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Global Alliance for TB Drug Development 5° ° ° ENI FarMed São Paulo, Brazil August 29-31, 2011
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Page 1: Global Alliance for TB Drug Development - IPDFarmaipd-farma.org.br/uploads/paginas/file/palestras/carlos...Global Alliance for TB Drug Development 5 ENI FarMed São Paulo, Brazil August

Global Alliance for TB Drug DevelopmentDevelopment

5°°°° ENI FarMed

São Paulo, Brazil

August 29-31, 2011

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• 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

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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

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PHARMA BIOTECH

GOVERNMENTS

Major Partnerships

TB Alliance

ACADEMIA INSTITUTES

FOUNDATIONS

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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

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TB Alliance Vision

2 – 4 months

10 days

6 – 30 months

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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

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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)

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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

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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

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Launch of the Critical Path to TB Drug Regimens

(CPTR)

11

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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

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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

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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

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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

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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

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FMDFMD

4

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Thank you !