global alliance for tb drug development -...
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Global Alliance for TB Drug DevelopmentDevelopment
5°°°° ENI FarMed
São Paulo, Brazil
August 29-31, 2011
• Independent not-for-profit (501c3)
• Founded in 2000
The TB Alliance
• Virtual organizational model – Experienced R&D and
Market Access capabilities
• Independent Board of Directors and Stakeholders
Association
• Scientific Advisory Committee with expertise in TB • Scientific Advisory Committee with expertise in TB
and pharmaceutical R&D
• Global Market Access Advisory Committee
TB Alliance Mission
• Develop new, better treatments for TB• Develop new, better treatments for TB
• Ensure that new regimens are affordable,
adopted for use, and made widely available
• Coordinate and act as catalyst for global TB
drug development activities
PHARMA BIOTECH
GOVERNMENTS
Major Partnerships
TB Alliance
ACADEMIA INSTITUTES
FOUNDATIONS
Current TB Therapy and Unmet Needs
Patient Population
CurrentTherapy
UnmetNeeds
Drug-Susceptible TB 4 drugs; ≥6 month therapy Shorter, simpler therapyDrug-Susceptible TB 4 drugs; ≥6 month therapy Shorter, simpler therapy
Drug-ResistantM(X)DR-TB
Few drugs (including injectables); ≥18 months therapy; toxicities
Totally oral, shorter, more efficacious and safer therapy
TB/HIVCo-Infection
Drug-drug interactions with HIV medications
Ability to co-administer TB regimens with ARVs
Latent TBLatent TBInfection
6-9 months of treatment Shorter, safer therapy
► Significant improvements in therapy are needed for all patient populations
TB Alliance Vision
2 – 4 months
10 days
6 – 30 months
Target Profiles of New Regimens
• Significantly shorten duration of treatment
• Effective against MDR- and XDR-TB (novel MOA)
• Co-administration with ARVs
• Pediatric “friendly”
• Orally bioavailable and maximum of once daily dosing
• Improved safety and tolerability
• Low cost of goods
Achieve the greatest impact by meeting all or most of the target profiles
Sustainable Operating Model
• In-licensing and independent development
Virtual R&D approach with tremendous resource leveraging:
PA-824 (Chiron/Novartis)
• Collaborative R&D with affordability commitment
Moxifloxacin (Bayer); GSK and Astra Zeneca mini portfolios (GSK and Astra
Zeneca); TB drug portfolio (Novartis); TMC-207 (J&J)
• Contracted R&D with enabling IP rights
Quinolone (KRICT); Nitroimidazole (ACSRC); Riminophenazine (IMM);
Confidential
Quinolone (KRICT); Nitroimidazole (ACSRC); Riminophenazine (IMM);
Phenotypic screening (UIC); Energy metabolism (UPenn); Protease (IDRI);
Tryptanthrine (KRICT); RNAP (Rutgers); LeuRS (Anacor); Menaquinone (CSU);
Topo I (NYMC); Natural products (IMCAS)
Changing the Way TB Drugs are Developed
• For the first time in history, a clinical TB drug
pipeline is available
• Optimized novel combinations are needed to • Optimized novel combinations are needed to
address requirements for significant treatment
shortening for drug sensitive and resistant
disease and TB/HIV co-infection
• Current TB drug development approach replaces
one drug at a time, requiring decades to introduce
a new regimen that consists of even three new a new regimen that consists of even three new
agents
• New paradigm needed for rational selection and
development of new combinations
Optimizing DS-TB Drug Development Testing regimens containing multiple novel agents for
drug sensitive TB
E A G C H DBF
ABCD BCDE CDEF DEFG EFGH
E A G C H DBF
Conventional Development Paradigm
ABCD CDEF EFGH
EF AB CDGH
Alternative Development Paradigm
24 years
Paradigm
12 years
ABCD EFGH
ABCD EFGH
6 years
Alternative Development Paradigm
Launch of the Critical Path to TB Drug Regimens
(CPTR)
11
Novel Regimen Development• Use animal model(s) to identify most promising
regimens
• Conduct full preclinical, Phase I and Phase II EBA • Conduct full preclinical, Phase I and Phase II EBA evaluations of each individual drug
• Explore drug-drug interactions and, as necessary,
preclinical toxicology of combinations
• Take combinations/regimens into clinical development (Phase II, III)
CONFIDENTIAL
(Phase II, III)
Build regimen bottom up rather than from
standard of care
Bactericidal Activity of Different Treatment Regimens in the Mouse
8
9
Untreated
1
2
3
4
5
6
7
Untreated
RHZ
PaMZ
PaM
PaZ
MZ
Log10 CFU in Lungs
R= rifampin
H= isoniazid
Z= pyrazinamide
CONFIDENTIAL
0
1
0 4 8
Weeks
Z= pyrazinamide
Pa= PA-824
M= moxifloxacin
TARGET OR CELL-BASED
SCREENING
Natural Products
IMCAS
Whole-Cell Hit to Lead
ProgramGSK
Nitroimidazoles
U. of Auckland/
U. Ill Chicago
PA-824
Novartis
Moxifloxacin (+ H, R, Z)
BayerMycobacterial Gyrase
InhibitorsGSK
InhA Inhibitors
GSK
TMC207
Tibotec
Moxifloxacin (+ R, Z, E)
BayerProtease Inhibitors
IDRI Malate Synthase
InhibitorsGSK/TAMU
LEAD IDENTIFICATION LEAD OPTIMIZATION CLINICAL PHASE I CLINICAL PHASE II CLINICAL PHASE III
Preclinical TB
Regimen Development JHU/U. Ill Chicago
Clinical DevelopmentDiscovery Preclinical Development
TB Alliance Portfolio
Topoisomerase I
InhibitorsAZ/NYMC
Whole-Cell Hit to Lead
ProgramAZ
Diarylquinolines
Tibotec/U. of AucklandPA-824/PyrazinamideTB Drug Discovery Portfolio
NITD
Riminophenazines
IMM/BTTTRI
TMC207/PyrazinamideGyrase B Inhibitors
AZ
Pyrazinamide Analogs
Yonsei
PA-824/
Moxifloxacin/Pyrazinamide
Folate Biosynthesis
Inhibitors AZ
GSK/TAMU
RNA Polymerase
InhibitorsAZ
JHU/U. Ill Chicago
� AstraZeneca (AZ)� Johnson & Johnson / Tibotec (Tibotec)
OUR R&D PARTNERS
PA-824/TMC207
Phenotypic Hit to Lead
ProgramU. Ill Chicago
Menaquinone
Biosynthesis Inhibitors CSU
Energy Metabolism
Inhibitors AZ/U. Penn
� AstraZeneca (AZ)
� Bayer Healthcare AG (Bayer)
� Beijing Tuberculosis and Thoracic Tumor
Research Institute (BTTTRI)
� Colorado State University (CSU)
� GlaxoSmithKline (GSK)
� Infectious Disease Research Institute (IDRI)
� Institute of Materia Medica (IMM)
� Institute of Microbiology, Chinese Academy of
Sciences (IMCAS)
� Johns Hopkins University (JHU)
� Johnson & Johnson / Tibotec (Tibotec)
� New York Medical College (NYMC)
� Novartis Institute for Tropical Diseases (NITD)
� Novartis Pharmaceutical (Novartis)
� Texas A&M University (TAMU)
� University of Auckland (U. of Auckland)
� University of Illinois at Chicago (U. Ill Chicago)
� University of Pennsylvania School of Medicine (U.
Penn)
� Yonsei University (Yonsei)
Novel TB
regimen development
Current first-line TB
treatment consists of
Isoniazid (H) +
rifampicin (R) +
pyrazinamide (Z) +
ethambutol (E)
November 2010
HERZ +Mpbo
HR +Mpbo
HRRegimen 1
630 patientsComparison 1
M substituted for H
REMox Phase III TB Trial(Randomized, Double Blind, Placebo Control, Noninferiority)
MERZ +Hpbo
MR +Hpbo
Hpbo+Rpbo
MHRZ +Epbo
HR +M
Hpbo+Rpbo
Regimen 2
630 patients
Regimen 3
630 patients
M substituted for H
(4 vs 6 mo)
Comparison 2
M substituted for E(4 vs 6 mos.):
H = isoniazid ; E = ethambutol; R = rifampin; Z = pyrazinamide; M = moxifloxacin; pbo = placebo
Months 0 2 4 6 12 18
Visits
Screening Follow-UpContinuationIntensiveActive Phase
H = isoniazid ; E = ethambutol; R = rifampin; Z = pyrazinamide; M = moxifloxacin; pbo = placebo
REMox Sites (38)
Guadalajara
Nairobi
Delhi (15)
Bangkok (2) Malaysia
Tianjin
Moshi M’beya
Beijing
Shanghai
Tembisa
Eldoret
Lusaka(2)
Kericho
Johannesburg
Brits Cape Town
Stellenbosch
Tembisa
Durban (3)
Soweto
FMDFMD
4
Thank you !