Hope in the Pipeline I

Development of Drugs to Treat TB

IUALTD 2011 - J2J Symposium

Daniel Everitt, MD

TB Alliance

Development of Drugs to Treat TBOutline of Discussion

• Current and historic regimens to treat TB• Treatment needs for the future and our historic

opportunity• The steps and realities of TB drug development

– Specific examples from TB Alliance collaborations• A paradigm shift for drug development • Drugs in the pipeline• Optimism for international collaboration to develop

superior treatments for TB

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Treatment Evolution for“Drug Sensitive” TB

1950 2005

1952 1st regimen:• Streptomycin• PAS• Isoniazid (H)

1963 Rifampin (R) discovered

1974 BMRC 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 Therapy 2 months: R, H, Z, E

+4 months: R, H

Rx shortened to 6 months

19801960

1946Strepto-mycin 1st

used for TB

1998 Rifapentine approved

1961 Ethambutol (E)

discovered

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The Burden of Therapy for Multi-drug Resistant TB

Example of a typical regimen for MDR-TB•Intensive phase of 6-9 months – aim to directly observe 6 days/week:

– Six drug combination, one given by injection•Continuation phase of 18 months:

– Four drugs•A patient may need longer therapy if sputum is not clear of TB at month 4

Note: If the patient has HIV, he/she may need to take 3 additional anti-retroviral drugs

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► Significant improvements in therapy are needed for all patient populations

Patient Population

CurrentTherapy

UnmetNeeds

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, more efficacious, safer and lower cost therapy

TB/HIVCo-Infection

Drug-drug interactions with HIV medications

Ability to co-administer TB regimens with ARVs

Latent TBInfection

6-9 months of treatment Shorter, safer therapy

Children4 drugs; ≥6 month therapy

Shorter, simpler therapy with pediatric-friendly dosing

Current TB Therapy and Unmet Needs

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TB Alliance

• Founded in 2000

• Not-for-profit Product Development Partnership (PDP) headquartered in New York, with offices in Brussels and Pretoria

• Entrepreneurial, virtual drug development 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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TB Alliance VisionFDCs

2 – 4 months

6 – 30 months

10 days

Success will require novel multi-drug

combinations

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The need for new TB drugs

• The need to ensure adherence can put a huge burden on patients

• Shorter therapies equals > adherence, > cure, < burden on patients, and < emergence of drug resistance

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Adherence to Therapy (DOTS)

Effective Medications

Health Care System to Diagnose TB, Treat, and Confirm Cure

Financing of Medications and the Health Care System

What is Needed to Cure a Patient with TB?

Health

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Classic Phases of Drug Development

(Data based on: Brown, D.; Superti-Furga, G. Drug Discovery Today 2003, 8, 1067-1077)

Discovery Preclinical Clinical

50 31 19 12 7 4 2ONE

approved drug

5 Years 1.5 Years 6 Years

Num

ber

of P

roje

cts

Global TB Drug PipelineGlobal TB Drug Pipeline

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

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New Development Paradigm: Combination testing of novel regimens

• Under the new paradigm, the regimen, not an individual drug, becomes the unit of development

• New drugs are tested in combinations in clinical trials simultaneously, rather than successively

Combination approach

reduces time to market by

~3/4ths

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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

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Drug Development – the Preclinical Phase

• Many steps to develop a promising molecule

• Safety evaluations typically done in two animal species (e.g. rat and dog)

• Pharmacology studies to evaluate efficacy on a relevant endpoint– Aim to find a blood concentration that

correlates with the maximum effect

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Bactericidal Activity of Different Treatment Regimens in the Mouse

0

1

2

3

4

5

6

7

8

9

0 4 8

Untreated

RHZ

PaMZ

PaM

PaZ

MZ

Log10 CFU in Lungs

Weeks

R= rifampin

H= isoniazid

Z= pyrazinamide

Pa= PA-824

M= moxifloxacin

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Phase 1 Studies – From the lab in to HumanTolerability, pharmacokinetics – often healthy volunteers

Time (h)

0 12 24 36 48 60 72 84 96Mea

n P

lasm

a P

A-8

24 C

once

ntra

tions

(ng

/mL)

0

500

1000

1500

2000Phase A - 200 mg fedPhase A - 200 mg fasted

Time (h)

0 12 24 36 48 60 72 84 960

100

200

300

400

500

600Phase B - 50 mg fedPhase B - 50 mg fasted

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Example of Phase 1 Study -Single dose pharmacokinetics in healthy volunteers under fed and fasted conditions

Phases 2 and 3 – Evaluate the Effect of the Drug in Patients with the Disease

• Some Key Considerations:

– Where can we find patients with the disease?

– Where can we find investigators who can do a clinical trial with high quality?

– What do we measure to show the drug has been effective?

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Where in the World are Patients with Tuberculosis?

www.worldmapper.org

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Where in the World are Patients with Tuberculosis?

www.worldmapper.org

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Doctors Working in the World

www.worldmapper.org

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The Community of Kibera, KenyaTB is a Disease of Poverty

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How Are We Exposed to the TB Bacteria?

Most TB is spread in droplets from the lungs of persons infected with active TB.

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51 year old Kenyan man with a cough, weight loss, confusion; wife died 3 years earlier with tuberculosis

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Rooms for Sputum Collection

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Sputum Sample in Collection Cup

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The Research Lab at Kibera

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Tuberculosis (Acid Fast Bacillus – “AFB”) from a Sputum Smear Under the Microscope

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The Tuberculosis Bacteria from a Sputum Sample Growing in a Culture

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TB Colony Forming Units “CFUs” – Now Countable – from a Diluted Sputum Specimen

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Trial Medication Card

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Clinical Research Community Engagement Workers

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PA-824: Phase 2 Dose Selection2 week study in patients with TB to choose a

dose for later studies

RHZE

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From a Single Drug to a Multi-Drug Regimen to Treat Tuberculosis

• Study NC-001 Just Completed– A Phase 2 study of the 3-drug regimen in patients

over a 2 week period• PA-824 combined with moxifloxacin and pyrazinamide• Results will be presented at IUATLD Symposium #46,

Sunday

• Next Step – a 2 month study of the regimen compared to the standard 4 drug combination

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Implications of Study NC-001 for a Regimen to Treat DS & MDR TB

• PaMZ is a well tolerated viable regimen to advance for further testing in both DS & MDR patients sensitive to the regimen

• It is safe and feasible to progress from a study of a single drug in patients to a study of that drug in a full regimen as a next step

• The mouse model was predictive of the bacterial-killing activity of single drugs and regimens in this short-term human study

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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

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The Global TB Development Pipeline

From the Stop TB Partnership Working Group on New Drugs

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A New Regimen Approved by Regulatory Agencies is Not Enough

• How does the new regimen fit in the current WHO/country therapy recommendations?

• What will be the barriers to acceptance?

• Who are the decision makers?

• What work needs to be done before a new regimen is approved?

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What Countries Want Value Proposition StudyPublished August 2009

Most stakeholders would welcome treatment shortening as the primary goal. Unacceptable trade-offs in all countries:

• Decreased efficacy

• Additional safety concerns or side effects requiring monitoring or expensive adjuvant therapies

• Significant drug interactions with other commonly-used drugs (including ARVs)

Unacceptable trade-offs in some countries:

• Treatment frequency significantly different from current TB program (e.g., India)

• Unavailability in fixed-dose combination (FDC)

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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 in developing countries

• Ensured through negotiation of agreements, cost-of-goods considerations in development process

Our “AAA” Mandate

Affordability

Adoption

Availability

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40 Years Has Been Too Long to Wait!

Shorter, effective, safe regimens for TB therapy are within sight if we work together toward this compelling goal

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