Hope in the Pipeline II: Pharmaceuticals (Ann Ginsberg, M.D., Ph.D.)

8/7/2019 Hope in the Pipeline II: Pharmaceuticals (Ann Ginsberg, M.D., Ph.D.)

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The TB Drugs Pipeline:

From Drugs to Regimens (CPTR and NC-001)

Dr. Ann Ginsberg

Chief Medical Officer, TB Alliance

November 12, 2010

Berlin, Germany


2/25

The Threat of TB

TB remains one of the worlds deadliest infectious

diseases second only to HIV/AIDS killing one personevery 20 seconds

Each year, TB kills more than 1.8 million people, and

there are 9.4 million new cases, primarily in developing

countries TBs complex and deadly interaction with HIV/AIDS has

even further exacerbated the global TB epidemic

There is an urgent unmet need for better treatments.


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Current TB Therapy and Unmet Needs

Patient Population Current

Therapy

Unmet

Needs

Drug-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, moreefficacious, safer and lowercost therapy

TB/HIVCo-Infection

Drug-drug interactions with HIVmedications

Ability to easily co-administerTB regimens with ARVs

Latent TB

Infection

6-9 months of treatment Shorter, safer therapy

All treatments for active TB must be multidrug regimens Significant improvements in therapy are needed for all patient populations


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TB Treatment Evolution

1950 2005

19521st regimen: Streptomycin PAS Isoniazid

1963 Rifampin(R) discovered

1974BMRC Trials

add R & Z

1970

1954Pyrazinamide (Z)

discovered but liver

toxicity

Rx lasts from 12-24 months

Standard Regimen by 1960s based on 1952 drugs

1970BMRC

Trials

add R

Rx shortened to 9 months

Standard Therapy2 months: R, H, Z, E

+

4 months: R, H

Rx shortened to 6 months

19801960

1946

Strepto-

mycin 1st

used for TB

1998Rifapentine

approved

1961

Ethambutol (E)discovered


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Product Development Partnerships

(PDPs)

Non-profit enterprises to accelerate the R&D and adoption of new,affordable global health products

Create and manage partnerships and resources across public, privateand philanthropic sectors

Utilize a portfolio management approach to maximize efficiency andprioritize resources to the most promising candidates

Act as a catalyst to advance the field of new tools for all participants

PDPs are a proven model to fill critical scientific gaps andaccelerate the development and delivery of new health technologies


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TB Alliance

Founded in 2000 Not-for-profit Product

Development Partnership(PDP) headquartered in NewYork, with offices in Brusselsand Pretoria

Entrepreneurial, virtual drugdevelopment approach

Largest portfolio of TB drug

candidates in history

TB

Alliance

PHARMABIOTECH

ACADEMIA INSTITUTES

GOVERNMENTS

FOUNDATIONS


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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

development activities


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New regimens must be made available to patients in countries

that adopt them Ensured by developing a robust manufacturing and

distribution plan with pharmaceutical partners, generics,

countries, donors, and other actors

Public programs and private sector must accept and

implement new regimens Ensured through acceptability studies, engagement with local

communities, and direct negotiations with country programs,

WHO, and other stakeholders to bring about guideline change

Regimens must be sufficiently low cost to be procured indeveloping countries

Ensured through negotiation of agreements, cost-of-goods

considerations in development process

Commitment to AAA

Affordable

Adoptable

Available


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TB Alliance VisionFDC

s

2 4 months

6 >24 months

10 days

Success will requirenovel multi-drugcombinations


10/25

TARGET OR CELL-BASED

SCREENING

Natural ProductsIMCAS

Whole-Cell Hit to LeadProgram

GSK

NitroimidazolesU. of Auckland/

U. Ill Chicago

PA-824Novartis

Moxifloxacin (+ H, R, Z)Bayer

Topoisomerase I

InhibitorsAZ/NYMC

Whole-Cell Hit to LeadProgram

AZ

Mycobacterial GyraseInhibitors

GSK

InhA Inhibitors

GSK

TMC207

Tibotec

Moxifloxacin (+ R, Z, E)

BayerProtease Inhibitors

IDRI

Phenotypic Hit to Lead

Program

U. Ill Chicago

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

Malate Synthase

InhibitorsGSK/TAMU

RNA Polymerase

Inhibitors

AZ/Rutgers

Menaquinone

Biosynthesis Inhibitors

CSU

Energy Metabolism

InhibitorsAZ/U. Penn

LEAD IDENTIFICATION LEAD OPTIMIZATION CLINICAL PHASE I CLINICAL PHASE II CLINICAL PHASE III

Preclinical TB

Regimen DevelopmentJHU/U. Ill Chicago

Novel TB

regimen development

Clinical DevelopmentDiscovery Preclinical

Development

TB Alliance Portfolio

November 2010


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MoxifloxacinPhase of Development: 3Partner: BayerPotential use against DS- and MDR-TB; currently being tested in DS-TB

PA-824

Phase of Development: 2Partner: In-licensed from Chiron, which was subsequently acquired by NovartisNew mechanism of actionPotential use against DS-, MDR- and XDR-TB

TMC-207

Phase of Development: 2Partner Tibotec/Johnson & JohnsonNew mechanism of actionPotential use against DS-, MDR- and XDR-TB, currently being tested in both DS

and MDR patients

TB Alliance 3 Clinical Stage

Compounds


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Clin


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Historic Opportunity

For the first time in history, the

opportunity exists to develop truly

novel regimens, containing multiple

new chemical entities with novel

mechanisms of action

TB treatment of 2-4 months


14/25

Paradigm Change in TB Drug

Development

Current TB drug development approach

replaces one drug at a time, requiring decades

to introduce a new regimen that consists ofmultiple novel agents

New paradigm needed for rational selection

and development of new combinations


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New Development Paradigm:

Combination testing of novel regimens

Under the new paradigm, the regimen, not an individual drug, is the

unit of development New drugs are tested in combinations in clinical trials simultaneously,

rather than successively

Combination

approachreduces

time tomarket toas little as

1/4th


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From Drugs to Regimens:

CPTR and NC-001

How We Are Shifting the Paradigm


17/25

Launch of Critical Path to TB Drug

Regimens (CPTR)- BMGF, Critical Path Institute and TB Alliance

Please visit: CPTRinitiative.org for more information

US FDA Commissioner,

Dr. Margaret Hamburg18 March 2010


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Critical Path to TB Drug Regimens

(CPTR) Accelerates the development of new regimens by testing promising new drugs together,

rather than by sequential testing of individual drugs

Overcomes intellectual property barriers to private sector collaboration

Commitment to access puts patients before profits

Collaboration maximizes synergy, reduces cost, increases efficiency

Engages regulatory authorities to develop new pathways and guidances for combination

testing and approval

Endorsed by donors, governments, multilaterals, corporations, civil society, and non-

profits

A model for other therapeutic areas that require combinations, such as cancer andhepatitis


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The New Opportunity: trial NC-001

For the first time, there is an opportunity to treat

both drug-sensitive (DS-TB) and multidrug-

resistant TB (MDR-TB) with the same regimen,

and alter the course of the TB pandemic by

shortening and simplifying treatment worldwide

3-drug regimen in NC-001 =

Moxifloxacin(TB Alliance, Bayer) + PA-824(TB Alliance) +

Pyrazinamide(existing antibiotic)


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Potential to:

treat DS-TB and MDR-TB with the same regimen: would simplifytreatment and delivery

shorten treatment for drug-sensitive and MDR-TB to less than 6

months

simplify treatment for people with TB/HIV (should not havesignificant interactions with antiretrovirals no rifampicin)

enable scale-up of MDR-TB treatment - shorter, simpler (no

injectables), more affordable treatment for MDR-TB

Sets stage for new era in TB drug development: new drugs

tested in combination, enabling delivery of new treatments in

years vs. decades

Significance of NC-001 Trial


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Current TB Therapy and Unmet Needs

Patient Population Current

Therapy

Unmet

NeedsDrug-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, moreefficacious, safer and lower cost

therapy

TB/HIVCo-Infection

Drug-drug interactions with HIVmedications

Ability to easily co-administer TBregimens with ARVs

Latent TBInfection

6-9 months of treatment Shorter, safer therapy

Significant improvements in therapy are needed for all patient populations

This trial addresses at least three major unmet needs in TB therapy


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Thank You


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DISCOVERY: Identify lead structural series; optimize activity in vitro, efficacy in animals, and

other pharmacological properties. Perform preclinical safety studies allowing filing of a new

drug application. Use combination testing to identify the best potential new regimens for

clinical development.

PHASE I: Test drug candidates and regimens in small numbers of healthy volunteers forsafety, tolerability, and pharmacokinetic properties.

PHASE II: Evaluate single drug candidates (Phase IIa) and multidrug regimens (Phase IIb) in

TB patients for potential efficacy and further assessment of safety.

PHASE III: Test multidrug regimens in large numbers of TB patients for efficacy and safety.

REGULATORY APPROVAL: Regulatory authorities license the drug/regimen after reviewing

all preclinical and clinical results (also called registration)

ADOPTION/ AVAILABILITY: National TB control programs adopt the new drug/regimen.

The Drug Development Process

Phase II


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Need for a Stronger Global TB Drug

Pipeline

(Data based on: Brown, D.; Superti-Furga, G. Drug Discovery Today2003, 8, 1067-1077)

Discovery Preclinical Clinical

50 31 19 12 7 4 2

ONE

approved

drug

5 Years 1.5 Years 6 Years

NumberofProje

ct

s

Global TB Drug PipelineGlobal TB Drug Pipeline

(10)(10) (7) (7)(7) (7) (2) (6)(2) (6) (2)(2)

Documents

Hope in the Pipeline II: Pharmaceuticals (Ann Ginsberg, M.D., Ph.D.)