Upcoming TB Alliance Studies. CPRT DST Review September, 2014

Transcription

1 Upcoming TB Alliance Studies CPRT DST Review September, 2014

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3 STAND PaMZ Ph 3

4 STAND: Phase 3 Trial of the Pa-M-Z Regimen Participants with newly diagnosed smear positive DS- and MDR-TB DS Pa(100mg)-M-Z N=350 Pa(200mg)-M-Z N=350 Pa(200mg)-M-Z N= months of treatment 12 & 24 mos f/u after randomization Randomize Rifafour N=350 6 months of treatment DR Pa(200mg)-M-Z N= up to 350 Z = pyrazinamide at 1500mg Pa = PA-824 M = moxifloxacin 4

5 Where in the World is STAND? 5

6 Pa-M-Z Development Timeline and the STAND Trial Finalize Protocol: April, 2014 File to Regulatory Authorities worldwide: May to September, 2014 Planned First Patient Enrolled: November, 2014 Initial File for Registration at 12 Mo: May,

7 NC-005 JPaZ Ph 2b

8 NC005 Design 8 week SSCC Study of J-Pa-Z J, Pa, Z and M Containing Regimens Participants with newly diagnosed smear positive DS and MDR TB J (registered dosing) Pa - Z DS Randomize J (200mg daily) Pa - Z Rifafour 8 Weeks MDR J Pa - M - Z 60 per DS group Up to 60 MDR Serial 16 hour pooled sputum samples for TTP/CFU Count Z=pyrazinamide (1500mg daily), M = moxifloxacin 400mg daily, Pa = PA mg daily, J (registered dosing) = bedaquilline 400mg for 14 days then 200mg three times a week, J (200mg daily) = bedaquiline 200mg daily BMGF Review August 13,

9 NC-005 Timeline Final protocol submitted to MCC March 15, 2014 Investigator Meetings August, 2014 First patient enrolled September 2014 Last patient enrolled September 2015 Top-line results 2Q2016 BMGF Review August 13,

10 NiX-TB JPaOx Ph 3

11 The Dismal Prognosis of Patients with XDR-TB Pietersen E et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet Published Online January 17, S (13) Patients with XDR-TB in S. Africa dx d Treated empirically with median of 8 drugs Died Failed Treatment Defaulted 24 mo f/u 46% 23% 7% 16% 60 mo f/u 73% 10% 4% 11% Cured or Continuing BMGF Review August 13,

12 Background to NiX-TB as a Rescue Study for Patients with XDR-TB 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 available Linezolid is an available oxazolidinone while awaiting availability of a potentially safer follow-up compound Aim is to help XDR-TB patients now, under carefully controlled conditions, while learning how to use the drugs/regimens and advance an entirely novel regimen BMGF Review August 13,

13 NiX-TB Rescue Study Patients with XDR TB or Who Have Failed MDR Treatment Pa mg Follow up for relapse-free cure over 24 months XDR TB Bedaquiline 200 mg tiw after 2 week load* Linezolid 600 mg bid** 6 months of treatment Additional 3 months if sputum positive at 4 months *May adjust dosing Based on NC-005 **May adjust based on linezolid EBA study Serial 16 early morning sputum samples in liquid culture Sites: Durban, Sizwe, Brooklyn Chest, SA BMGF Review August 13,

14 NiX TB The Population - Patients with Pulmonary XDR TB Ages 14 and up HIV infected with CD4 >50 cells/mm3 Minimal exclusion criteria Primary Endpoint: Incidence of bacteriologic failure or relapse or clinical failure through follow up until 24 months after the end of treatment. Interim Analysis Regular DSMC Meetings Repeated futility analyses based on time to event approach evaluating failure/relapse (including death) BMGF Review August 13,

15 LIN-CL001 Dose-Ranging Linezolid Study 2 Week Safety, Tolerability and Bactericidal Activity Study Participants with newly diagnosed smear positive DS TB Linezolid 300 mg QD Linezolid 300 mg BID DS Randomize Linezolid 600 mg QD Linezolid 600 mg BID Linezolid 1200 mg QD Rifafour 15 per group 14 daily doses Serial 16 hour pooled sputum samples for CFU Count [Enter Presentation Title in Insert > Header & Footer] 15

16 Timing for NiX-TB April, 2014 May, 2014 November, 2014 Protocol finalized CTA submitted to South Africa MCC Initiate trial; enroll first patient BMGF Review August 13,

17 DST Priority = PZA PZA everything works better with pyrazinamide FLQ (moxi) included in PaMZ Nitroimidazoles delaminid already on the market; pretomanid (Pa-824) in Phase 3 and TBA-354 entering Phase 1 Diarylquinolines bedaquiline already on the market for MDR and about to enter Phase 2 for DS/MDR and Phase 3 for XDR Oxazolidinones linezolid entering Phase 3 for XDR BMGF Review August 13,