Transcript 6 years - TB Alliance

A New Paradigm for TB
Drug Development
Mel Spigelman, M.D.
Stakeholders’ Association Meeting
October 17, 2005
TB Alliance Drug Portfolio 2004
Compounds, Analogs and Derivatives
Discovery
Preclinical
Clinical Testing
Nitroimidazole Analogs
(Novartis Institute for Tropical Diseases, NIAID)
Nitroimidazole PA-824
(Chiron)
Moxifloxacin
(Bayer Pharmaceutical, EDCTP)
Carboxylates
(Wellesley College)
Pyrrole LL-3858
(Lupin Limited)
Novel chemical entities
Quinolones
(KRICT/Yonsei University)
Non-Fluorinated Quinolone
(Procter & Gamble)
Macrolides
(University of Illinois at Chicago)
Quinolone KRQ-10018
(KRICT/ Yonsei University)
Novel Targets
(Partner to be announced)
New Compound Classes
(Partner to be announced)
Methyltransferase inhibitors
(Anacor Pharmaceuticals)
Rifalazil Analogs
(ActivBiotics)
Under contract
In discussion/finalization stages
Terminated
TB Alliance support
Global TB Drug Portfolio
September 2005
Discovery
Preclinical
Clinical Testing
Carboxylates
TB Alliance, Wellesley College
Nitrofuranylamides
NIAID, University of Tennessee
Diamine SQ-109
Sequella Inc.
Diarylquinoline TMC207
Johnson & Johnson
Cell Wall Inhibitors
Colorado State University, NIAID
Nitroimidazole Analogs
Dipiperidines (SQ-609)
Sequella Inc.
Gatifloxacin
NIAID, Novartis Institute for Tropical Diseases,
TB Alliance
OFLOTUB Consortium, Lupin, NIAID TBRU,
Tuberculosis Research Centre, WHO TDR
Dihydrolipoamide Acyltransferase
Inhibitors
Cornell University, NIAID
Novel Antibiotic Class
GlaxoSmithKline, TB Alliance
Non-Fluorinated Quinolone
TaiGen
Moxifloxacin
InhA Inhibitors
GlaxoSmithKline, TB Alliance
Picolinamide Imidazoles
NIAID, TAACF)
Synthase Inhibitor FAS20013
FASgen Inc.
Nitroimidazole PA-824
Chiron Corporation, TB Alliance
Isocitrate Lyase Inhibitors (ICL)
GlaxoSmithKline, TB Alliance
Pleuromutilins
GlaxoSmithKline, TB Alliance
Translocase I Inhibitors
Sequella Inc., Sankyo
Nitroimidazo-oxazole OPC-67683
Otsuka
Macrolides
TB Alliance, University of Illinois at Chicago
Quinolones
Nitroimidazo-oxazole Back-up
Otsukai
Pyrrole LL-3858
Lupin Limited
Methyltransferase Inhibitors
Anacor Pharmaceuticals
Screening and Target Identification
AstraZeneca
Natural Products Exploration
Thiolactomycin Analogs
NIAID, NIH
BIOTEC, California State University, ITR, NIAID,
TAACF, University of Auckland
KRICT/ Yonsei University, NIAID,
TAACF, TB Alliance
Bayer Pharmaceuticals, CDC TBTC, Johns
Hopkins University, NIAID TBRU, TB Alliance
The Challenge and
Opportunity of Success
Active TB - Strategy
Shorten: 6 months to 2-3 months
then
Simplify: daily to weekly
130 doses
10 doses
Long-term Goal
Active Disease
7-10 days of treatment
But - very difficult to achieve without
advances in understanding the biology of
“persistence”
“TB Crystal Ball”
All present first-line drugs (HRZE) have
suboptimal profiles
–
–
–
–
pharmacokinetics
cytochrome P450 interactions
poor sterilizing activities (except R)
antagonistic interactions (E with HRZ; H with RZ)
None of present first-line drugs will
ultimately be part of an “optimized” regimen
H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol
Conventional TB Clinical Paradigm


Goal of a development program is to
substitute one new drug for one of the
conventional drugs
HRZE
MRZE or HRZM
Approximate (aggressive) timelines:
Phase I
1 year
Phase II
2 years
Phase III
3 years
6 years
H = isoniazid; R = rifampin; Z = pyrazinamide; E = ethambutol; M = moxifloxacin
Dilemma
Conventional TB Clinical Development Paradigm
E
A
ABCD
F
B
BCDE
6 years
ABCD
G
C
CDEF
6 years
D
DEFG
6 years
24 years
H
EFGH
6 years
EFGH
Strategic Shift
Advancing novel COMBINATIONS
rather than single drugs through the
later drug development pipeline.
Alternative TB Clinical Development Paradigms
EF
#1:
ABCD
6 years
ABCD
AB
GH
CDEF
12 years
CD
6 years
EFGH
EFGH
Alternative TB Clinical Development Paradigms
EFGH
#2:
ABCD
ABCD
ABCD
6 years
6 years
EFGH
EFGH
“Milestones” of Combination
Development Paradigm





All preclinical candidates potentially
included in combination in vitro/in vivo
studies
Compounds tested individually through
standard Phase I and EBA studies
Phase I combination studies
EBA combination studies
Phase II and III combination studies
The Unfolding Solution
CFU Counts after 2 Months’
Treatment
CFU counts
after 2 months treatment
8
Log(10) CFU count
7
6
5
Lung
4
Spleen
3
2
1
0
Pre-Rx
RMZ
RMZPa
PaMZ
Regimen
RPaZ
RMPa
Meeting the Regulatory Challenge
TB Drug Development Forum
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December 6-7, 2005 in DC area
Co-sponsored by TB Alliance, STOP TB
Working Group on New Drugs and Bill and
Melinda Gates Foundation
Funded primarily by unrestricted grant from
AstraZeneca
Significant FDA participation; EMEA and SA
MCC invited
A New TB Drug Development
Paradigm
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Process begins at the preclinical stage
once individual compounds meet
preset criteria
Feasible with present technologies
Engage major regulatory authorities
Think and act “comprehensively”– all
compounds are part of one large
portfolio
new concepts of partnerships