Issues and Challenges for the Development of a New Medication for Treatment of MultidrugResistant Tuberculosis

Charles D. Wells, MD Director, TB Products Unit OPDC - Rockville, Maryland June 3, 2009

Challenges and Issues

Background OPC-67683 Global MDR TB epidemic Microbiology laboratory Infection control MDR TB treatment MDR TB patient population Determining safety profile of new agents Endpoints

OPC-67683 In vitro MICs for Sensitive and Resistant Strains

O N N O N 2
(R)-2-Methyl-6-nitro-2-{4-[4-(4-trifluoromethoxyphenoxy)piperidin1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole

O O C F 3

OPC-67683 M.tuberculosis H37Ra H37Rv H37Rv RFP-r H37Rv INH-r H37Rv EB-r H37Rv SM-r H37Rv PZA-r Aoyama B Erdman Kurono TU-26 M.bovis BCG Pasteur Montreal Glaxo Tokyo (Otsuka Study No. 019064) 0.006 0.012 0.006 0.012 0.012 0.012 0.012 0.024 0.012 0.012 0.012 0.006 0.006 0.012 0.012

RFP 0.05 0.78 >100 0.39 0.2 0.78 0.78 0.1 0.39 0.39 >100 0.2 0.1 0.05 0.2

INH 0.1 0.1 0.1 >100 0.2 0.1 0.2 0.05 0.1 0.1 12.5 0.2 0.1 0.2 0.1

EB 1.56 1.56 1.56 3.13 50 3.13 1.56 3.13 1.56 3.13 12.5 1.56 1.56 1.56 3.13

SM 1.56 1.56 0.78 0.78 0.78 >100 1.56 1.56 1.56 0.78 6.25 0.39 0.78 0.78 0.78

Values are represented as MICs (minimum inhibitory concentrations, g/mL)

OPC-67683 Completed Trials

Phase
I I I I I I I I II II

Design
Single dose First-into-Human (2004) Multiple dose Single and multiple dose Single dose Multiple dose Multiple dose Drug-drug interaction Single dose (Mass Balance) Multiple dose (Dose bridging) Multiple dose (EBA) First patient trial Multiple dose (14-day EBA)

Country
UK UK UK Japan Japan US UK US South Africa South Africa

Subjects
56 52 104 56 24 30 6 36 24 54

# OPC-67683
42 36 78 42 18 21 6 36 12 48

Total Subjects Receiving OPC: 279 healthy volunteers, 60 TB patients

242-07-204 Treatment of MDR TB Phase 2B - Study Design

Screening Period Treatment Period
OPC-67683 (100 mg bid) + OBR N = 143 430 sputum culture+ MDR TB patients; Stratified by: -CXR cavitation (disease severity)

Post-Treatment Period

OPC-67683 (200 mg bid) + OBR N = 143

28-day post-IMP treatment

Placebo 4 tabs bid + OBR N = 143

Hospitalization for entire 56-day treatment period Frequent ECG monitoring and PK sampling 15 sites in 8 countries

Estimated Annual MDR TB Incidence* N ~ 500,000

*WHO, 2009

More than 50 000 cases From 10 000 to 50 000 cases From 1 000 to 9 999 cases From 100 to 999 cases Less than 100 cases

Global Scale-up of MDR TB Treatment under Green Light Committee-Approved Conditions, 2000-2007
Total for 2000-2007 1,680 10,699 452 13,222 2,243 1,910 30,206

WHO Region Africa Americas Eastern Mediterranean Europe South-East Asia W. Pacific Total

2007 190 386 86 2,960 1,075 555 5,252

Quality program conditions required for clinical trials: Treatment according to WHO guidelines - OBR Patient centered management with directly observed therapy (DOT) Labs with quality-controlled & assured culture and DST Good infection control practices Guaranteed drug supply 1% of 3,000,000 estimated cases for 2000-2007 brought under treatment

GLC annual report, 2008

Laboratory Issues

Laboratory capacity for culture and drug susceptibility testing (DST) as major limitation for MDR TB treatment scale-up and clinical trials Central microbiology laboratory for international trials not feasible Biohazards Delays from transport degradation of samples Need results locally for clinical management No international accreditation process in place for culture and DST Must build local laboratory capacity and strategy for standardizing practices and processes

Use one automated system for culture and DST Use comprehensive laboratory manual Implement intensive quality control process for all sites Perform periodic external audits

Infection Control Thinking Globally and Acting Locally

For safety in trials: protecting staff and patients in clinics & hospitals to avoid cross infection For efficacy in trials: cross infection and sample contamination can affect results Limited application of good control practices in most sites; site specific approaches required: -Administrative -Engineering -Personal respirator protection
Photos by Dr. Paul Jensen, Infection Control specialist with US CDC

Trial Design: Background Regimen for MDR TB

Fixed regimen not feasible variable drug resistance patterns across countries & settings Design approach - combination therapy (optimized background regimen) based on WHO Guidelines and investigational compound or placebo Optimized regimen usually with 4 drugs Rx for 18-24 mos; 12 months after sputum conversion Initial treatment broader and empiric while awaiting DST results then regimen adjusted; full DST results rarely available at outset Assumption that range of agents across trial arms will be comparable Use of DOT as standard of care for MDR TB: Promote adherence without burdening patients and families Administered in community, at health centers, or hospitals DOT for MDR TB more complex than for drug-susceptible TB

WHO Guidelines for Programmatic Management of Drug Resistant TB, 9/08

Patient Population (1)

Challenges with selecting optimal population for assessing treatment effect Highly heterogeneous patient population in terms of treatment history and DST; trial population should reflect disease population No prior trials on which to base selection Patient populations from cohort studies New (no previous treatment) 10%-15% st Previous 1 -line 40%-50% st nd Previous 1 - & 2 -line 40%-50% Balancing between achieving enrollment targets and available populations; need to generalize for overall MDR TB population for unmet medical need

Patient Population (2)

People Living with HIV/AIDS (PLWH)

High and early mortality for PLWH with MDR/XDR TB makes enrollment for trials complex: MDR TB: mortality > 70% (outbreaks); time to death 4-8 weeks XDR TB: mortality of 98% (S. Africa); time to death 16 days Rapid initiation of MDR TB treatment and earlier initiation of ARV treatment considered critical for survival

Use of rapid DST and epidemiologic profiles critical to reduction of mortality and enrollment in trials Determine DDI of investigational compound with ARVs Insure appropriate safety profile of investigational compound for immunocompromised patient populations

Wells et al. CID, 2007; Gandhi et al., CID, 2006.

Safety Assessment and Side Effects with OBR

MDR TB Treatment Side Effects, Tomsk, Russia, 2000-04
Adverse Event Arthralgia Depression Diarrhea Hepatitis Hypokalemia Hypothyroidism Nausea/ vomiting Nephrotoxicity Neuropathy Ototoxicity Psychosis Rash Seizure

Frequency (N=608) 298 (49%) 49 (8%) 238 (39%) 94 (15%) 231 (38%) 61 (10%) 427 (70%) 39 (6%) 42 (7%) 78 (13%) 53 (9%) 85 (14%) 57 (9%)

Evaluation of compounds in earlier development for MDR TB requires close monitoring, including hospitalization, given 2nd-line drug toxicities Safety profile must be derived from use in combination therapy with frequently toxic 2nd-line drugs Lack of information on PK and therapeutic drug levels of 2nd-line drugs makes design of DDI studies complex

Keshavjee et al, Lancet 2008

Endpoints

Comparison of cure rates at 24 months problematic lengthy delays in addressing critical unmet medical need Sputum conversion correlates well with final outcomes and is medically significant: Conversion in 4 months = higher likelihood of cure Earlier conversion ( 2 months) = stronger correlation with successful outcomes Correlates with clinical improvement with benefit to patients as demonstrated in clinical trials of drug susceptible TB Sputum conversion as public health benefit Assessing improvement in early mortality difficult; requires large sample size: Overall mortality among cohorts (across full treatment course): * Tomsk, Russia, 2000-04: 5% Riga, Latvia, 2000: 8% Lima, Peru, 1999-02: 21%
Holtz et al, Ann Intern Med 2006; BMRC TB Chemotherapy Trials Committee, BMJ 1953; *Kashavjee et al, Lancet 2008; Mitnick et al, NEJM 2008