1. R&D Update
Carl M. Mendel, M.D. SHA Meeting October 28, 2013 Paris, France

2. 2013 Q3 Discovery Early Development Late Development
Lead identification
Lead Optimization
PRECLINICAL DEVELOPMENT
Phase 1
Phase 2A
Phase 2B
Phase 3
Phase 4
TBA-354
Preclinical TB Regimen Development
JHU
TBI-166
IMM
ATP Synthesis Inhibitors Calibr
Energy Metabolism Inhibitors AZ/University of Penn
Whole-Cell Hit-to-Lead Program AZ
Whole-Cell Hit-to-Lead Program Sanofi
Whole-Cell Hit-to-Lead Program NITD
GSK
RNA Polymerase Inhibitors Rutgers University
Mycobacterial
Gyrase Inhibitors GSK
Pyrazinamide Analogs Yonsei University
Diarylquinolines Janssen/University of Auckland/UIC
Indazoles GSK
DprE Inhibitors Calibr
Cyclopeptides Sanofi
Macrolides Sanofi
Novel Structural Series NITD
Ureas Sanofi
NC-003
Bedaquiline/ Clofazimine/ Pyrazinamide
PA-824/ Bedaquiline/ Clofazimine/
Pyrazinamide
PA-824/ Bedaquiline/ Clofazimine
PA-824/ Bedaquiline/ Pyrazinamide
NC-002
REMox-TB
Optimized Pediatric Formulations
PA-824/ Moxifloxacin/ Pyrazinamide (PaMZ)
Moxifloxacin/ Isoniazid/ Rifampin/ Pyrazinamide
Bayer, MRC, UCL
Moxifloxacin/ Rifampin/ Pyrazinamide/ Ethambutol
Isoniazid/ Rifampin/ Pyrazinamide/ Ethambutol
TB Alliance R&D Partners:
AstraZeneca (AZ)
New York Medical College
Bayer Healthcare AG (Bayer)
Rutgers University
Beijing Tuberculosis and Thoracic Tumor Research Institute
Sanofi
Stellenbosch University
Calibr
University College London (UCL)
GlaxoSmithKline (GSK)
University of Auckland
Institute of Materia Medica (IMM)
University of Illinois at Chicago (UIC)
Janssen (Johnson & Johnson)
University of Pennsylvania School of Medicine
Johns Hopkins University (JHU)
Medical Research Council (MRC)
Yonsei University
Novartis Institute for Tropical Diseases (NITD)

3. TB Alliance Strategic Focus
R&D portfolio progression
Novel regimen development
Unified DS/DR development pathway (even for MDR market)
Driven by target product profile
Discovery, preclinical, early clinical, Phase 3, market
Connect the dots
Maximize impact
Delivering products to markets
Understanding of/focus on market needs
Full approval at launch
Know how (and how long) to use regimen at launch—can still be accelerated
Time to impact, time to achieve, cost
Pediatric drug development
Partnering/sustainable funding models

4. 2013 Progress--Discovery
IND filing of next generation nitroimidazole (TBA-354)
Enter Ph 1 clinical trials next quarter
Multiple lead optimization programs continue to advance
Identification of novel, non-cytotoxic, potent chemical matter sensitive to known drug-resistant Mtb clinical isolates
Continuing identification of promising drug combinations in mouse models
Continuing improvement of understanding of preclinical models

5. 2013 Progress--Clinical Clinical trials in 2013 REMox NC-002 NC-003
TMC207/rifabutin DDI (with NIH)
PA-824/efavirenz DDI (with NIH)
PA-824 TQT study (with NIH)

6. Phase 3 REMoxTB Trial Design
Randomized, Double-blind; Non-inferiority
Treatment Duration (months) 1 2 3 4 5 6
Intensive
Continuation
630 participants
Standard Regimen
HRZE HR
Placebos
630 participants
Moxifloxacin
for
Ethambutol
HRZM
HRM
Placebos
630 participants
Moxifloxacin
for
Isoniazid
MRZE MR
Placebos
All participants followed for 12 months post-treatment
H = isoniazid; M = moxifloxacin; R = rifampin; Z = pyrazinamide; E = ethambutol 6

7. REMox Study Status Update
Number of Patients Randomized: 1931
First Patient In: 1Q08
Last Patient In: 21Jan12
Last Patient Last Visit (M18): 29July13
Laboratory Data Entry: 15Nov13
Database Lock: 25Nov13
Topline Results: Jan14
Clinical Study Report: March14
New Drug Application: July14 7

8. Z = pyrazinamide Pa = PA-824 M = moxifloxacin
First Novel Combo SSCC: NC-002 In patients with TB sensitive to Pa, M, and Z
Participants with newly diagnosed smear positive DS TB
Pa(200mg)-M-Z
N=60
Pa(100mg)-M-Z
Rifafour
N=50 DS
2 months of treatment
Randomize DR
Serial 16 hour pooled sputum samples for CFU Count
Z = pyrazinamide Pa = PA M = moxifloxacin

9. Third Novel Combo BA Study: NC-003
Z=pyrazinamide, C=clofazimine, Pa=PA-824, J=bedaquiline
Participants with newly diagnosed smear positive DS TB C
J-C-Z
J-Pa-C
J-Pa-C-Z
Rifafour Z
14 daily doses
Randomize
15 per group
Serial 16 hour pooled sputum samples for CFU count
J-Pa-Z

10. 2013 Progress – Capacity Building
Biomarker repository
Multi-site quantitative culture capabilities in Ph 2
Ph 3 site and laboratory selection
Capabilities, regulatory environment, geographic diversity
Bactericidal activity analytics (manual plus program)
“Universal” mycolaboratory manual

11. Major Accomplishments 2013
2013 witnessed a huge amount of progress
Completion of REMox TB: significant undertaking (48 sites in 9 countries); potential to be 1st new (new class) DS-TB treatment in 50 years
Completion of NC-002: 1st regimen trial to move beyond today’s treatment paradigm; potential to shorten treatment for DS & some MDR-TB, promising for HIV/TB co-infection
Completion of NC-003: Second-generation regimen trial; potential to dramatically expand the number of people that can benefit from bedaquiline
Initiation of Pediatric Program: Work underway to deliver a FDC of the first-line treatment by 2016
2014 will be an exciting year!

12. TB Alliance Supporters
Thanks to all those who support our mission for better, faster-acting TB regimens
United States Agency for International Development
Bill & Melinda Gates Foundation
UNITAID
UK aid
United States
Food and Drug Administration
National Institute of Allergy and Infectious Diseases
AIDS Clinical
Trials Group
European
Commission
Global Health Innovative Technology Fund
Australian AID
Irish Aid