Collaborating with Public-Private Partnerships: The Global Alliance for TB Drug Development Gerald J. Siuta, Ph.D. Consultant, Business Development 5th Anti-Infectives Partnering & Deal-Making Summit Philadelphia, PA March 7, 2008

What is a 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

Types of PPPs Basic Knowledge/Research SNP Consortium Improvement of Access to Health Products International Trachoma Initiate Global Coordinating/Funding Mechanisms Global Fund to Fight AIDS, Tuberculosis and Malaria Health Services Strengthening Global Campaign for Microbicides Public Education and Advocacy Corporate Council on Africa Regulation, Quality and Standards Anti-Counterfeit Drug Initiative Product Development Partnership (PDP) Global Alliance for TB Drug Development

PDP Operations Provide specific disease expertise Fill development gaps Have purchasing power – US$1B for TB alone Unique deals, not charity projects Undertake clinical development Build extensive networks for market access in developing countries Provide credibility with advocates, NGOs and activists

How PDPs Work

Who are PDPs?

Case Study: TUBERCULOSIS

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 for TB 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 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

Our Vision FDCs 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

TB Alliance Portfolio TB ALLIANCE PROGRAMS DISCOVERY CLINICAL DEVELOPMENT Lead Identification Lead Optimization Preclinical Phase I Phase II Phase III Moxifloxacin PA-824 Quinolones Nitroimidazoles Pleuromutilins Mycobacterial Gyrase Inhibitors InhA Inhibitors Multifunctional Molecules Riminophenazines GSK Focused Screening Phenotypic Screening Malate Synthase Inhibitors STRATEGIC INITIATIVES Evaluation of New Drug Combinations Fast-tracking the testing of new regimens Mouse Model of Tuberculosis Optimizing a preclinical research model Product Profile Analysis Defining the value proposition of new regimens Identification of Biomarkers Identifying new determinants of successful treatment Market Analysis Identifying market dynamics that affect availability Regulatory Mapping Understanding pathways in high-burden countries Clinical Trial Site Assessments Identifying clinical research sites and targeting improvements Regulatory Preparation Forums Learning what is needed for registration

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 Pleuromutilins Focused screening Malate synthase inhibitors

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 multi-functional 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-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 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 TB Drug Development www.tballiance.org