62574

CONFIDENTIAL
NATIONAL INSTITUTE FOR HEALTH AND CLINICAL

EXCELLENCE
Premeeting briefing
Pegloticase for treating severe debilitating chronic
tophaceous gout
This premeeting briefing is a summary of:
the evidence and views submitted by the manufacturer, the consultees and
their nominated clinical specialists and patient experts and
the Evidence Review Group (ERG) report.
It highlights key issues for discussion at the first Appraisal Committee meeting
and should be read with the full supporting documents for this appraisal.
Please note that this document is a summary of the information available
before the manufacturer has checked the ERG report for factual inaccuracies.
Key issues for consideration

Clinical effectiveness
The manufacturers submission presented a treatment pathway based on
British Society for Rheumatology (BSR) guidelines and the European
League Against Rheumatism (EULAR) guidelines. It stated that, in patients
whose serum uric acid has not normalised and whose signs and symptoms
are inadequately controlled with xanthine oxidase inhibitors at the
maximum medically appropriate dose, or for whom these medicines are
contraindicated, current standard care is best supportive care consisting of
non-steroidal anti-inflammatories (NSAIDs), colchicine and corticosteroids.
The Evidence Review Group (ERG) and the its clinical advisers agreed
with the manufacturer that pegloticase is likely to be implemented in clinical
practice only after the first 2 lines of treatment recommended in the BSR
and EULAR guidelines (xanthine oxidase inhibitors and uricosurics) have
been exhausted. Does the Committee agree that best supportive care is
the only available treatment in clinical practice for the patient population
likely to be covered in the UK marketing authorisation for pegloticase?
National Institute for Health and Clinical Excellence
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Premeeting briefing Pegloticase for treating severe debilitating chronic tophaceous gout
Issue date: November 2012
CONFIDENTIAL
Given that:
The professional groups highlighted that allopurinol intolerance is often
wrongly diagnosed in clinical practice, without appropriate titration of
dosage or any attempt of desensitisation.
Patients in the trial population described in the manufacturers
submission either couldnt have allopurinol because it was
contraindicated or their uric acid levels had not normalised despite 3 or
more months of treatment with the maximum medically appropriate dose
determined by the treating clinician.
The ERG stated that it was not clear from the manufacturers submission
whether desensitisation to allopurinol hypersensitivity had been
attempted before trial entry.
Does the Committee consider that the results of these trials can be
generalised to clinical practice in the NHS in England and Wales?
Clinical effectiveness evidence in the manufacturers submission was
based predominantly on the findings from simple pooled analyses of
primary and secondary efficacy data from 2 phase III trials. The
manufacturer stated that because these trials were replicates, a metaanalysis of the combined estimate of effects would not be appropriate. But
the ERG pointed out that simple pooling of data may yield counterintuitive
results. Does the Committee consider simple pooling of outcome data
acceptable?
The manufacturers submission stated that that there were no unexpected
imbalances in drop-outs between groups in the trials. But the ERG
highlighted that in the 2 key trials a higher proportion of patients in the
pegloticase every 2 weeks arms had dropped out at the end of the study
(30% in trial C0405 and 28% in trial C0406) than in the placebo arms (5%
in trial C0405 and 13% in trial C0406). The ERG stated that the
manufacturer did not explain or adjust for the imbalances in these the dropout rates, particularly in the patients who dropped out because of adverse
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events in both trials. Does the Committee think that this dropout may have
biased the results?
According to the manufacturers submission, one of the inclusion criteria
used to define chronic refractory gout in the phase III trials was gouty
arthritis, while in the published results from the trials (Sundy et al., 2011),
it was referred to as gouty arthropathy . At clarification stage the
manufacturer stated that gouty arthritis was used as an eligibility criterion,
but that the term gouty arthritis was not defined. It was left to the clinical
judgement of the investigator to decide whether or not the patient had this
condition. The ERG stated that it was unclear how gouty arthritis was
defined and applied as one of the inclusion criteria in the key clinical trials.
The marketing authorisation for pegloticase is for the treatment of severe
debilitating chronic tophaceous gout in adult patients who may also have
erosive joint involvement. Does the Committee consider that these terms
(gouty arthritis, gouty arthropathy or erosive joint involvement) refer to the
same condition?
In one treatment arm of the phase III trials patients were given pegloticase
8 mg every 2 weeks. The ERG stated that the impact of repeated courses
of pegloticase on uric acid levels, secondary outcomes, immunogenicity
and adverse events was not clear from the clinical effectiveness evidence
in the manufacturers submission. What is the Committees view on the
possible loss of efficacy and increased risk of adverse events because of
pegloticases potential immunogenicity?
Cost-effectiveness
In the manufacturers economic model, patients receiving pegloticase are
separated into responder, non-responder and non-completer groups.
The manufacturers submission stated that the primary reason for patients
becoming non-completers was adverse events and in clinical practice this
would occur within the first month of treatment. Data from the trials on the
proportion of non-completers who had withdrawn from pegloticase
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treatment by one month and the time to treatment cessation for noncompleters were unavailable. The ERG stated that it was uncertain how
patients in the non-completer groups would be identified in clinical
practice. What is the Committees view on this group in light of UK clinical
practice?
In the manufacturers health economic model it is assumed that the
maximum duration of pegloticase treatment would be 6 months. But data
from an open-label extension study of the patients included in the phase III
trials suggest average treatment duration of ************** in pegloticase
responders. Does the Committee accept that pegloticase would not be
used for more than 6 months in UK clinical practice?
The economic model presented in the manufacturers submission assumes
that the benefits of pegloticase treatment to responders during the 6-month
treatment period can be maintained in the long-term by allopurinol or
febuxostat treatment. The manufacturer did not provide direct clinical
evidence to support a maintained treatment effect using these treatments.
The ERG considered that this was an area of substantial uncertainty
because there was no direct evidence about effectiveness of maintenance
treatment. What is the Committees view on this uncertainty?
In the manufacturers model, persistence with maintenance treatment
(allopurinol or febuxostat) after pegloticase treatment in responders was
extrapolated based on indirect evidence. The ERG noted that 34% of the
incremental quality-adjusted life year (QALY) gains were accrued more
than 10 years after pegloticase treatment and the incremental costeffectiveness ratio (ICER) was sensitive to the discontinuation rate of
maintenance treatment. Does the Committee think the assumption about
persistence with maintenance treatment in the model is justifiable?
The ERG noted that treatment effectiveness is captured in the model by
patient-related outcomes including serum uric acid, frequency of gouty
flares and tophi resolution. Does the Committee think that a lower serum
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uric acid level could result in additional utility benefits over and above that
associated with reduced gout flares and tophi resolution?
The manufacturers model made assumptions about rheumatology visits,
accident and emergency visits and hospital admissions associated with
higher levels of serum uric acid. Does the Committee consider that
resource use would be higher with higher serum uric acid levels over and
above that associated with gout flares?
The manufacturers model captured treatment effectiveness by changes in
4 patient-related outcomes: serum uric acid, quality of life, frequency of
flares and tophi resolution. The ERG noted that the clinical continuation
rule in the manufacturers model differed from the definition of response
applied in the phase III trials, and that additional analyses were performed
on the trial data to inform its health economic model. Also, primary end
points in the trials were based on plasma uric acid level but while in the
manufacturers health economic model the end points were based on
serum uric acid level. What is the committees view on the data used in the
manufacturers modelling?
1
1.1
Background: clinical need and practice

Gout is a chronic, progressive and destructive condition that
causes acute, intermittent and painful attacks of arthritis in the
joints of the foot (especially the big toe), knee, hand and wrist. It is
caused by elevated uric acid levels in the blood (hyperuricaemia)
which leads to formation of monosodium urate crystals in and
around joints. Release of these crystals into the joint space
initiates an acute inflammatory response. With persistently high
levels of uric acid in the blood, gout may progress from acute
episodic attacks to a disabling, chronic, deforming arthropathy,
with destructive deposits of urate crystals (tophi) in bones, joints,
subcutaneous tissue and other organs. Renal damage may occur
because of urate crystal deposition and urinary tract stones
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composed entirely or partly of uric acid crystals. Severe gout with
recurrent flares and tophi has a significant impact on the patient
leading to pain, fatigue, progressive loss of mobility and function
and a worsening of quality of life.
1.2
The estimated prevalence of gout between 2000 and 2005 in the

UK was 1.4%. It affects more men than women. Prevalence
significantly increases with age, and was reported to be 7.3% in
men over 65, with the highest prevalence estimates in older men.
Both the incidence and prevalence of gout are increasing. This is
likely to be because of an ageing population, increasing levels of
obesity, and dietary changes. In line with the anticipated
marketing authorisation the manufacturer has estimated that ****
people in England and Wales will be eligible for treatment with
pegloticase.
1.3
Gout is treated by diet and lifestyle changes and drug treatments

tailored to risk factors and clinical stage. The aim of treatment is
to manage acute flares and, in patients with chronic gout, reduce
recurrent flares and tophi by reducing serum uric acid
concentration. Acute gout flare is self-limiting and generally lasts
for 7 to 10 days if untreated. Treatment relieves pain and speeds
recovery. Acute flares can last longer if the person has severe
gout or if the flare is inadequately managed. Drugs used to treat
acute gout flares include NSAIDs, colchicine and corticosteroids.
Practical measures such as applying ice and diet and lifestyle
changes can also help reduce the number and severity of flares.
Treatment to lower uric acid is recommended for patients with
recurrent acute episodes. The aim is to reduce serum levels to
below saturation point so the urate crystals dissolve and no new
crystals can form. The 2006 EULAR guideline recommends
reducing serum uric acid to below 360 micromol/litre while the
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British Society for Rheumatology and the British Health
Professionals in Rheumatology guideline for the management of
gout (BSR guideline) recommends a stricter target of
300 micromol/litre.
1.4
Two classes of uric acid lowering drugs are available: xanthine

oxidase inhibitors (allopurinol and febuxostat) and uricosurics
drugs (sulphinpyrazone, probenecid and benzbromarone). Both
the BSR and EULAR guidelines recommend allopurinol as a firstline treatment. Febuxostat for the management of hyperuricaemia
in people with gout (NICE technology appraisal guidance 164)
recommends febuxostat as an option for managing chronic
hyperuricaemia in gout only for people who are intolerant of
allopurinol or for whom allopurinol is contraindicated. Both the
BSR and EULAR guidelines recommend uricosuric drugs
(sulphinpyrazone, benzbromarone [BSR guideline]; probenecid
and sulphinpyrazone [EULAR guideline]) second line as an
alternative to allopurinol. There are no data to suggest that
uricosuric drugs are effective in reducing tophi in patients with
severe tophaceous gout. Currently standard care for patients
whose serum uric acid has failed to normalise and whose signs
and symptoms are inadequately controlled with xanthine oxidase
inhibitors at the maximum medically appropriate dose, or for
whom these medicines are contraindicated, is best supportive
care consisting of treatment with NSAIDs, colchicine and
corticosteroids. Best supportive care manages acute flares but
does not provide the patient with effective long-term treatment to
reduce uric acid levels and improve clinical outcomes such as
resolution of tophi.
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2
2.1
The technology
Pegloticase (Krystexxa, Savient), is a polyethylene glycol
conjugate of recombinant uricase (urate oxidase). It catalyses the
oxidation of uric acid to allantoin, which is water soluble and can
be excreted in urine resulting lowered serum uric acid.
2.2
Pegloticase does not currently have a UK marketing authorisation.

It has received a positive opinion from the Committee for
Medicinal Products for Human Use (CHMP) recommending the
granting of a marketing authorisation for: The treatment of severe
debilitating chronic tophaceous gout in adult patients who may
also have erosive joint involvement and who have failed to
normalise serum uric acid with xanthine oxidase inhibitors at the
maximum medically appropriate dose, or for whom these
medicines are contraindicated.
2.3
The recommended dose of pegloticase is 8 mg given as an

intravenous infusion every 2 weeks. Before starting treatment with
pegloticase, patients should stop taking oral urate-lowering
medication. To minimise the risk of infusion-related reactions,
patients should receive pre-medication such as an antihistamine
the evening before, and again approximately 30 minutes before
the infusion. They should also take paracetamol and a
corticosteroid immediately before each infusion. The serum uric
acid level should be monitored before each infusion. Pegloticase
should be stopped if the patient has 2 consecutive serum uric acid
levels above 6 mg/dl (360 micromol/litre). Pegloticases optimal
treatment duration has not been established. Treatment duration
should be based on maintenance of response (serum uric acid
levels below 6.0 mg/dl) and clinical judgment.
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2.4
The summary of product characteristics lists the following most

common adverse reactions for pegloticase: infusion-related
reactions, gout flare, nausea, dermatitis, urticaria, pruritus, skin
irritation, dry skin, anaphylaxis, influenza-like illness, joint
swelling, vomiting, hyperglycaemia, hyperkalaemia, cellulitis and
haemolysis. For full details of adverse reactions and
contraindications, see the draft summary of product
characteristics (appendix 1of the manufacturers submission).
2.5
The acquisition cost of pegloticase has not been finalised. The

anticipated price for a single vial containing 8 mg of pegloticase
concentrate for 1 infusion is 1770 (excluding VAT). The CHMPs
summary of positive opinion states: The decision to treat with
[pegloticase] should be based on an ongoing assessment of the
benefits and risks for the individual patient. The average cost of a
course of 6 months treatment, as presented in the manufacturers
submission, is estimated to be 23,010. Costs may vary in
different settings because of negotiated procurement discounts.
3
3.1
Remit and decision problem(s)

The remit from the Department of Health for this appraisal was:
To appraise the clinical and cost effectiveness of pegloticase
within its licensed indication for the treatment of hyperuricaemia in
people with symptomatic gout whose disease is refractory to
conventional urate-lowering therapy, or in whom conventional
urate-lowering therapy is contraindicated or not tolerated.
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Population
3.2
Final scope issued by NICE
Decision problem addressed in the

submission
Adults with hyperuricaemia and

symptomatic gout whose
disease is refractory to
conventional urate-lowering
therapy or in whom
conventional urate-lowering
therapy is contraindicated or not
tolerated.
Adult patients with severe debilitating

chronic tophaceous gout who have
failed to normalise serum uric acid with
xanthine oxidase inhibitors at the
maximum medically appropriate dose,
or for whom these medicines are
contraindicated.
The population in the decision problem addressed in the

submission is more restrictive than the final scope. The
manufacturer highlighted that the likely anticipated indication was
a small subset of the refractory chronic gout population defined in
the scope. The CHMP positive opinion has a further restrictive
clause that treatment should be in adult patients who may also
have erosive joint involvement. But this clause isnt included in
the description of the population addressed in the submission.
The ERG did not have any major concerns with the
generalisability of trial populations to UK clinical practice.
However, it noted that the terms gouty arthritis and gouty
arthropathy had not been defined in the trials and also that it was
not clear whether these terms indicate erosive joint involvement.
The ERG also noted that in the phase III trials patients either
couldnt have allopurinol because it was contraindicated or their
uric acid levels had failed to normalise despite 3 or more months
of treatment with the maximum medically appropriate dose
(determined by the treating doctor). The ERG noted that it was
unclear from the manufacturers submission whether
desensitisation to allopurinol hypersensitivity had been attempted
before trial entry because no data were available on the maximum
doses or duration of previous urate-lowering treatments.

submission
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Intervention
3.3
Pegloticase
The manufacturer submission stated that, while the phase III trials
were 6 months long, the optimal treatment course has not been
established. It stated that treatment duration should be based on
a maintained response (serum uric acid below 360 micromol/litre)
and clinical judgement. The manufacturer estimated that the
average length of a course of pegloticase treatment for patients
whose condition responded to treatment (and who maintain serum
uric acid levels below 360 micromol/litre was 6 months. The
treatment duration for patients whose condition did not respond to
pegloticase treatment was estimated as 2 months. The average
duration of treatment across all patients receiving pegloticase was
estimated by the manufacturer to be 4 months. The manufacturer
also reported that no information was available about the
anticipated number of repeat courses and treatments that may be
needed by patients receiving pegloticase and that the intervals
between treatments would be patient dependent. Further details
received at clarification stage on time to treatment stopping
across all pegloticase trials suggests average treatment duration
of around ******* in pegloticase responders.
Comparators

submission
The standard comparators to be

considered include:
Best supportive care
Best supportive care.

Febuxostat for adults who
are intolerant to allopurinol
or for whom allopurinol is
contraindicated.
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3.4
The manufacturer stated that febuxostat is not an appropriate

comparator because patients whose serum uric acid normalises
with febuxostat (which is a xanthine oxidase inhibitor) will be
outside the licensed indication for pegloticase. The ERG pointed
out that the BSR and EULAR guidelines for the management of
gout both recommend using uricosuric drugs as a second-line
treatment after treatment with allopurinol. The ERG agreed that
uricosurics drugs are likely to be tried before pegloticase and
therefore best supportive care is an appropriate comparator for
the population likely to receive pegloticase in clinical practice.
Outcomes
The outcome measures to be

considered include:
Serum and plasma urate levels

Gout flares
serum urate levels
Tophus resolution
gout flares
Pain
reduction in tophus
Tender and swollen joint count
pain
Physical function
tender and swollen joint
Adverse effects of treatment
physical function
Health related quality of life (Health

Assessment Questionnaire [HAQ],
HAQ disability index and SF-36)
adverse effects of treatment

health-related quality of life.
3.5

submission
The manufacturers submission included both serum and plasma

urate levels as the primary outcomes. Plasma uric acid was
preferred over serum uric acid as the primary outcome. This is
because during serum processing pegloticase could cause
enzymatic degradation of the uric acid in blood samples left at
room temperature, resulting in inaccurately low uric acid levels.
This does not happen when plasma is used to measure plasma
uric acid levels because the processing conditions limit the
enzymatic activity of pegloticase. The methods used to measure
plasma and serum uric acid levels were described by the
manufacturer as validated methods available in clinical
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laboratories. The manufacturer tested the observed plasma and
serum uric acid for agreement using the kappa coefficient and
obtained a value of 0.74 (p<0.001), on a scale of 0 to 1 (0
indicating no agreement and 1 indicating complete agreement
between methods).

Economic
evaluation
3.6
The reference case stipulates

that the cost effectiveness of
treatments should be expressed
in terms of incremental cost per
quality-adjusted life year.
The reference case stipulates
that the time horizon for
estimating clinical and cost
effectiveness should be
sufficiently long to reflect any
differences in costs or
outcomes between the
technologies being compared.
Costs will be considered from
an NHS and personal social
services perspective.

submission
Cost-effectiveness is presented as
an incremental cost per qualityadjusted life year (QALY).
Comparator is best supportive care
with clinical outcomes based on 2
phase III clinical trials of
pegloticase compared with
placebo.
The time horizon for modelling is a
life time but with shorter timelines
explored.
Perspective: NHS and personal social
services
The ERG identified no significant deviations from the NICE

reference case although some of the data sources used in the
health economic analysis were poorly described. The
manufacturers revised health economic model submitted at
clarification stage, which incorporated appropriate treatment
pathways for patients for whom allopurinol or febuxostat are
contraindicated or who are intolerant of them, was considered by
the ERG to address the decision problem as specified in the
scope.
4
4.1
Clinical-effectiveness evidence
The systematic review conducted by the manufacturer identified a
single published journal article and 6 conference abstracts. The
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published article (Sundy et al. 2011) presented the results of
2 phase III trials of pegloticase: C0405 and C0406. The abstracts
presented data on some aspects of these trials and an open-label
extension study C0407. Data from the abstracts were not included
in the submission. The clinical data presented in the submission
were from the published article, an internal report on the
integrated summary of efficacy of these trials as well as an
unpublished clinical study report of open-label extension safety
study (C0407).
4.2
C0405 and C0406 were identical, randomised, double-blind,

placebo-controlled, multicentre, 3-armed trials of 6 months
duration conducted in the USA and Canada (C0405) and the USA
and Mexico (C0406). The trial patients were 18 years or older,
had a baseline serum uric acid level of at least 480 micromol/litre
and at least 1 of the following criteria: 3 or more self-reported gout
flares during the previous 18 months; 1 or more tophi; and gouty
arthropathy (clinical or radiographic evidence of joint damage due
to gout). Patients also had to either have a contraindication to
treatment with allopurinol or their uric acid levels must have failed
to normalise despite 3 or more months of treatment with the
maximum medically appropriate allopurinol dose (determined by
the treating doctor). Exclusion criteria were glucose-6-phosphate
dehydrogenase (G6PD) deficiency, previous treatment with a
uricase-containing drug, pregnancy, unstable angina, uncontrolled
hypertension (blood pressure higher than 150/95 mm Hg) or
cardiac arrhythmia, uncompensated congestive heart failure, renal
dialysis, or solid organ transplant. Intravenous pegloticase 8 mg
every 2 weeks and intravenous pegloticase 8 mg every 4 weeks
were compared with placebo. During the trial all patients received
prophylaxis against gout flare with colchicine or an NSAID, which
started 1 week before the first infusion of pegloticase and
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continued throughout the trial. Patients also received prophylaxis
against infusion reactions with oral fexofenadine 60 mg the
evening before each infusion, 60 mg oral fexofenadine and 1 g
oral paracetamol the morning of the infusion and intravenous
hydrocortisone 200 mg immediately before each infusion.
Although the trials included 2 pegloticase dosing regimens (8 mg
every 2 weeks or every 4 weeks) only the results of the patients
receiving the anticipated licensed dose (pegloticase 8 mg every
2 weeks) were included for the estimate of efficacy in the
submission.
4.3
The primary outcome was the proportion of patients whose

plasma uric acid responded to treatment in each pegloticase
treatment group compared with placebo. In the trials, a responder
was defined as a patient with a plasma uric acid level below
360 micromol/litre for at least 80% of the time during months 3
and 6. Plasma uric acid level was measured at baseline and 2
and 24 hours after the first infusion, before each biweekly infusion
and at 5 additional prespecified time points in month 3 and month
6 (2 hours, 1 day and 7 days after the week 9 and week 21
infusions and 2 hours and 7 days after the week 11 and week 23
infusions).
4.4
Secondary end points were assessed at baseline, week 13,

week 19 and week 25 and included resolution of tophi (defined as
a 100% decrease in area of at least 1 prespecified target tophus
without progression or appearance of a new tophus), reduction in
gout flares (frequency and incidence) and the number of flares per
patient during months 13 and 46, improvement in tender and
swollen joint count, improvement in quality of life (SF-36) and
improvement in functional status (Health assessment
questionnaire [HAQ] disability index and the HAQ pain scale).
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4.5
A total of 225 patients (109 in C0405 and 116 in C0406) were

randomised to the 3 trial groups (pegloticase every 2 weeks or
every 4 weeks, or placebo) in a 2:2:1 ratio. All urate-lowering,
clinical efficacy, and tolerability analyses (except deaths) were
carried out on a modified intent-to-treat population (n=212; 104 in
C0405 and 108 in C0406) comprising all randomised patients who
received at least 1 infusion. Baseline characteristics were similar
across the trials and treatment groups except for chronic kidney
disease (defined as a creatinine clearance below 60 ml/min),
which was markedly lower in the placebo group in C0406 (13%)
compared with the intervention groups in both the trials and the
placebo group in C0405 (2833%). Metabolic and cardiovascular
disorders were also common. More than 80% of trial patients had
cardiovascular comorbidities (see table 6.5, page 40 of the
manufacturers submission).
4.6
Plasma uric acid normalised within 24 hours of the first infusion

for all patients receiving pegloticase. But over time some patients
lost the urate-lowering response whereas others maintained a uric
acid level under 360 micromol/litre throughout the trials. The
number of responders in the treatment arms receiving 8 mg
pegloticase every 2 weeks (responders defined as patients whose
plasma uric acid level is under 360 micromol/litre for at least 80%
of the time during months 3 and 6) was 20/43 (47%) in C0405 and
16/42 (38%) in C0406. The primary end point was not achieved in
any placebo-treated patient and the results demonstrated a
significant difference for both trials (p<0.001 for each trial) as well
as for the pooled analysis (36/85 [42%] for patients receiving 8mg
pegloticase every 2 weeks compared with 0/43 [0%] for patients
receiving placebo, p<0.001).
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4.7
The results of the secondary outcomes are presented as pooled

data from the pegloticase every 2 weeks arms of the 2 trials.
Resolution of tophi was measured in patients with tophi at
baseline. The proportion with complete resolution at month 6 was
statistically significantly higher in the pegloticase treatment group
than the placebo group (21/52 [40%] and 2/27 [7%] respectively,
p=0.002). The incidence of gout flares increased in the
pegloticase treatment group compared with the placebo treatment
group during the first 3 months of treatment (64/85 [75%] and
23/43 [53%] respectively, p=0.02). But with continued treatment,
statistically significant reductions in the incidence of flares during
months 4 to 6 were seen in the pegloticase treatment group
compared with placebo (28/69 [41%] and 29/43 [67%]
respectively, p=0.007). Similarly, during the first 3 months of
treatment, flare frequency (number of flares per patient) was
statistically significantly higher (p=0.001) in the pegloticase
treatment group (mean 2.3, standard deviation [SD] 2.1) than the
placebo group (mean 1.2, SD 1.5). During months 4 to 6 there
were fewer flares per person in the pegloticase group (mean 0.8,
SD 1.2) than in the placebo group (mean 1.3, SD 1.5) but this was
not statistically significant (p=0.06).
4.8
Patients in the pegloticase group also experienced reductions in

the number of tender and swollen joints at final visit from baseline
compared with those in the placebo group. The reduction in the
average number of tender joints was statistically significant in the
pegloticase group compared with the placebo group (7.4 and
1.2 respectively, p=0.01). There was also a greater reduction in
the number of swollen joints in the pegloticase group than in the
placebo group but this was not statistically significant (5.5 and
2.6 respectively, p=0.18).
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4.9
Patient-reported outcomes were also reported to be improved with

pegloticase. Statistically significant changes from baseline in HAQ
disability index scores and SF-36 physical component summary
(PCS) scores were observed, with the changes meeting or
exceeding the established minimum clinically important
differences.
4.10
HAQ disability index was measured by administering a survey

consisting of 20 questions about various physical activities
including activities of daily living. The patients were asked to
score their functional ability from 0 (no difficulty) to 3 (unable to do
without help or use of aids). The individual scores were averaged
to obtain a final score between 0 and 3. The mean change in the
HAQ disability index scores from 13 months to the final visit in
the pegloticase group was 0.22 (SD 0.64) compared with 0.02
(SD 0.41) for the placebo group. This was statistically significant
(p=0.01). The minimum clinically important difference reported in
the literature on the HAQ disability index for inflammatory arthritis
is 0.22.
4.11
The HAQ pain score was measured on a visual analogue scale

from 0 to 100 mm. The pain score at baseline was lower in the
pegloticase group (44.2 [SD 27.7]) than the placebo group (53.9
[SD 28.1]) although the difference was not statistically significant
(p=0.07). The reduction in pain score at final visit in the
pegloticase group was 11.4 (SD 33.8), which was greater than
the minimum clinically important difference for inflammatory
arthritis reported in the literature (0.10) as well statistically
significantly better (p=0.03) than the change in the placebo group
(1.4 [SD 30.0]).
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4.12
All patients in the pegloticase treatment group with data at

end point also reported statistically significant improvements in
their SF-36 PCS scores compared with placebo (p=0.01).
4.13
Secondary outcomes were also presented for plasma uric acid

responders compared with non-responders. Results for the
pooled analysis are in table 1. Compared with non-responders,
the responder group had a higher proportion of patients with
complete tophus response, a reduced incidence of flares during
months 1 to 3, a numerically higher reduction in the number of
swollen or tender joints and greater improvement in mean HAQ
pain and SF-36 PCS scores.
Table 1 Secondary endpoints responders compared with non-responders

(pooled analysis)
Pegloticase 8 mg every 2 weeks
Responders
Non-responders
(n=25 )
(n=37)
Resolution of tophi (as defined in section 4.4)
No. of patients/no.
evaluable patients
13/21 (61.9)
8/31 (25.8)
at final visit (%)
Flare incidence
Months 13
n/N (%)
************
************
Months 46
n/N (%)
************
************
Flare frequency per patient
Months 13
n
**
**
Mean (SD)
**********
**********
Months 46
n
**
**
Mean (SD)
**********
**********
Swollen and tender joints
n
**
**
Change from
**************
************
baseline to final
visit. Mean (SD)
HAQ pain
N
**
**
Placebo (n=29)
2/27 (7.4)
23/43 (53.5)
29/43 (67.4)
43
1.2 (1.62)
43
1.3 (1.49)
43
3.9 (22.71)
43
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Change from
**************
baseline to final
visit. Mean (SD)
HAQ disability index
N
**
Change from
*************
baseline to final
visit. Mean (SD)
SF36 physical component summary
N
**
Change from
***********
baseline to final
visit. Mean (SD)
4.14
*************
1.37 (30.04)
**
*************
43
0.02 (0.408)
**
***********
43
0.30 (8.97)
The safety data presented by the manufacturer were from a

pooled analysis of adverse events reported in patients in the
pegloticase 8 mg every 2 weeks groups in the 2 phase III trials
(C0405 and C0406), and long-term safety data from an open-label
extension study (C0407).
4.15
The pooled analysis showed that serious adverse events were

more frequent (24%) in patients in the pegloticase group than in
the placebo group (12%). Similarly, the rate of adverse events
leading to discontinuation was 18% in the pegloticase group and
2% of patients in the placebo group. The most commonly reported
adverse events were gout flare (76% in the pegloticase group and
81% in the placebo group), infusion-related reactions (26% in the
pegloticase group and 5% in the placebo group despite
prophylaxis against infusion-related reactions), headache (9% in
the pegloticase group and 9% in the placebo group), and nausea
(12% in the pegloticase group and 2% in the placebo group).
4.16
All patients who completed C0405 or C0406 were invited to

participate in the open-label extension study C0407 of up to
30 months duration. The primary objective of the open-label
extension study was to assess the long-term safety of
pegloticase. A secondary objective was to evaluate the treatment
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effects of pegloticase in patients who continued to receive active
treatment from the phase III trials and in those originally
randomised to placebo, and the duration of benefit. Outcomes
included the plasma and serum uric acid response, tophus
response, incidence and frequency of gout flares, swollen joint
count (SJC), tender joint count (TJC), SF-36, HAQ and Clinical
global assessment of disease activity.
4.17
A total of 151 patients entered the open-label extension study

(C0407). Of these patients, 57 had received pegloticase 8 mg
every 2 weeks, 53 had received pegloticase 8 mg every 4 weeks,
and 39 patients had received placebo in the previous trials.
Two patients (3%) who had previously received pegloticase 8 mg
every 4 weeks selected the option of not receiving any further
pegloticase but participated in the study for observation only.
Twenty three out of 39 patients who had received placebo in
previous trials, opted for pegloticase 8 mg every 2 weeks regimen
while remaining 16 received pegloticase 8 mg every 4 weeks in
the open-label extension study (C0407).
4.18
The regimen switches (pegloticase 8 mg every 2 weeks to every

4 weeks and vice versa) were permitted i) after week 25 and
ii) once the results of the double-blind trials were available. The
manufacturer did not provide a summary of why patients switched
and how many switched because of loss of pegloticase efficacy.
4.19
Overall safety observations in the open-label extension were

consistent with those reported in the 2 phase III trials, suggesting
no cumulative risk with continued exposure to pegloticase. Gout
flare was the most commonly reported adverse event, occurring in
71.1% of patients. But the overall percentage of patients with gout
flare decreased throughout the study, particularly in the
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responders to pegloticase treatment group. Infusion reactions
were the second most commonly reported adverse events,
occurring in 34.6% of patients. Infusion reactions were less
frequent in pegloticase responders. There were 4 deaths in the
open-label extension study, 1 (from sepsis) while receiving
pegloticase, 3 (from cellulitis/sepsis, pneumonia, worsening of
myelodysplastic disorder) at various times after the last dose of
pegloticase.
4.20
A total of 51 (34.2%) patients experienced 106 serious adverse

events across all treatment groups. Of these, 13 were considered
to be possibly or probably related to pegloticase; 11 infusion
reactions, 1 event of nephrolithiasis (kidney stone) and 1 event of
skin necrosis. The remainder were considered unlikely to be
related to the study drug and were consistent with the high degree
of pre-existing comorbidities and polypharmacy that characterised
the study population and the chronic gout refractory to
conventional treatment population more generally.
4.21
A completed non-randomised, non-controlled, open-label,

multicentre re-exposure trial (NCT00675103) (C0409) was
identified by the ERG that was not included in the manufacturers
submission. This small-scale trial evaluated efficacy and safety
outcomes in patients receiving a 24-week course of pegloticase
whose last exposure to pegloticase was at least 1 year before trial
entry. The manufacturer provided a brief synopsis of this trial,
which evaluated efficacy and safety outcomes in a small number
(n=7) of patients who were re-exposed to a subsequent course of
pegloticase treatment after an initial course of treatment.
***************************************************************************
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**.
4.22
Pre-planned subgroup analyses of the individual phase III trials

(C0405 and C0406) and of the pooled data for treatment
responder were undertaken by the manufacturer according to sex,
age (55 years or younger, older than 55 years), body mass index
(30 kg/m2 or less, more than 30 kg/m2), absence or presence of
tophi, disease duration (less than 5 years, 5 years or more), and
baseline HAQ disability index score (1 or less, more than than 1)
creatinine clearance (less than 50 ml/min, 50 ml/min or more) and
antibody status. These compared plasma uric acid responders in
the pegloticase and placebo groups using Fishers exact test (see
table 6.12 in the manufacturers submission). The manufacturer
stated that results for the pooled data did not indicate any clear
pattern or trend of improved efficacy in any subgroup.
4.23
The ERG was satisfied that all available phase III trials were
included in the submission but noted that in the two phase III trials
a higher proportion of patients in the pegloticase every 2 weeks
arms had dropped out at the end of the study (30% in C0405 and
28% in C0406) than in the placebo arms (5% in C0405 and 13%
in C0406). The ERG stated that the manufacturer did not explain
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or adjust for the imbalances in these the drop-out rates,
particularly in the patients who dropped out because of adverse
events in both trials.
4.24
The ERG highlighted the manufacturers approach of pooling data

from the two phase III trials and pointed out that simple pooling of
data may yield counterintuitive or false results and that a metaanalysis would have been a better approach to combining the
results of the 2 trials. The ERG performed a fixed and random
effects exploratory meta-analysis for plasma uric acid responder
status and tophi resolution. These outcomes were selected
because plasma uric acid responder status was the primary
efficacy outcome and tophi resolution was a key driver in the costeffectiveness model. The ERG stated that the software used to
perform exploratory meta-analysis automatically applied a
correction of 0.5 to the placebo arms of both trials if no events
were observed and noted that this may introduce uncertainty to
the results.
4.25
The ERGs meta-analysis for the primary efficacy endpoint of

plasma uric acid responder status confirmed that response was
significantly greater in the pegloticase 8 mg every 2 weeks
treatment group than the placebo group (relative risk [RR] 18.99,
95% confidence interval [CI] 2.69 to 133.94, p=0.003). When a
fixed effects model was applied, the relative risk was very similar
(RR 19.01 95% CI 2.69 to 134.24). It was not possible to calculate
a precise relative risk in the pooled data because there were no
events in the placebo arm. However, using a similar correction to
that applied in the meta-analysis (see section 4.24) the relative
risk was 37.35 (95% CI 2.35 to 549.24).
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4.26
At the clarification stage the manufacturer stated that tophi

resolution responses were conducted on the tophus-evaluable
population, which included patients with a tophus at baseline and
patients who developed new tophi during the trial. This means
that the number of tophus-evaluable patients was greater than the
number of patients with tophi at baseline. The ERG considered
that it was unclear how data relating to the total size of the
tophus-evaluable population at final visit had been derived and
why the number of patients with tophi at baseline had not been
used in the analyses of tophi resolution at final visit. So the ERG
conducted 2 separate exploratory meta-analyses for complete
tophus resolution, based on the tophus-evaluable population and
the number of patients with baseline tophi.
4.27
The results of the ERGs meta-analysis of tophus resolution

based on a tophus-evaluable population showed a relative risk of
4.17 (95% CI 1.25 to 13.92), which statistically significantly
favoured pegloticase over placebo. For comparison, the ERGs
calculation of the relative risk based on the simple pooled data
was 5.45.The ERGs exploratory meta-analysis based on number
of patients with baseline tophi generated a relative risk of 3.62
(95% CI 1.07 to 12.27). With the fixed effects model the combined
relative risk was broadly similar (RR 4.04, 95% CI 1.19 to 13.71).
The relative risk calculated for the simple pooled data was 4.91.
The ERG commented that basing the calculation on the baseline
number of patients with tophi better reflected the intention-to-treat
population than using the manufacturers preferred tophusevaluable population.
4.28
The ERG also highlighted that the impact of repeated courses of

pegloticase on uric acid levels, secondary outcomes,
immunogenicity and adverse events was not clear from the
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manufacturers submission. It stated that limited evidence from
the small scale re-exposure trial (C0409) suggested that there
***************************************************************************
****************************************************************. The
ERG also stated that it was not clear whether the benefits of
pegloticase would be maintained after pegloticase treatment
stopped or whether maintenance treatment with other uratelowering drugs would be successful in maintaining low uric acid
levels and other benefits in the long-term.
5
5.1
Comments from other consultees

Professional organisations pointed out that gout is poorly
understood and managed in primary care. GPs often fail to
properly titrate the first course of urate-lowering treatment
because of an initial increase in flare rates and incorrectly classify
patients as intolerant. In particular, allopurinol intolerance is often
reported when it has simply been associated with triggering a flare
of gout, without any attempt to perform desensitisation.
Professional and patient organisation emphasised that
desensitisation should always be tried first in patients before
categorising them as allopurinol intolerant. Uricosuric drugs like
probenecid, sulphinpyrazone and benzbromarone (used outside
their marketing authorisation but recommended by EULAR) are
rarely used in clinical practice in the UK and are considered of
limited value. Professional organisation also highlighted the
uncertainty in the evidence base about the best sequence of
treatment after allopurinol. Professional organisations stated that
adjunctive treatment with oral, intramuscular or intra-articular
corticosteroids is often overlooked in the clinical practice.
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5.2
Professional organisations stated that that the treatment of gout in

patient with significant comorbidities, for example severe kidney
disease, cardiac failure, and haematological disorders is
particularly challenging because many of the available treatments
are contraindicated in these patients. Professional organisations,
while acknowledging the lack of data, hope that pegloticase may
be particularly useful in this group of patients because of its
unique mode of action compared with existing therapies. However
they highlighted that the trials did not report on this subgroup of
patients with significant comorbidities, despite including patients
with moderate renal impairment and cardiovascular comorbidities.
5.3
Professional organisations were also concerned about the

external validity of the trial data given that the trials were relatively
short but gout is a lifelong condition. There was a particular
concern because of a potential immune response to pegloticase,
which may reduce its efficacy and cause adverse reactions.
5.4
Patients group said preventing acute episodes of gout was the

most important treatment outcome and that reducing severity of
pain, swelling, tenderness, joint erosion and the size and number
of tophi were also important treatment outcomes. In particular,
they said that reducing the severity of gout attacks may mean that
patients can conduct day-to-day activities and improve their
quality of life. But members of the patient groups had no personal
experience of pegloticase because the trials were outside the UK.
5.5
A potential disadvantage of pegloticase identified by the patient

groups was frequent intravenous infusions, which take between 2
and 4 hours each time. Patients would have to weigh up how
often attacks happen against the benefit of treatment when
deciding whether to be treated. The patient groups also
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highlighted concerns about the reported incidence of infusion
reactions (2637.5%) which led to up to 10% of patients stopping
pegloticase, and delayed hypersensitivity reactions despite
corticosteroid or antihistamine prophylaxis. The patient groups
further highlighted a high incidence of gout flare, lack of clarity
about the optimal duration of treatment and the development of
anti-pegloticase antibodies, leading to loss of efficacy. Additionally
they said there is a potential risk of cardiovascular adverse
effects, particularly in a population at increased risk of
cardiovascular disease because of the association between gout
and the metabolic syndrome.
5.6
The patient groups said they see pegloticase as a bridging option

in patients with refractory tophaceous gout, for the first 6 months
of treatment, to allow rapid resolution of tophi. Patients could then
revert to standard treatment. The patient groups also emphasised
on the need of data collection to determine long term tolerability
and toxicity.
6
6.1
Cost-effectiveness evidence
The manufacturer identified 1 economic evaluation of pegloticase
in patients with refractory chronic gout performed from a US
healthcare perspective (Wang et al. 2012) but did not consider it
relevant for this appraisal. The manufacturer therefore submitted
a de novo model comparing pegloticase with best supportive care
in patients with chronic gout refractory to xanthine oxidase
inhibitors. Each branch of the decision tree structure (see figure 1)
is coupled with a Markov model for extrapolation to the 20-year
base-case time horizon. There are 4 health states in the Markov
model based on patients serum uric acid levels:
below 360 micromol/litre
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360 or higher but below 480 micromol/litre
480 or higher but below 600 micromol/litre
600 micromol/litre or higher.
Death is also included as a Markov state in the model.
Figure 1 Decision analytical structure
6.2
In the pegloticase arm, patients are separated into responder,

non-responder and non-completer groups:
Responders are defined in the manufacturers submission as
people responding to pegloticase, that is, maintaining serum uric
acid levels below 360 micromol/litre. These patients are
assumed to gain the most clinical benefit from pegloticase. After
the treatment course with pegloticase (lasting a maximum of
6 months in the base-case analysis), patients are switched to
maintenance treatment with either allopurinol or febuxostat.
Based on the trial data of persistence with pegloticase (68%)
and response rate (60%), the manufacturer estimated that
40.8% of the cohort would be classified as responders.
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The non-responders are defined as those who discontinue
pegloticase treatment because serum uric acid levels exceed the
limit set out in the summary of product characteristics: increase
to above 360 micromole/litre on 2 consecutive observations. In
the base-case analysis, patients were assumed to be identified
as non-responders after 2 months of pegloticase treatment.
These patients, estimated to be 27.2% of original cohort, were
switched to best supportive care. Based on the clinical trial data,
it is assumed that some clinical benefit was still obtained in this
patient group.
The non-completer group was defined in the manufacturers
submission as patients who are non-persistent to pegloticase
treatment, but subsequently the manufacturer clarified that this
included patients who failed to complete the full 6 month
treatment course for any reasons, primarily due to adverse
events, but could also include other reasons such as patient
dislike of intravenous administration. These patients are
assumed to not gain any clinical benefit from pegloticase
treatment although pegloticase treatment costs are incurred. In
the base-case analysis, it was assumed that a non-completer
could be identified by 1 month of pegloticase treatment. In the
manufacturers model 32.0% of patients do not complete
pegloticase treatment and are switched to best supportive care
after 1 month.
6.3
In the manufacturers model patients in the best supportive care

arm are not treated with pegloticase. This group was modelled
from the placebo treatment group in the clinical trials.
6.4
The model assumed that all patients who respond to pegloticase

treatment will progress to maintenance treatment with either
allopurinol (70%) or febuxostat (30%). Discontinuation of
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maintenance treatment was modelled with data derived from an
observational study of allopurinol (Annemans et al. 2008) and
from a randomised trial of febuxostat (EXCEL). Patients who
discontinued maintenance treatment (non-persistent patients)
were switched to best supportive care. It was assumed that
maintenance treatment was effective in maintaining the serum
uric acid levels achieved by pegloticase treatment, and that with
non-persistence with maintenance treatment serum uric acid
levels returned to baseline levels. The probability of becoming
non-persistent on maintenance treatment, and therefore
progressing to best supportive care, was modelled using a
constant hazard for febuxostat, and a decreasing hazard for
allopurinol. The rate of discontinuation for febuxostat was derived
by taking the average proportion (434/590=26%) who were nonpersistent at the end of the 2-year EXCEL trial across the 2 doses
(80 mg/day and 120 mg/day) and assuming a constant hazard
(exponential survival curve) to convert this proportion to a monthly
rate of 1.3%, which is equivalent to an annual rate of 14%. The
rate of discontinuation for allopurinol was derived by fitting a
Weibull survival curve to retrospective 2-year observational data
from 7443 UK patients with chronic gout, of whom 89% were
receiving allopurinol. In the economic model, the manufacturer
stated that a Weibull curve was fitted to the second year of data
from the trial to reflect long-term persistence (as opposed to
persistence from the start of treatment).
6.5
The baseline characteristics of the modelled population were

defined according to age (56 years), serum uric acid level
(9.6 mg/dl) and baseline utility values (0.6) based on the baseline
demographic characteristics of the 2 phase III trials. No natural
disease progression was modelled because tophaceous gout was
considered the final stage of gout.
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6.6
Each of the responder, non-responder and non-completer groups

has a distinct set of health states with no transitions allowed
between the groups. For each of these groups, the model has
health states defined according to the treatment being given and
the serum uric acid level at that time point. In the comparator arm,
all patients receive best supportive care for the duration of the
model so the health states are defined solely according to serum
uric acid level.
6.7
The model estimated the distribution of patients across the 4

serum uric acid levels by assuming a normal distribution around
the mean serum uric acid level for each group in the pegloticase
arm (responders, non-responders, non-completers) and for the
comparator arm population as a whole. Transitions to the death
state are possible at any time and do not depend on the treatment
being given or the patients serum uric acid level and are therefore
the same across the whole population of the model.
6.8
Treatment effectiveness is captured within the model by changes

in 4 patient-related outcomes: serum uric acid, quality of life,
frequency of flares and tophi resolution. Patient-level data were
available from the 2 replicate trials (C0405 and C0406) for all
4 outcomes. Mean values for serum uric acid, frequency of flares,
tophi resolution and quality of life are presented in tables 7.2, 7.3
7.4 and 7.7 of the manufacturers submission for the pegloticase
responder, pegloticase non-responder and best supportive care
groups. No outcomes are presented for the pegloticase noncompleter group.
6.9
In the model, serum uric acid levels in responders were based on

data from the pegloticase arm for the first 6 months and then
maintained at 0.17 mg/dl during maintenance treatment. After
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patients became non-persistent with maintenance treatment,
serum uric acid levels were based on trial data from the
pegloticase non-responder group for months 6 to 12 of the model
and on the baseline level for the whole trial cohort for the
remainder of the model. Serum uric acid levels in non-responders
were based on data from non-responders in the pegloticase arm
of the trials for 2 months and then on data from the placebo arms
of the 2 phase III trials for the remaining 4 months once the
patients have progressed to best supportive care. Serum uric acid
levels in non-completers were based on data from the placebo
arms of the 2 phase III trials for the full 6 months. The baseline
serum uric acid level was modelled beyond 6 months for nonresponder and non-completer patients.
6.10
Frequency of flares in the pegloticase arm was based directly on

trial outcomes in the first 6 months for responders receiving
pegloticase. Frequency of flares in the pegloticase non-responder
group was based on trial data from non-responders for 2 months
and then estimated on the serum uric acid level once the nonresponders progress to best supportive care. Frequency of flares
in the pegloticase non-completer group was based on trial data
from the placebo arm for 1 month and then on the serum uric acid
level once the non-completer progress to best supportive care.
Frequency of flares for patients receiving best supportive care in
the comparator arm in the first 6 months was derived directly from
the trial data and later on based on the serum uric acid level.
6.11
Tophi resolution was assumed to increase linearly over the first

6 months to the level seen at month 6 in the pooled data of the
2 key trials. The resolution of tophi achieved during pegloticase
treatment was assumed to be maintained in 100% of responders
and 50% of non-responders for the entire time-horizon of the
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model. For non-completers and patients in the best supportive
care arm of the model tophi resolution achieved at 6 months in the
pooled analysis of the placebo arms of the trials was modelled
and maintained for entire time horizon of the model.
6.12
Short term utility estimates (first 6 months) were based on SF-6D

utilities derived from the SF-36 data collected in the pegloticase
phase III trials and validated against the EQ-5D. Modelled utility
values were corrected for differences in baseline utility of different
patient groups. No disutilities associated with adverse drug
reaction were included in the model. The manufacturer said this
was because utility data for the entire duration of pegloticase
treatment in the model were collected in the trial, and therefore
the disabilities associated with adverse effects would already be
captured.
6.13
Long-term utilities were based on estimates derived from

guidance on febuxostat for hyperuricaemia in gout (NICE
technology appraisal guidance 164) and Scottish Medicines
Consortium guidance (367/10) on febuxostat. These values were
based on a European observational study in chronic gout patients
with health-related quality of life and utility measured by EQ-5D
and utilities for each serum uric acid state derived by regression
analysis. The utility values applied in the model after 6 months
(and in some patients before 6 months, for instance in nonresponders after 2 months and in non-completers after 1 month)
were based on a combination of serum uric acid level, frequency
of flares and tophi resolution.
6.14
The anticipated acquisition cost of pegloticase was used in the

model. Other costs included the costs of intravenous drug
administration, prophylaxis for acute gout flares and infusion
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reactions, adverse event costs, refractory chronic gout
management, treatment for acute flares, and tophus surgery.
Resource use for the management of severe debilitating
refractory chronic gout according to serum uric acid level was
estimated by clinical expert survey and the in-depth clinician
interview. Drug cost incurred for prophylaxis for acute gout flares
and infusion reactions, adverse event costs, refractory chronic
gout management, acute flares treatment were based on costs in
the British National Formulary (BNF) 63 All other resource use
cost was estimated using NHS reference costs and Health
Related Groups for 201011. The resource use for 2 adverse
drug effects (infusion reactions and vomiting) was modelled for
the pegloticase arm and assumed 0 for best supportive care,
which was assumed to consist of standard medical care with
NSAIDS, colchicine and corticosteroids but no urate-lowering
treatment. However, a cost for drug treatment associated with the
best supportive care comparator was not included in the
economic model in the original submission. The cost used in the
model of managing an episode of acute flare was 295 based on
a Scottish Medicines Consortium guidance (637/10) on
febuxostat.
6.15
In the manufacturers submission the base-case ICER for

pegloticase compared with best supportive care was reported to
be 29,946 per QALY gained based on incremental costs of
9466 and an estimated QALY gain of 0.316. The ICER
generated by probabilistic analysis was 29,833 (after correction
by the ERG for an error identified in the computer program used
to run the probabilistic sensitivity analysis).
6.16
The deterministic sensitivity analyses conducted by the

manufacturer showed that the cost effectiveness of pegloticase
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was particularly sensitive to changes in baseline levels of serum
uric acid, the disutility associated with higher serum uric acid
levels and patients age. The sensitivity analyses also show that
the disutility associated with higher serum uric acid levels is a
significant driver of cost effectiveness, which is important given
the significant uncertainty about this assumption. The costeffectiveness results were also fairly sensitive to changes in the
utility value for patients with serum uric acid level under the target
value and the baseline utility value. The cost-effectiveness results
were also moderately sensitive to the parameter values for
treatment efficacy and persistence with pegloticase treatment.
6.17
The scenario analyses showed the sensitivity of the ICER to

several structural changes in the models clinical pathways. The
most sensitive variables were related to how long patients receive
pegloticase for and how soon non-responders stop treatment with
pegloticase. ICERs in the scenario analyses for pegloticase
compared with best supportive care ranged from 19,817 per
QALY gained (assuming duration of treatment with pegloticase
5 months instead of 6 months as in the base case) to 38,025 per
QALY gained (assuming evaluation of non-completer after
3 months instead of 1 month as in the base case).
6.18
At the clarification stage, several assumptions in the

manufacturers model were questioned. The model assumed that
all patients who responded to pegloticase treatment will progress
to maintenance treatment with either allopurinol (70%) or
febuxostat (30%). However, the ERG stated that this treatment
sequence would not have been appropriate for patients in whom
conventional urate-lowering therapies are contraindicated or not
tolerated. Furthermore the ERG was concerned that the original
model did not include any drug costs for best supportive care. The
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manufacturer responded with a revised model in which 10% of the
responders were assumed to switch to best supportive care,
instead of maintenance treatment with xanthine oxidase inhibitors,
after pegloticase treatment. The revised model also included drug
costs for best supportive care. Best supportive care treatment was
considered to consist of an NSAID (for instance naproxen 500 mg
per day) in about 90% of patients, colchicine (for instance
1000 mg per day) in about 10% of patients and corticosteroids (for
instance prednisolone 1015 mg per day) in about 75% of
patients. The deterministic results for this revised base-case
analysis (referred to as the revised model) showed an incremental
cost of 9452 and incremental QALY of 0.305, compared with
best supportive care resulting in an ICER of 31,027 per QALY
gained. A probabilistic sensitivity analysis (after correcting for an
error identified in the computer program used to run the
probabilistic sensitivity analysis) of 10,000 samples using the
revised assumptions yielded a mean ICER of 31,031 per QALY
gained (incremental cost of 9491 and a QALY gain of 0.306).
6.19
In response to additional concerns by the ERG, the manufacturer

also provided a number of additional deterministic sensitivity
analyses, including:
exploring the effect of using alternative data to calculate
persistence with allopurinol
incorporating costs of G6PD screening
more frequent serum uric acid level monitoring
pharmacy time with a specialist consultation for pegloticase nonresponders and non-completers at the start and end of the
treatment
assuming no extra decrease in utility in patients with tophi,
based on the assumption that the impact of tophi on quality of
Page 37 of 51
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life had already been captured in the 4 serum uric acid health
states
assuming no correlation between serum uric acid levels and
utility
different mortality rates.
The revised ICERs were particularly sensitive to assumptions that
tophi resolution influences utility and that serum uric acid levels are
correlated with utility. The ICER increased to 43,614 per QALY
gained when no extra decrease in utility was assumed in patients
with tophi, and to 38,535 when serum uric acid levels were
assumed not to be correlated with utility.
6.20
The ERG questioned several assumptions in the manufacturers

submission. It noted that in the 2 key trials, it took up to ******** for
all patients who eventually lost response or withdrew from
pegloticase to be identified, however the model assumed that
responders can be identified after 2 months of pegloticase
treatment. Additionally, the ERG stated that the group termed
non-completers by the manufacture would be difficult to identify
in clinical practice. It also noted the assumption that noncompleters could be identified in the first month of treatment was
arbitrary because there were no data on time to stopping
treatment from the trials.
6.21
The ERG suggested that an alternative modelling approach could

have classified each non-completer patient as a non-responder
and incorporated their outcomes within the mean result for nonresponders. This would have been a more accurate reflection of
the trials.
6.22
The ERG noted that in the revised model the proportion of

pegloticase responders who progressed to best supportive care
Page 38 of 51
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without having intervening maintenance treatment was assumed
to be 10% but the proportion of trial patients who were eligible to
participate because of intolerance or contraindication to
allopurinol was ***** in trial C0406 and ***** in trial C0405.
6.23
The ERG commented that the revised model assumed that

patients switching to best supportive care have a rapid return of
high serum uric acid levels and the only treatment benefits
maintained are those associated with tophi resolution. This may
have underestimated treatment benefits in the responders who
were intolerant to allopurinol or for whom allopurinol is
contraindicated. It said that the rise in serum uric acid could be
assumed to be more gradual, but that this remained uncertain
because there were no data.
6.24
The ERG was concerned that that the length of time on treatment
in clinical practice could be greater than the 6 months assumed in
the model. It noted that the draft summary of product
characteristics did not limit treatment to 6 months but also
acknowledged the lack of data to support long-term treatment.
The combined data from the 2 key trials (C0405 and C0406) and
the open-label extension study (C0407) showed that the mean
number of treatments received by responders was ****
(median=**, SD=*****). A Kaplan-Meier plot of the time to stopping
treatment for responders to pegloticase all 3 trials showed that the
proportion continuing to receive pegloticase treatment was fairly
high at over *** until around *******, with
*****************************************. The ERG also noted that in
the open-label extension study patients were allowed to continue
pegloticase treatment for up to a maximum of 30 months
(2.5 years).
Page 39 of 51
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6.25
The economic model assumes that the benefits of pegloticase

treatment in responders during the 6-month treatment period can
be maintained in the long term by treatment with allopurinol or
febuxostat. The ERG considered that this was uncertain because
there was no direct evidence on persistence with either allopurinol
or febuxostat in the population receiving maintenance treatment in
the economic model (patients with severe debilitating chronic
tophaceous gout who had not responded to or are intolerant to
xanthine oxidase inhibitors and who had responded to treatment
with pegloticase). The ERG noted that in the manufacturers
original model 34% of the incremental QALY gains were accrued
more than 10 years after starting pegloticase treatment. The ERG
considered that the extrapolation of benefits over such a long
period was a significant area of decision uncertainty because no
direct evidence had been presented by the manufacturer to show
that the serum uric acid levels after response to pegloticase
treatment can be maintained by treatment with allopurinol or
febuxostat treatment in the long term.
6.26
The ERG also had concerns about the survival model used to
extrapolate persistence with allopurinol, and noted that in the
scenario analysis the ICER was sensitive to the rate of
discontinuation of allopurinol. The ERG noted that an alternative
approach to modelling allopurinol persistence could be a Weibull
fit for all the 2-year data available from the UK observational study
(Annemans et al. 2008) as opposed to the Weibull fit for only the
second year data, as in the original model. The ERG noted that a
sensitivity analysis conducted by the manufacturer at the
clarification stage using this approach increased the ICER to
37,981 per QALY gained from the revised base-case ICER of
31,027 per QALY gained.
Page 40 of 51
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6.27
The ERG noted that published data from modified intention-totreat analysis of the trials (see section 4.5) were not used to
calculate the clinical effectiveness in the model, and that there
was additional analysis of the trial data to inform the health
economic model. Primary end points in the trials were based on
plasma uric acid level while in the economic model the end points
were based on serum uric acid. However, the ERG noted that
plasma and serum uric acid levels had a degree of correlation and
that serum uric acid levels would likely be used in clinical practice.
The ERG agreed that long-term maintenance of serum uric acid
below 360 micromol/litre could be expected to result in clinically
meaningful changes in patient-related outcomes, although it noted
that the BSR guideline recommended maintaining serum uric acid
levels below 300 micromol/litre.
6.28
The ERG noted that the effectiveness of tophi resolution (in terms
of proportion of patients with resolved tophi) was applied to all
patients in the model and not only to the subgroup with tophi at
baseline. The ERG considered that the model might have
overestimated the treatment benefit of tophi resolution and
therefore biased the analysis in favour of the pegloticase arm. The
ERG also commented that the proportion of patients receiving
pegloticase in clinical practice who have tophi at baseline may be
higher than what was observed in the trials because of the
wording of the draft license indication, which includes the term
tophaceous gout.
6.29
The ERG had concerns that the method for calculating utility from
a combination of serum uric acid level, frequency of flares and
tophi resolution may result in quality of life improvements being
double counted because all 3 are likely to be correlated in an
individual. For example, tophi resolution is likely to be correlated
Page 41 of 51
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with low serum uric acid levels, but the model assumes that the
probability of having tophi resolution is the same irrespective of
the serum uric acid level, and applies a utility benefit for both tophi
resolution and low serum uric acid levels.
6.30
The ERG stated there was a similar risk of double counting when
capturing both the benefits of reduced flares and lower serum uric
acid level, because the frequency of flares is assumed to be
related to the serum uric acid level but in the model both are
treated as independent factors in determining utility. This type of
double counting was more problematic because both utility gains
were applied to all patients from 6 months and to patients in the
pegloticase arm of the model who receive best supportive care
before 6 months. The ERG suggested the potential for double
counting benefits in this manner may have been avoided if the
data on the relationship between serum uric acid and utility had
been properly adjusted to take into account the frequency of flares
as a confounding factor, providing an estimate of the disutility per
serum uric acid state in the absence of flares.
6.31
The ERG was concerned about the assumption that the resource
use would be greater in patients with a higher serum uric acid
level over and above the difference determined by gout flares. It
therefore conducted an analysis in which the resource use for
patients with a serum uric acid over 360 micromol/litre was set to
the same value as for those under 360 micromol/litre. It also
assumed that the number of rheumatology visits associated with
pegloticase treatment would be reduced to 3 (from 5 in the
manufacturers model) in year 1 and none thereafter but assumed
that 2 visits would be needed even in patients classified as nonresponders or non-completers, giving a net reduction in the cost
Page 42 of 51
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of rheumatology visits associated with pegloticase (see section
6.33).
6.32
The ERG also noted that limited details were available about the
methods used to derive the relationship between serum uric acid
level and utility in the model beyond 6 months, which were based
on data from guidance on febuxostat for hyperuricaemia in gout
(NICE technology appraisal guidance 164). The ERG noted that
the relationship between serum uric acid level and underlying
utility was considered uncertain by NICEs Appraisal Committee
during appraisal of TA164.
6.33
The ERG conducted exploratory analyses examining the impact

of varying several parameters in the economic model, including:
incorporating alternative modelling approach as mentioned in
section 6.21 (which involves assuming persistence with
pegloticase to be 100% and a response rate of 42%, which was
the rate observed in the pooled analysis of the 2 phase III trials)
assuming that 5% of pegloticase responders receive febuxostat
as maintenance treatment instead of 30% in the revised model
because in clinical practice the proportion of patient eligible for
febuxostat is likely to be low
doubling the annual mortality applied in the model to reflect that
the risk of death in the population eligible to receive pegloticase
may be higher
assuming a zero rate of tophi surgery because tophi surgery is
not considered a part of current UK gout management
varying the cost of gout flare from 0 to 500 because the
manufacturer provided limited information on the methodology
used to derive the cost of 295 used in the model
Page 43 of 51
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making alternative assumptions about resource used as outlined
in section 6.31
applying the proportion of patients unable to take xanthine
oxidase inhibitors based on the trial population (**** as
mentioned in section 6.22
assuming that utility benefits are driven solely by the frequency
of flares and the resolution of tophi and not directly by the serum
uric acid level to minimise double counting of clinical benefits
(see section 6.296.30)
assuming that utility is based solely on flares
assumed that only 71% of patients have tophi at baseline
because the manufacturers base case implicitly assumes that
100% have tophi at baseline (see section 6.28)
a combined analysis of alternative assumptions about resource
use and utility benefits based only on the frequency of flares and
the tophi resolution (assuming a disutility linked to serum uric
acid level of 0).
Page 44 of 51
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Table 2 Deterministic sensitivity analysis varying some structural
assumptions (from tables 3041of the ERG report)
Incremental cost
(pegloticase best
supportive care)
Incremental
QALY
(pegloticase
best supportive
care)
ICER
(/QALY)
Revised base case
9,452
0.305
31,027
Pegloticase
persistence (100%)
and response rate
(42%)
10,748
0.331
32,492
5% of pegloticase
responders receive
febuxostat
8,955
0.314
28,535
Applying double the

annual mortality risk
assumed in the base
case
9,624
0.285
33,793
The rate of tophi

surgery to 0
9,580
0.305
31,449
The cost of a gout

flare to 0
9,606
0.305
31,534
The cost of a gout

flare to 500
9,345
0.305
30,678
Assumptions about
resource use
12,492
0.305
41,008
Applying the
proportion unable to
take xanthine oxidase
inhibitors in the trial
population to the
modelled population
*******
*****
9,452
0.230
41,118
That utility is based

solely on flares
9,452
0.018
529,771
When 71% of the

population have tophi
at baseline rather
than 100%
9,489
0.226
42,000
12,492
0.230
ERGs
scenario 2
*******
Alternative
assumptions about
utility gains
When combining
alternative
assumptions about
utility gains with
alternative
assumptions about
resource use
(scenario 2 plus 3)
ERGs
scenario 1
54,345
ERGs
scenario 3
ERGs
scenario 4
(ERGs
preferred
scenario)
Page 45 of 51
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6.34
The results of the exploratory analyses conducted by the ERG are

summarised in the table 2. The ERG described the scenario
explored in the last analysis (combining the alternative
assumptions about utility gains with alternative assumptions about
resource use) as its preferred scenario. This scenario
incorporated the following changes to the base case:
no disutility for higher serum uric acid levels
a disutility of 0.076 for patients with tophi compared with those
without
a utility of 0.68 for patients with tophi (and without flares)
no increased resource use for higher serum uric acid levels
no additional rheumatology visits for pegloticase treatment after
year 1
rheumatology visits for starting and stopping treatment in nonresponders and non-completers.
In this scenario (the ERGs base case), pegloticase was associated
with an incremental cost of 12,492 and an incremental QALY gain
of 0.230 when compared with best supportive care, resulting in an
ICER of 54,345 per QALY gained. This ICER was still associated
with many uncertainties about the structural assumptions in the
model but the ERG indicated that it could be a starting point for the
discussion about the most plausible ICER.
6.35
The ERG conducted deterministic sensitivity analyses to assess

the effects of other structural uncertainties on the ICER generated
from its preferred scenario (the ERG base case). It showed that
the ICER is sensitive to the duration of pegloticase treatment in
responders as well as the longer duration of pegloticase treatment
in non-completers. The results have been summarised in table 3.
Page 46 of 51
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Table 3 Deterministic sensitivity analysis of ERGs base case varying some
structural assumption (from table 44 of the ERG report)
Incremental cost
(pegloticase best
supportive care)
ERGs preferred
scenario
12,492
12,634
6.36
54,345
ERGs
scenario 4
0.228
55,529
ERGs
scenario 8
Assuming 3 months
treatment in those
who are noncompleter with
pegloticase
Maintenance therapy
unable to maintain
low serum uric acid
levels
0.230
ICER
(/QALY)
ERGs
scenario 7
Assuming lower
persistence on
allopurinol based on 2
year data from
(Annemans et al.)
With a longer duration

of pegloticase
treatment in
responders
Incremental QALY
(pegloticase best
supportive care)
15,084
0.226
66,696
ERGs
scenario 9
Substantial
increase
Marginal increase
Increased
ERGs
scenario 10
Increased
Decreased
Increased
The EGR also conducted subgroup analyses to assess the

difference in ICER for patients unable to take maintenance
treatment (with allopurinol or febuxostat) because of intolerance
or contraindication and for those who can take maintenance
treatment. In the manufacturers base case, in patients unable to
take maintenance treatment with xanthine oxidase inhibitors,
pegloticase was associated with an ICER of 60,793 per QALY
gained compared with best supportive care, while in patients who
could take maintenance treatment the ICER was 28,922 per
QALY gained. Similarly, in the ERGs base case, in patients
unable to take maintenance treatment with xanthine oxidase
inhibitors, pegloticase was associated with an ICER of 62,961
per QALY gained compared with best supportive care, but for
patients who could take maintenance treatment the ICER was
53,517 per QALY gained. The results are summarised in table 4.
Page 47 of 51
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Table 4 Subgroup analysis of patients who can or cannot take maintenance

treatment (with allopurinol or febuxostat) (from tables 42,43 and 44 of the
ERG report)
Incremental cost
(pegloticase best
supportive care)
Incremental QALY
(pegloticase best
supportive care)
ICER
(/QALY)
Subgroup analysis for manufacturers revised base case

Manufacturers
revised base case
9,452
0.305
31,027
For subgroup unable

to take xanthine
oxidase inhibitors
12,235
0.201
60,793
For subgroup able to

inhibitors
9,142
ERGs
scenario 1
Table 42 of
ERG report
Table 43 of
ERG report
0.316
28,922
0.230
54,345
Subgroup analysis for ERG base case

ERGs base case
For subgroup unable
to take xanthine
oxidase inhibitors
For subgroup able to
inhibitors
7
7.1
12,492
ERGs
scenario 4
ERGs
scenario 5
12,698
0.202
62,961
ERGs
scenario 6
12,496
0.233
53,517
Equalities issues
During the scope development some consultees pointed out that
pegloticase is contraindicated in people with glucose-6-phosphate
dehydrogenase (G6PD) deficiency, which is more common
among people with African or Mediterranean ancestry. This was
discussed at the scoping workshop. The attendees at the scoping
workshop agreed that it did not seem to be an equalities issue
that needs addressing in the appraisal, given that people with
G6PD deficiency would not be considered for treatment with
pegloticase because of the specific contraindication.
Page 48 of 51
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8
8.1
Innovation
The manufacturer stated that currently best supportive care is the
only treatment option available for patients for whom pegloticase
would be indicated. The manufacturer stated that pegloticase is
an effective treatment option that reduces uric acid levels and
provides significant disease-modifying benefits including tophus
resolution, reduction in flares (after 3 months of treatment) and
improvements in patients quality of life.
Authors
Anwar Jilani
Technical Lead
Dr Pall Jonsson
Technical Adviser
with input from the Lead Team (Henry Marsh, Katherine Payne and Judith
Wardle).
Page 49 of 51
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Appendix A: Supporting evidence

Related NICE guidance
Published
Febuxostat for the management of hyperuricaemia in people with gout.
NICE technology appraisal guidance 164 (2008). Available from
www.nice.org.uk/guidance/TA164
Page 50 of 51
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CONFIDENTIAL

NATIONAL INSTITUTE FOR HEALTH AND CLINICAL

Key issues for consideration

National Institute for Health and Clinical Excellence

National Institute for Health and Clinical Excellence

Background: clinical need and practice

National Institute for Health and Clinical Excellence

The estimated prevalence of gout between 2000 and 2005 in the

Gout is treated by diet and lifestyle changes and drug treatments

National Institute for Health and Clinical Excellence

Two classes of uric acid lowering drugs are available: xanthine

National Institute for Health and Clinical Excellence

Pegloticase does not currently have a UK marketing authorisation.

The recommended dose of pegloticase is 8 mg given as an

National Institute for Health and Clinical Excellence

The summary of product characteristics lists the following most

The acquisition cost of pegloticase has not been finalised. The

Remit and decision problem(s)

National Institute for Health and Clinical Excellence

Final scope issued by NICE

Decision problem addressed in the

Adults with hyperuricaemia and

Adult patients with severe debilitating

The population in the decision problem addressed in the

Final scope issued by NICE

National Institute for Health and Clinical Excellence

Decision problem addressed in the

Final scope issued by NICE

Decision problem addressed in the

The standard comparators to be

Best supportive care

Best supportive care.

National Institute for Health and Clinical Excellence

The manufacturer stated that febuxostat is not an appropriate

The outcome measures to be

Serum and plasma urate levels

serum urate levels

Tender and swollen joint count

tender and swollen joint

Adverse effects of treatment

Health related quality of life (Health

adverse effects of treatment

Decision problem addressed in the

The manufacturers submission included both serum and plasma

National Institute for Health and Clinical Excellence

Final scope issued by NICE

The reference case stipulates

Decision problem addressed in the

The ERG identified no significant deviations from the NICE

National Institute for Health and Clinical Excellence

C0405 and C0406 were identical, randomised, double-blind,

National Institute for Health and Clinical Excellence

The primary outcome was the proportion of patients whose

Secondary end points were assessed at baseline, week 13,

National Institute for Health and Clinical Excellence

A total of 225 patients (109 in C0405 and 116 in C0406) were

Plasma uric acid normalised within 24 hours of the first infusion

National Institute for Health and Clinical Excellence

The results of the secondary outcomes are presented as pooled

Patients in the pegloticase group also experienced reductions in

National Institute for Health and Clinical Excellence

Patient-reported outcomes were also reported to be improved with

HAQ disability index was measured by administering a survey

The HAQ pain score was measured on a visual analogue scale