PDPs and Alternative IP Management/Tech Transfer Strategies for Improved Global Health Gerald J. Siuta, Ph.D. Consultant, Business Development Biotechnology Industry Organization Annual Meeting Atlanta, GA May 20, 2009

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

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 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

Industrial Partners Bayer HealthCare Chiron/Novartis GlaxoSmithKline Novartis Institute for Tropical Diseases sanofi-aventis

Academic Partners Infectious Disease Research Institute Institute of Materia Medica (China) Johns Hopkins University Korea Research Institute of Chemical Technology and Yonsei University (South Korea) Rutgers, The State University of New Jersey Texas A&M University University of Auckland (New Zealand) University of Illinois at Chicago University of Pennsylvania New York Medical College

Lead Identification Lead Optimization PreclinicalPhase IPhase IIPhase III Malate Synthase Inhibitors Riminophenazines GSK Focused Screening InhA Inhibitors Mycobacterial Gyrase Inhibitors Nitroimidazoles Quinolone TBK-613 Multifunctional Molecules PA-824 Moxifloxacin TB Alliance Portfolio TB ALLIANCE PROGRAMS DISCOVERY CLINICAL DEVELOPMENT Phenotypic Screening March, 2009 Protease Inhibitors Energy Metabolism Inhibitors NITD Portfolio RNA Polymerase Inhibitors Topoisomerase I Inhibitors Tryptanthrines April 2009

Chiron/Novartis PA-824 – 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

PA-824 Worldwide exclusive license in 2002 for the treatment of tuberculosis Defined scientific milestones Grant-back option Manufacturing rights No royalties in endemic countries Presently in Phase II clinical trials

Bayer HealthCare Moxifloxacin - fluoroquinolone antibiotic Orally active Once-a-day dosage Marketed in 141 countries for the treatment of several acute respiratory and uncomplicated skin and soft tissue infections

Moxifloxacin for TB Novel mechanism of action: kills M.tb. by inhibition of DNA gyrase In vivo mouse studies showed that 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

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)

GlaxoSmithKline Joint drug discovery program at GSK’s Diseases of the Developing World facility in Tres Cantos, Spain Four individual projects: –Mycobacterial gyrase inhibitors –InhA inhibitors –Malate synthase inhibitors –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

Global Alliance for TB Drug Development