New York Product Development Partnerships for Global Health:

The Global Alliance for TB Drug Development

Gerald J. Siuta, Ph.D.Consultant, Business Development

New York Biotechnology Association 17th Annual MeetingNew York City, NY

May 20, 2008

Global Tuberculosis Epidemic

• One-third of the world’s population is infected with Mycobacterium tuberculosis (M.tb.)– 2 billion people

• 8-9 million develop active disease annually• 2 million deaths occur each year

– 1 person dies every 15 seconds

• 400,000 cases of MDR-TB each year• Leading cause of death in HIV-positive people

– 12 Million people are TB/HIV co-infected

TB’s economic toll: $16 billion a year

Current TB Drug Therapy

• Active TB– Standard therapy – 4 drugs (isoniazid, rifampin, pyrazinamide &

ethambutol) for 2 months, followed by isoniazid and rifampin for 4 months

• Latent TB– Standard therapy – isoniazid for 9 months

• Multi-Drug Resistant TB (MDR-TB)– Individualized, prolonged therapy, few available drugs, poorly

tolerated and difficult to administer• TB/HIV Co-Infection

– Treatment as in active TB, but drug interactions with antiretroviral agents make simultaneous therapy difficult

• Extensively Drug Resistant TB (XDR-TB)– No treatment available

The Need for New TB Drugs

• Complex 6-9 months treatment with a 4 drug combination regimen

• No new anti-TB drug in over 40 years

• TB/HIV co-infections fueling each other

• MDR-TB is on the rise

• Unattractive market for private sector

• No capitalization of public sector research

History of the TB Alliance

• Cape Town Declaration – February 2000– Hosts: Rockefeller Foundation and the Medical Research

Council of South Africa– Over 120 organizations (health, science, philanthropy and

private industry)

• Results – Support goals of Stop TB Initiative– Create Scientific Blueprint– Develop Pharmacoeconomic Analysis

Build a Global Alliance forTB Drug Development

The TB Alliance

• Independent, international Product Development Partnership founded in October 2000

• Non-profit organization• Headquarters in New York City

– Offices in Brussels and Cape Town

• Entrepreneurial, virtual R&D approach– Out-source R&D to public and private partners

• Pro-active fundraising– Over US $200 million raised

• Support ~ 200 FTE worldwide and 35 FTE in-house

Our Mission

• Develop an entirely new therapeutic regimen that will shorten or simplify the treatment of tuberculosis

• Coordinate and act as catalyst for global TB drug development activities

• Ensure Affordability, Adoption and Access (AAA Strategy)

AAA Strategy

• Affordability– Appropriate pricing in developing countries

• Adoption– Ensure that new drugs are incorporated into

existing treatment programs

• Access– Procurement and distribution to those patients

who need them most

Our VisionFDCs

10 Days

2 Months

6 Months

Profile of a New TB Drug

• Shorten treatment to less than 2 months

• Novel mechanism of action (MDR/XDR-TB)

• Orally active

• Once daily or intermittent therapy

• Compatible with HIV treatment

• Low cost of goods

Financial Support

• Bill and Melinda Gates Foundation

• Rockefeller Foundation

• Netherlands Ministry for Development Cooperation

• United States Agency for International Development (USAID)

• Governments of Great Britain and Ireland

Types of Deals

• In-Licensing

• IP Assignment

• Sponsored R&D

• Collaborative R&D

• Freedom to Operate

• Clinical Trials

Lead Identification

Lead Optimizati

onPreclinical Phase I Phase II Phase III

Malate Synthase Inhibitors

Riminophenazines

GSK Focused Screening

Multifunctional Molecules

Mycobacterial Gyrase Inhibitors

Pleuromutilins

Nitroimidazoles

Quinolones

InhA Inhibitors

PA-824

Moxifloxacin

TB Alliance Portfolio

TB ALLIANCE TB ALLIANCE PROGRAMSPROGRAMS

DISCOVERYDISCOVERY CLINICALCLINICAL DEVELOPMENTDEVELOPMENT

Phenotypic Screening

Protease Inhibitors

Energy Metabolism Inhibitors

Chiron/Novartis

• PA-824 – A novel nitroimidazole

• Discovered by Pathogenesis, Inc.

• Distinct mechanism of action

• Potent activity against both active and slow growing M.tb.

• Possesses both bactericidal and sterilizing activity

Chiron/Novartis

• Worldwide exclusive license for the treatment of tuberculosis

• Defined scientific milestones

• Grant-back option

• Manufacturing rights

• No royalties in developing world

Development of PA-824

• Phase I clinical trials began June 3, 2005– Preclinical development completed in 3 years– Drug was well tolerated with no definitive

dose-limiting adverse events

• Phase II extended Early Bactericidal Activity (EBA) study has begun in Cape Town, South Africa

University of Auckland

• Synthesis of PA-824 analogs

• Identified many new pharmacophores, several of which have demonstrated potent activity against TB

• Optimization has led to nitroimidazole analogs that have in vitro activity greater than PA-824

GlaxoSmithKline

• Joint drug discovery program at GSK’s Diseases of the Developing World facility in Tres Cantos, Spain

• Five individual projects:– Mycobacterial gyrase inhibitors– InhA inhibitors– Malate synthase inhibitors – Pleuromutilins– Focused screening

GlaxoSmithKline

• Project oversight by Joint Steering Committee• TB Alliance helps to support 25 full-time

scientists at GSK working exclusively on the TB drug program

• GSK absorbs all remaining overhead costs• GSK contributes a matching number of staff• Any resulting medicines will be made affordable

and accessible to those most in need

Korea Research Institute of Chemical Technology (KRICT)

• Located in Daejeon, South Korea

• Synthesized more than 600 quinolones, pyridones & quinolizines

• In vitro and in vivo biological testing at the Yonsei University College of Medicine in Seoul, South Korea

• Four lead compounds have been selected for further preclinical evaluation

Cumbre Pharmaceuticals

• Joint program on the design, synthesis and optimization of multifunctional antibiotics

• The TB Alliance has exclusive rights to these compounds for the treatment of tuberculosis and other neglected diseases

• Cumbre retains rights to pursue the compounds for use in other infectious disease areas

Institute of Materia Medica

• Joint research partnership for the design, synthesis and evaluation of a class of compounds known as riminophenazines– Class was discovered in the 1950s

• The collaboration will utilize IMM's expertise and integrated capabilities in chemistry, pharmacology and manufacture

The TB Alliance-BayerMoxifloxacin Deal

Moxifloxacin

• Fluoroquinolone antibiotic

• Orally active

• Once-a-day dosage

• Approved in 104 countries for the treatment of bacterial respiratory and skin infections

Moxifloxacin for TB

• Novel mechanism of action: kills M.tb. by inhibition of DNA gyrase

• In vivo studies showed moxifloxacin reduced treatment time by two months when substituted for isoniazid

• Safe to use with antiretroviral agents since it is not metabolized by the cytochrome P-450 enzyme system

October 18, 2005

TB Alliance and Bayer HealthCare announced a partnership to

coordinate a global clinical trial program to study the potential of

moxifloxacin to shorten the standard six-month treatment of TB

The Partnership

• Clinically assess the efficacy and safety of moxifloxacin as a front-line agent for the treatment of TB

• If clinical trials are successful, register moxifloxacin for a TB indication

• Committed to making the product affordable and accessible to patients in the developing world

Moxifloxacin Clinical Trials

• Evaluate whether substitution of moxifloxacin for one of the standard TB drugs (isoniazid or ethambutol) eliminates TB infection faster than current standard therapy

• Trials to be run in Brazil, Canada, South Africa, Spain, Tanzania, Uganda, the United States and Zambia

• More than 3,000 TB patients will be enrolled

Bayer Commitments

• Donate moxifloxacin for each clinical trial site

• Cover costs of regulatory filings

• Provide moxifloxacin at an affordable price for patients with TB in the developing world

TB Alliance Commitments

• Coordinate and help cover the costs of the clinical trials

• Ensure coordination of information and results towards the goal of registration

• Leverage substantial support from:– U.S. Centers for Disease Control and

Prevention (CDC)– Orphan Products Development Center of the

U.S. Food & Drug Administration– European and Developing Countries Clinical

Trials Partnership (EDCTP)

Global Alliance for TBDrug Development

www.tballiance.org