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

Unified Drug Sensitive/Drug Resistant Development Pathway for Novel TB Drug Regimens. Stephen Murray, MD, PhD & Daniel Everitt, MD Global Alliance for TB Drug Development. CPTR, Oct 2012 TBA Update. Current MDR Development Approach. Add single agent to Standard of Care

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

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  1. Unified Drug Sensitive/Drug Resistant DevelopmentPathway for Novel TB Drug Regimens Stephen Murray, MD, PhD & Daniel Everitt, MD Global Alliance for TB Drug Development CPTR, Oct 2012 TBA Update

  2. Current MDR Development Approach • 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)

  3. Unified DS/DR Development Path Paradigm Shift • 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

  4. Unified Drug Sensitive/Drug Resistant Regimen Development Path Stage Pre clinical Phase 1 Phase 2 Phase 3 Testing Model Study Attributes Go/No-Go Criteria: PK to support daily dosing As good as HRZE standard Clear effect to reduce CFU count Better Than HRZE

  5. NiX-TB New Chemical Entities in XDR-TB Proposed Collaborative “Rescue” Study for XDR/TDR.

  6. Background • 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

  7. Proposed “Rescue” Study in XDR-/TDR-TB • 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

  8. Ongoing Novel Combination Studies

  9. NC-002: First Novel Combo “SSCC” StudyIn Patients with M.TB Sensitive to Pa, M, and Z Pa(200mg)-M-Z N=60 Pa(100mg)-M-Z N=60 DS Rifafour N=60 2 months of treatment Pa(200mg)-M-Z N=50 Randomize DR Serial 16 hour pooled sputum samples for CFU Count Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin Participants with newly diagnosed smear positive DS TB

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

  11. Third Novel Combo EBA: NC-003 Z C J-C-Z J-Pa-C 14 daily doses J-Pa-C-Z J-Pa-Z Rifafour 15 per group Serial 16 hour pooled sputum samples for CFU Count Randomize Z=pyrazinamide, C=clofazimine , Pa = PA-824 , J = TMC207 11 Participants with newly diagnosed smear positive DS TB

  12. Phase 3 Studies of Regimens to Shorten Treatment Duration • 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

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