North American IUATLD Meeting

1 March 2018

Daniel Everitt, MD

Update from TB Alliance Clinical Studies

• The TB Alliance Pipeline and Portfolio

• The BPaL Regimen for Treatment of Infection with XDR-TB and MDR-TB Not Responsive to or Intolerant to Treatment

– Update on the Nix-TB Trial

– Update on the ZeNix Trial

• The BPaMZ Regimen for the Treatment of Infection with Drug Sensitive and Drug Resistant TB

– The NC-005 Phase 2b Trial

– SimpliciTB Trial

• Phase 1 Studies of New Entities

– Sutezolid

– TBA7571

• Preclinical Compounds

Outline of Discussion

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Our commitment to patients, providers, and programs ensures our efforts benefit TB patients around the world. TB Alliance products will be:

TB Alliance access strategy

AAA Mandate

Adopted Available Affordableinto treatment policies and drug registries

in public and private sectors

cost effective for patients, countries, and donors

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Paradigm Shift: Treatment For All

People with MDR-TB (~ 4% of TB Patients)

BPaMZ BPaLTreatment using…

People with Drug Sensitive TB (~ 95% of TB Patients)

People with XDR-TB/pre-XDR (<1% of TB Patients)

Shorter, Simpler Treatment for XDR-TB

One day of XDR treatment today Treatment duration: 2+ years

One day of BPaL regimen in Nix-TB trialTreatment duration: 4-6 months

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Patients with XDR-TB, Pre-XDR-TB or who have failed or are intolerant to MDR-TB Treatment

Nix-TB Pilot Phase 3 Trial in XDR-TB

Pretomanid 200 mg qd

Bedaquiline 200 mg tiw after 2 week load

Linezolid 1200 mg qd*

Sites

Sizwe Hospital, Johannesburg, South Africa

Brooklyn Chest Hospital, Cape Town, South Africa

King Dinuzulu Hospital, Durban, South Africa

6 months of treatment

Additional 3 months if sputum culture positive at 4 months

XDR-TB

Follow up for relapse-free cure over 24 months

*Amended from 600 mg bid strategy

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• 109 participants enrolled as of end enrollment November 15, 2017

• Status on February 1, 2018:– 82 have completed treatment– 63 have reached their primary endpoint (6 months after end of treatment;

NDA cutoff)– 11 patients have completed the study (Month 30)

• Overall relapse-free cure of TB disease among the first 30 followed to primary endpoint 6 months after end of therapy:– 26 / 30 = 87% (vs. historical up to 85% failure rate)– 4 deaths early in treatment– Continuing results consistent with the first 30

Status of Participants in Nix-TB

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• Overall, linezolid has the well described toxicity of myelosuppression and neuropathy, but has been manageable

– 67% of Participants had at least one interruption of linezolid• Maximum mean duration of dose interruption = 23 days

– 55% had at least one reduction of linezolid dose– 4 months was the minimum total amount of exposure time to linezolid– Myelosuppression requiring interruption or reduction generally in the first 2-3

months– Neuropathy requiring interruption or reduction generally in months 4-6• Data on resolution of neuropathies is evolving

Experience with Linezolid Toxicity

Regulatory File for Pretomanid in the BPaL Regimen

• FDA and MHA agreed they would review a file based on the first 45 Nix trial participants who meet the primary follow up endpoint (6 months after completion of therapy)

– FDA file planned for 4Q2018

• Based on Nix Clinical Study Report on first 45

• With all available data from trial in ISS and addendum to study report

• Supplemented by all pretomanid development information (nearly 1000 persons treated)

– MAA file in EU planned for 1Q2018

• Based on same data as FDA file

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• The ZeNix trial will seek to optimize linezolid as part of a novel regimen for those suffering from the most severe forms of drug-resistant TB.

• This trial will :

– Evaluate the linezolid dose

– Evaluate the linezolid duration

• Expected to be conducted across 10 trial sites in South Africa, Georgia, Belarus, and Russia.

• The trial will run concurrent with FDA and EMA file review and after initial approval

ZeNix Clinical Trial

BPaL Regimen: Moving Forward

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ZeNix: Linezolid Optimization Trial

Pa dose = 200 mg daily; B Dose = 200 mg daily x 8 weeks, 100 mg x 18 weeks

6 months of treatment

Additional 3 months if sputum culture positive at 4 months

1o follow up for relapse-free cure 6 months after end of treatment; Full f/u 24 mos after end of treatment

B-Pa-LL=1200 mg/d x 6 mos

B-Pa-LL=1200 mg/d x 2 mos

B-Pa-LL=600 mg/d x 6 mos

B-Pa-LL=600 mg/d x 2 mos

Randomize

N=30 XDR-TB per group AND up to 15 pre-XDR or intolerant/non-responsive MDR-TB per group

Patients with XDR-TB, Pre-XDR-TB or who have failed or are intolerant to MDR-TB treatment

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• 1st Patient enrolled December, 2017 in Tbilisi, Georgia

• Screening is open at 3 sites in South Africa

• Regulatory and Central Ethics Approvals Complete

– Russia and Belarus – Expect screening to start late February

Status Update on the ZeNix Trial

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Potential Therapeutic Algorithm

RIF resistantRIF sensitive

BPaMZ (3-4 months) Rapid FQL test

FQL resistantFQL sensitive

BPaL (6 months)

*BPaMZ duration dependent on PZA sensitivity; if unknown, 6 months

BPaMZ (3-6 months*)

Empiric Assessment or GeneXpert MTB/RIF (based on current practice)

• Where available, RIF resistance to be used as a proxy indicator for PZA resistance

• RIF resistant patients can go on to rapid FQL testing to determine appropriate regimen

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The BPaMZ Regimen for DS and MDR-TB

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• STAND PaMZ Trial Not Resumed When off Clinical Hold

– Superior results available from trial of the BPaMZ regimen (NC-005)

• NC-005 Phase 2b Trial Results

• SimpliciTB Trial

– Evaluate the BPaMZ regimen to evaluate cure in DS and MDR-TB

Development of the BPaMZ Regimen

NC-005: Testing Combinations of Bedaquiline, Pretomanid, Pyrazinamide and Moxifloxacin (BPaZM)

Key Results

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B, Pa, Z and M containing regimens

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

B(200mg daily) - Pa - Z

Rifafour

B(200mg daily) - Pa - Z - M

B(registered dosing) - Pa - Z

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

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

60 per DS groupUp to 60 MDR

DS

Randomize 8 Weeks

Serial 16 hour pooled sputum samples for TTP/CFU Count

MDR

Primary Analysis

2 Years

Survival Follow-up Visits at 6, 12, 18 and 24 Months

NC-005 – 8 week SSCC Study of B-Pa-Z-M

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Overnight Spot Overnight Spot

B(loading)PaZ 67% 84%* 89% 88%*

B(200mg)PaZ 76%* 79% 84% 92%*

BPaZM (MDR) Z-sensitive

96%* 89%* 100%* 97%*

BPaZM (MDR) Z-resistant

80%* 95%*

HRZE control 51% 63% 86% 79%

Liquid Culture Solid Culture

Percent of Patients Culture Negative at 2 Months

*Statistically significant vs HRZE

Kaplan-Meyer Analysis

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Liquid Culture Solid Culture

B(loading)PaZ 1.8* (1.1 – 2.9) 1.3 (0.9 – 1.8)

B(200mg)PaZ 2.0* (1.3 – 3.2) 1.1 (0.8 – 1.6)

BPaZM (MDR) Z-sensitive 3.3* (2.1 – 5.2) 2.2* (1.5 – 3.2)

BPaZM (MDR) Z-resistant 2.2* (1.3 – 3.9) 2.6* (1.4 – 4.5)

HRZE Control -- --

Hazard Ratio vs HRZE (95% CI)

Time to Culture Negativity

*Statistically significant vs HRZE

NC-002 Liquid Culture Solid Culture

PaMZ 1.7* (1.1 – 2.7) 1.6* (1.1 – 2.2)

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• BPaZ and BPaZM active and well tolerated– BPaMZ > BPaZ > PaMZ > HRZE in both clinical and preclinical data

• BPaZM appears to be markedly superior to HRZE in terms of time to culture negativity and potentially time to cure– Additional advantages over both PaMZ and BPaZ in MDR• Patients with Z resistance can be treated• Rapid DST for Z not needed, DST for Z not needed at all in some algorithms

• B(200mg) appears at least as active and safe as B(labeled dose)

• BPaZM in particular appears advantaged and worthy of progressing

Conclusions

NC-008 (B-Pa-Z-M) [Phase 2c/3]

Patient population:

DS-TB: Drug-Sensitive Tuberculosis

DR-TB: Drug Resistant Tuberculosis

For this particular protocol DR-TB is defined as TB participants with 1. mono-resistance to rifampicin or isoniazid, OR2. resistance to both rifampicin and isoniazid (MDR-TB)

(participants with fluoroquinolone resistance are excluded)

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

HRZE [Rifafour] (“CONTROL”)(n= 150)

B- Pa - M -Z (n= up to 150)

B- Pa - M - Z(n= 150)

Z = Pyrazinamide (1500 mg daily), M = Moxifloxacin (400 mg daily), Pa = Pretomanid - PA-824 (200 mg daily) ,

B = Bedaquiline (200 mg daily for 8 weeks then 100mg daily )

DS

Randomize

8 Weeks

MDR

Primary Analysis

4 months

NC-008 (B-Pa-Z-M)

6 months

2 Years > Follow-up

Time to culture negativity over 8 weeks treatment (Kaplan-Meier analysis)

Safety Efficacy TolerabilityPharmacokinetics/Pharmacodynamics (PK/PD):Mycobacterial Characterization

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• Phase 1– Sutezolid oxazolidanone– TBI 7371 DPRE1 inhibitor

• Preclinical Development – Plan for FIH in 2018– TBI 223 oxazolidanone– TBAJ 587 diarylquinoline

Compounds in Phase 1 and Preclinical Development

Towards Safer Oxazolidinones as

components of Universal Regimen for TB

TBI 223

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Reduced activity against MPS led to reduced bone marrow toxicity

TBI 223 In Vivo Safety and Toxicity - MPS vs. Bone Marrow Toxicity and Hematological

Compound Linezolid OTB-223

MIC (µg/mL) 0.23 – 0.63 0.8 - 1.9

MPS (µM) 8.5 > 74

Mouse/human bone marrow progenitor cell suppression assay (µM)

24-60 >150

MED AUC (hr·µg/mL) 131 179

Bone Marrow Histopathology, platelet ↓, reticulocyte↓

(Rat 28 day study at mg/kg dose)

150 mg/kg (AUC 425 µg·hr/mL)

NOAEL at 20 mg/kg (IB)

> 300 mg/kg (AUC 1685 µg·hr/mL)

Bone Marrow Histopathology, platelet↓, reticulocyte↓

(Dog 14 day study at mg/kg dose)NOAEL at 20 mg/kg (IB)

> 150 mg/kg (AUC 789 µg·hr/mL)

CommentsDeath (day 11,12) at 300 mg/kg

Death (day 21) at 150 mg/kg

TB Alliance Donors

Bill & Melinda Gates Foundation

United States Food and Drug Administration

Irish Aid

National Institute of Allergy and

Infectious Disease UK aidUnited States Agency for

International Development

Global Health Innovative Technology Fund

UNITAID

Australian Aid

IndonesiaHealth Fund

Dutch Ministry of Foreign Affairs

German Federal Ministry of Education

and Research

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