Overview of Trial Results – Nix-TB Mel Spigelman, President and CEO, TB Alliance About TB Alliance: A Product Development Partnership

Catalyzing and advancing new TB cures

• Established in 2000 • Developing new regimens that treat all forms of TB • Largest TB drug pipeline in history; approximately 30 active drug R&D programs • “AAA Mandate”: All new regimens will be adopted, available and affordable

5 Pretomanid

Pretomanid is the third new anti-TB drug approved for use by U.S. FDA, after rifapentine and bedaquiline • Pretomanid is the first anti-TB drug to be developed and registered by a not-for-profit organization • Approved as part of a discrete regimen • First introduction of a regimen since HRZE

Artist’s rendering of the pretomanid compound

6 Nix-TB Phase 3 Clinical Trial

Patients with pulmonary XDR-TB and treatment-intolerant or non-responsive MDR-TB

Followed throughout 30 months

Pretomanid 200 mg qd Extensively Drug-Resistant Bedaquiline + 200 mg tiw after 6-9 months of TreatmentTreatment-Intolerant-intolerant 2 week load TREATMENT** oror nonNon-Responsiveresponsive MultidrugMultidrug--Resistantresistant Linezolid TBTB Participants Participants 1200 mg qd*

Sites Sizwe Hospital, Johannesburg, South Africa Brooklyn Chest Hospital,Cape Town, South Africa King Dinuzulu Hospital, Durban, South Africa

*Amended from 600 mg bid strategy **If sputum culture is positive at 4 months, patients received an additional 3 months of treatment

7 Primary Endpoint: Clinical Endpoint, Not Biomarker or Surrogate

• Primary endpoint - clinical and bacteriologic status 6 months after end of treatment • Patient outcome categorized as either – Unfavorable outcome • Clinical or bacteriologic failure during treatment • Bacterial relapse post-treatment • Patients requiring alternative treatment at any point, withdrawal, or any death in ITT analysis, unless prior relapse OR – Favorable outcome • Secondary endpoint – 2 years after end of treatment

8 Demographics in Nix-TB

BPaL Regimen N=109 Age, years, mean (range) 35.6 (17 – 60) Male 52.3% Race Black 76.1% White 0.90% Mixed Race 22.9% BMI, kg/m2, mean (range) 20.6 (12.4 – 41.1)

9 Patient Disease Characteristics in Nix-TB

BPaL Regimen N=109 Current TB diagnosis XDR-TB 65.1% MDR-TB non-responsive 17.4% MDR-TB treatment intolerant 17.4% Duration since original TB diagnosis, months, median (range) 12.1 (0.5 – 141.0) HIV Positive 51.4% Duration since HIV diagnosis, years, mean (range) 4.7 (0.2 – 14.3) Chest cavity x-ray results compatible with TB Unilateral 46.8% Bilateral 37.6% None 15.6%

10 Primary Efficacy Analysis (ITT Analysis Population)

After six months of treatment and six months post-treatment follow-up

Total XDR-TB TI/NR MDR-TB Outcome Total assessable 107 71 36

Success (culture negative status Success 95 (89%) 63 (89%) 32 (89%) at 6 months post-treatment)

Death 7 6 1

Relapse post-treatment 2 1* 1 Failure Withdrawal, loss to follow-up, or 3 1 2 contaminated cultures Total Failure 12 (11%) 8 (11%) 4 (11%)

TI/NR MDR-TB = treatment-intolerant or non-responsive multidrug-resistant tuberculosis XDR-TB = extensively drug-resistant tuberculosis *The patient died at Day 486

11 Nix-TB: Adverse Events Overview

BPaL Regimen Adverse Events N=109 n (%) Any AE 109 (100) SAE 19 (17) AEs by severity Grade 1 8 (7) Grade 2 43 (39) Grade 3 41 (38) Grade 4 17 (16)

Grading according to DMID scale

12 Nix-TB: Adverse Events Occurring in > 15% of Patients

BPaL Regimen Adverse Events N=109 n (%) Peripheral sensory neuropathy 75 (69) Anemia 40 (37) Nausea 40 (37) Vomiting 37 (34) Headache 28 (26) Dermatitis acneiform 26 (24) Dyspepsia 26 (24) Decreased appetite 24 (22) Pleuritic pain 20 (18) Upper respiratory tract infection 20 (18) Gamma-glutamyltransferase increased 18 (17) Rash 17 (16)

13 Patient Management with the BPaL Regimen

• Treating physicians could – Interrupt entire regimen – Interrupt, dose adjust, or discontinue linezolid alone for linezolid-associated toxicities

14 Nix-TB: Interruptions of BPaL Regimen

• All but the 6 patients who died completed treatment • Entire regimen interrupted in 20 patients for adverse events – All patients who interrupted (excluding deaths) able to complete full 6 months of therapy or were ongoing • Linezolid interruption, dosages adjustment or cessation allowed: – 50 patients interrupted and resumed linezolid – 33 patients permanently discontinued linezolid, with all surviving patients (27) completing treatment with bedaquiline and pretomanid – 34 patients had no linezolid dose interruptions • Patients on regimen need to be followed carefully

15 Overcoming Challenges in Treatment of Highly-Resistant TB

Treatment Challenges Opportunities with BPaL

Too long: 18+ months 6-month regimen

Too complicated: ≥ 5 drugs, some IM / IV, 3 drug, all oral, set regimen no defined regimen Manageable tolerability, few Highly toxic, leading to discontinuations discontinuations Poor efficacy: ~20% cure rate pre- ~90% cure rate bedaquiline era in South Africa

16 Pretomanid Research: Moving Forward

• The ZeNix trial seeks to optimize linezolid dosing within the BPaL regimen. – Evaluates the linezolid dose and duration • The FDA approval requires additional studies, including a five-year global pharmacovigilance surveillance study. • Different regimens are being studied further in ongoing trials

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