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TB Drugs in the Pipeline
Carl M. Mendel, MDTB Alliance
IUATLD MeetingSan 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
TB Alliance
PHARMABIOTECH
ACADEMIA INSTITUTES
GOVERNMENTS
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
TARGET OR CELL-BASED SCREENING
Natural ProductsIMCAS
Whole-Cell Hit to Lead ProgramGSK
TBA-354U. of Auckland/ U. Ill Chicago
PA-824Novartis
Moxifloxacin (+ H, R, Z)Bayer
Topoisomerase I InhibitorsAZ/NYMC
Whole-Cell Hit to Lead ProgramAZ
Mycobacterial Gyrase InhibitorsGSK
TMC207Tibotec
Moxifloxacin (+ R, Z, E)Bayer
PA-824/Pyrazinamide
TB Drug Discovery PortfolioNITD
RiminophenazinesIMM/BTTTRI
TMC207/Pyrazinamide
Gyrase B InhibitorsAZ
Pyrazinamide AnalogsYonsei
PA-824/Moxifloxacin/Pyrazinamide
Folate Biosynthesis Inhibitors AZ
RNA Polymerase InhibitorsAZ
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 DevelopmentDiscovery Preclinical Development
TB Alliance Portfolio
PA-824/TMC207
DiarylquinolinesTibotec/U. of Auckland
THPP SeriesGSK
TB Drug/RegimenDiscovery and Development Process
Drug Candidate
Pool
Discovery
Phase II Phase III
Identification of New DrugCandidates
Selection of Potential New Regimens
Compound 1
Compound 2
Compound 3
Compound 5
Compound 4
Regimen A
Regimen B
Regimen C
Single CompoundPreclinical Development
Phase I EBA
Regimen Identification
Modes of Action
DNA
mRNAReactiveSpecies
Peptide
H+ADP ATP
Bio-reduction
Multiple Targets PA-824 OPC-67683
DNA Gyrase Gatifloxacin Moxifloxacin
RNA Polymerase Rifapentine
Ribosome PNU-100480 AZD-5847
ATP Synthase TMC-207
Cell-WallSynthesis SQ-109
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)– J-Z synergy– Pa-Z additivity– Pa-J antagonism– Pa-M-Z an enhanced novel regimen
Pa = PA-824; M = moxifloxacin; Z = pyrazinamide; J = TMC207
EBA = early bactericidal activity
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
All Treatment Groups: Bi-linear Regression Mean of LogCFU Over Day; Change from Baseline (Day X – Day 0)
-2.5
-2-1
.5-1
-.5
0.5
log
CF
U c
han
ge fr
om b
ase
line
0 2 4 6 8 10 12 14Day
TMC207 TMC207 & PyrazinamideTMC207 & PA-824 PA-824 & Pyrazynamide PA-824 & Pyr & Moxifloxacin Rifafour e275
Bi-linear Regression: logCFU change from baseline
All Treatment Groups: Bi-linear Regression Mean of TTP Over Day; Change from Baseline (Day X – Day 0)
05
01
001
502
00T
TP
cha
nge
from
ba
selin
e
0 2 4 6 8 10 12 14Day
TMC207 TMC207 & PyrazinamideTMC207 & PA-824 PA-824 & Pyrazynamide PA-824 & Pyr & Moxifloxacin Rifafour e275
Bi-linear regression: TTP change from baseline
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-002In 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 = PA-824; M = moxifloxacin; Z = pyrazinamide
Pa(200mg)-M-Z (MDR)Z dose = 1500mg
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
Dose ranging in cidal
Only combos in sterilizing
Dose ranging here for single drugs
DS only
Best doses usedin combos
All final regimenstested here
MDR also
Mouse model
2-wk EBA
2-wk Combo
EBA
2-mo SSCC
Ph3
cidal sterilizing
SD, MD;DDI if needed
Completeregimens as
good as HRZE
Betterthan HRZE
DS + DRsensitive totest regimen
DS vs HRZE
MDR notrandomized
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
United Kingdom Department for International Development
European Union
United States Agency for International Development
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