Funding in Return for Rights Outside the Developed World: Public-Private Partnerships Gerald J. Siuta, Ph.D. Consultant, Business Development September 27, 2007

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 Public-Private Partnerships 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 worlds 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 TBs 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 –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 FDC s 6 Months 2 Months 10 Days

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 Discovery Compounds, Analogs and Derivatives Nitroimidazole Analogs (U. of Auckland/U. of Illinois at Chicago) Quinolones (KRICT/Yonsei University) Multi-Functional Molecules (Cumbre) Mycobacterial Gyrase Inhibitors (GlaxoSmithKline) InhA Inhibitors (GlaxoSmithKline) Screening and Target Identification (AstraZeneca) Nitroimidazole PA-824 (Chiron/Novartis) Clinical Development Active TB Alliance program TB Alliance in discussion Focused Screening (GlaxoSmithKline) Pleuromutilins (GlaxoSmithKline) Moxifloxacin (Ethambutol Substitution) (Bayer) Malate Synthase Inhibitors (GlaxoSmithKline/Rockefeller U./Texas A&M U.) New Targets (University of Pennsylvania) Riminophenazines (Institute of Materia Medica/BTTTRI) Protease Inhibitors (Queen Mary, University of London) Proteasome Inhibitors (Cornell University) Moxifloxacin (Isoniazid Substitution) (Bayer)

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 GSKs Diseases of the Developing World facility in Tres Cantos, Spain Four individual projects: –Mycobacterial gyrase inhibitors –InhA 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 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)

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