction in the clinical trials in
subjects who are previously untreated and subjects who have failed previous therapy as a supportive
therapy for the management of anaemia (see sections 4.4 and 4.8). Guidelines used for erythropoietin
during clinical trials are presented in Table 9. Please refer to the Summary of Product Characteristics for
ribavirin for additional information regarding dose adjustment.

Table 9.
Guidelines used for clinical trials of erythropoietin for patients with anaemia

Haemoglobin Value Management Monitoring
< 10 g/dl Initiate erythropoietin
40,000 units subcutaneous,
weekly (long acting
formulations of erythropoietin
MUST be avoided).
After initiation of erythropoietin
therapy, weekly monitoring of
haemoglobin values is
recommended.
> 10 to < 12 g/dl If receiving erythropoietin,
reduce the dose of
erythropoietin by 25% to 50% if
haemoglobin levels increase by
> 1 g/dl within 2 weeks or
> 2 g/dl within 4 weeks.
If serum haemoglobin is stable
on 4 consecutive weekly
measures while on a stable
dosing regimen of
erythropoietin, then decrease the
monitoring of haemoglobin to
every 2 weeks, and then if stable
to every 2 to 4 weeks.
> 12 g/dl Hold the next erythropoietin
dose with subsequent tapering
of the dose to maintain target
range (10 12 g/dl).
Continue to monitor at every
4 weeks of therapy, or more
frequently if clinically indicated.

97
Across all Victrelis-containing arms and control arms in both study populations, anaemia was consistently
associated with higher SVR rates, with the majority of the anaemic subjects having received
erythropoietin to manage their anaemia. SVR rates were between 8% and 32% higher in anaemic subjects
compared to non-anaemic subjects in the Victrelis-containing arms of the two studies. SVR was also
increased in those subjects receiving erythropoietin compared to those subjects who did not receive
erythropoietin.

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Victrelis
in one or more subsets of the paediatric population in chronic viral hepatitis C (see section 4.2 for
information on paediatric use).

5.2 Pharmacokinetic properties

Absorption
Boceprevir was absorbed following oral administration with a median Tmax of 2 hours. Steady state AUC,
Cmax and Cmin increased in a less-than dose-proportional manner and individual exposures overlapped
substantially at 800 mg and 1,200 mg, suggesting diminished absorption at higher doses. Accumulation is
minimal and pharmacokinetic steady state is achieved after approximately 1 day of three times daily
dosing.

In healthy subjects who received 800 mg three times daily alone, boceprevir medicine exposure was
characterized by AUC() of 6,147 ng.hr/ml, Cmax of 1,913 ng/ml, and Cmin of 90 ng/ml. Pharmacokinetic
results were similar between healthy subjects and HCV-infected subjects.

The absolute bioavailability of Victrelis has not been studied.

Effects of food on oral absorption
Victrelis should be administered with food. Food enhanced the exposure of boceprevir by up to 60% at the
800 mg three times daily dose when administered with a meal relative to the fasting state. The
bioavailability of boceprevir is regardless of meal type (e.g., high-fat vs. low-fat) or whether taken
5 minutes prior to eating, during a meal, or immediately following completion of the meal.

Distribution
Boceprevir has a mean apparent volume of distribution (Vd/F) of approximately 772 l at steady state.
Human plasma protein binding is approximately 75% following a single dose of Victrelis 800 mg.
Boceprevir is administered as an approximately equal mixture of two diastereomers which rapidly
interconvert in plasma. At steady-state, the exposure ratio for the two diastereomers is approximately 2:1,
with the predominant diastereomer being pharmacologically active.

Biotransformation
Studies in vitro indicate that boceprevir primarily undergoes metabolism through the aldo-ketoreductase
(AKR)-mediated pathway to ketone-reduced metabolites that are inactive against HCV. After a single
800-mg oral dose of
14
C-boceprevir, the most abundant circulating metabolites were a diasteriomeric
mixture of ketone-reduced metabolites with a mean exposure approximately 4fold greater than that of
boceprevir. Boceprevir also undergoes, to a lesser extent, oxidative metabolism mediated by CYP3A4/5.

Elimination
Boceprevir is eliminated with a mean plasma half-life (t) of approximately 3.4 hours. Boceprevir has a
mean total body clearance (CL/F) of approximately 161 l/hr. Following a single 800 mg oral dose of
14
C-
boceprevir, approximately 79% and 9% of the dose was excreted in faeces and urine, respectively, with
98
approximately 8% and 3% of the dosed radiocarbon eliminated as boceprevir in faeces and urine. The data
indicate that boceprevir is eliminated primarily by the liver.

Special populations

Hepatic impairment
In a study of patients with varying degrees of stable chronic liver impairment (mild, moderate and severe),
no clinically significant differences in pharmacokinetic parameters were found, and no dose adjustment is
recommended. Victrelis, in combination with peginterferon alpha and ribavirin, is contraindicated in
cirrhotic patients with a Child-Pugh score > 6 (class B and C) (see section 4.3).

Renal impairment
No clinically significant differences in pharmacokinetic parameters were observed between patients with
end-stage renal disease (ESRD) and healthy subjects. Boceprevir is not eliminated by dialysis No dose
adjustment is required in these patients and in patients with any degree of renal impairment.

Gender
No gender-related pharmacokinetic differences in the phase III studies have been observed in adult
patients.

Race
Population pharmacokinetic analysis of Victrelis indicated that race had no apparent effect on exposure.

Age
Population pharmacokinetic analysis of Victrelis indicated that age had no apparent effect on exposure.

5.3 Preclinical safety data

In repeat-dose toxicity studies Victrelis showed testicular degeneration in rats at systemic exposures lower
than those in humans at the recommended human therapeutic dose. This is not observed in mice or
monkeys.

Victrelis was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity,
human peripheral blood lymphocyte and mouse micronucleus assays.

In 2-year carcinogenic studies, no carcinogenicity was observed, but the incidence of hepatocellular
adenomas was increased in mice at systemic exposures 5.7fold higher than those in humans at the
recommended therapeutic dose. There was no increase in incidence at the next highest dose which
corresponded to systemic exposure greater than the human exposure at the recommended 800 mg three
times daily clinical dose. No carcinomas or adenomas were observed in rats. The hepatocellular tumours
are considered due to enzyme induction and therefore not relevant for humans.

Boceprevir/medicine derived material was shown to be transferred into the milk of lactating rats. Exposure
to boceprevir in nursing human infants is estimated to be less than 1% of the dose.

In rats, boceprevir induced reversible effects on fertility and early embryonic development in female rats
at exposures 1.2-fold the human exposure at the recommended therapeutic dose of 800 mg three times
daily. Boceprevir was shown to be devoid of embryonic or teratogenic potential in both rats and rabbits at
maternotoxic dose levels. Decreased fertility was also observed in male rats, most likely as a consequence
of testicular degeneration. No testicular degeneration has been observed in mice or monkeys.

99

Rapporteurs comments
The applicant agreed on most changes proposed at D120 by the Rapporteurs. Based on the evaluation of
the applicants responses to the CHMP LOQ, the following changes are requested:
5.3 Preclinical safety data
In safety pharmacology studies, boceprevir prolonged the action potential duration with reverse use
dependency, which clinical relevance remains uncertain (see section 4.4)
In repeat-dose toxicity studies Victrelis showed testicular degeneration in rats at systemic exposures lower
than those in humans at the recommended human therapeutic dose. This is not observed in mice or
monkeys.
Victrelis was not genotoxic in a battery of in vitro or in vivo assays, including bacterial mutagenicity,
human peripheral blood lymphocyte and mouse micronucleus assays.
In 2-year carcinogenic studies, no carcinogenicity was observed, but the incidence of hepatocellular
adenomas was increased in mice at systemic exposures 5.7fold higher than those in humans at the
recommended therapeutic dose. There was no increase in incidence at the next highest dose which
corresponded to systemic exposure greater than the human exposure at the recommended 800 mg three
times daily clinical dose. No carcinomas or adenomas were observed in rats. The hepatocellular tumours
are considered due to enzyme induction and therefore not relevant for humans.
Boceprevir/medicine derived material was shown to be transferred into the milk of lactating rats. Exposure
to boceprevir in nursing human infants is estimated to be less than 1% of the dose.
In rats, boceprevir induced reversible effects on fertility and early embryonic development in female rats
at exposures 1.2-fold the human exposure at the recommended therapeutic dose of 800 mg three times
daily. Decreased fertility was also observed in male rats, most likely as a consequence of testicular
degeneration. N (no testicular degeneration has been observed in mice or monkeys). Boceprevir was
shown to be devoid of embryonic or teratogenic potential in both rats and rabbits at maternotoxic dose
levels.
Data obtained in juvenile rats suggest that the pharmacokinetic profile of boceprevir may be different than
in adult rats, possibly due to immaturity of some metabolic pathways. No clinical paediatric exposure data
is available (see section 4.2).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Capsule contents:
Sodium lauryl sulfate
Microcrystalline cellulose
Lactose monohydrate
Croscarmellose sodium
Pre-gelatinized starch
Magnesium stearate

Capsule shell
Gelatin
Titanium dioxide (E171)
Yellow iron oxide (E172)
Red iron oxide (E172)

100
Red printing ink containing:
Shellac
Red iron oxide (E172)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months at 2C 8C of which 3 months could be outside the refrigerator at or below 30C

6.4 Special precautions for storage

Storage by the pharmacist
Store in a refrigerator (2C 8C).

Storage by the patient
Store in a refrigerator (2C 8C) until expiry.
OR
Store outside of the refrigerator at or below 30C for a period of not more than 3 months until
expiry.
Store in the original blister in order to protect from moisture.

6.5 Nature and contents of container

The hard capsules are packaged in clear polychlorotrifluoroethylene /PVC/aluminium blisters containing 4
hard capsules per blister cavity. Each blister cavity is heat sealed closed with the peelable lidding in a
configuration of 3 blister cavities per blister card and packaged
7 blister cards per folding carton and 4 folding cartons per outer carton.

6.6 Special precautions for disposal

No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme Ltd
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
101

<{DD/MM/YYYY}> <{DD month YYYY}>

10. DATE OF REVISION OF THE TEXT

{MM/YYYY}

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu

102

ANNEX III

LABELLING AND PACKAGE LEAFLET

103

A. LABELLING
104

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Carton for multi-packs

Carton for individual packs


boceprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 200 mg boceprevir.

3. LIST OF EXCIPIENTS

Also contains lactose.
See package leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Multipack containing
336 (4 packs of 84) hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Oral use.
Do not push through blister.
Take with food.
Take 3 times per day; morning, afternoon and evening.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

105

8. EXPIRY DATE

EXP
Date of removal from refrigerator :
New expiry date :

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator until expiry.
OR
expiry.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

Any unused product or waste material should be disposed of in accordance with local requirements.

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

United Kingdom


EU/0/00/000/000

13. BATCH NUMBER
Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE
Victrelis
106

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING

Carton for individual packs - without blue box


boceprevir

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each hard capsule contains 200 mg boceprevir.

3. LIST OF EXCIPIENTS

Also contains lactose.
See leaflet for further information.

4. PHARMACEUTICAL FORM AND CONTENTS

Component of multipack comprosing 4 packs, each containing 84 hard capsules

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Do not push through blister.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN


7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

107
EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator until expiry.
OR
expiry.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

Any unused product or waste material should be disposed of in accordance with local requirements

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

United Kingdom


EU/0/00/000/000

13. BATCH NUMBER<, DONATION AND PRODUCT CODES>

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

Medicinal product subject to medical prescription.

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE
Victrelis
108
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

BLISTER


boceprevir

2. NAME OF THE MARKETING AUTHORISATION HOLDER


3. EXPIRY DATE

EXP

4. BATCH NUMBER<, DONATION AND PRODUCT CODES>

Lot

5. OTHER

Open here
109

B. PACKAGE LEAFLET
110
PACKAGE LEAFLET: INFORMATION FOR THE USER
boceprevir

Read all of this leaflet carefully before you start taking this medicine.
Keep this leaflet. You may need to read it again.
If you have any further questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.

In this leaflet:
1. What Victrelis is and what it is used for
2. Before you take Victrelis
3. How to take Victrelis
4. Possible side effects
5. How to store Victrelis
6. Further information

1. WHAT VICTRELIS IS AND WHAT IT IS USED FOR

What Victrelis is
Victrelis contains the active ingredient called boceprevir which acts differently than interferon medicines
to stop hepatitis C multiplication. Victrelis works with two interferon-type medicines called peginterferon
alpha and ribavirin.
Victrelis must always be used together with two other medicines. These are called peginterferon alpha and
ribavirin. Victrelis must not be used by itself.

What Victrelis is used for
Victrelis, in combination with peginterferon alpha and ribavirin, is used for chronic hepatitis C virus
infection in adults of 18 years and older (also called HCV infection).
Victrelis may be used in adults who are new to HCV infection treatment or who have previously used
medicines called interferons and pegylated interferons.

How Victrelis works
Victrelis works by lowering the amount of HCV in your body.
Victrelis, in combination with peginterferon alpha and ribavirin, is contraindicated in:
Co-administration with medicines that are highly dependent on CYP3A4/5 for clearance, and for
which elevated plasma concentrations are associated with serious and/or life-threatening events
such as orally administered midazolam and triazolam, amiodarone, bepridil, pimozide,
propafenone, quinidine, lumefantrine, halofantrine, tyrosine kinase inhibitors, and ergot
derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine).

2. BEFORE YOU TAKE VICTRELIS

Do not take Victrelis in combination with peginterferon alpha and ribavirin if you:
are allergic (hypersensitive) to boceprevir or any of the other ingredients of Victrelis (listed in
Section 6)
are pregnant
have a serious liver problem
have a condition called autoimmune hepatitisor any other problem with your immune system
111
are taking bepridil, pimozide, oral midazolam, oral triazolam, amiodarone, propafenone, quinidine,
ergot type medicines (such as dihydro-ergotamine mesylate, ergonovine, ergotamine tartrate or
methylergonovine), lumefantrine, halofantrine, and tyrosine kinase inhibitors.
Do not take Victrelis if any of the above apply to you. If you are not sure, talk to your doctor or
pharmacist before taking Victrelis.
Reminder: Please also read the Do not use section of the Package Leaflets for peginterferon alpha and
ribavirin before you start taking Victrelis.

Take special care with Victrelis
Check with your doctor or pharmacist before taking your medicine in combination with peginterferon
alpha and ribavirin if you:
have ever had a blood problem like anaemia (Lack enough healthy red blood cells which are the
main transporters of oxygen to your organs. The body may not get enough oxygen).
have a liver problem (as well as hepatitis C infection)
have HIV (human immunodeficiency virus) or have ever had any other problems with your immune
system
If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before
taking Victrelis.

Tests
Your doctor will give you regular blood tests. These blood tests are taken for a number of reasons:
to check your blood
so your doctor knows if the treatment is working for you
to help your doctor decide how long you will be treated with Victrelis.

Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines. This
includes medicines obtained without a prescription and herbal medicines.
In particular, do not take this medicine and tell your doctor or pharmacist if you are taking any of the
following medicines:
bepridil used for heart problems
pimozide used for mental health problems
oral midazolam or oral triazolam a sedative, when given by mouth
amiodarone, propafenone or quinidine used for heart-beat problems
ergot type medicines, such as dihydro-ergotamine mesylate, ergonovine, ergotamine tartrate or
methylergonovine
lumefantrine and halofantrine anti-malaria medicines
tyrosine kinase inhibitors used as anti-cancer medicines

Do not take Victrelis if any of the above apply to you. If you are not sure, talk to your doctor or
pharmacist before taking Victrelis.

Also, tell your doctor or pharmacist if you are taking any of the following:
birth control medicines.

Pregnancy and breast-feeding
Pregnancy must be avoided due to the use with ribavirin during treatment and for 6 months after treatment
has been completed. Treated patients and their partners must use two effective forms of contraceptive
methods when boceprevir is used in combination with peginterferon alpha and ribavirin.

112
Reminder: Please also read the Pregnancy and breast-feeding section of the Package Leaflets for
peginterferon alpha and ribavirin before you start taking Victrelis.

Driving and using machines
Victrelis does not affect your ability to drive or use tools or machines. However, peginterferon alpha may
make you feel tired, sleepy or confused. If this happens, do not drive or use any tools or machines.
Important information about some of the ingredients of Victrelis
Victrelis contains lactose (a type of sugar). If you have been told by your doctor that you cannot tolerate or
digest some sugars (have an intolerance to some sugars), such as Lapp lactase deficiency, or glucose
galactose malabsorption, talk to your doctor before taking this medicine.

3. HOW TO TAKE VICTRELIS

Always take Victrelis exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.

How much to take
The usual dose of Victrelis is 4 capsules three times a day (a total of 12 capsules a day). Take the capsules
in the morning, the afternoon and the evening with a meal or light snack.

How to take this medicine
Peel back the tab to get to the capsule - do not push the capsule through the blister.
Take this medicine by mouth.
This medicine should be taken with a meal or light snack.

Reminder: Please also read the Undesirable Effects section of the SmPC for peginterferon alpha and
ribavirin before you start taking Victrelis.

If you take more Victrelis than you should
If you take more Victrelis than you should, talk to a doctor or go to the nearest hospital emergency room
straight away.

If you forget to take Victrelis
If you forget a dose and it is more than 2 hours before your next dose is due, take the missed dose
with food. Then continue taking your capsules as normal.
However, if it is less than 2 hours before your next dose is due, skip the missed dose.
Do not take a double dose to make up for a forgotten dose.
If you have any questions about what to do, talk to your doctor.

If you stop taking Victrelis
Do not stop taking Victrelis unless your doctor tells you to.
If you have any further questions on the use of this product, ask your doctor or pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all medicines, Victrelis can cause side effects, although not everybody gets them. The following side
effects may happen with this medicine:
Stop taking Victrelis and see a doctor straight away if you notice any of the following serious side
effects you may need urgent medical treatment:
difficulty breathing, wheezing or hives these are signs of an allergic reaction.

Other side effects include:
Very common (affects more than 1 in 10 people)
113
General: headache; chills, fever; feeling sick (nausea); feeling dizzy; not being able to sleep; low
appetite, weight loss; shortness of breath
Mouth, nose or throat: cough; dry mouth; funny taste
Skin and hair: dry skin, flu-like symptoms, itching, rash; hair loss or thining of hair
Joints and muscles: unusual weakness; painful, swollen joints; muscle ache not caused by exercise
Stomach and gut: diarrhoea; being sick (vomiting)
Mental illness: feeling anxious; feeling of deep sadness or being of no worth; feeling irritable, tense
and restless
Blood: drop in the number of red blood cells the signs may include feeling tired, headaches, being
short of breath when exercising; low number of white blood cells the signs may include
getting more infections than usual - including fever, severe chills, a sore throat or mouth
ulcers

Common (affects less than 1 in 10 people)
General: shaking; fainting; difficulty breathing, low energy; feeling thirsty; trouble sleeping;
throbbing headache; generally feeling unwell; feeling like you are spinning
Eyes or ears: dry eyes; ringing in the ears; changes in your vision
Mouth, nose or throat: mouth pain, tooth ache; pain when swallowing; nose bleed, stuffy nose; a
change in how things smell; sore and raised patches in the mouth; feeling
very thirsty with a dry mouth or dry skin; swelling of the thyroid gland,
neck or voicebox; sores or swelling in the mouth, burning feeling on the
tongue; feeling of tension or fullness in the nose, cheeks and behind the
eyes - sometimes with a throbbing ache, fever or stuffy nose
Skin and hair: cold sores, tingling or numbness of the skin; reduced feeling or sense of touch; skin
rash, patchy skin rash, red skin; red raised skin rash sometimes with pus-filled
blisters; hot, tender and red skin, sometimes with fever and chills; skin disease
with thick patches of red skin often with silvery scales
Joints and muscles: muscle spasm; feeling tired, muscle weakness, feeling cold; back pain, neck
pain, pain in the arms or legs
Stomach and gut: pain in stomach and in the upper right side of the stomach or back; a burning
feeling in the stomach, upset stomach; feeling bloated, burping (belching)
Anus: wind (flatulence); piles (haemorrhoids); difficulty passing stools (faeces)
Urinary: going to the toilet to pass water more than usual
Sexual: a decrease in sex drive; difficulty getting or keeping an erection
Mental illness: changes in mood, feeling agitated; memory loss, trouble concentrating
Chest: difficulty breathing; chest discomfort, chest pain; heavy feeling in the chest, with difficulty
breathing or wheezing
Heart or circulation: fast or uneven heart-beat; high or low blood pressure
Blood: drop in the number of blood platelets the signs may include bleeding or bruising more
easily than usual

Uncommon (affects less than 1 in 100 people)
General: fainting; light-headedness, arthritis; tendency to bleed; swollen glands in neck or armpit
or groin; intense burning or stabbing pain; increased sensitivity to light, sound, what is
felt, or food one tastes
Eyes or ears: pink eye; eye pain; cannot hear; trouble hearing; swelling around the eyelid;
increased tearing; draining from the ear or eye; abnormal feeling around the eye, red
patch on the white of an eye
Mouth, nose or throat: hoarseness, dry throat or lips; painful or bleeding gums; sensitive tooth or
toothache; tongue swollen, discoloured, or has sores; blistering by the
tongue; severe pain when swallowing; chest pain close to the lungs; chest
pain worsens when taking a deep breath; uncontrolled salivating, yellow
eyes
Skin and hair: hives; increased sweating; open sore; intolerance to heat; markedly red face; pale
face; yellow skin; rash due to sunlight; wound does not heal normally
114
Feet or hands or legs or arms: sensation of pain, numbness, tingling or prickling; blood clot in a
vein; feeling cold in an arm or leg
Stomach and gut: lower stomach pain; pancreatitis
Urinary: painful when urinating (pass water); burning feeling or difficulty urinating; get up several
times during the night to urinate
Rectum or anus: anal itching; cannot pass stools or discoloured stools; more frequent bowel
movements; haemorrhoids or bleeding from anus
Sexual: missing menstrual period; heavy or prolonged menstrual period; uterine bleeding
Mental illness: anger; hostile attitude or behaviour; threatening behaviour; abnormal behaviour;
feeling of confusion; thoughts of suicide; sudden intense fear or apprehension;
feeling you are being persecuted; difficulty solving problems
Muscles: pain in your bones; local or widespread pain
Chest: pneumonia
Heart or circulation: abnormal or rapid heart rate; heart disease caused by poor blood flow in the
heart
Blood: high potassium levels in your blood

Rare (affects less than 1 in 1,000 people)
General: difficult breathing and swallowing; tumour of the thyroid; infection of the blood; swelling
or lumps in organs of the body; disease which leads to increasing muscle paralysis;
disease of the brain signs may include headache and fever, paralysis of a part of the
body, a stiff neck or being sensitive to light
Eyes or ears: ear ache; poor vision or blurred vision
Skin and hair: reddening of the skin; bacterial skin infection
Stomach and gut: problems digesting food; vomiting blood; diarrhoea, cramps or severe stomach
(abdominal) pain
Sexual: drop in levels of sperm
Mental illness: changes in mood; medicine abuse problems; feeling like your life is falling apart;
seeing, feeling or hearing things that are not real; thoughts of killing yourself
(suicide), trying to kill yourself; feeling of great happiness (mania) and then a
feeling of deep sadness or not being worthy
Chest: being short of breath when lying flat; serious lung infection like pneumonia; sharp chest
pains which are worse when breathing; pain behind breast bone which can spread to neck
and shoulders
Heart or circulation: heart attack; stopping breathing; blood clot in the leg or arm; decreased blood
flow to parts of the brain

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.

5. HOW TO STORE VICTRELIS


Do not use Victrelis after the expiry date which is stated on the label after EXP. The expiry date refers to
the last day of that month.

Storage by the pharmacist
Store in a refrigerator (2C 8C).

Storage by the patient
.Store in a refrigerator (2C 8C) until expiry.
OR
expiry.
115

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help protect the environment.

6. FURTHER INFORMATION

What Victrelis contains
The active substance is boceprevir. Each hard capsule contains 200 mg of the boceprevir.
The other ingredients are sodium lauryl sulfate, microcrystalline cellulose, lactose monohydrate,
croscarmellose sodium, pre-gelatinized starch, magnesium stearate, yellow iron oxide (E 172), red
iron oxide (E 172), titanium dioxide (E171), gelatin, and shellac.

What Victrelis looks like and contents of the pack

The hard capsules have a yellowish-brown cap with the "MSD" logo printed in red ink and an off-white
body with "314" printed in red ink.
Peelable blisters containing 12 hard capsules (3x4 capsule blister strip).
7 blisters per folding carton and 4 folding cartons per outer carton.

Marketing Authorisation Holder Manufacturer
Merck Sharp & Dohme Ltd S-P Labo NV
Hertford Road, Hoddesdon Industriepark 30
Hertfordshire B-2220 Heist-op-den-Berg
EN11 9BU Belgium
United Kingdom

For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:

Belgique/Belgi/Belgien
MSD Belgium SPRL/BVBA
Succursale belge/Belgisch bijhuis
Tl/Tel: +32 (0) 800 38693
MSDBelgium_info@merck.com

Luxembourg/Luxemburg
MSD Belgium SPRL/BVBA
Succursale belge
Tl: +32 (0) 800 38693
MSDBelgium_info@merck.com

.: +359 2 819 3737
info-msdbg@merck.com

Magyarorszg
MSD Magyarorszg Kft.
Tel.: +361 888 53 00
hungary_msd@merck.com

esk republika
Merck Sharp & Dohme IDEA, Inc., org. sl.
Tel.: +420 233 010 111
msd_cr@merck.com

Malta
Merck Sharp & Dohme Cyprus Limited
Tel: +357 22866700
malta_info@merck.com

116
Danmark
MSD Danmark ApS
Tlf: +45 4482 4000
dkmail@merck.dk

Nederland
Merck Sharp & Dohme B.V.
Tel: +31 (0) 800 9999000
(+31 (0) 23 5153153)
medicalinfo.nl@merck.com

Deutschland
MSD SHARP & DOHME GMBH
Tel: +49 (0) 89 4561 2612
Infocenter@msd.de

Norge
MSD (Norge) AS
Tlf: +47 32 20 73 00
msdnorge@msd.no

Eesti
Merck Sharp & Dohme O
Tel.: +372 613 9750
msdeesti@merck.com

sterreich
Merck Sharp & Dohme G.m.b.H.
Tel: +43 (0) 1 26 044
msd-medizin@merck.com

E
MSD .....
: +30 210 98 97 300
cora.greece.gragcm@merck.com

Polska
MSD Polska Sp.z o.o.
Tel.: +48 22 549 51 00
msdpolska@merck.com

Espaa
Merck Sharp & Dohme de Espaa, S.A.
Tel: +34 91 321 06 00
Victrelis@msd.es
Portugal
Merck Sharp & Dohme, Lda
Tel: +351 21 4465700
clic@merck.com

France
34 avenue Lonard de Vinci
F-92400 Courbevoie
Tl: + 33-(0)1 80 46 40 40

Romnia
Merck Sharp & Dohme Romania S.R.L.
Tel: + 4021 529 29 00
msdromania@merck.com

Ireland
Merck Sharp and Dohme Ireland (Human Health)
Limited
Tel: +353 (0)1 2998700
medinfo_ireland@merck.com

Slovenija
Merck Sharp & Dohme, s.r.o.
Tel: + 386 1 5204201
msd.slovenia@merck.com

sland
Vistor hf.
Smi: +354 535 7000
ISmail@merck.com

Slovensk republika
Merck Sharp & Dohme IDEA, Inc.
Tel.: +421 2 58282010
msd_sk@merck.com

talia
MSD Italia S.r.l.
Tel: +39 06 361911
doccen@merck.com

Suomi/Finland
MSD Finland Oy
Puh/Tel: +358 (0) 9 804650
info@msd.fi

Merck Sharp & Dohme Cyprus Limited
: +800 00 673
(+357 22866700)

Sverige
Merck Sharp & Dohme (Sweden) AB
Tel: +46 (0) 8 626 1400
medicinskinfo@merck.com

117
Latvija
SIA Merck Sharp & Dohme Latvija
Tel: +371 67364 224
msd_lv@merck.com.

United Kingdom
Merck Sharp and Dohme Limited
Tel: +44 (0) 1992 467272
medicalinformationuk@merck.com

Lietuva
UAB Merck Sharp & Dohme
Tel.: +370 5 278 02 47
msd_lietuva@merck.com

This leaflet was last approved in {MM/YYYY}

Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu

03 - Rapport FR-PB J150

Transféré par

Informations du document

Titre original

Copyright

Formats disponibles

Partager ce document

Partager ou intégrer le document

Options de partage

Avez-vous trouvé ce document utile ?

Ce contenu est-il inapproprié ?

Droits d'auteur :

Formats disponibles

03 - Rapport FR-PB J150

Transféré par

Droits d'auteur :

Formats disponibles

JOINT RAPPORTEURS

Assessment Report on the Applicants responses to the

assay with a limit of detection of

assay with a limit of detection of

Rates for patients who

Victrelis-RGT Subjects received peginterferon alfa-2b and ribavirin for 4 weeks,

Vous aimerez peut-être aussi