CPRT DST Review

September, 2014

Upcoming TB Alliance Studies

STAND – PaMZ Ph 3

Participants with newly diagnosed smear positive DS- and MDR-TB

STAND: Phase 3 Trial of the Pa-M-Z Regimen

Pa(100mg)-M-Z N=350

Pa(200mg)-M-Z N=350

Rifafour N=350

Pa(200mg)-M-Z

N= up to 350

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

4 months of treatment

Randomize

DS

DR

4

Pa(200mg)-M-Z

N= 350

6 months of treatment

12 & 24 mos f/u after randomization

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Where in the World is STAND?

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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, 2018

NC-005 – JPaZ Ph 2b

8 BMGF Review August 13, 2014

J, Pa, Z and M Containing Regimens

Participants with newly diagnosed smear positive DS and MDR TB

NC005 Design – 8 week SSCC Study of J-Pa-Z

J(200mg daily) – Pa - Z

Rifafour

J – Pa - M - Z

J(registered dosing) – Pa - Z

Z=pyrazinamide (1500mg daily), M = moxifloxacin 400mg daily, Pa = PA-824 200mg daily , J(registered dosing) =

bedaquilline 400mg for 14 days then 200mg three times a week, J(200mg daily) = bedaquiline 200mg daily

60 per DS group Up to 60 MDR

DS

Randomize 8 Weeks

Serial 16 hour pooled sputum samples for TTP/CFU Count

MDR

• 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

NC-005 Timeline

BMGF Review August 13, 2014 9

NiX-TB – JPaOx Ph 3

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Pietersen E et al. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet 2014. Published Online January 17, 2014 http://dx.doi.org/10.1016/ S0140-6736(13)62675-6

107 Patients with XDR-TB in S. Africa dx’d 2002 – 2008 Treated empirically with median of 8 drugs

Died Failed Treatment

Defaulted Cured or Continuing

24 mo f/u 46% 23% 7% 16%

60 mo f/u 73% 10% 4% 11%

The Dismal Prognosis of Patients with 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 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

Background to NiX-TB as a Rescue Study for Patients with XDR-TB

BMGF Review August 13, 2014

Patients with XDR TB or Who Have Failed MDR Treatment

NiX-TB Rescue Study

Pa-824 200 mg

Bedaquiline 200 mg tiw after 2 week load*

Linezolid 600 mg bid**

Sites: Durban, Sizwe, Brooklyn Chest, SA

6 months of treatment

Additional 3 months if sputum positive at 4 months

Serial 16 early morning sputum samples in liquid culture

XDR TB

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Follow up for relapse-free cure over 24 months

BMGF Review August 13, 2014

*May adjust dosing Based on NC-005 **May adjust based on linezolid EBA study

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• 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)

NiX TB

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2 Week Safety, Tolerability and Bactericidal Activity Study

Participants with newly diagnosed smear positive DS TB

LIN-CL001 Dose-Ranging Linezolid Study

Linezolid 300 mg QD

Linezolid 300 mg BID

Linezolid 600 mg BID

Rifafour

15 per group

Linezolid 600 mg QD DS

Randomize

14 daily doses

Serial 16 hour pooled sputum samples for CFU Count

Linezolid 1200 mg QD

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• April, 2014 Protocol finalized

• May, 2014 CTA submitted to South Africa MCC

• November, 2014 Initiate trial; enroll first patient

Timing for NiX-TB

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• 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

DST Priority = PZA