TB Drug DevelopmentGerald J. Siuta, Ph.D.Business Development

May 8, 2007

Tuberculosis One-third of the world’s population is infected

with Mycobacterium tuberculosis – 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

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)– Prolonged therapy, few available drugs, poorly tolerated

and difficult to administer TB/HIV Co-Infection

– Drug interactions with antiretroviral agents - simultaneous therapy difficult

The Need for New TB Drugs

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

No new anti-TB drug in over 30 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 – Feb 2000– Hosts: Rockefeller Foundation & MRC S. 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

International Public-Private Partnership Non-profit organization Based in New York City, Brussels and

Cape Town Entrepreneurial, virtual R&D approach

– Out-source R&D to public or private partners Pro-active fundraising

Public-Private Partnership

An organization that pursues a social mission by employing the best

practices of the private sector and drawing upon resources from the

public and private realms

TB Alliance Mission

To ensure equitable access to a faster tuberculosis cure

that will advance global health and prosperity

Profile of New TB Drug

Shorten the duration of TB treatment or otherwise simplify its completion

Be effective against multi-drug resistant tuberculosis (MDR-TB)

Improve the treatment of latent TB Be compatible with HIV treatment

Goals and Objectives

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

Coordinate and catalyze TB drug development activities worldwide

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

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/Agreements

Licensing Sponsored Projects Outsourcing/Contracts Co-Development Co-Investments Partnerships Others

TB Alliance PortfolioDiscovery

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Nitroimidazole Analogs (University of Auckland, Novartis ITD, NIAID)

Quinolones(KRICT/Yonsei University)

Multi-Functional Molecules(Cumbre)

Bacterial Topoisomerase Inhibitors(GlaxoSmithKline)

InhA Inhibitors(GlaxoSmithKline)

Malate Synthase Inhibitors(GlaxoSmithKline/Texas A&M)

Nitroimidazole PA-824 (Chiron/Novartis)

Preclinical Clinical

Active TB Alliance program

TB Alliance in discussion

Focused Screening – Two Projects(GlaxoSmithKline)

Pleuromutilins(GlaxoSmithKline)

Moxifloxacin (Bayer HealthCare AG)

Proteasome Inhibitors(Cornell University)

New Targets(University of Pennsylvania)

Riminophenazines(Institute of Materia Medica)

Chiron

Novel anti-TB compound (PA-824) Discovered by Pathogenesis, Inc. Exclusive worldwide license Defined scientific milestones Grant-back option Manufacturing rights No royalties in high endemic countries

PA-824

Novel nitroimidazole Potent activity against both active and

slow growing M.tb. Possesses both bactericidal and sterilizing

activity Phase I clinical trials began June 3, 2005

– Preclinical development completed in 3 years

University of Auckland Synthesis of PA-824 analogs Joint program with:

– Novartis Institute of Tropical Diseases (Singapore)

– National Institute of Allergy and Infectious Diseases

Aims to discover new nitroimidazopyrans that may have improved profiles over PA-824

GlaxoSmithKline

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

Four individual projects:– Bacterial topoisomerase inhibitors– InhA inhibitors– Pleuromutilins– Focused screening (two projects)

Korea Research Institute of Chemical Technology (KRICT)

Daejeon, South Korea Three year research funding

– Quinolones, pyridones & quinolizines Chemical synthesis at KRICT In vitro and in vivo biological testing at

Yonsei University College of Medicine in Seoul, South Korea

Clinical compound selection in progress

Cumbre Pharmaceuticals

Joint program on the design, synthesis and optimization of two different classes of multi-functional antibiotics

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

Cumbre will retain the rights to pursue the compounds for use in other infectious diseases

Institute of Materia Medica Member of the Chinese Academy of Medical Sciences

that is one of the primary institutions for drug research in China

Joint research partnership for the design, synthesis and evaluation of a class of compounds known as riminophenazines– Originally discovered to be active against TB in the 1950s– Has not been used due to side effect profile

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

Phase II program will 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

Nearly 2,500 TB patients are being 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)

Special Recognition

Licensing Executives Society

On September 13, 2006, the Licensing Executives Society Industry/University and Government

Laboratory Transactions Industry Sector presented the TB Alliance and Bayer its Deals of Distinction

Award which recognizes worthy transactions involving licensing and transfer of intellectual property and promote creative and innovative

solutions to business issues

Scrip – World Pharmaceutical News

The TB Alliance-Bayer deal was also one of six finalists for the Scrip 2006 Best Partnership

Alliance Award which recognizes the importance of partnerships involving pharmaceutical and/or

biotech companies, focusing on deals that require strong strategic input from both partners, are

mutually beneficial to both parties, hold promise to address an unmet medical need and demonstrate

strategic potential as well as an innovative business model

Global Alliance for TBDrug Development

www.tballiance.org