TB Drugs in the Pipeline
Carl M. Mendel, MD
TB Alliance
IUATLD Meeting
San Antonio, February 24, 2012
TB Alliance
• 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
GOVERNMENTS
PHARMA
BIOTECH
TB
Alliance
ACADEMIA
INSTITUTES
FOUNDATIONS
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
TB Alliance Portfolio
Discovery
TARGET OR CELL-BASED
SCREENING
Natural Products
IMCAS
Preclinical
Development
LEAD IDENTIFICATION
LEAD OPTIMIZATION
Whole-Cell Hit to Lead
Program
GSK
Mycobacterial Gyrase
Inhibitors
GSK
THPP Series
GSK
TB Drug Discovery Portfolio
NITD
Topoisomerase I
Inhibitors
AZ/NYMC
Gyrase B Inhibitors
AZ
CLINICAL PHASE II
CLINICAL PHASE III
TBA-354
U. of Auckland/
U. Ill Chicago
PA-824
Novartis
Moxifloxacin (+ H, R, Z)
Bayer
Preclinical TB
Regimen Development
JHU/U. Ill Chicago
TMC207
Tibotec
Moxifloxacin (+ R, Z, E)
Bayer
PA-824/Pyrazinamide
Folate Biosynthesis
Inhibitors
AZ
Diarylquinolines
Tibotec/U. of Auckland
TMC207/Pyrazinamide
Whole-Cell Hit to Lead
Program
AZ
Riminophenazines
IMM/BTTTRI
Energy Metabolism
Inhibitors
AZ/U. Penn
Current first-line TB
treatment consists of:
isoniazid (H) +
rifampicin (R) +
pyrazinamide (Z) +
ethambutol (E)
CLINICAL PHASE I
Pyrazinamide Analogs
Yonsei
RNA Polymerase
Inhibitors
AZ
Novel TB
regimen development
Clinical Development
PA-824/TMC207
PA-824/
Moxifloxacin/
Pyrazinamide
TB Drug/Regimen
Discovery and Development Process
Discovery
Compound 1
Single Compound
Preclinical Development
 Phase I  EBA
Compound 2
Compound 3
Regimen A
Drug
Candidate
Pool
Compound 4
Compound 5
Phase II  Phase III
Regimen Identification
Identification of New Drug
Candidates
Regimen B
Regimen C
Selection of Potential New
Regimens
Modes of Action
Multiple Targets
 PA-824
 OPC-67683
Cell-Wall
Synthesis
 SQ-109
Bioreduction
DNA
DNA Gyrase
 Gatifloxacin
 Moxifloxacin
RNA Polymerase
 Rifapentine
Reactive
Species mRNA
H
ADP + ATP
Peptide
ATP Synthase
 TMC-207
Ribosome
 PNU-100480
 AZD-5847
TB Regimen Testing: A
New Approach
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)
NC-001
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)
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–
–
–
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
First Novel Combo EBA: NC-001
Pa-M-Z
Pa-Z-(M pbo)
J-Z
2 weeks of treatment
J -(Z pbo)
J-Pa
Rifafour
Pa = PA-824: M = moxifloxacin; Z = pyrazinamide; J = TMC207
All Treatment Groups: Bi-linear Regression Mean of
LogCFU Over Day; Change from Baseline (Day X – Day 0)
0
-.5
-1
-1.5
-2
-2.5
logCFU change from baseline
.5
Bi-linear Regression: logCFU change from baseline
0
2
4
6
8
10
12
14
Day
TMC207
TMC207 & PA-824
PA-824 & Pyr & Moxifloxacin
TMC207 & Pyrazinamide
PA-824 & Pyrazynamide
Rifafour e275
All Treatment Groups: Bi-linear Regression Mean of
TTP Over Day; Change from Baseline (Day X – Day 0)
200
150
100
0
50
TTP change from baseline
Bi-linear regression: TTP change from baseline
0
2
4
6
8
10
12
14
Day
TMC207
TMC207 & PA-824
PA-824 & Pyr & Moxifloxacin
TMC207 & Pyrazinamide
PA-824 & Pyrazynamide
Rifafour e275
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
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
NC-002: First Study to Examine
DS- and MDR-TB Together Using
the Same Treatment for Both
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
First Novel Combo SSCC: NC-002
In patients with M.tb sensitive to Pa, M, and Z
Pa(200mg)-M-Z
Pa(100mg)-M-Z
2 months of treatment (plus 2-wk EBA substudy)
Rifafour
Pa(200mg)-M-Z (MDR)
Z dose = 1500mg
Pa = PA-824; M = moxifloxacin; Z = pyrazinamide
Unified DS/DR Development Path
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
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
Unified DS/DR Regimen Development Path
Complete
regimens as
good as HRZE
SD, MD;
DDI if needed
Mouse
model
cidal
2-wk
EBA
2-wk
Combo
EBA
sterilizing
Dose ranging in
cidal
Only combos in
sterilizing
Dose ranging
here for single
drugs
Best doses used
in combos
Better
than HRZE
2-mo
SSCC
DS + DR
sensitive to
test regimen
All final regimens
DS vs HRZE
tested here
DS only
MDR also
MDR not
randomized
Ph3
2-4 mos
DS vs HRZE
MDR for
consistency
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
Thank You!
And Thank You To Our:
Funders
Partners
Stakeholders
Staff
Patients
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