Unified Drug Sensitive/Drug Resistant Development Pathway for Novel TB Drug Regimens

CPTR, Oct 2012TBA Update

Stephen Murray, MD, PhD& Daniel Everitt, MDGlobal Alliance for TB Drug Development

Unified Drug Sensitive/Drug Resistant DevelopmentPathway for Novel TB Drug Regimens

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• Add single agent to Standard of Care– Complex regimen with long period of treatment and follow up

• Greater unmet need on a per patient basis has resulted in calls for accelerated approval of drugs for MDR/XDR TB– But how will we know how to use the drugs? And for how long? – Will still have to perform Ph 3

• Requires separate development program from DS-TB • Standard of care (SOC) treatment (control group) for MDR-TB is

lengthy, difficult, toxicity prone, not efficacious and expensive.• A new regimen for MDR-TB could be much shorter than SOC, but

the timepoint for comparison will still be defined by the SOC control group (24 mos vs 6 mos)

Current MDR Development Approach

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• Patients should be treated based on what they are sensitive to--rather than on what they are resistant to– “MDR” as a label doesn’t apply in setting of new chemical entities

• Proposed Indication: “Drugs X, Y, and Z in combination are indicated for the treatment of tuberculosis caused by M.tb strains that are sensitive to drugs X, Y, and Z.”– Only patients sensitive to drugs X, Y, Z included in clinical trials– Traditional “MDR” or “DS” not an exclusion

Paradigm ShiftUnified DS/DR Development Path

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Mouse Model

• Single drug• Combo in

regimen• Relapse-free

sterilizing activity

Healthy Subjects

• Single and repeat dose

• Safety, tolerability

• PK• Drug

Interactions

Monotherapy EBA

• Single drug• Dose ranging• DS patients

only

Combination/Regimen EBA

• Optimized dose Regimen

• Test final regimen

• DS patients only?

Regimen 2-Month Study

• DS and DR sensitive to regimen

• DS vs HRZE standard

• DR for consistency

Registration

• 2 to 4 month treatment, eg

• DS vs HRZE for non-inferiority

• DR for consistency

Unified Drug Sensitive/Drug Resistant Regimen Development Path

As good as HRZE standard

Phase 2Pre clinical Phase 1 Phase 3

Better Than HRZE

Stage

Testing Model

Study Attributes

Go/No-Go Criteria: PK to support

daily dosingClear effect to

reduce CFU count

NiX-TB

Proposed Collaborative “Rescue” Study for XDR/TDR.

New Chemical Entities in XDR-TB

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• DS-TB is a curable disease• MDR-TB is a curable disease with treatment options• XDR- / TDR-TB is a disease where existing treatment options are

limited– Optimal therapy should consist of at least 3 effective drugs to which M.tb is

susceptible– New chemical entities without pre-existing resistance are currently in

development, but not yet available– Aim is to help XDR-TB patients now, under carefully controlled conditions,

while learning how to use the drugs/regimens

Background

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• Foundation: a number of drugs without pre-existing resistance could have promising data by END2013– Bedaquiline, delamanid, PA-824, sutezolid, SQ109– Clofazimine?

• Proposal: initiate global study of combinations of NCEs in patients with XDR-/TDR-TB at select centers with aim of cure – Potential collaborators: Tibotec, Otsuka, TB Alliance, Pfizer, Sequella– Once collaborators have committed, mouse relapse data of combination(s) to

predict duration of treatment– By providing complete regimen, prevent emergence of resistance– Pre-approval study; not intended for MDR-TB or to expand access beyond XDR

• Not compassionate use: highly selected centers, more intensive data collection, long-term follow up with definitive outcomes, learn to use regimen, learnings to be rapidly incorporated into treatment

Proposed “Rescue” Study in XDR-/TDR-TB

Ongoing Novel Combination Studies

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Participants with newly diagnosed smear positive DS TB

NC-002: First Novel Combo “SSCC” StudyIn Patients with M.TB Sensitive to Pa, M, and Z

Pa(200mg)-M-ZN=60

Pa(100mg)-M-ZN=60

RifafourN=60

Pa(200mg)-M-Z

N=50

Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin

2 months of treatment

Randomize

Serial 16 hour pooled sputum samples for CFU Count

DS

DR

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• Moves a novel regimen from a 2 week EBA study to a 2 month “SSCC” study– Allows us to look at the predictability of 2 week EBA data within a 2 month

study• Enrolls DS and DR subjects in a single trial treated with the same

regimen – moves to a new paradigm beyond the traditional “MDR” definition

• Evaluates “MDR” patients in an EBA study• Evaluates fixed dose PZA in a rigorous trial• Consistent quantitative CFU data across myco labs

NC-002 - Many “firsts” in Steps Forward for TB Drug Development

Third Novel Combo EBA: NC-003Participants with newly diagnosed smear positive DS TB

C

J-C-Z

J-Pa-C

J-Pa-C-Z

Rifafour

Z

Z=pyrazinamide, C=clofazimine , Pa = PA-824 , J = TMC207

14 daily doses

Randomize

15 per group

Serial 16 hour pooled sputum samples for CFU Count

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J-Pa-Z

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• REMox– Standard 6 month HRZE regimen compared to 2 arms of 4 month therapy:• Moxifloxacin substituting for ethambutol, or• Moxifloxacin substituting for isoniazid

– Fully enrolled with 1931 subjects; all have completed treatment– Top line results expected at end, 2013

• Oflotub Phase 3 Study – Analysis is moving forward– Design – HRZE X 6 months

vs gatifloxacin substitution for ethambutol X 4 months• ~ 2000 patients

– Sponsored by TDR / WHO– Database issues resolved by transfer to new database– Results expected Summer, 2013

Phase 3 Studies of Regimens to Shorten Treatment Duration