1. TB Drugs in the Pipeline
Carl M. Mendel, MD
TB Alliance
IUATLD Meeting
San Antonio, February 24, 2012

2. TB Alliance
TB Alliance
PHARMA
BIOTECH
ACADEMIA
INSTITUTES
GOVERNMENTS
FOUNDATIONS
Founded in 2000
Not-for-profit Product Development Partnership (PDP) headquartered in New York, with office in Pretoria
Entrepreneurial, virtual approach to drug discovery and development
Largest portfolio of TB drug candidates in history

3. TB Alliance Mission Develop new, better treatments for TB that are:
Faster-acting and less complex
Compatible with anti-retrovirals for HIV/AIDS coinfection
Active against drug sensitive and drug resistant strains
Ensure that new regimens are affordable, adopted for use, and made widely available
Coordinate and act as catalyst for global TB drug discovery and development activities

4. TB Alliance Portfolio Clinical Development Discovery
Target Or Cell-Based Screening
Natural Products
IMCAS
Whole-Cell Hit to Lead Program
GSK
TBA-354 U. of Auckland/ U. Ill Chicago
PA-824
Novartis
Moxifloxacin (+ H, R, Z)
Bayer
Topoisomerase I Inhibitors
AZ/NYMC AZ
Mycobacterial Gyrase Inhibitors
TMC207
Tibotec
Moxifloxacin (+ R, Z, E)
PA-824/Pyrazinamide
TB Drug Discovery Portfolio
NITD
Riminophenazines
IMM/BTTTRI
TMC207/Pyrazinamide
Gyrase B Inhibitors
Pyrazinamide Analogs
Yonsei
PA-824/ Moxifloxacin/ Pyrazinamide
Folate Biosynthesis Inhibitors AZ
RNA Polymerase Inhibitors
Energy Metabolism Inhibitors AZ/U. Penn
Lead identification
Lead Optimization
Clinical Phase I
Clinical Phase II
Clinical Phase III
Preclinical TB Regimen Development JHU/U. Ill Chicago
Novel TB regimen development
Current first-line TB treatment consists of: isoniazid (H) + rifampicin (R) + pyrazinamide (Z) + ethambutol (E)
Clinical Development
Discovery
Preclinical Development
THPP Series
GSK
Diarylquinolines
Tibotec/U. of Auckland
PA-824/TMC207

5. TB Drug/Regimen Discovery and Development Process
Drug Candidate Pool
Discovery
Phase II  Phase III
Identification of New Drug
Candidates
Selection of Potential New Regimens
Compound 1
Compound 2
Compound 3
Compound 5
Compound 4
Regimen A
Regimen B
Regimen C
Single Compound
Preclinical Development
 Phase I  EBA
Regimen Identification

7. Modes of Action Bio- reduction DNA Reactive Species mRNA H+ ADP ATP
Peptide H+
ADP
ATP
Bio-
reduction
Multiple Targets
PA-824
OPC-67683
DNA Gyrase
Gatifloxacin
Moxifloxacin
RNA Polymerase
Rifapentine
Ribosome
PNU
AZD-5847
ATP Synthase
TMC-207
Cell-Wall
Synthesis
SQ-109

8. TB Regimen Testing: A New Approach

9. Approach to Novel Regimen Development
Use animal model(s) to identify most promising combinations
Conduct full preclinical, Phase I and Phase II EBA evaluations of each drug singly
Explore drug-drug interactions and, as appropriate, preclinical tox of the combination
Take combination (regimen) into clinical development (Phase II, III)

10. NC-001

11. NC-001 (first novel combination EBA study)
NC-001: Use of EBA to Test Principles Learned From Animal Models and to Begin Clinical Development of Novel Regimens
NC-001 (first novel combination EBA study)
J-Z synergy
Pa-Z additivity
Pa-J antagonism
Pa-M-Z an enhanced novel regimen
EBA = early bactericidal activity
Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

12. First Novel Combo EBA: NC-001
Pa-Z-(M pbo)
J-Z
J -(Z pbo)
J-Pa
2 weeks of treatment
Rifafour
Pa-M-Z
Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207

13. All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X – Day 0)

14. All Treatment Groups: Bi-linear Regression Mean of TTP Over Day; Change from Baseline (Day X – Day 0)

15. NC-001 Conclusions
Validation of mouse data: J-Z synergy, Pa-Z additivity, Pa-J antagonism
Pa-M-Z an enhanced novel regimen in 2-wk study
All three compounds contribute to observed effect
EBA can distinguish between treatments
Just as it has previously distinguished between doses
CFU and TTP give similar results
Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

16. Post NC-001 Study: Next Steps
Develop Pa-M-Z for both DS- and DR-TB (in setting of appropriate resistance testing)
2-month “SSCC” study (NC-002) as next step
In patients whose M.tb is sensitive to Pa, M, and Z
Build on J-Z and Pa-Z backbones
Explore J-Pa building block
Continue to examine potential regimens in mouse models and bring promising new regimens into clinical development
Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207

17. NC-002: First Study to Examine DS- and MDR-TB Together Using the Same Treatment for Both

18. NC-002 Objectives Pa-M-Z vs Rifafour in DS-TB
Pa-M-Z in MDR-TB consistent with Pa-M-Z in DS-TB
DS vs MDR in 2-wk EBA
2-wk EBA vs 2-mo “SSCC”
Feasibility of multicenter “EBA” study
Pa = PA-824; M = moxifloxacin; Z = pyrazinamide

19. 2 months of treatment (plus 2-wk EBA substudy)
First Novel Combo SSCC: NC-002 In patients with M.tb sensitive to Pa, M, and Z
Pa(100mg)-M-Z
2 months of treatment (plus 2-wk EBA substudy)
Rifafour
Pa(200mg)-M-Z
Pa(200mg)-M-Z (MDR)
Pa = PA-824; M = moxifloxacin; Z = pyrazinamide
Z dose = 1500mg

20. Unified DS/DR Development Path

21. Current MDR Development Path Issues
Requires separate development program from DS-TB
Standard of care (SOC) treatment (control group) for MDR-TB is
Lengthy (24+ months)
Toxicity-prone / difficult
Of limited efficacy
Expensive
A new regimen for MDR-TB could be much shorter than SOC, but the timepoint for comparison will still be defined by the SOC control group

22. Unified DS/DR Development Path: Paradigm Shift
Indication: “Drugs X, Y, and Z in combination are indicated for the treatment of tuberculosis caused by M.tb strains that are sensitive to drugs X, Y, and Z.”
Patients should be treated based on what they are sensitive to--rather than what they are resistant to
“MDR” label doesn’t apply in setting of new chemical entities

23. Unified DS/DR Regimen Development Path
Better
than HRZE
Complete
regimens as
good as HRZE
SD, MD;
DDI if needed
2-wk
Combo
EBA
Mouse
model
2-wk
EBA
2-mo
SSCC
Ph3
cidal sterilizing
DS + DR
sensitive to
test regimen
DS vs HRZE
MDR not
randomized
Best doses used
in combos
All final regimens
tested here
MDR also
2-4 mos
DS vs HRZE
MDR for consistency
Dose ranging in
cidal
Only combos in
sterilizing
Dose ranging here for single
drugs
DS only

24. Coming This Year SQ109 EBA study results PNU100480 EBA study results
NC-002 (Pa-M-Z x 2 mos in DS and MDR pts)
NC-003
2-wk EBA study examining four new regimens:
J-Pa-Z, J-Pa-C, J-Z-C, J-Pa-Z-C
TBA-354 (nitroimidazole) FIM study
Expansion of biobanking initiative
Gatifloxacin Ph 3 results

25. Thank You! And Thank You To Our:
Funders
Partners
Stakeholders
Staff
Patients 25

26. TB Alliance Supporters
Bill & Melinda Gates Foundation
United States Food and Drug Administration
European Union
United Kingdom Department for International Development
United States Agency for International Development