Christo van Niekerk, M.D. IUATLD Meeting, Cape Town December 5, 2015 TB Alliance Ongoing Clinical Trials in DS-, MDR-and XDR-TB

2 TB Alliance Overview The STAND tests the PaMZ regimen PaMZ = Pretonamide, moxifloxacin, and pyrazinamide First Phase 3 trial to test a regimen in patients with drug-sensitive and drug- resistant TB (must be sensitive to drugs in the regimen) Holds potential to transform treatment of both drug-sensitive and especially drug- resistant TB Shortening Treatments by Advancing Novel Drugs STAND: A Global Phase 3 Trial

3 TB Alliance Overview Phase 3 STAND launched in 2015 Potential benefits of PaMZ regimen: – Drug cost reduced by 90% or more in some regions for MDR-TB – Reduced treatment time from 24 months to 4-6 months – No injectables – No weight banding, easing supply and administration PaMZ: A Potential Game-Changer

Participants with newly diagnosed smear positive DS- and MDR-TB STAND: Phase 3 Trial of PaMZ Pa(100mg)-M-Z N=300 Pa(200mg)-M-Z N=300 H-R-Z-E N=300 Pa(200mg)-M-Z N= up to 300 Pa = PA-824 M = moxifloxacin Z = pyrazinamide at 1500mg 4 months of treatment Randomize DS DR 4 Pa(200mg)-M-Z N= months of treatment 12 & 24 mos f/u after randomization TB Alliance Overview

5 NC-005 tests regimens containing bedaquiline, PA-824, and pyrazinamide with the potential to even further shorten treatment for TB and MDR- TB 2-month Phase 2b trial Enrolls both drug-sensitive and drug-resistant patients with the potential to shorten, improve treatment Conducted at 10 sites in South Africa, Tanzania, and Uganda Launched October 2014 Phase 2b trial testing combinations of bedaquiline, PA-824, and pyrazinamide NC-005 trial: BPaZ

6 J, Pa, Z and M Containing Regimens Participants with newly diagnosed smear positive DS and MDR TB NC-005 – 8 week SSCC Study of JPaZ TB Alliance Overview J (200mg daily) – Pa - Z Rifafour J – Pa - M - Z J (registered dosing) – Pa - Z J (registered dosing) = bedaquilline 400mg for 14 days then 200mg three times a week, J (200mg daily) = bedaquiline 200mg daily Pa = PA mg daily Z=pyrazinamide (1500mg daily), M = moxifloxacin 400mg daily 60 per DS group Up to 60 MDR DS Randomize 8 Weeks Serial 16 hour pooled sputum samples for TTP/CFU Count MDR

7 Launched in May 2015, Nix is the first clinical trial for a novel XDR-TB regimen with minimal pre-existing resistance; all pills, no injections Regimen includes bedaquiline, pretomanid, and linezolid Potential to be a 6-9 month simple, effective treatment for XDR-TB Regimen could be first “universal” treatment; if safe and effective the study will expand to include people with MDR-TB and drug-sensitive TB New Investigational Drugs for XDR-TB Nix-TB: Accelerating solutions for XDR-TB TB Alliance Overview Novel treatments to fight XDR-TB are urgently needed. In a recent review in South Africa, only 16% of people with XDR-TB were cured.

8 Patients with XDR-TB or who have failed MDR-TB treatment Nix-TB Clinical Trial TB Alliance Overview Pretomanid 200 mg Bedaquiline 200 mg tiw after 2 week load Linezolid 600 mg bid Conducted in South Africa at Durban, Sizwe, Brooklyn Chest sites 6 months of treatment Additional 3 months if sputum positive at 4 months Serial 16 early morning sputum samples in liquid culture XDR-TB Follow up for relapse-free cure over 24 months

9 2 Week Safety, Tolerability and Bactericidal Activity Study Participants with newly diagnosed smear positive DS TB LIN-CL-001: 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 days of therapy Serial 16 hour pooled sputum samples for CFU Count Linezolid 1200 mg QD

10 Bayesian NLME Regression Model LIN-CL-001: Data from Andreas Diacon and Rod Dawson Posterior Estimates and 95% BCIs of Mean EBA TTP (0-14)

11 TB Alliance Overview TB Alliance Supporters Bill & Melinda Gates Foundation European Commission United States Food and Drug Administration Irish Aid US NIAID UK aid United States Agency for International Development Global Health Innovative Technology Fund UNITAID Australian Government Thanks to all those who support our mission for better, fast TB drugs Indonesia Health Fund

12 TB Alliance Overview Most Importantly Thank you to the people with TB who selflessly agree to participate in clinical trials