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 TB Outline 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

Treatment Evolution for Drug Sensitive TB

1950
1946
Streptomycin 1st used for TB 1st

1960
1952
regimen: Streptomycin PAS Isoniazid (H)

1970
1974
BMRC Trials add R & Z

1980

2005
1998
Rifapentine approved

1963 Rifampin 1970

(R) discovered BMRC Trials add R 1961 Ethambutol (E) discovered 1954 Pyrazinamide (Z) discovered but liver toxicity

Standard Therapy 2 months: R, H, Z, E + 4 months: R, H

Standard Regimen by 1960s based on 1952 drugs

Rx shortened to 6 months Rx shortened to 9 months Rx lasts from 12-24 months

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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Current TB Therapy and Unmet Needs

Patient Population
Drug-Susceptible TB Drug-Resistant M(X)DR-TB TB/HIV Co-Infection

Current Therapy
4 drugs; 6 month therapy Few drugs (including injectables); 18 months therapy; toxicities Drug-drug interactions with HIV medications

Unmet Needs
Shorter, simpler therapy Totally oral, shorter, more efficacious, safer and lower cost therapy Ability to co-administer TB regimens with ARVs

Latent TB Infection
Children

6-9 months of treatment

4 drugs; 6 month therapy

Shorter, safer therapy

Shorter, simpler therapy with pediatric-friendly dosing

Significant improvements in therapy are needed for all patient populations

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TB Alliance
Founded in 2000
GOVERNMENTS

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

PHARMA

BIOTECH

TB Alliance
ACADEMIA INSTITUTES

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 development activities

TB Alliance Vision

10 days 2 4 months

6 30 months

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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What is Needed to Cure a Patient with TB?

Effective Medications Adherence to Therapy (DOTS)

Health

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

Financing of Medications and the Health Care System

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Classic Phases of Drug Development

Discovery Preclinical Clinical

Target or Cellbased Screening

Lead Identification

Lead Optimization

Preclinical development

Clinical Phase I

Clinical Phase II

Clinical Phase III

Number of Projects

ONE

50

31

19

12

approved drug

Global TB Drug Pipeline

(10) 5 Years (7) (7) 1.5 Years (2) (6) 6 Years (2)

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

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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/Regimen Discovery and Development Process

Discovery Single Compound Preclinical Development Phase I EBA Phase II Phase III

Compound 1
Compound 2 Compound 3 Compound 4 Compound 5

Regimen A
Drug Candidate Pool

Regimen B

Regimen Identification

Regimen C

Identification of New Drug Candidates

Selection of Potential New Regimens

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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

9 8 7

Untreated RHZ PaMZ PaM PaZ MZ

R= rifampin H= isoniazid Z= pyrazinamide Pa= PA-824

Log10 CFU in Lungs

6 5 4 3 2 1 0 0 4 8

M= moxifloxacin

Weeks
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Phase 1 Studies From the lab in to Human

Tolerability, pharmacokinetics often healthy volunteers
Mean Plasma PA-824 Concentrations (ng/mL)
600 2000 Phase A - 200 mg fed Phase A - 200 mg fasted 500

Phase B - 50 mg fed Phase B - 50 mg faste

1500

Example of Phase 1 Study Single dose pharmacokinetics 400 in healthy volunteers under fed and fasted conditions
300

1000 200 500 100

0 0 12 24 36 48 60 72 84 96

0 0 12 24 36 48 60 72 84

Time (h)

Time (h)

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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, Kenya TB 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 Selection 2 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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TB Alliance Portfolio
Discovery
TARGET OR CELL-BASED SCREENING LEAD IDENTIFICATION LEAD OPTIMIZATION

Preclinical Development
Whole-Cell Hit to Lead Program GSK Mycobacterial Gyrase Inhibitors GSK THPP Series GSK Pyrazinamide Analogs Yonsei Diarylquinolines Tibotec/U. of Auckland Riminophenazines IMM/BTTTRI TBA-354 U. of Auckland/ U. Ill Chicago Preclinical TB Regimen Development JHU/U. Ill Chicago

Clinical Development
CLINICAL PHASE I CLINICAL PHASE II CLINICAL PHASE III

Natural Products IMCAS

PA-824 Novartis TMC207 Tibotec PA-824/Pyrazinamide

Moxifloxacin (+ H, R, Z) Bayer
Moxifloxacin (+ R, Z, E) Bayer

TB Drug Discovery Portfolio NITD Topoisomerase I Inhibitors AZ/NYMC Gyrase B Inhibitors AZ Folate Biosynthesis Inhibitors AZ Whole-Cell Hit to Lead Program AZ RNA Polymerase Inhibitors AZ

TMC207/Pyrazinamide

PA-824/TMC207

PA-824/ Moxifloxacin/ Pyrazinamide

Energy Metabolism Inhibitors AZ/U. Penn

Novel TB regimen development

Current first-line TB treatment consists of: isoniazid (H) + rifampicin (R) + pyrazinamide (Z) + ethambutol (E)

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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 Study
Published 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 commonlyused 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) 38

Our AAA Mandate

Regimens must be sufficiently low cost to be procured in developing countries Ensured through negotiation of agreements, cost-of-goods considerations in development process

Affordability

Adoption

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 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

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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