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