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R&D Update
Carl M. Mendel, M.D.
SHA Meeting
October 28, 2013
Paris, France
2013 Q3
Discovery
LEAD
IDENTIFICATION
ATP Synthesis
Inhibitors
Calibr
Energy Metabolism
Inhibitors
AZ/University of
Penn
Whole-Cell Hit-toLead Program
AZ
Whole-Cell Hit-toLead Program
Sanofi
Whole-Cell Hit-toLead Program
NITD
Whole-Cell Hit-toLead Program
GSK
RNA Polymerase
Inhibitors
Rutgers University
LEAD
OPTIMIZATION
PRECLINICAL
DEVELOPMENT
TBA-354
Pyrazinamide
Analogs
Yonsei University
TBI-166
IMM
Indazoles
GSK
DprE Inhibitors
Calibr
PHASE 1
PHASE 2A
NC-003
Mycobacterial
Gyrase Inhibitors
GSK
Diarylquinolines
Janssen/University
of Auckland/UIC
Late Development
Early Development
Preclinical TB
Regimen
Development
JHU
Bedaquiline/
Clofazimine/
Pyrazinamide
PHASE 2B
NC-002
PA-824/
Moxifloxacin/
Pyrazinamide
(PaMZ)
PA-824/
Bedaquiline/
Clofazimine/
Pyrazinamide
PA-824/
Bedaquiline/
Clofazimine
PHASE 3
PHASE 4
REMox-TB
Optimized
Pediatric
Formulations
Moxifloxacin/
Rifampin/
Pyrazinamide/
Ethambutol
Bayer, MRC, UCL
Isoniazid/ Rifampin/
Pyrazinamide/
Ethambutol
Moxifloxacin/
Isoniazid/ Rifampin/
Pyrazinamide
Bayer, MRC, UCL
PA-824/
Bedaquiline/
Pyrazinamide
Cyclopeptides
Sanofi
Macrolides
Sanofi
Novel Structural
Series
NITD
Ureas
Sanofi
TB Alliance R&D Partners:
AstraZeneca (AZ)
Bayer Healthcare AG (Bayer)
Beijing Tuberculosis and Thoracic Tumor
Research Institute
Calibr
GlaxoSmithKline (GSK)
Institute of Materia Medica (IMM)
Janssen (Johnson & Johnson)
Johns Hopkins University (JHU)
Medical Research Council (MRC)
Novartis Institute for Tropical Diseases (NITD)
New York Medical College
Rutgers University
Sanofi
Stellenbosch University
University College London (UCL)
University of Auckland
University of Illinois at Chicago (UIC)
University of Pennsylvania School of
Medicine
Yonsei University
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
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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
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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)
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Phase 3 REMoxTB Trial Design
Randomized, Double-blind; Non-inferiority
Treatment Duration (months)
1
630 participants
Standard Regimen
2
3
4
5
Intensive
Continuation
HRZE
HR
6
Placebos
630 participants
Moxifloxacin
for
Ethambutol
630 participants
Moxifloxacin
for
Isoniazid
HRZM
HRM
Placebos
MRZE
MR
Placebos
All participants followed for 12 months post-treatment
H = isoniazid; M = moxifloxacin; R = rifampin; Z = pyrazinamide; E = ethambutol
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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
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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
DS
Pa(100mg)-M-Z
N=60
2 months of treatment
Randomize
DR
Rifafour
N=60
Pa(200mg)-M-Z
N=50
Serial 16 hour pooled sputum samples for CFU Count
Z = pyrazinamide
Pa = PA-824 M = moxifloxacin
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Third Novel Combo BA Study: NC-003
Z=pyrazinamide, C=clofazimine, Pa=PA-824, J=bedaquiline
• Participants with newly diagnosed smear positive DS TB
Z
C
J-C-Z
J-Pa-C
14 daily doses
J-Pa-Z
J-Pa-C-Z
Rifafour
15 per group
Randomize
Serial 16 hour pooled sputum samples for CFU count
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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
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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!
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TB Alliance Supporters
Thanks to all those who support our mission for better, faster-acting TB regimens
UK aid
Bill & Melinda
Gates Foundation
National Institute of Allergy
and Infectious Diseases
Global Health Innovative
Technology Fund
AIDS Clinical
Trials Group
UNITAID
United States Agency for
International Development
United States
Food and Drug
Administration
European
Commission
Australian AID
Irish Aid
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