Gerald J. Siuta, Ph.D. Business Development May 3, 2007 TB Drug Development Gerald J. Siuta, Ph.D. Business Development May 3, 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 for TB 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 Adoption Access 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

Compounds, Analogs and Derivatives TB Alliance Portfolio Discovery Preclinical Clinical Compounds, Analogs and Derivatives Nitroimidazole Analogs (University of Auckland, Novartis ITD, NIAID) Moxifloxacin (Bayer HealthCare AG) Quinolones (KRICT/Yonsei University) Nitroimidazole PA-824 (Chiron/Novartis) Multi-Functional Molecules (Cumbre) Bacterial Topoisomerase Inhibitors (GlaxoSmithKline) InhA Inhibitors (GlaxoSmithKline) Pleuromutilins (GlaxoSmithKline) Focused Screening – Two Projects (GlaxoSmithKline) Riminophenazines (Institute of Materia Medica) Active TB Alliance program Malate Synthase Inhibitors (GlaxoSmithKline/Texas A&M) TB Alliance in discussion Proteasome Inhibitors (Cornell University) New Targets (University of Pennsylvania)

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-Bayer Moxifloxacin 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 TB Drug Development www.tballiance.org