Closing the Global Health Innovation Gap
Transcription
Closing the Global Health Innovation Gap
BIO Ventures for Global Health 1225 Eye Street, NW, Suite 1010 Washington, DC 20005 USA Phone: +1 202-312-9260 Fax: +1 443-320-4430 www.bvgh.org Closing the Global Health Innovation Gap BIO Ventures for Global Health Building Biotech Solutions for Diseases of the Developing World Closing the Global Health Innovation Gap A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases BIO Ventures for Global Health Closing the Global Health Innovation Gap A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Closing the Global Health Innovation Gap: A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Copyright© 2007 BIO Ventures for Global Health. All rights reserved. This report was written by Joanna E. Lowell with contributions from Christopher D. Earl, Michael C. Venuti, Wendy Taylor, and Julie S. Klim. Acknowledgments BVGH wishes to thank L.E.K. Consulting for its role in the research underlying this report; the individuals who reviewed this document—Maria Freire, Carl Nathan, Tito Serafini, Natalie Barndt, and the BVGH Board of Directors; Anastasia Semienko, who assisted in the final push to complete the project; and the many individuals from the global health community and biopharmaceutical industry who participated in our interviews and shared their enthusiasm and ideas. Special thanks to Dr. Corey Goodman for the initial inspiration for this project. To request additional print copies of this report or other information from BVGH, please contact: BIO Ventures for Global Health 1225 Eye Street, NW, Suite 1010 Washington, DC 20005 Tel: +1 202.312.9260 Fax: +1 443.320.4430 E-mail: [email protected] Web: www.bvgh.org The full text of this report is also available online at the BVGH website: http://www.bvgh.org/documents/InnovationMap.pdf Cover Image by J. Mainquist, courtesy of NIH’s National Human Genome Research Institute. The Kalypsys suite of ultra-high throughput robotic technologies can screen the biological activity of more than one million chemical compounds per day. Design and layout by Bussolati Associates. Illustrations for Figures 3.4 and 3.6 by Jennifer Fairman. Contents List of Select Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . 3 List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 List of Tables and Sidebars. . . . . . . . . . . . . . . . . . . . . . . . . 5 Chapter 1: Executive Summary. . . . . . . . . . . . . . . . . . . . . 7 Chapter 2: Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . 10 Chapter 3: The Innovation Gap in Discovering New Therapeutics for Neglected Diseases . . . . . . . . . . . . 14 Chapter 4: Harnessing Discovery Resources. . . . . . . . . . . 27 Chapter 5: Mapping Biotechnology Capabilities to Neglected Diseases . . . . . . . . . . . . . . . . . . 35 Chapter 6: Building a New Discovery Pipeline. . . . . . . . . 45 Chapter 7: Conclusions and Recommendations. . . . . . . . 52 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Appendix I: Why Small Molecule Drug Discovery Is a Risky Business . . . . . . . . . . . . . . . . . 57 Appendix II: Snapshots of the Drug Development Pipelines for Malaria, TB, and HAT. . . . . . . . . . . . . . . . . 59 Appendix III: Academic and Company Interviewees . . . . 60 Appendix IV: List of 50 Focus Companies . . . . . . . . . . . 61 About BVGH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 Select Abbreviations ACT. . . . . . . . . . artemisinin-based combination therapy ADME . . . . . . . . absorption, distribution, metabolism, and excretion ARV. . . . . . . . . . anti-retroviral ATP . . . . . . . . . . adenosine triphosphate BBB . . . . . . . . . . blood-brain barrier BVGH . . . . . . . . BIO Ventures for Global Health CRO. . . . . . . . . . contract research organization DALY. . . . . . . . . disability-adjusted life year DNDi. . . . . . . . . Drugs for Neglected Diseases Initiative EMEA. . . . . . . . . European Medicines Agency FDA. . . . . . . . . . United States Food and Drug Administration GPCR. . . . . . . . . G protein–coupled receptor HAT. . . . . . . . . . human African trypanosomiasis hGH. . . . . . . . . . human growth hormone HTS. . . . . . . . . . high-throughput screening IDRI. . . . . . . . . . Infectious Disease Research Institute iOWH . . . . . . . . Institute for OneWorld Health IND. . . . . . . . . . investigational new drug MDGs. . . . . . . . . Millennium Development Goals MLSCN . . . . . . . Molecular Libraries Screening Center Network MMV. . . . . . . . . Medicines for Malaria Venture NCE. . . . . . . . . . new chemical entity NGO . . . . . . . . . nongovernmental organization NIH. . . . . . . . . . United States National Institutes of Health PDE. . . . . . . . . . phosphodiesterase PDP. . . . . . . . . . product development partnership R&D. . . . . . . . . . research and development SAR . . . . . . . . . . structure-activity relationship SBRI. . . . . . . . . . Seattle Biomedical Research Institute TB . . . . . . . . . . . tuberculosis TB Alliance. . . . . Global Alliance for TB Drug Development TDR. . . . . . . . . . Special Programme for Research and Training in Tropical Diseases TPP . . . . . . . . . . target product profile WHO. . . . . . . . . World Health Organization A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Figures Figure 3.1: Drug Discovery and Development— the Necessary Prelude to New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 17 Figure 4.4: The Composition and Tasks of a Drug Discovery Team. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Figure 3.2: Risks and Benefits of Expanding Use of Existing Drugs Versus the Creation of New Chemical Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Figure 4.5: Target Class Focus of 50 Focus Companies. . . . . . . . . 34 Figure 3.3: Attrition Rates and Current Neglected Disease Pipelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Figure 5.1: Target Validation and Drug Discovery Tools Available for P. falciparum, M. tuberculosis, and T. brucei. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 Figure 3.4: The Innovation Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Figure 5.2: Target Classes Are Transferable Across Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 Figure 3.5: Annual R&D Spending by Biotechnology Companies and PDPs. . . . . . . . . . . . . . . . . . . . . . . . . . 23 Figure 5.3: Target Classes Shared by P. falciparum, M. tuberculosis, and T. brucei. . . . . . . . . . . . . . . . . . . 41 Figure 3.6: Building a Continuum of Players to Move from Basic Research to Product Registration . . . . . . . . 26 Figure 6.1: Hurdles to the Biotechnology Industry’s Involvement in Neglected Disease Drug Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 Figure 4.1: The Origins of Small Molecule Drugs in Clinical Trials (January 2007). . . . . . . . . . . . . . . . . . . . . . . . . 28 Figure 4.2: Biotechnology Companies Can Be Segmented by Capabilities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Figure 4.3: The Financial Strength of the 50 Focus Companies: Equity Capital Raised . . . . . . . . . . . . . . . . . . . 31 Closing the Global Health Innovation Gap Figure 6.2: The Costs of Producing a Single New Drug. . . . . . . . . 47 Figure 6.3: Possible Roles for a Discovery-Focused PDP . . . . . . . 50 Tables Sidebars Table 2.1: initial Assessment of the Need for New Therapeutics and the Scientific Feasibility of Creating Them for Key Neglected Diseases. . . . . . . . . . . . . . . . . 13 Sidebar 2.1: List of select global health product development partnerships (PDPs). . . . . . . . . . . . . . . . . . . . 11 Sidebar 2.2: Examples of new global health products. . . . . . . . . 11 Table 3.1: Malaria, Tuberculosis, and Human African Trypanosomiasis. Summary of Disease Characteristics, Pathogen, and Current Standard of Care. . . . . . . . . . . . . . . . . . . . . . 15 Sidebar 4.1: Characteristics of small molecule drugs. . . . . . . . . . 27 Sidebar 4.2: Company selection process . . . . . . . . . . . . . . . . . . . . . . 30 Table 3.2: PDP Drugs Registered or in Clinical Trials . . . . . . . . . . . 18 Sidebar 5.1: The tool kit for modern drug discovery. . . . . . . . . . . 35 Table 3.3: Biopharmaceutical and Consortium-Based Drugs in Clinical Trials. . . . . . . . . . . . . . . . . . . . . 18 Table 3.4: Target Product Profiles for Uncomplicated P. falciparum Malaria, Active Pulmonary TB, and Late-stage HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Sidebar 5.2: Critical tools for future development. . . . . . . . . . . . . 39 Sidebar 5.3: Harnessing diverse biotechnology solutions . . . . . 44 Sidebar 6.1: Solving the innovation gap for neglected disease drug discovery: How much will it cost? . . . . . . . . . . . . . . . 51 Table 3.5: Treatment Goals for Malaria, TB, and HAT . . . . . . . . . . 21 Table 4.1: Summary of 50 Focus Companies . . . . . . . . . . . . . . . . . . 29 Table 4.2: The Assets and Infrastructure Used in Drug Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Table 5.1: Drug Targets Favored by Biotechnology Companies and the Tools Available to Tackle Them. . . . . . . . . . . 40 Table 5.2: Validated Targets in Neglected Disease Pathogens for Which the Tools and Expertise of Biotechnology Companies Might Be Leveraged . . . . . . . . . . . . 42 A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Chapter 1: Executive Summary Ninety percent of the world’s expenditure on medical care benefits the richest fifth of the world’s population. Technological breakthroughs fueled by billions of dollars of investment have transformed health care for the affluent, yet patients in resource-poor countries cannot afford highquality care. They lack the purchasing power that would draw investment in new medicines to treat infectious diseases that are unknown, or long since eradicated, in wealthy countries. The devastation caused by these “neglected diseases” has attracted renewed attention in the past decade, as it’s been recognized that focused investment and commitment could yield powerful new vaccines, drugs, and diagnostics based on the same technologies that have revolutionized health care for the affluent. For the first time, several hundred million dollars from donors such as the Bill & Melinda Gates Foundation are being invested annually in important research and development (R&D) for diseases such as malaria and tuberculosis. But relatively little of this investment is devoted to the discovery of drugs with the potential for providing breakthrough therapeutic benefits. As a result, an innovation gap is increasingly apparent in the discovery of new medicines for neglected diseases. This innovation gap stems from insufficient investment devoted to early-stage drug discovery, limited public sector access to key technologies and drug discovery expertise, and the scarcity of capable innovators devoted to creating new medicines for neglected diseases. Today, product development for neglected diseases is mainly carried out in the public and nonprofit sectors, with for-profit companies serving as partners and subcontractors in a number of cases. In contrast, the vast majority of new treatments for diseases with markets in the developed world are created by biotechnology and pharmaceutical companies, which together have the expertise and the infrastructure to carry discovery and development of products from bench to bedside. Although biotechnology companies are best known for developing protein drugs such as human growth hormone and monoclonal antibodies, they are also now leading innovators in small molecule drugs—the type of therapeutic best suited to meet developing-world needs for oral delivery, thermostability, and affordability. The challenge is to bring the biotechnology industry’s discovery assets, know-how, and project management capabilities—developed over 30 years and with nearly $400 billion of equity capital—to the fight against diseases of the developing world. In this study, BIO Ventures for Global Health (BVGH) examined the core capabilities of the biotechnology industry, academia, and the nonprofit entities that focus on clinical development of new drugs for neglected diseases. Based on a preliminary assessment that reviewed areas of significant alignment between biotechnology industry capabilities, basic disease understanding, and unmet medical need, we focused on three classes of diseases—malaria, tuberculosis, and trypanosomal diseases (human African trypanosomiasis, Chagas disease, and leishmaniasis). Central to our findings is the transferability of the technologies used to address cardiovascular disease, neurological disease, and cancer to the infectious diseases of the developing world caused by parasites and bacteria. Several families of proteins that have served as principal targets for drug discovery for chronic diseases of the industrialized world are also present in infectious pathogens and can serve as targets for drug discovery. In principle, this means that biotechnology companies are in an advantageous position to apply their discovery resources and expertise to neglected diseases. To narrow the scope of our study, we focused on a select group of over 120 companies that have capability, scale, and track records of innovation in small molecule discovery that could be highly relevant to neglected disease drug discovery. We further chose to analyze 50 companies in greater depth, including the originators of more than 20 small molecule drugs now approved by the FDA. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Key findings Drug discovery for neglected diseases is hindered by an “innovation gap.” Despite a revolution in funding for neglected diseases and the evolution of new R&D partnerships, the current neglected disease pipeline will not fully address key treatment goals (e.g., substantially shortening the duration of certain treatments). The investment in product discovery and “translational” research for neglected diseases remains a fraction of the level necessary to move promising discoveries from academic laboratories into commercial settings—far too little to ensure a steady stream of new medicines for neglected diseases. Long-term investments in innovation are needed to build a sustainable pipeline of drugs that meet the needs of patients and offer hope of alleviating the suffering from these diseases. Bringing drug discovery assets built for developedworld diseases to bear on neglected diseases is scientifically feasible. For malaria, tuberculosis, and trypanosomal diseases, sufficient scientific tools exist for drug discovery R&D efforts to be initiated. Importantly, for many human molecular targets that have received extensive attention from drug discovery companies, there are analogous targets in neglected disease pathogens. This means, in particular, that researchers can employ proprietary compound libraries used for drug discovery for major diseases for neglected disease drug discovery. Biotechnology companies that focus on small molecule drugs and have taken novel small molecules into clinical development are well positioned to address the innovation gap. Hundreds of biotechnology companies have resources that could contribute to the fight against neglected diseases. Many of these are well positioned to take the lead in developing new drugs, vaccines, or diagnostics to address these diseases. For example, many proprietary compound libraries used by biotechnology companies for small molecule drug discovery have been optimized around target classes that are also relevant to neglected diseases. These resources and capabilities would be prohibitively expensive to duplicate in the nonprofit sector. Moreover, biotech- Closing the Global Health Innovation Gap nology companies have the speed, flexibility, and persistence to take leadership roles in attacking new challenges to create new products. Substantial investment in discovery will be required. The pharmaceutical industry typically allocates up to 40 percent of its R&D budget to discovery. Using similar criteria, to build a discovery pipeline that will feed the existing development infrastructure for diseases such as tuberculosis and malaria will require substantial additional investment. We estimate that a sustained investment of at least $40 million per year for each disease is required to ensure a pipeline that delivers a new, approved therapeutic every three years. Significant hurdles hinder biotechnology industry involvement. Three major hurdles have discouraged many biotechnology companies from becoming engaged in global health product discovery: n Information hurdles. Companies need to become much more familiar with neglected diseases, potential markets, and partners. n Managerial hurdles. They need to build expertise in managing collaborations with partners in the not-for-profit and academic sectors. n Financial hurdles. They need market incentives to invest in R&D and overcome “opportunity cost”— the potential profit lost by not working on a core business project. New approaches will be required for effective investment in discovery. There is a great need to encourage collaborations between biotechnology companies with discovery expertise and academic experts with deep understanding of the target diseases and sophisticated biochemical and molecular tools useful in drug discovery. Such partnerships can lower the barriers to industry involvement. Managerial and financial hurdles must be overcome to attract biotechnology companies to participate in global health initiatives. Recommendations 1. The biotechnology industry’s most capable innovators have an integral role in closing the innovation gap. Biotechnology companies have track records of employing advanced technologies to create new therapeutics that have met with success in human clinical trials. This expertise can and should be applied to neglected diseases. 2. New partnerships are needed to lower barriers for biotechnology companies to invest their resources. Most biotechnology compa- nies are unfamiliar with neglected diseases. To take advantage of their technology platforms, they need to access disease expertise and biochemical assays that are resident in academia, research institutions, and product development partnerships (PDPs). R&D collaborations are the best way to combine strengths and increase productivity. 3. Expanded research funding is needed to build an early-stage pipeline. To produce a new, approved therapeutic every three to five years for a single disease, the minimum investment required for new discovery R&D is comparable to the annual funding for two small biotechnology companies—increasing over several years to roughly $40 million per year per disease. This investment will fund several parallel drug discovery programs and accommodate attrition at typical industry rates, while allowing surviving programs to enter preclinical development. Among the options: n Independent consortiums of companies, academic labs, and PDPs that work together to transform neglected disease drug targets into optimized lead compounds and preclinical drug candidates. n Direct donor investment in company-led programs with accompanying R&D management and monitoring. n Creation of a discovery PDP that can serve as a “portfolio manager” for new neglected disease discovery programs with a mission of augmenting the pipelines of existing PDPs. Such an organization could efficiently enlist the most experienced innovators; forge partnerships among companies, development-focused PDPs, and academics; and manage and monitor numerous discovery projects. Biotechnology companies could contribute substantially to the discovery and development of new therapeutics for neglected diseases. This document provides a road map for enlisting their capabilities in this fight. By employing existing advanced drug discovery technologies, donor community funds will be used to maximum effect, novel drugs will be developed faster, and more lives will be saved. 4. Effective investment will depend on dedicated portfolio managers. Many of the current participants in global health product development lack deep expertise in managing early-stage drug discovery. The scope of the partnerships and investments we recommend call for project management capabilities that would stretch the current capabilities of any single public sector organization. Dedicated project management to maximize R&D productivity can be infused into PDPs or donor organizations, or it can be built as an independent discovery PDP. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Chapter 2: Introduction The challenge of neglected diseases Major advances in biotechnology over the last 30 years have transformed medicine in the industrialized world, but these innovations have yet to reach the world’s poorest countries, where 3 billion people live on less than two dollars a day. Each year more than 10 million people in the developing world die of infectious diseases such as HIV/AIDS, malaria, tuberculosis, diarrheal diseases, and acute lower respiratory infections. Millions more suffer from debilitating parasitic diseases, which often incapacitate people in their most productive years. The burden of infectious illness falls most heavily on children and pregnant women. In poor countries, the magnitude of suffering caused by infectious diseases makes economic development nearly impossible [1]. Many of these infectious diseases have earned the label “neglected”1 because health-care markets in the afflicted countries are insufficient to attract biopharmaceutical industry2 investment in research and development (R&D). Over the past decade, a revolution has occurred in public sector investment combating infectious diseases of the developing world. Governments, multilateral organizations, and foundations spend billions of dollars purchasing treatments. Millions more are invested each year in neglected disease R&D. Most of the R&D investment devoted to neglected diseases is deployed through public-private, not-for-profit, product development partnerships (PDPs). Since 1996, over a dozen PDP organizations have arisen to tackle the development of new vaccines, drugs, and diagnostics for developing-world diseases (see Sidebar 2.1). In addition, several research institutes, a few large pharmaceutical companies, and a handful of biotechnology companies initiated their own programs, in many cases working with PDPs. The challenge now is to augment these public and private sector efforts. What today’s partnerships lack most is access to the biotechnology industry’s most advanced technologies and expertise for discovering and developing new medicines.3 Today’s medicines are insufficient A fundamental transformation in commitment to solving global health problems has occurred during the first decade of the 21st century. In 2000, the United Nations adopted the Millennium Development Goals (MDGs), setting forth ambitious health-related objectives: cutting child mortality by two-thirds, reducing maternal mortality by three-quarters, and reversing the tide of HIV/AIDS, malaria, and other major infectious diseases. In response, governments, foundations, and international nongovernmental organizations (NGOs) in the developed world have provided billions of dollars to purchase existing vaccines and drugs for patients in the developing world. The global health crisis demands a comprehensive and integrated response that begins with faster delivery of existing drugs, vaccines, and diagnostics to those most in need. While programs to ensure access to current medicines can yield substantial benefits, they will not offer complete solutions. Many of the treatments available today are decades old and are often limited by problems of drug resistance, inadequate safety, and efficacy. For example, current treatments for river blindness (onchocerciasis) only kill immature parasitic worms in early stages of infection and are ineffective for advanced disease. The sole therapy for a major form of human African trypanosomiasis is marginally effective, requires intravenous administration, and is so toxic that it can kill up to 5 percent of patients. No effective vaccine exists for any disease on the World Health Organization’s Special Programme for Research and Training in Tropical Diseases (WHO/TDR) list of neglected diseases (see Footnote 1). Diagnostics, where they exist, are often impractical for field use in the developing world. 1 The 10 critical “neglected diseases” as defined by the WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR) are African trypanosomiasis, Chagas disease, dengue, leishmaniasis, leprosy, lymphatic filariasis, malaria, onchocerciasis (river blindness), schistosomiasis, and tuberculosis. Other major killers include diarrheal diseases and lower respiratory tract infections. Although HIV disproportionately affects the developing world, it is not considered a neglected disease because billions of dollars are going into product development for the developed world. 2 For the purpose of this report, the “biopharmaceutical industry” comprises the 20 large, innovative pharmaceutical companies and the biotechnology industry. 3 The term “medicine” is used here to encompass vaccines, drugs, and diagnostics. 10 Closing the Global Health Innovation Gap Sidebar 2.1: List of select global health product development partnerships (PDPs) Aeras Global TB Vaccine Foundation (Aeras) Focus: TB vaccine development Headquarters: Rockville, MD, USA Founded: 1997 International AIDS Vaccine Initiative (IAVI) Focus: HIV vaccine development Headquarters: New York, NY, USA Founded: 1996 Drugs for Neglected Diseases Initiative (DNDi) Focus: Drug development for malaria and trypanosomal diseases Headquarters: Geneva, Switzerland Founded: 2003 International Partnership in Microbicides (IPM) Focus: Microbicide development for HIV prevention Headquarters: Silver Spring, MD, USA Founded: 2002 Foundation for Innovative New Diagnostics (FIND) Focus: Diagnostic development for TB, malaria, and human African trypanosomiasis Headquarters: Geneva, Switzerland Founded: 2003 Medicines for Malaria Venture (MMV) Focus: Malaria drug development Headquarters: Geneva, Switzerland Founded: 1999 Global Alliance for TB Drug Development (TB Alliance) Focus: TB drug development Headquarters: New York, NY, USA Founded: 2000 Malaria Vaccine Initiative (MVI) Focus: Malaria vaccine development Headquarters: Bethesda, MD, USA Founded: 1999 as an independent program within PATH Pediatric Dengue Vaccine Initiative (PDVI) Focus: Dengue vaccine development Headquarters: Seoul, Korea Founded: 2003 Human Hookworm Vaccine Initiative (HHVI) Focus: Vaccine development for hookworm Headquarters: Washington, DC, USA Founded: 2000 Institute for OneWorld Health (iOWH) Focus: Drug development for visceral leishmaniasis, malaria, and diarrheal diseases Headquarters: San Francisco, CA, USA Founded: 2000 Fortunately, PDPs, research institutes, and a small but growing cadre of biopharmaceutical companies are building a growing development pipeline of promising products to address neglected diseases. The bulk of R&D investment to date—$1.2 billion as of early 2006—flowed to treatment and prevention of HIV/AIDS, tuberculosis, and malaria [2]. The remainder is being devoted to other viral, bacterial, protozoan, and helminth (worm) infections where new medicines are desperately needed. Several PDPs, often through outsourcing and partnering, have assembled substantial clinical development infrastructures. PDPs also manage sophisticated clinical programs in multiple developing countries. Their efforts, and those of a small number of biopharmaceutical companies, are beginning to pay off. New products have succeeded in clinical trials, and a few have already been registered for sale in developing countries (Sidebar 2.2). Program for Appropriate Technology in Health (PATH) Focus: Development of health technologies Headquarters: Seattle, WA, USA Founded: 1977 Sidebar 2.2: Examples of new global health products l Paromomycin: A drug to treat visceral leishmaniasis (Kala-Azar), developed by the Institute for OneWorld Health (iOWH), registered in India in 2006. l Rotarix®: Novel rotavirus vaccine, developed by Avant Immunotherapeutics and licensed to GlaxoSmithKline (GSK), approved for use in 90 countries since 2004. l Pyramax®: Combination therapy (pyronaridine-artesunate) for malaria, developed by Medicines for Malaria Venture (MMV), currently in phase III clinical trials. l RTS,S/ASO2A: Malaria vaccine, developed jointly through the Malaria Vaccine Initiative (MVI) and GSK, has completed phase II trials. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 11 These products offer important opportunities to improve standards of care for key neglected diseases, but are just a start. Continued investment will be required to expand the pipeline of products that can keep improving care for neglected diseases. For example, we need: n a shorter course of TB therapy that works against drug-resistant microbes; n a safe and affordable treatment for human African trypanosomiasis; n a diagnostic that distinguishes between malaria and bacteremia in a feverish child; n a drug that kills adult forms of the many species of worm, causing such diseases as lymphatic filariasis, that deform and incapacitate millions of patients; and n new vaccines to prevent millions of deaths each year. An innovation gap impedes progress Achieving the most ambitious public health goals for the treatment and prevention of neglected diseases will require extensive discovery efforts supported by long-term funding. Most of today’s global health product pipeline in therapeutics, however, focuses on products amenable to rapid clinical development, mainly by repurposing known drugs for new uses. Finding new uses for existing drugs makes sense because it speeds development and makes it possible to reach those in need in the shortest possible time. Currently, a relatively small portion of the investment in R&D for neglected diseases is directed to discovering new chemical entities (NCEs)—that is, novel compounds with the potential of providing breakthrough therapeutic benefits. This report highlights the current innovation gap in the discovery of new medicines for neglected diseases. The investments in product discovery and “translational” research necessary to move promising discoveries from academic laboratories into commercial settings are at a very early stage and are insufficient in scale to ensure a steady stream of new medicines for neglected diseases. Without increased effort and investment in discovery research, bringing neglected diseases under control will be delayed by years, perhaps even decades. Long-term investments in innovation are needed to build a sustainable pipeline of drugs meeting the needs of patients now and into the future. Experience has shown that returns on pharmaceutical R&D investments are measured in decades, not years. Moreover, the lesson from all experience with treatments for infectious diseases—whether it’s antibiotics for streptococcal bacteria or anti-retrovirals (ARVs) for HIV/AIDS—is that the pathogens eventually develop resistance to drugs. Researchers must constantly fight back by inventing new drugs that kill pathogens through novel mechanisms of action. Study approach and objectives BIO Ventures for Global Health (BVGH) undertook this study to assess whether the biotechnology industry’s diverse technology platforms and expertise can be applied to inventing products for neglected diseases and, if so, how. We focused on opportunities and challenges facing development of therapeutics for key neglected diseases: tuberculosis (TB), malaria, and three diseases caused by trypanosomatids4—human African trypanosomiasis (HAT, also known as African sleeping sickness), leishmaniasis, and Chagas disease. For simplicity’s sake, at several points in this report we use Trypanosoma brucei, the cause of HAT, to represent all trypanosomatids. We focused on therapeutics in this report because it gave us the opportunity to include the largest number of biopharmaceutical companies. The vast majority of innovative biopharmaceutical companies develop therapeutics; a smaller number focus on vaccines and diagnostics. Drugs represent the largest segment of global pharmaceutical markets. We selected TB, malaria, and the three trypanosomal diseases for several reasons: Each is associated with a high disease burden; current treatments have serious limitations; and each has strong scientific foundations upon which new therapeutic R&D might be based (see Table 2.1). We should emphasize that our goal was to be inclusive, not exclusive. Biopharmaceutical companies can clearly contribute in many other areas. Future studies can and should assess biotechnology innovation in other diseases and interventions, including diagnostics and vaccines. 4 Trypanosomatids are flagellated, parasitic protozoa (single-celled eukaryotic organisms) with complex life cycles during which they alternate between vertebrate hosts and insect vectors. 12 Closing the Global Health Innovation Gap Table 2.1: Initial Assessment of the Need for New Therapeutics and the Scientific Feasibility of Creating Them for Key Neglected Diseases Disease Global burden (DALYs)* Problems with existing treatments Scientific foundation for new R&D TB 34.7 M Resistance and long treatment times Pathogen genome sequenced; genetic manipulation possible; animal models of disease Malaria 46.4 M Resistance Pathogen genome sequenced; genetic manipulation possible; primate models of disease HAT 1.5 M Safety, efficacy, resistance, long treatment time, treatment administration Pathogen genome sequenced; genetic manipulation facile; animal models of disease Chagas Disease 0.7 M No treatments available for chronic form of disease Pathogen genome sequenced; genetic manipulation possible; animal models of disease Leishmaniasis 2.1 M Safety, administration, and long treatment time pathogen genome(s) sequenced; genetic manipulation possible; animal models of disease *One disability adjusted life year (DALY) is equivalent to one year of healthy life lost. Source of DALY information: WHO/TDR. We began our analysis by interviewing academic researchers focused on TB, malaria, and trypanosomal diseases (see Appendix III). We aimed to determine the availability of biological and molecular tools for drug discovery and identify critical bottlenecks. We then evaluated current product pipelines against international public health goals and drug target product profiles (TPPs) to determine where new discovery efforts are required for each disease. fill it for each of the diseases we evaluated. Chapter 4 describes the critical role that the biotechnology industry has played in developed-world drug discovery and the wealth of biotechnology industry expertise and infrastructure that can be applied to neglected disease drug discovery. Chapter 5 evaluates the status of the molecular tools for TB, malaria, and HAT, and it maps biotechnology industry capabilities against drug targets for the three diseases. To evaluate whether industry has the capability and relevant tools to address the gaps we identified, we selected 50 leading biotechnology companies from the hundreds focused on small molecule drug discovery. These companies were chosen for their discovery capabilities in small molecule therapeutics, the scale of their discovery efforts, and their track records of bringing NCEs into the clinic. These are some of the most experienced companies in small molecule drug discovery today. They are listed in Appendix IV, and their capabilities are described further in Chapter 4. Applying biotechnology to global health will call for new collaborative models and financial incentives to encourage industry to take on the risk and cost of product development. This will require vision, new partnerships, risk-taking, innovative business strategies, and financial commitment. Chapter 6 explores these issues and proposes several approaches to investing in new global health R&D. Chapter 7 outlines our conclusions and recommendations. This report makes the case that there is a compelling role for the biopharmaceutical industry in building the global health product pipeline and shortening the critical R&D timelines on the way to achieving that goal. Chapter 3 defines the innovation gap and what may be needed to The obstacles to developing new drugs for neglected diseases are formidable. But they are not insurmountable. If the worldwide health-care community can make the same progress against malaria, tuberculosis, and trypanosomal diseases that it has in the past 20 years against cancer, diabetes, and cardiovascular disease, we can look forward to millions of lives saved and a better world for us all. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 13 Chapter 3: The Innovation Gap in Discovering New Therapeutics for Neglected Diseases Creating innovative pharmaceutical products is a complex process that typically takes 10 to 15 years. Donor funding and the emergence of product development partnerships has led to an unprecedented number of late-stage candidate medicines in the pipeline for neglected diseases. R&D efforts at the drug discovery stage, however, are insufficient to ensure a continuous flow of products entering clinical development. This innovation gap results from insufficient investment, limited access to key technologies and drug discovery expertise, and difficulties in assembling the collaborations necessary to transform a laboratory discovery into an investigational new drug. Failure to address the innovation gap will impede the creation of the next generation of treatments for malaria, tuberculosis, and trypanosomal diseases. urged. Artemisinin-based combination therapies (ACTs) have proven especially efficacious. Artemisinin, a structurally complex natural product, is comparatively expensive to manufacture, which, until recently, precluded the use of ACTs in many impoverished countries. New drugs for old diseases Many of the available medicines for neglected diseases are outdated, impractical, insufficiently efficacious, or subject to pathogen resistance and unacceptable toxicities [3-5]. New medicines are urgently needed for tuberculosis, all diseases caused by protozoan parasites, and many of the helminth (worm) infections. First-line treatment for active TB consists of two or four antibiotic drugs taken in combination for a minimum of six to nine months. The duration of the regimen, combined with the medications’ toxicities, causes many patients to fail to complete the full course of treatment [7]. This, in turn, has hampered TB control programs and fueled the proliferation of antibiotic-resistant M. tuberculosis strains. Recently, extensively drug-resistant TB (XDRTB) has entered communities with high HIV prevalence and is killing people at alarming rates [8, 9]. This study focuses on the need for new drugs for malaria, tuberculosis, and trypanosomal diseases. Each disease is summarized below and in Table 3.1, along with the status and limitations of today’s treatments. Malaria. More than 40 percent of the world’s population is at risk for malaria, and up to 500 million people develop the disease each year. Malaria results from infections by parasitic protozoa from the genus Plasmodium. Young children and pregnant women, especially those living in sub-Saharan Africa where the more virulent Plasmodium falciparum parasite is dominant, are most vulnerable to malaria and account for the majority of the 1 million deaths estimated to occur annually. Commonly used antimalarials are increasingly ineffective due to widespread drug resistance. To combat the emergence of resistance to the drugs remaining in the antimalarial arsenal, use of combination therapies has been 14 Closing the Global Health Innovation Gap Tuberculosis. One-third of the global population—more than 2 billion people—harbors a latent or asymptomatic infection by Mycobacterium tuberculosis, the bacterium causing tuberculosis (TB). About 10 percent of those infected will develop active TB at some point during their lifetime, translating into nearly 9 million cases of active disease and more than 2 million deaths annually. In immunocompromised populations, such as those with HIV, rates of active TB are extremely high. Worldwide, TB is now the leading cause of death among AIDS patients [6]. Trypanosomal diseases. Three major classes of trypanosomal diseases affect humans: human African trypanosomiasis (HAT), Chagas disease, and leishmaniasis. n HAT (also referred to as African sleeping sickness) is found only in sub-Saharan Africa, where 60 million people are at risk for the disease. Each year, there are up to 300,000 cases, resulting in nearly 50,000 deaths. n Chagas disease is endemic in rural areas in South and Central America, placing an estimated 25 million at risk. In total, as many as 9 million people may be infected with the Chagas parasite. Annually, 14,000 deaths result from Chagas cardiomyopathy associated with the chronic form of the disease and often occurring 10 to 20 years after initial infection. Table 3.1: Malaria, Tuberculosis, and Human African Trypanosomiasis: Summary Of Disease Characteristics, Pathogen, and Current Standard of Care Disease Malaria A parasitic disease transmitted by Anopheles mosquitoes. Malaria is categorized as either uncomplicated (fever, chills, body aches, nausea, headache, vomiting, and diarrhea) or severe (anemia, acute respiratory distress syndrome, coma, and death). Deaths per Year > 1 million Epidemiology Pathogen Cases Population Other per Year at Risk 300-500 40% of global Children and Plasmodium million population pregnant species; women P. falciparum are most is the most susceptible deadly Current Standard of Care (launch year): Limitations Chloroquine (1945): resistance Primaquine (1948): safety Fansidar (1961): resistance Mefloquine (1984): resistance, safety Artemisinin (1994): cost, compliance, Good Manufacturing Practice Atovaquone/proguanil (1999): cost TB A bacterial disease that most commonly affects the lungs. In otherwise healthy individuals, most infections are latent and asymptomatic. About 10% of those infected develop active pulmonary disease; symptoms include a cough lasting more than two weeks, coughing up blood, fatigue, fever, chills, night sweats, and weight and appetite loss. 2 million HAT A parasitic disease transmitted by tsetse flies. HAT progresses from fever and fatigue (early-stage disease) to severe neurological conditions (late-stage or chronic disease). Untreated HAT is fatal. 50,000 9 million (active TB) Immuno- Mycobacterium Pandemic; 2 billion are compromised tuberculosis infected with populations are at latent TB. highest risk All first-line treatments have issues concerning resistance, toxicity, and treatment length (6-9 months): Rifampicin (1963) Ethambutol (1962) Streptomycin (1955) Pyrazinamide (1954) Isoniazid (1952) Up to 300,000 60 million; (sub-Saharan Africa) Trypanosoma brucei (subspecies gambiense and rhodesiense) Pentamidine (1941): lacks oral formulation, side effects, early-stage specific, most effective against T. b. gambiense Suramin (1921): lacks oral formulation, side effects, early-stage specific, first-line treatment against T. b. rhodesiense Melarsoprol (1949): toxicity, resistance Eflornithine (1980): toxicity, administration, spectrum of activity, supply, cost, only effective against T. b. gambiense Chagas disease A parasitic disease that over time causes damage to the nervous system, digestive tract, and the heart. The disease is contracted via the feces of an infected Reduviid bug. 14,000 Leishmaniasis A collection of parasitic diseases transmitted by the Phlebotomine sandfly that affects the skin, mucosa, or internal organs, resulting in severe disfigurement, disability or death. >50,000 750,000 8-9 million Trypanosoma 25 million; are currently cruzi (Latin infected America and Caribbean) Chronic disease - no treatments available Acute disease Nifurtimox (1960): resistance, safety, efficacy Benznidazole (1970s): resistance, safety, efficacy 1.5-2 million 350 million 12 million ~20 Leishmania Visceral leishmaniasis: species are currently Miltefosine (2003): safety infected Paromomycin (2006): delivery Pentosam (1944), Amphotericin B (1950s), Ketoconazole (1980s), Pentamidine (1941), and antimony-containing compounds: resistance, efficacy Sources: WHO/TDR and Hotez, P.J., et al., Control of neglected tropical diseases. N Engl J Med, 2007. 357(10): p. 1018-27. n Leishmaniasis is a collection of diseases; there are cutaneous, mucosal, and visceral forms. Worldwide, about 350 million people are at risk for leishmaniasis. Cutaneous and mucosal forms cause severe disfigurement and disability. The visceral form is fatal if untreated. An estimated 12 million people are infected with leishmania, and each year there are over 50,000 deaths. HAT, Chagas disease, and all forms of leishmaniasis are caused by divergent species of single-celled protozoa called trypanosomatids. These pathogens share many unusual molecular and biochemical pathways, but their infectious cycles and target tissues for infection are very different. While there is precedent that a treatment designed for one pathogen may have efficacy toward another [5, 10], it is likely that drug discovery and development will mostly A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 15 proceed independently for different species. For simplicity’s sake, at several points in this report we use Trypanosoma brucei, the cause of HAT, to represent the entire class. Problems associated with existing drugs for trypanosomal diseases include lack of efficacy, drug resistance, long treatment duration, availability, expense, and safety. For instance, melarsoprol, the only treatment for HAT caused by one subspecies of T. brucei, is so toxic that it kills up to 5 percent of those who receive it [11]. There are no drugs to treat the chronic form of Chagas disease. Visceral leishmaniasis treated with paromomycin requires 21 days of injections. An orally available alternative, miltefosine, is unsafe for pregnant women. The drug development process To understand the serious challenges presented by today’s global health drug pipeline, we must first understand the process of creating a new drug. More complex and time-consuming than nearly any other commercial endeavor, pharmaceutical R&D requires technological and scientific expertise, teamwork, leadership, risk-taking, time—and most of all, money. The steps of the process are commonly broken into three phases: basic research that establishes biological knowledge of disease causality and creates tools for R&D; discovery, the innovative steps by which new therapeutic compounds are identified and evaluated; and development, or testing first in animals of small numbers of compounds winnowed from the discovery steps, leading to a single, promising candidate compound to evaluate for therapeutic efficacy and safety in human clinical trials. Basic research refers to the scientific exploration of disease and, in the case of infectious diseases, the pathogens that cause them. The goal of most basic research is to develop a molecular, genetic, and biochemical understanding of disease pathology in the hope that this knowledge will lead to treatments and cures. Developing this knowledge requires an extensive set of tools for research. The process of inventing research tools is in itself another component of basic research. Drug discovery refers to the earliest stages of generating an actual product. It begins with the difficult process of translating findings from basic research into candidate molecules with the potential to treat disease. Researchers organize their work around a target product profile (TPP), essentially a list of minimum characteristics a drug must possess to warrant development and use in people. “Small molecule” drug discovery is a chemistry-intensive process in which a library of thousands or even millions of compounds is screened for molecules with druglike activity potentially meeting TPP requirements. The compounds identified by screening, often called “hits,” are then refined for other essential drug-like properties into “leads.” A lead is a compound that interacts with acceptable potency and selectivity with a cellular “target” macromolecule such as a protein. For an infectious disease, the target is usually a macromolecule belonging to the pathogen, and ideally the interaction between the drug and its target kills the pathogen and cures the disease. In an iterative process, lead compounds are optimized and retested for improved activity, specificity, potency, and safety. A more detailed discussion of the intricacies of the small molecule drug discovery process is presented in Appendix I. There is no hard-and-fast point where the iterative process of drug discovery ends. Drug development is most simply defined as the point at which an optimized lead compound with good efficacy in animal models and acceptable toxicity and pharmacokinetic5 properties is selected for preclinical evaluation [12]. Once a “preclinical candidate” has been chosen, it must pass a rigorous series of tests designed to ensure safety in animals and provide persuasive indications of efficacy. With a successful preclinical compound in hand, researchers may then apply to the U.S. Food and Drug Administration (FDA) for investigational new drug (IND) status, which permits the compound to be tested in humans. The IND candidate’s safety, dosing, and efficacy in humans are then established by clinical trials. Products with demonstrated efficacy and safety in humans 5 “Pharmacokinetics” refers to the study of how an externally administered agent behaves in animals or humans—“what the body does to a drug.” Routinely examined pharmacokinetic properties of a drug are its absorption, distribution, metabolism, excretion, and toxicological properties (ADME/Tox). 16 Closing the Global Health Innovation Gap Figure 3.1: Drug Discovery and Development—the Necessary Prelude to New Drugs Drug Development Drug Discovery Screening for Hits Lead Identification 3-6 years Lead Optimization Preclinical Phase I Clinical 1 year are approved by regulatory authorities such as the FDA or European Medicines Agency (EMEA) and registered in the countries in which they will be sold. Together, projects in discovery and development make up the product “pipeline.” As illustrated in Figure 3.1, the process of discovering and developing drugs requires an average of 10–15 years [13, 14]. Although the failure rate is greatest at the earliest stages of discovery, products can fail at any point. Indeed, high rates of attrition partially explain why the process of inventing a drug takes so long. According to the Pharmaceutical Research and Manufacturers of America (PhRMA), for every 5,000–10,000 compounds that enter the pipeline, only one becomes a registered product [14]. Thus, because of attrition, the vast majority of compounds that enter drug discovery and development will never progress to success in clinical trials [15]. New players build the therapeutics pipeline for neglected diseases From 1975 to 2004, out of 1,556 new drugs approved by the FDA, EMEA, and other government authorities, only 21 were registered for tuberculosis, malaria, and other neglected diseases [16, 17]. This oft-cited statistic reflects the lack of incentives for biopharmaceutical companies to invest in products for which there are insufficient paying markets. In 2006 alone, U.S. pharmaceutical and biotechnology companies invested over $55 billion of their own resources to invent medicines for diseases of the developed world [18]. Yet, they directed only a fraction of that sum—we estimate based on two recent studies less than $100 million—for R&D aimed at two of the world’s biggest killers, malaria and tuberculosis [19, 20]. To remedy this imbalance, over the past decade new public sector R&D efforts have arisen to build a pipeline of new products for neglected diseases, with over $1.2 billion of Phase II Phase III Registration Trials 6-7 years 1 year investment since 1999 [2]. Although certain large pharmaceutical companies, academic centers, and biotechnology companies have begun to participate, the driving forces for therapeutic R&D in global health have been PDPs [21]. PDPs are not-for-profit organizations funded and championed by the donor community6 to develop novel vaccines, drugs, and diagnostics for specific neglected diseases. Like many forprofit biopharmaceutical companies, PDPs drive preclinical and clinical development of new product portfolios, picking and choosing which products to advance through the pipeline, including which to launch or terminate. In contrast to for-profit companies, many PDPs are “virtual” organizations with comparatively small staffs and no laboratories of their own. Most, if not all, of the projects in their portfolios are carried out by partners, including researchers in academic institutions, contract research organizations (CROs), and large pharmaceutical companies. The larger PDPs oversee and coordinate projects occurring all over the globe. Four leading PDPs focus on therapeutics for malaria, TB, and trypanosomal diseases: n The Medicines for Malaria Venture (MMV) promotes new antimalarials. n The Global Alliance for TB Drug Development (TB Alliance) focuses exclusively on drug development for tuberculosis. n The Drugs for Neglected Disease Initiative (DNDi) creates new drugs to treat trypanosomal diseases and malaria. n The Institute for OneWorld Health (iOWH) concentrates on leishmaniasis, malaria, and diarrheal diseases. All four are mostly virtual and work extensively with nonprofit and for-profit partners to conduct discovery and development. By supporting PDPs, donors have created centers of expertise for each disease area. 6 We use the term “donor community” to refer to governments, nonprofit organizations, and foundations. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 17 Table 3.2: PDP Drugs Registered or in Clinical Trials Product Disease* Development Stage Drug Type PDP Sponsor Paromomycin Visceral leishmaniasis Registered in 2006 (India) Phase III (East Africa) Existing (new use) iOWH DNDi Artesunate-amodiaquine Malaria Registered in 2007 (Morocco) Existing (new combination therapy) DNDi Artesunate-mefloquine Malaria Phase III Existing (new combination therapy) MMV Cholorproguanil-dapsone (Lapdap™)-artesunate Malaria Phase III Existing (new combination therapy) MMV Coartem® dispersible tablet Malaria Phase III New formulation of existing combination therapy MMV Dihydroartemisinin-piperaquine Malaria Phase III Existing (new combination therapy) MMV Pyronaridine-artesunate (Pyramax®) Malaria Phase III Existing (new combination therapy) MMV Moxifloxicin (Avalox®) TB Phase II/III Existing (new use) TB Alliance PA-824 TB Phase II New Chemical Entity (NCE) TB Alliance Nifurtimox-eflornithine HAT various Existing (new combination therapy) DNDi *In this analysis, we are considering only drugs in development for P. falciparum malaria or P. falciparum and P. vivax malaria, but not P. vivax malaria alone. Sources: DNDi, iOWH, MMV, and TB Alliance. Table 3.3: Biopharmaceutical and Consortium-Based Drugs in Clinical Trials Product Disease Development Stage Drug Type Sponsor Zithromax® chloroquine Malaria Phase III Existing (new combination therapy) Pfizer Ferroquine Malaria Phase II NCE* Sanofi-Aventis Fosmidomycin-clindamycin Malaria Phase II Existing (new combination therapy) Jomaa Pharma Gmbh Gatifloxacin TB Phase III Existing (new use) OFLOTUB consortium** TMC 207 TB Phase II NCE Tibotec (Johnson & Johnson) OPC-67683 TB Phase II NCE Otsuka SQ-109 TB Phase I NCE Sequella LL-3858 TB Phase I NCE Lupin Pharmaceuticals DB289 (pafuramidine) HAT Phase III NCE UNC Consortium for Parasitic Drug Development *New chemical entity **OFLOTUB is a consortium of European and African partners focused on carrying out phase II and III clinical trials to test the safety and efficacy of a gatifloxacin-containing regimen against TB. 18 Closing the Global Health Innovation Gap Evaluation of neglected disease drug pipelines Eager to show early results in bringing new treatments to afflicted populations, PDPs initially focused on testing existing drugs registered for other diseases against the target pathogens. These efforts have borne fruit, with two products launched (paromomycin and artesunate-amodiaquine) and eight additional products in clinical trials (Table 3.2). Through the efforts of industry and various consortiums, several other promising compounds or combination therapies are also in clinical trials (Table 3.3). A snapshot of the current therapeutic pipelines for malaria, TB, and HAT is presented in Appendix II. Products in neglected disease drug pipelines can be divided into n existing drugs being evaluated for new indications, n drugs in new formulations, n novel fixed-dose combinations, or n new chemical entities (NCEs). Tables 3.2 and 3.3 show these classifications for products currently in clinical trials. Figure 3.2 compares risks and benefits of expanding uses for existing drugs versus creating NCEs. A key advantage of using existing drugs is that often they have extensive records of safety in humans and do not require years and millions of dollars to establish safety in treating neglected diseases. NCEs, on the other hand, are much riskier to invent than expanding the use of existing drugs. But with risks come benefits. NCEs targeted for potency, specificity, and lack of toxicity have greater potential to provide breakthrough therapeutic benefits within a wide safety margin. Thus, in the long run, substantial improvement over existing treatments will require discovering NCEs. Figure 3.2: Risks and Benefits of Expanding Use of Existing Drugs Versus the Creation of New Chemical Entities A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 19 Requirements for effective drugs for neglected diseases Any new drug emerging from the pipeline for neglected diseases must be safe, inexpensive to manufacture, practical to administer, stable in harsh climates, potent against resistant strains, and effective within time frames comparable to or better than existing products. In addition, as illustrated in Table 3.4, each disease has a specific, minimum TPP that a new product must meet [22, 23]. The World Health Organization (WHO), via the Stop TB partnership and TDR, has drawn together the views of leading scientists in global health into a set of ambitious goals for discovering new treatments for tuberculosis, malaria, HAT, and other neglected diseases [12, 24]. Table 3.5 summarizes these goals. New medicines that fulfill these objectives might halt and even reverse the spread of these diseases. Table 3.4: Target Product Profiles for Uncomplicated P. falciparum Malaria, Active Pulmonary TB, and Late-stage HAT Necessary Desirable P. falciparum malaria TB Resistance Low capacity to generate resistant organisms Effective against drug-resistant strains No cross resistance with other drugs Dosing Oral formulation Short dosing duration Fast acting Pediatric formulation Safety Safe/low toxicity Safe in pregnant women—no adverse effects on fetus Manufacturing Inexpensive manufacturing to ensure low cost Stability in tropical climate—no special storage considerations Broad Spectrum Efficacy against multiple disease stages Efficacy against all important species or sub-species of the pathogen Combination Use Evaluate for use in combination with other drugs Pharmacokinetics and dynamics compatible with dosing regimen No adverse interactions with anti-retrovirals (ARVs) Other Ability to cross blood-brain barrier Sources: DNDi, MMV, TB Alliance, and Nwaka, S., and A. Hudson, Innovative lead discovery strategies for tropical diseases. Nat Rev Drug Discov, 2006. 5(11): p. 941-55. 20 Closing the Global Health Innovation Gap HAT Table 3.5: Treatment Goals for Malaria, TB, and HAT Disease Goal Ability of drugs in development to meet goal Malaria Single-dose curative treatment Goal unlikely to be met TB Reduce treatment time to 2 months or less Goal unlikely to be met Shorten therapy of latent disease Unknown Efficacy against all stages of disease and all subspecies Goal unlikely to be met HAT Sources: WHO/TDR, DNDi, MMV, TB Alliance, and Stop TB Partnership The activity and safety of the drugs now in development will be fully apparent only upon completion of clinical trials. But it is clear already that these drugs will not meet some of the ambitious goals in Table 3.5, such as shortening the duration of TB treatment to two months or less [25], reducing malaria treatment to a single, curative dose, and developing a treatment effective against all stages of HAT. For these advances, a new generation of therapeutics will be required. An innovation gap impedes creation of the next generation of drugs As the current generation of drug candidates advances toward clinical success and registration, or toward clinical failure and abandonment, a new generation of drug candidates must follow that offers the promise of achieving more ambitious goals. Similar to drug development for cancer and diabetes, neglected disease drug development pipelines require “high-quality” discovery programs7 backed by substantial, sustained investment as occurs when the biopharmaceutical industry tackles diseases such as cancer or diabetes. For instance, a major biopharmaceutical company intent on developing a new oral treatment for a chronic disease market such as heart disease would explore 10 to 20 targets generated by genomics and biochemistry, and advance five to 10 targets in parallel into high-throughput screening. Each project would initially screen thousands to millions of compounds. Most of these projects will fail because of myriad interrelated reasons: for example, inability to express the target protein and develop an assay, lack of credible screening hits, failure to optimize efficacy versus toxicity, lack of oral bioavailability, and failure in animal proof-of-concept models. Project failure rates before identifying an IND candidate are routinely over 75 percent. Subsequent attrition due to clinical failures, safety concerns, and market forces reduces the success rate to less than 5 percent, sometimes only 1 to 2 percent. Thus, a credible effort to develop a new drug in the biopharmaceutical industry requires substantial numbers of discovery projects—enough to ensure that a product with the desired TPP will emerge from the pipeline. The pipeline of clinical-stage programs for malaria, TB, and HAT is expected to yield several new products in the next few years [21]. However, as Figure 3.3 shows, a major disparity exists between early-stage pipelines of these diseases and the profile of a typical industry-driven program for a disease with an established market. For instance, our analysis found that there are five, six, and one discovery projects in the lead optimization stage for malaria, TB, and HAT, respectively. Assuming that the average industry project failure rates will also apply to neglected disease projects, these numbers are far shy of the 20 projects typically required to yield a single new drug. Indeed, for all of the neglected diseases we examined, none has a drug discovery effort sufficient to ensure that the next generation of candidate compounds will be ready to enter clinical development in the coming years. This observation has also been noted by others [26]. This deficiency, or innovation gap, restricts the flow of new, approved medicines for neglected diseases (Figure 3.4). 7 A high-quality program is defined as having the following characteristics: 1) a solid molecular target associated with disease pathology, validated by genomics, molecular biology, cellular systems, and animal pharmacology; 2) a druggable target—one where a small molecule drug would exert a positive therapeutic effect; 3) creating new compositions-of-matter that have the desired effect or improve upon known compounds, with low or no side effects; 4) the ability to manufacture the drug at reasonable cost for desired benefit; 5) the ability to get a clear clinical answer in a defined population quickly; and 6) a clearly defined path to regulatory approval. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 21 Figure 3.3: Attrition Rates and Current Neglected Disease Pipelines 100.0 100 Out of 100 programs entering the screening phase of discovery, on average 1.3 drugs will successfully reach the market 12–14 years later Number of Programs Entering Each Phase of Drug Discovery and Development 90 Expected program survival rate Malaria 80 TB 70 Innovation Gap HAT 60 50 40 30.0 30 19.5 20 10.7 10 Phase 0 Screening for Hits Lead Identification Lead Optimization Preclinical 5.8 4.0 Phase I Phase II 1.9 Phase III 1.3 Registration Sources : MMV, DNDi, TB Alliance, PharmaProjects, and BVGH/L.E.K. analysis Figure 3.4: The Innovation Gap Developed World Disease Drug Development Neglected Disease Drug Development Thousands of Potential Gene Targets Thousands of Potential Gene Targets Hundreds of Validated Targets Dozens of Validated Targets Tens of Chemical Leads Few Chemical Leads 8 - 10 Preclinical Candidates Few Preclinical Candidates 5 Clinical Candidates Limited Clinical Candidates 1 Approved Drug Novel Drugs Rarely Approved 22 Closing the Global Health Innovation Gap 1.3 Approved Insufficient investment in discovery The cost of clinical development is high—estimated in the hundreds of millions of dollars for the cumulative successes and failures required to bring a single new drug to market in the developed world. The discovery stage of this process also requires substantial investments of time and money to n create an initial population of biologically active molecules; n optimize them through multiple iterations of medicinal chemistry and pharmacologic assays; and n select a small number for further development. Industry studies show that innovative pharmaceutical and large biotechnology companies typically spend between 35 and 40 percent of their R&D budget on discovery [27]. The need for this level of investment stems from the difficulties of finding a compound that meets all the pharmacologic criteria required for proceeding into development. Typically, thousands of compounds are intensely evaluated for two to four years before a clinical candidate is selected. Indeed, most discovery programs fail before an IND application can be filed to initiate clinical trials. It is not an exaggeration to say that the likelihood that any single compound will reach the clinic is vanishingly small. By contrast, PDPs have focused smaller proportions of their R&D investments on drug discovery, although they recognize the need to build sustainable pipelines and have continually supported work on new compounds. Based on publicly available information [28-30], these partnerships have only been able to devote between 15 and 30 percent of their funds to discovery, with MMV and the TB Alliance putting the greatest investments into discovery. PDPs have increased their discovery program productivity by partnering with large pharmaceutical companies that make matching in-kind contributions of manpower and resources. While the upper limits of the proportion of their R&D investments devoted to drug discovery is similar, the absolute level of PDP investment in drug discovery is low compared with commercial discovery efforts. Depending on the size of the discovery team, drug discovery companies typically spend between $2 million and $4 million per year per preclinical lead optimization project [27]. Even if a hypothetical PDP had a $50 million budget, 30 percent still represents only $15 million, which will support a pipeline of only three to six early-stage projects to advance lead compounds to IND candidate stage. Current PDP investments are far less than this. Among the biotechnology companies we examined for this report, “discovery-only” and “early-development” companies8 spend a median of $20.9 million and $30.8 million per year, respectively, on research that does not include clinical trial activities. This is substantially more than the hypothetical PDP defined previously (Figure 3.5). Companies typically view their levels of investment as the minimum to maintain a discovery team and generate an IND drug candidate at least every other year. Figure 3.5: Annual R&D Spending by Biotechnology Companies and PDPs Median Annual R&D Spending 35 30 Millions of Dollars Causes of the innovation gap The innovation gap results from insufficient investment devoted to early-stage drug discovery, limited access to key technologies and drug discovery expertise, and difficulties in assembling the collaborations necessary to transform a laboratory discovery into an IND. We explore these problems in detail below. 25 20 15 5 0 arly-Development E Company Discovery-Only Company Hypothetical PDP Sources: Company SEC Filings and BVGH/L.E.K analysis 8 Discovery-only companies are defined as those capable of screening for hits and generating leads and optimized lead compounds. Few carry out preclinical work except on a contract basis. Early-development companies possess comparable capabilities to discovery-only companies, but they can also carry out preclinical work and phase I clinical trials. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 23 Access to technology and expertise and limited scale of operations The technological platforms, assets, and expertise necessary to transform biological findings into NCEs are well established (see Chapter 4). Biotechnology and pharmaceutical companies engaged in drug discovery have purchased or synthesized large compound libraries. They have assembled capabilities in advanced technologies such as high-throughput screening, X-ray crystallography, and computational modeling. They have teams of scientists with expertise in assay development, medicinal chemistry, and pharmacology. Academic centers and individual investigators carrying out neglected disease research have identified compelling new targets for therapeutic intervention [26, 31, 32]. For the most part, however, they lack the tools available to industry to extend their research into drug discovery. Even with the advent of academic- and government-based high-throughput drug screening (HTS) initiatives such as the NIH Roadmap for Medical Research [33], advances in neglected disease biology are not adequately matched with the tools and expertise that lead to the discovery of NCEs [34]. In interviews with academic leaders in malaria, tuberculosis, and trypanosomal diseases (for list, see Appendix III), we found they face three key obstacles in progressing beyond generating hits through small molecule screening: first, limited access to the most advanced drug discovery technology and compound libraries; second, lack of drug discovery experience and expertise; and third, insufficient scale of operations. Limited access to the best compound libraries Compound libraries are collections of organic chemicals assembled by purchase or custom synthesis for repeated screening in multiple biological assays. An industrial compound library is organized around a biological target class, drug-like properties, or chemical structural diversity. A company’s organized, selected, and annotated compound library is a core, proprietary asset. Publicly available compound libraries, on the other hand, are largely limited to diversity libraries obtained from commercial sources. Many academic research facilities have assembled libraries from commercial sources, but few if any compare with those available in industry. The most wellconstructed and diverse public library is a new collection of over 100,000 small molecules accessible through the NIH Molecular Libraries Screening Center Network (MLSCN).9 With a few exceptions, publicly available libraries do not have the target-class focus common to proprietary, purpose-built libraries in biotechnology and pharmaceutical companies. Commercial libraries are based almost solely on structural novelty, much like the early combinatorial libraries used by industry, as opposed to relevance to the targets of interest. Screening large numbers of such unbiased compounds against a target may generate hits, but hit rates are extremely low (less than 1 in 1,000) and can be expected to identify a distracting number of false positives [35]. Although these concerns limit the utility of publicly available libraries, two trends may make it possible for public sector researchers to avoid some of these pitfalls. First, there are now commercial sources of target-focused libraries. These libraries offer much higher yields when screened against members of a target family. Second, it is possible and cost-effective to engage chemistry CROs, many of which are offshore, to design certain types of custom compound libraries. Nonetheless, the public sector still does not have access to the breadth of target-focused libraries available to industry—a reality that limits the types of NCEs that can emerge from a neglected disease drug discovery campaign. Limited access to discovery infrastructure and chemistry expertise In recent years, high-throughput screening centers—facilities allowing chemical compounds to be tested for activity against putative or established drug targets in highthroughput mode—have been installed at universities and public research institutes all over the world. These centers are particularly abundant in North America and Europe 9 MLSCN is an NIH-funded consortium that provides the following: high-throughput screening (HTS) to identify compounds active in target- and phenotype-based assays; medicinal chemistry to transform hits into tool compounds; and deposition of screening data into a freely accessible public database. See Austin, C.P., et al., NIH Molecular Libraries Initiative. Science, 2004. 306(5699): p. 1138-9. 24 Closing the Global Health Innovation Gap [23, 36]. To capitalize on the potential value of their own technology, many academic institutions now vie to establish themselves in drug discovery by creating “translational research” centers. These initiatives have facilitated target validation and hit generation, but they represent only part of the infrastructure required to transform an academic laboratory into a true drug discovery facility. Without industry expertise, resources, and scale, such efforts are unlikely to be efficient generators of NCEs that can be entered into commercial development. This limitation holds true as well for academic translational research initiatives for neglected diseases. Converting hits to lead compounds is an iterative, chemistry-intensive process requiring expertise in analytic, synthetic, and medicinal chemistry. For academic biologists and biochemists pursuing drug discovery, accessing chemists—particularly those with medicinal chemistry expertise—requires collaboration with academic chemists sharing an interest in the biological target or disease. Because of the expense and long timelines associated with lead-optimization medicinal chemistry, and the high expected failure rate, it can be challenging to identify and engage academic groups with organic chemistry resources essential to optimize leads into true drug candidates. Insufficient Scale Many of the organizations working on neglected disease drug discovery are limited by the scale of their efforts. For example, TDR reports that its medicinal chemistry network devoted to tropical diseases consists of 11 postdoctoral fellows scattered in eight organizations all over the world to address all of their programs [23]. In contrast, even the smallest drug discovery companies have coordinated teams of at least eight in-house or contract chemists per project [27]. Additionally, few universities possess the instrumentation and expertise required for high-throughput assay development, X-ray crystallography, computational modeling, and in vitro pharmacokinetics and toxicology studies—all of which are essential tools in drug discovery. Current joint industry-PDP efforts provide a good model for future collaborations, but the number of projects being pursued in these programs is far from sufficient to ensure a robust pipeline for any of the neglected diseases. In the biopharmaceutical industry, the limited discovery research under way for neglected diseases mostly takes place in three companies: GSK, Novartis, and AstraZeneca.10 Two of these programs are partnered with MMV and TB Alliance. Building a continuum of players The innovation gap is not only a problem of investment, access to infrastructure, technology, and expertise. It is also a problem of recruiting organizations experienced in different aspects of product development that together can ensure that the fruits of R&D flow efficiently from the laboratory into the clinic, and then to the patient’s bedside. For diseases with a developed-world market, such a system of collaborating organizations has been in place for many years. It begins with commercially viable ideas and inventions created in academia and research institutions. Biotechnology and pharmaceutical companies then license these innovations, where industrial scientists, experienced in translating basic science into nascent products, undertake drug discovery. R&D typically concludes with completion of clinical and regulatory activities by the biotechnology industry innovator or a large pharmaceutical company that may license the product once it shows persuasive evidence of preclinical or clinical efficacy. Biotechnology companies often partner with multinational pharmaceutical companies that have the financial resources to carry out phase II and phase III clinical trials and handle regulatory applications for approval to enter the marketplace on a worldwide scale. Unfortunately, this well-worn path in the private sector has yet to evolve fully for global health product development (Figure 3.6). Opportunities for collaboration and technology transfer that exist for developed-world diseases have, in many cases, not materialized for neglected diseases due to a lack of market-based incentives. 10 GSK’s Diseases of the Developing World program in Tres Cantos, Spain; the Novartis Institute for Tropical Diseases (NITD) in Singapore; AstraZeneca’s TB Research Programme in Bangalore, India. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 25 Figure 3.6: Building a Continuum of Players to Move from Basic Research to Product Registration Diseases with a paying market Academia and Research Institutions Basic Research Multinational Pharmaceutical Companies Biotechnology Companies Screening for Hits Lead Identification Lead Optimization Preclinical Phase I Phase II Phase III Registration CLINICAL TRIALS NEGLECTED DISEASES Multinational Pharmaceutical Companies Academia and Research Institutions Innovation Gap Product Development Partnerships Legend: Neglected disease R&D lacks the continuum of players and handoffs that has evolved for developed-world diseases. Many academics pursuing neglected disease research have developed tools and technologies that might be put to work in drug discovery. But the options for transferring their findings to industry are limited, in part because an appropriate structure for licensing arrangements that may not generate revenue has yet to be established. As a result, organizations lack sufficient incentives to overcome barriers to forming partnerships and moving neglected disease product development forward [34]. Closing the innovation gap Achieving the ambitious goals for treatment of tuberculosis, malaria, and human African trypanosomiasis will entail extensive drug discovery efforts requiring longterm commitment and funding that does not exist today. 26 Closing the Global Health Innovation Gap If not addressed soon, the innovation gap could delay for years, and potentially decades, victory over neglected diseases. Moreover, these efforts need to be sustained; no new drug, no matter how powerful, can forever evade the development of drug resistance. Researchers must constantly fight back with drugs that have new mechanisms of action. It is essential that neglected disease pipelines include large numbers of high-quality discovery programs to ensure continuing improvements in care. The innovation gap cannot be closed with money alone. We must also do a better job aligning the efforts of basic researchers with biotechnology drug discovery tools and expertise— described in detail in the next chapter. Chapter 4: Harnessing Discovery Resources Addressing the innovation gap in neglected disease therapeutics requires access to small molecule discovery capabilities. The biotechnology industry has evolved from having an early focus on protein-based therapeutics to becoming leading innovators of small molecule drugs. Today, biotechnology companies supply large pharmaceutical companies with novel small molecule drug candidates for clinical development. Biotechnology companies with successful track records in small molecule discovery and development could play a similar role in building the neglected disease drug pipeline. In this chapter, we assess their infrastructure and skills; in the next chapter, we look at how their resources are applicable to neglected diseases. The biotechnology industry has been built with over $377 billion of equity capital [37, 39] and hundreds of billions of dollars more in partnership financing from large pharmaceutical companies. Indeed, between 1998 and 2006, nearly 200 discovery alliances were forged each year between biotechnology companies and pharmaceutical companies [27]. In 2006, public biotechnology companies had estimated revenues of $82 billion and another $47 billion of income from partnering and financing deals [39]. By the end of 2006, the combined market capitalization of publicly traded biotechnology companies was $490 billion, a sum exceeding the valuation of the top five U.S. pharmaceutical companies [39]. The biotechnology industry In wealthy countries, drugs are invented, developed, tested, registered, and marketed by pharmaceutical and biotechnology companies. The pharmaceutical industry evolved from chemical companies founded in the late 1800s and early 1900s and is now dominated by about 20 large, “innovative” companies that develop new drugs. The biotechnology industry is much younger. It originated in academic research laboratories following the invention of recombinant DNA technology in the mid-1970s. Through three decades of technology innovation and investment, it has grown to approximately 5,000 companies worldwide [37], of which we estimate 1,500 in the United States and Europe are financed with institutional investment.11 The emerging role of biotechnology in small molecule discovery Until the early 1990s, biotechnology companies used their drug discovery technologies primarily to develop large-molecule biologics—therapeutically active proteins such as hormones and monoclonal antibodies. Early product successes included erythropoietin (EPO), human growth hormone (hGH), and tissue plasminogen activator (tPA). These products were created by cloning human genes through recombinant DNA technologies, expressing the genes in cell culture, and scaling up manufacture of the proteins. In the early days, biotechnology companies did not compete with the pharmaceutical industry in discovering small molecule drugs (see Sidebar 4.1). Instead, pharmaceutical companies dominated small molecule discovery through their enormous manpower and historical expertise in synthetic, medicinal, and process-scale chemistry. The first generation of public biotechnology companies was launched in the early 1980s. These companies focused on making “large molecule” protein drugs, often referred to as “biologics” because they were produced from living cells using recombinant DNA technology. Initially, biotechnology companies had neither the financial resources nor the capabilities to develop their own drugs and depended on large pharmaceutical companies to develop and commercialize their discoveries. Today, the biotechnology industry rivals the global pharmaceutical industry in size, scope, and capabilities. Over 250 therapies and vaccines that originated in the biotechnology industry have been approved by regulatory authorities [38]. Sidebar 4.1: Characteristics of small molecule drugs A small molecule drug is either a natural product or a synthetic organic compound made by chemical synthesis. It is not a protein. In general, compounds suitable as orally available, small molecule drugs have low molecular weight (typically less than 500 daltons), limited ability to form and accept hydrogen bonds, and intermediate hydrophobicity [40]. To synthesize small molecule drugs, medicinal chemists typically make analogs of core structures (scaffolds) and alter side chains to improve specificity and efficacy while lowering toxicity. 11 “Institutional” investment refers to commercial public and private equity investors. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 27 Over the past decade and a half, industry’s landscape changed dramatically. Biotechnology companies recognized the increasing demand for treatments using small molecules, especially for orally administered drugs against chronic diseases. Taking advantage of a revolution in miniaturization, discovery technologies, and vast increases in throughput in screening small molecules for drug activity, biotechnology companies became leading originators of small molecule drugs. This change is critical to whether biotechnology can contribute to developing new drugs for neglected diseases. This is because most large molecule biologics (excluding vaccines) are produced in small quantities, are comparatively expensive (in many cases extremely expensive), must be stored in the cold, and are delivered only by injection. The profile of most drugs envisioned for the developing world demands the opposite: large quantities produced at very low cost, heat stability, and oral delivery. Only small molecule drugs typically achieve this profile. The biotechnology industry has achieved therapeutic success with small molecule anti-infectives, anticancer agents, and cardiovascular disease drugs. As of 2005, the top 10 small molecule drugs originating in biotechnology had sales totaling $7.5 billion. More than half of the drugs that originated in biotechnology companies and received regulatory approval in 2004–2006 were small molecules [41]. Between 1998 and 2006, more than 25 Small Molecule Drugs in Clinical Development Figure 4.1: The Origins of Small Molecule Drugs in Clinical Trials (January 2007) 600 512 500 400 346 300 200 161 100 0 Phase I Phase II Phase III Source: PharmaProjects 28 Closing the Global Health Innovation Gap Originating from large pharmaceutical companies Originating from biotechnology companies percent of the new medicines approved by the FDA originated from biotechnology company R&D [27, 42]. In early 2007, nearly two-thirds of the small molecule drug candidates in clinical trials originated in biotechnology companies (Figure 4.1). By this measure, the biotechnology industry has overtaken large pharmaceutical companies and assumed the leading role in innovation of small molecule drugs. Large pharmaceutical companies have traditionally devoted significant resources to making drug analogs (modified versions of known compounds) or creating new drugs that act on previously validated drug targets. A defining characteristic of biotechnology companies has been their willingness to take on risk and engage in innovation, and thus the biotechnology industry has taken a different approach. Capitalizing on breakthroughs in understanding of the biochemistry of disease and technical advances such as genomics and proteomics, biotechnology companies developed technologies for screening compound libraries for activity against novel molecular targets or new target classes, such as cell receptors or intracellular messengers that regulate biochemical processes involved in disease. These technologies are competitive with the drug discovery capabilities of pharmaceutical companies, and they routinely enable screening millions of compounds against a new biological target in a matter of weeks [35, 43]. Biotechnology companies focused on drug discovery can be segmented by capabilities. As summarized in Figure 4.2, companies can be classified as fully integrated, early development, or discovery only: n Many larger, mature biotechnology companies have fully integrated discovery and development capabilities. They can advance lead compounds emerging from their in-house discovery programs through preclinical development and into the clinic without needing outside development expertise. n Early-development companies are smaller and younger than fully integrated companies. They possess strong discovery platforms that they have used to identify lead compounds. Their capabilities support IND filing, and they have advanced compounds through early preclinical development. To drive clinical development, these companies must partner with larger organizations. Figure 4.2: Biotechnology Companies Can Be Segmented by Capabilities Basic Research Target Target Identification Validation Screening for Hits Lead Lead Identification Optimization Phase I Phase II Phase III Examples: • OSI Pharmaceuticals • Exelixis • Vertex • Gilead Fully Integrated Examples: • Pharmacopeia • Kalypsys Early Development Discovery Only Preclinical Core Discovery Offering Examples: • Amphora • Kémia • Locus Well-developed Less well-developed n Discovery-only companies are typically young and privately held. They have some of the most novel drug technology platforms. Lacking in-house preclinical capabilities, they contract with CROs and partner with larger companies to advance drug candidates through preclinical development and into IND status. Small molecule innovation in the biotechnology industry Given the risk and high attrition rate of drug discovery, biotechnology companies typically aim to develop truly novel products for high-impact therapeutic markets. Hence, few apply their skills to neglected diseases. But if markets and incentives were available, would the infrastructure of the industry be applicable to neglected diseases? Would companies be in a position to undertake discovery projects against unfamiliar pathogens? The diversity of biotechnology businesses bewilders even those steeped in the industry. Biotechnology companies develop platform technologies, vaccines, drugs and diagnostics, not to mention agricultural, environmental, and industrial products. To concentrate on the companies potentially most relevant to closing the drug discovery innovation gap for select diseases, we winnowed a list of over 1,500 U.S. and European companies12 down to approximately 120 that: (a) focus on small molecule drugs, (b) have significant discovery programs, (c) have succeeded in taking new compounds into human clinical trials, and (d) have sufficient scale to pursue multiple programs with at least some vertical integration (see Sidebar 4.2). To refine our analysis, we analyzed in depth 50 representative companies. These companies are listed in Appendix IV and are summarized as a group in Table 4.1. Table 4.1: Summary of 50 Focus Companies Approved drugs originating from focus companies 23 Programs in active clinical development (Jan 2007) 121 Programs in discovery and preclinical development (Jan 2007) >400 Equity capital raised since inception $20 billion 12 We elected to focus on U.S. and European biotechnology companies because they represent the most innovative companies. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 29 The companies we examined closely have collectively raised over $20 billion in public equity capital and received billions more in partnering revenues from collaborators. Their financial strength is also concentrated: just over half the $20 billion was raised by the five largest companies (Figure 4.3). The resources of the biotechnology industry Through interviews with executive and scientific management of many companies in our representative set, we found that the industry possesses three key resources for discovering new drugs for neglected diseases: infrastructure, technological assets, and expertise. Biotechnology companies have invested heavily in high-throughput compound screening facilities, X-ray crystallography, computational modeling, and other infrastructure to support drug discovery programs. Foremost among many companies’ technological assets are the combination of highly evolved compound libraries used in drug screening and proprietary assay technologies built on a scientific foundation in cellular biochemistry. At least as important—and even harder to import or build from scratch—is their drug discovery expertise. Companies have assembled highly experienced teams of biologists, structural biologists, pharmacologists, and chemists. Their skills are indispensable to “lead optimization,” the iterative process of synthesizing and testing compounds for potency, efficacy, and low toxicity. Biotechnology industry resources: Infrastructure Companies have used their equity and partnering revenues to build their infrastructure and develop their proprietary technologies (Table 4.2). To compete with the pharmaceutical industry in small molecule discovery and development, early-stage biotechnology companies had to innovate. Most biotechnology companies were founded upon a single technological insight and then focused on a therapeutic application of the technology. Subsequent partnering or outright sale of the technology funded further drug discovery programs. Most companies invest $100 million to $250 million to reach this point in early-stage development. Sidebar 4.2: Company selection process Many biotechnology companies have the potential to contribute to small molecule drug discovery for neglected diseases. For the purpose of this study, we chose to focus on a small subset of these companies that have the infrastructure, scale, and experience to undertake a substantial new discovery R&D program. We began with approximately 1,500 U.S. and European biotechnology companies focused on human therapeutics and applied successive “filters” to select a representative sample. About 1,000 of these firms concentrate on small molecule therapeutics as opposed to therapeutic proteins. Of these, 700 are originators that create new compounds rather than reformulating existing active molecules. Of these, about 160 have scale and capital sufficient to support diversified drug discovery programs—typically, they have at least 50–80 discovery scientists and spend more than $20 million per year on R&D. Of these 160 companies, 123 companies had a track record of advancing compounds into human clinical development. We further reduced this list to a sample of 50 companies to analyze in greater depth. Company Filter Description Total Biotechnology Industry 1,519 Companies More than 1,500 biotechnology companies are focused on therapeutics Small Molecule Therapeutic Focus 1,008 Companies 1,000 focus on small molecule therapeutics Chemistry-based Discovery Capabilities 733 Companies 700 are pursuing new small molecules Scale 162 Companies 160 have the scale to support new programs Development Experience 123 Companies Over 120 have a track record of taking new drugs into the clinic 50 Focus Companies 30 Closing the Global Health Innovation Gap We chose a sample of 50 companies to analyze A competitive clinical pipeline with potential to produce a portfolio of marketed drugs demands constant investment in mid- and late-stage discovery, preclinical development, and clinical development capabilities. Biotechnology companies eventually need the same technologies and skills resident in any pharmaceutical company, the major differences being only focus and scale. So biotechnology companies hire pharmaceutical industry veterans, expand facilities, and license or purchase established pharmaceutical assets. To reach this level of maturity, with multiple compounds in clinical development, likely represents more than half a billion dollars in total investment. Table 4.2: The Assets and Infrastructure Used in Drug Discovery Animal study capabilities Assay development: Cloning and expression of proteins Chemistry instrumentation (e.g., nuclear magnetic resonance, high performance liquid chromatography, mass spectrometry) Chemoinformatics Compound libraries Compound storage and retrieval systems Computational modeling (for structure-based design) High throughput screening robotics In vitro pharmacokinetic (ADME) and toxicology assays Biotechnology industry resources: Compound libraries Purification, fractionation, and identification equipment A key requirement of most small molecule drug discovery programs is a proprietary compound library that can be screened for drug activity. Although a high-quality library cannot ensure the success of a discovery program, the converse nearly always holds—a library composed of inferior chemical matter is unlikely to yield promising lead X-ray crystallography Figure 4.3: The Financial Strength of the 50 Focus companies: Equity Capital Raised Equity Capital Invested in Select Smaller Companies within Sample 25 250 20 200 Millions of Dollars Invested Billions of Dollars Invested Equity Capital Invested in the 50 Focus Companies 15 10 5 Median of all 50 companies 150 100 50 0 0 s ls m or tex g 45 nce niu rac tica Ver inin len Scie Sep ceu a a d m Mil a rm Re Gile Pha OSI al Tot ta Syn st cry Bio y Arra any Alb ys yps Kal Note: Equity capital invested based on additional paid in capital, capital surplus, and proceeds from venture rounds Sources: Company SEC filings, VentureXpert, and BVGH/L.E.K. analysis A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 31 compounds. There are no definitive rules on what makes a “good” compound library, but certain characteristics dictated in part by a compound’s backbone, or “scaffold,” have been proposed as predictive of orally available small molecule drugs [40]. Biotechnology companies have taken many approaches to building compound libraries. A diversity library, as its name implies, aims to capture a broad array of druglike molecules without selecting any particular target or scaffolds. This type of library can be employed in a wide range of drug discovery programs. A focused library strives for just the opposite: its compounds are biased by structure or function in favor of interaction with a specific target class. Because of the effort and inventiveness required to develop a refined and annotated collection of compounds, compound libraries are among drug discovery companies’ most important and closely guarded assets. An important advantage of developing highly focused libraries is that screens once requiring a few million compounds, many of which were unassociated with any biological activity, can now be performed with about 100,000 compounds, winnowed down by computer algorithms to represent a chosen attribute (function, shape, or target class). Highly focused libraries save time and money. They, and their associated computational modeling tools, provide potentially unique starting points for medicinal chemistry and lead optimization—and are critical to accelerating drug discovery and development for any disease. The majority of our 50 focus companies have been successful in discovering and developing novel small molecule drugs and clinical candidates. Each company generally possesses a mix of diversity and focused libraries. Proprietary compound libraries that have yielded lead compounds are likely to be of increasing value because of the inherent drug-like qualities of the compounds Figure 4.4: The Composition and Tasks of a Drug Discovery Team Exploratory Discovery Description Chemists are needed for compound library development Structural biologists and computationalists are needed for X-ray crystallography and target modeling Biologists are needed for screening and follow up Chemists are needed for hit characterization Computationalists are needed for structure-based design Lead Optimization Biologists and pharmacologists are needed for pharmacokinetic (ADME/ tox) assessment of analogs Chemists are needed for medicinal chemistry and analoging Computationalists are needed for structure-based design Preclinical Candidate selection Biologists are needed for target biology and assay development (cloning and expression) Lead Identification Biologists and pharmacologists are needed for in vitro IND-directed toxicity studies Chemists are needed for process chemistry and formulation CROs may provide additional animal capacity Representative Staff Biologists and Pharmacologists Chemists Structural Biologists/ Computationalists Outsourced Chemists 32 Closing the Global Health Innovation Gap Biologists and Pharmacologists and constant compound data annotation from screening campaigns. But no matter how well constructed and annotated, any library’s value rests in its repeated success in yielding tools for in vitro proof-of-concept experiments and hits for lead optimization. exploration has been carried out. Beyond the value of the specific contents of given compound libraries and annotations stored in databases, companies benefit from the collective knowledge of those who created and used the companies’ technologies. Unfortunately, the industry’s compound libraries have rarely been mined for hits and leads against targets relevant to global health. For neglected diseases, specific natural products (and small collections of such compounds) have historically been the main source of new lead compounds. But things have changed. Today, genomics technologies have identified molecular targets specific to neglected disease pathogens. This is of tremendous importance. It means that screening compound libraries using either phenotypic or target-based screens should significantly expedite neglected disease drug discovery programs. At successful biotechnology companies, the convergence of focus and expertise almost always augments the next level of development, where knowing how to develop drugs and knowing which drugs not to develop are equally important. Constant pipeline triage is instrumental to working quickly and within budget constraints. For example, our 50 focus companies have collectively discontinued more than 700 internal discovery programs [27]. Moreover, pipeline triage can accelerate project timelines to IND and result in more focused clinical trials. Combining this discipline with the inherent value of the company’s R&D infrastructure and proprietary assets continuously creates opportunities for evaluation and action. Biotechnology industry resources: Expertise As biotechnology companies evolved into leaders in small molecule discovery, they built teams with scientific expertise in many disciplines, including basic biology, structural biology, pharmacology, and analytic, synthetic, and medicinal chemistry. The composition of a typical drug discovery team at each stage of a project is summarized in Figure 4.4. Although the mixture of skills changes over the course of a project, advancing to lead optimization frequently requires a dozen or more medicinal chemists, making chemistry expertise integral to success. Our 50 focus companies report employing between 20 and 50 medicinal chemists each, either on staff or outsourced to CROs often located in India or China. Of those companies we examined, most have been in operation for more than 10 years. By assembling industry veterans and motivated younger scientists into small, highly focused teams, biotechnology companies build cohesive discovery-driven cultures and increase expertise in the specific areas of interest. Discovery teams in a successful company are likely to become internationally recognized leaders in their particular area. This special expertise is valuable to the company in ongoing efforts to build a pipeline of projects, and it also adds valuable corporate memory. For example, many companies have “legacy programs,” in which extensive medicinal chemistry Biotechnology industry resources: Target focus Companies focused on small molecule drug discovery are typically thought of in terms of the diseases they tackle. In fact, many are organized not around a disease but around specialized molecular targets that may underlie mechanisms of several unrelated diseases. Their targets are typically members of an extended target family, such as G protein–coupled receptors (GPCRs) (Arena Pharmaceuticals), kinases (OSI Pharmaceuticals, Exelixis, Ambit BioSciences), ion channels (Neuromed), and phosphodiesterases (PDEs) (Plexxikon) (Figure 4.5). Breakthrough drugs have been found in all these classes across a range of therapeutic indications, from the kinase inhibitor Gleevec® for treating chronic myelogenous leukemia, to PDE-5 inhibitors like Viagra® for cardiovascular function and erectile dysfunction. Target expertise is critical for a company’s competitive position. Concentrated expertise, technology, and intellectual property are why pharmaceutical companies seek commercial partnerships with biotechnology companies to build their pipelines. Target expertise can result in a continual source of compounds spanning many therapeutic areas, simply because specific members of the target family have been associated with different disease pathologies. A target- A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 33 Figure 4.5: Target Class Focus of 50 Focus Companies Host response Cytoskeleton General discovery Proteases/Metabolic enzymes Nucleic acid GPCRs Plexxikon Exelixis Sunesis OSI Cephalon Infinity Millennium Eisai Locus Kalypsys Vertex Telik Metabasis Pharmacopeia SRI International Synta ArQule Celgene Astex Ambit Ariad Kinex Amphora Array Kémia Rexahn Rigel Cytokinetics Vitae Immtech Sequella Optimer Replidyne Achillion Genelabs Gilead BioCryst Anadys ChemoCentryx ACADIA Arena Sepracor CV Therapeutics Neurogen Theravance Neuromed Icagen Renovis Lexicon Kinases Ion channels Kinases Proteases Metabolic enzymes Nucleic acid synthesis Cytoskeleton Host response Proteasomes Phosphodiesterases Nuclear receptors GPCRs Heat shock proteins Ion channels Note: Albany Molecular is not listed because it is a drug discovery CRO and does not have internal programs Source: PharmaProjects based approach allows companies to attack different diseases by attacking distinct proteins within a single target class. Often the same compound libraries and similar biochemical assays can be used to tackle entirely different diseases. The classic example of how a library developed for one disease was applied to another involved compounds originally made to inhibit the human enzyme renin, an aspartyl protease implicated in hypertension. These libraries were enlisted in drug discovery for HIV in the urgent early years of the pandemic. Screening of these very same compounds against the HIV aspartyl protease provided the first lead compounds against the viral target and yielded such breakthrough drugs as saquinavir (Fortovase®), indinavir (Crixivan®) and many more protease inhibitors in broad clinical use today. This example, repeated often in the last 20 years, provides a clear road map for target-based drug discovery, regardless of the disease. The very same approach can generate drugs for neglected diseases. 34 Closing the Global Health Innovation Gap ≥50% of Portfolio 10–50% of Portfolio <10% of Portfolio Can biotechnology industry drug discovery technologies be adapted to neglected diseases? Clearly, there are important questions to address. Can drug discovery tools be shared? Is the overlap among drug targets between noninfectious diseases like diabetes and many cancers and developing-world pathogens more than superficial? How relevant to drug discovery for neglected diseases are shared molecular structures? How can we harness the tools of the biotechnology industry that are so effective in developing new therapies for the affluent to develop new therapies for the poor? In the remaining chapters, we will examine the scientific rationale for extending biotechnology companies’ capabilities to neglected diseases, the hurdles that stand in the way, and new models for collaboration between the biotechnology industry, academic organizations, and PDPs. Chapter 5: Mapping Biotechnology Capabilities to Neglected Diseases Biotechnology companies have brought many innovative small molecule drugs from the test tube to the clinic. But does their expertise—built around cancer, cardiovascular disease, and other conditions that afflict the aging population of wealthy nations—offer hope for neglected diseases? The universality of biochemical mechanisms and adaptability of tools for drug discovery strongly suggest that the answer is yes. The unique biology of infectious disease–causing pathogens, however, creates distinct hurdles that will require new solutions by drug discovery scientists. Essential tools for drug discovery As Chapter 4 explains, general drug discovery infrastructure and skill sets resident in industry can play a critical role in creating drugs for neglected diseases. But scientists in drug discovery companies embarking on a discovery program for a neglected disease also need key pathogenspecific tools: n A comprehensive understanding of the disease process at molecular and cellular levels; n Biochemical, cellular, and in vivo assays to evaluate the efficacy, pharmacology, and toxicity of candidate compounds (see Sidebar 5.1); and n Validated targets against which to screen promising therapeutic compounds. Our analysis explored whether malaria, tuberculosis (TB), and human African trypanosomiasis (HAT) can be added to the list of diseases that can be tackled by small molecule drug discovery companies. To answer this question, we first assessed the state of the art of neglected disease drug discovery tools. Specifically, we asked whether neglected disease researchers have created bioinformatic and genetic tools, biochemical assays, and animal disease models that can be combined with the target-specific screening systems found in leading small molecule drug discovery companies. We also looked for target overlap between P. falciparum, M. tuberculosis, and T. brucei, the pathogens that cause malaria, TB, and HAT, respectively, and the diseases on which leading biotechnology companies currently focus their efforts. The choice of diseases . . . Malaria, TB, and the trypanosomal diseases have been studied for more than a century, and much is known about the basic biology of the pathogens that cause them [44-47]. Scientists in academia and at research institutes have suggested that disease understanding per se is not limiting, and they have developed tools and assays that support drug discovery. But they also caution that each pathogen has unusual features that complicate drug discovery [5, 48-50]. TB is caused by a single species of bacterium, Mycobacterium tuberculosis. In contrast, malaria and trypanosomal diseases are caused by several species of Sidebar 5.1: The tool kit for modern drug discovery Guided by the target product profile (TPP), drug discovery scientists know what biochemical and pharmacologic hurdles their candidate compounds must overcome. For rapid progress, discovering new drug candidates for neglected diseases requires the following: Understanding of biochemical pathways of infectious pathogens. Drug discovery is much more likely to succeed if the target pathways are understood. It is much more likely to produce unintended side effects if screening is done in a “black box” of unknown biochemical activity. Genomic information. A fully sequenced and annotated pathogen genome allows researchers to predict pathogen gene function, greatly facilitating target identification. Genetic tools. To “genetically validate” a target molecule requires tools that enable researchers to test if a gene is essential for virulence, pathogenesis, or viability. Discovery tools. Such tools include recombinant target protein expression, high-resolution protein crystal structure, and biochemical or whole-cell assays. Animal disease models. Screening small molecules for in vivo pharmaceutical activity is a prerequisite to further preclinical and clinical development. Animal models give an initial indication of the efficacy one hopes to see in humans, along with indications of toxicity, pharmacokinetics, drug half-life, and unanticipated side effects. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 35 protozoan parasites. In order to examine specific opportunities within protozoan diseases, we limited our analysis to P. falciparum (malaria) and T. brucei (HAT). Malaria is caused by four species of Plasmodium parasites, each with its own unique biology and pathology. Nearly all efforts to invent new malaria drugs, however, are directed at P. falciparum, the deadliest and best understood species and the most common throughout Africa. Leishmaniasis, Chagas disease, and HAT are caused by divergent species of protozoa (called trypanosomatids) with unique life cycles and insect vectors. Leishmaniasis is not a single disease. It exists in visceral, cutaneous, and mucosal forms and is caused by more than 20 separate Leishmania species. Although Leishmania, T. cruzi (the pathogen that causes Chagas disease), and T. brucei evolved from a common ancestor, and therefore share many molecular and biochemical pathways, their infection cycles and the tissues they target are very different. We focused our analysis on T. brucei because the set of research tools available for its study are better developed than for any other type of trypanosomatid. . . . and their challenges P. falciparum. The life cycle of P. falciparum is extraordinarily complex. The parasite targets several tissue types and shifts between living freely in the blood and entering and inhabiting the host’s cells. The parasite undergoes radical changes in morphology and metabolism as it passes through these stages. Drug discovery in P. falciparum, however, is effectively restricted to the red blood cell or erythrocytic stage of its life cycle—the stage responsible for the symptoms of uncomplicated malaria—because only this stage of the parasite can be cultured in the laboratory. Laboratory culture is not routine for the forms of the parasite that infect the liver or for those that survive ingestion by mosquitoes and complete the transmission cycle. These obstacles make developing a drug that relieves symptoms and also prevents infection and transmission much more difficult. M. tuberculosis. Even under optimal laboratory condi- tions, M. tuberculosis grows extremely slowly (a doubling time of about 24 hours). As a result, antibiotics that disrupt processes required for rapid growth are rendered 36 Closing the Global Health Innovation Gap much less effective than for bacteria with doubling times on the order of minutes. Furthermore, the thick, waxy surface coat of M. tuberculosis is not at all like a mammalian cell membrane and is an impossible barrier for many drug-like molecules to cross. In addition, due to a poorly understood phenomenon known as “persistence,” a fraction of M. tuberculosis in an individual with active disease can survive in the presence of currently available drugs for months [51]. T. brucei. T. brucei hides in privileged spaces, where it can be difficult for drugs to reach. In late-stage disease, the parasite leaves the bloodstream and enters the central nervous system and brain. For a drug to be effective in this stage, it must be able to cross the blood-brain barrier (BBB), a gradient mechanism that normally serves to protect the brain from most chemicals circulating in the blood. Designing a drug capable of crossing the bloodbrain barrier (BBB) without any associated toxicities presents an enormous challenge. Drug discovery tools for neglected diseases: The state of the art Several factors have primed M. tuberculosis, P. falciparum, and T. brucei for major therapeutic advances: n Their genomes have been sequenced and annotated; n Genetic tools have been developed to validate potential drug targets; and n Animal models of infection exist, making it possible to test the ability of compounds to kill pathogens in vivo. Each of these topics is described in more detail below. The importance of genomic information for target identification The revolution in DNA sequencing and bioinformatics, along with order-of-magnitude increases in speed and reductions in cost, has made it possible to sequence the genomes of dozens of infectious microbes. Beginning with the M. tuberculosis genome in 1998 [52], scientists have reported fully sequenced and annotated genomes for P. falciparum [53], T. brucei, [54] and closely related organisms [55-58]. Pathogen-specific genomic information is accessible through a variety of publicly available databases (see Figure 5.1) [59-61]. The availability of genomic information is important for drug discovery for several reasons. First, it greatly facilitates correlations between pathogenicity and specific genes. It also allows researchers to identify genes that, based on their known or predicted function, are potential drug targets. Finally, it has led to the routine application of molecular and recombinant techniques that may reveal more about a pathogen’s potential vulnerabilities to drugs. For example, with a pathogen genome sequence in hand, a researcher has all the information necessary to manipulate the pathogen genetically and to make pathogen proteins to determine protein crystal structure and to develop a biochemical assay. Conditional knock-outs are especially important for testing if a gene is essential to the pathogen when the pathogen infects a laboratory animal. This may reveal whether a gene’s function is required to maintain a chronic infection. In recent years, a tool known as RNA interference (RNAi/ siRNA) has proven to be a rapid way of testing whether a gene is essential in many eukaryotes,13 including the human infective form of T. brucei [62]. This technique does not disrupt the gene, but inhibits expression of the protein that the gene encodes. Unfortunately, RNAi cannot function in P. falciparum because the pathogen lacks key enzymes required to generate interfering RNAs. Likewise, RNAi is not relevant to a bacterium like M. tuberculosis. Target validation depends on genetic tools Target validation is the determination of whether a gene encoding a pathogen protein is essential to the viability or virulence of the pathogen. That is, can the pathogen survive under laboratory culture or infect an animal when a gene’s function is lost? If a parasite with a mutation in a specific gene dies, is severely weakened, or cannot maintain an infection, scientists may decide to design a drug to inhibit the function of the gene product to yield a similar outcome. A genetically validated target proves useful only if it is shown to be “druggable”: not only is the enzyme integral to the disease process, but it can also be inhibited through specific binding with small molecules. For reasons such as functional obscurity or redundancy, physical inaccessibility, or even the shape and size of a unique binding site (or lack thereof), many potential drug targets prove undruggable. For a neglected disease pathogen, most validated targets will be proteins or protein complexes. Inhibition of the activity of these proteins with an effective small molecule drug will cause the pathogen either to stop growing or die. Historically, most antibiotics have interfered with pathogen “housekeeping functions” such as DNA replication, RNA transcription, protein translation, or cell wall synthesis. Thus, pathogen genes involved in these processes continue to be viewed as potential drug targets. Several techniques can test if a gene is essential for viability. The most straightforward is to “knock out,” or permanently disrupt the target gene, thereby eliminating the production of the protein it ordinarily encodes. This genetic engineering technique has become routine for P. falciparum, M. tuberculosis, and T. brucei [48, 62, 63]. There are, however, technical limitations associated with gene knock-outs. To overcome them, M. tuberculosis and T. brucei researchers developed methods of “conditionally” knocking out gene function [64, 65]. That is, they are able to turn off a gene’s expression temporarily and then observe if the organism remains viable. The importance of mouse models in target validation Researchers depend on animal models of infectious disease to identify and validate potential drug targets. Mouse models are most often used in early-stage drug discovery because large numbers of experiments can be conducted at comparatively low cost to predict effects in humans. Researchers can test if a target that has been genetically validated in vitro is also required to initiate or maintain an infection in animals. A mouse model allows compounds identified on the basis of in vitro activity (for example, compounds identified for inhibiting a target pathogen protein in test tube experiments) to be tested for the ability to prevent infection or cure an infected animal. M. tuberculosis and T. brucei can be grown in mice with relative ease. For T. brucei, mouse models exist that mimic both acute and chronic stages of disease, making it possible to evaluate compounds for their ability to clear both types of infection. The latter is especially important because for a drug to cure chronic infections, it must cross the BBB. The chronic-infection mouse model allows researchers to test compounds for ability to kill T. brucei that have entered the central nervous system. 13 A eukaryote is most simply defined as an organism containing a nucleus. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 37 In contrast to M. tuberculosis and T. brucei, P. falciparum cannot normally survive in mice. Instead, the rodent malaria parasite P. berghei is commonly used as an imperfect substitute for infected animal studies. Establishing that a compound effective at killing P. falciparum in culture will kill P. berghei in a mouse via the homologous target is routine, but does require later confirmation because at the amino acid level P. berghei and P. falciparum proteins share on average just over 60 percent sequence identity [55]. In instances where the structure of the P. falciparum target differs substantially from that in P. berghei, the P. berghei gene can be replaced with the relevant P. falciparum gene Figure 5.1: Target Validation and Drug Discovery Tools Available for P. falciparum, M. tuberculosis, and T. brucei P. falciparum Basic Research: Target Identification Genome: sequenced and annotated; comparative genomics possible with other human and rodent species of Plasmodium Conditional gene knock-outs: in development Safety: BSL2 laboratory Proteomics: extensive Key databases: – genolist.pasteur.fr/TubercuList/ – webhost.nts.jhu.edu/target/ Can be grown on solid media, in liquid culture, or in animal models Safety: requires BSL3 laboratory Genome: sequenced and annotated; comparative genomics possible with Leishmania sp. and T. cruzi Key databases: – www.genedb.org/genedb/tryp/ – tdrtargets.org Bloodstream stage parasite can be grown in culture or in rodents Gene knock-outs: routine Conditional gene knock-outs: possible Transposon mutagenesis: routine RNAi: not relevant Lead Optimization Primate disease models available P. falciparum does not normally grow in rodents; new immunocompromised and ‘humanized’ mouse models emerging The rodent malarial parasite P. berghei is frequently used in place of P. falciparum; allelic replacement can be used to generate improved P. berghei Gene microarrays: available Crystal structures: not extensive Genome: sequenced and annotated; comparative genomics possible with Bacille Camille Guérin (BCG), M. smegmatis, M. leprae Whole-cell screening: routine under a variety of conditions; assay for growth For safety reasons, M. smegmatis is commonly used as a substitute for M. tuberculosis Animal models: mouse for acute and chronic disease; guinea pig, rabbit, and primate models also available No animal model for latent disease Gene microarrays: available Crystal structures: extensive and freely available - TB structural genomics consortium: www.doe-mbi.ucla.edu Gene knock-outs: routine Conditional gene knock-outs: routine RNAi: routine Gene microarrays: available, but polycistronic transcription limits usefulness Proteomics: limited Crystal structures: limited Safety: BSL1 for standard lab strain Well-developed tools Whole-cell screening: routine for erythrocytic stage; assay for DNA replication RNAi: no Erythrocytic-stage parasite can be grown in culture M. tuberculosis Gene knock-outs: increasingly routine (erythrocytic stage only) Lead Identification Transposon mutagenesis: possible Key databases: – www.plasmodb.org – tdrtargets.org T. brucei Screening: Target Validation Less well-developed tools 38 Closing the Global Health Innovation Gap Whole-cell screening: routine; assay for ATP production Animal models: mouse for acute and chronic (latestage) forms of disease [66]. Such a transgenic organism would be predicted to more closely mimic P. falciparum than normal P. berghei. Additional drug discovery tools for neglected diseases Modern drug discovery is supplemented by a variety of technologies that require specific molecular information or reagents. These technologies include the following: n Recombinant target proteins. Screening campaigns typically require that the target protein be cloned, expressed, and purified. The protein can then be used in high-throughput-screening biochemical assays. n High-resolution crystal structures. Protein crystals made of highly purified target protein and then subjected to X-ray diffraction provide researchers with structural information useful in designing and refining small molecule inhibitors by computational modeling. Co-crystallization of an inhibitor bound to the target protein aids lead optimization by providing additional high-resolution information on where the drug binds its target. n Biochemical or whole-cell assays. An assay suitable for screening thousands of compounds needs to be simple and highly reproducible. In many cases it is useful to screen compounds against whole organisms using medium-throughput in vitro assays to test if the compound inhibits pathogen growth. Figure 5.1 provides an overview of many of the tools available for P. falciparum, M. tuberculosis, and T. brucei. Drug discovery tools for neglected diseases: Conclusions Our interviews with scientists in academia and biotechnology companies strongly suggest that modern techniques of drug discovery are readily applicable to neglected diseases. In every case, the neglected disease knowledge base and early discovery work, from genomics to assay development, meet or exceed biopharmaceutical industry standards for initiating a discovery project. Moreover, these discovery assets in many cases are of sufficiently high quality to initiate high-throughput screening (HTS) projects to search for lead candidates or structure-based drug design projects. More work, however, is still needed on target validation and animal models for neglected diseases (see Sidebar 5.2). The search for validated targets Most of today’s standard treatments for diseases such as TB and HAT are over 40 years old [5, 71] and have severe limitations in potency, safety, and resistance profiles. Many of these drugs were discovered serendipitously or by traditional screening of drug compounds against whole organisms in vitro. While some traditional screening techniques are still useful, modern biotechnology now enables drug hunters to hone in on specific molecular targets in pathogenic microbes and understand from the start the mechanism of action.14 This approach significantly improves the likelihood of identifying compounds that are highly potent and specific to the target and potentially safe and efficacious. Sidebar 5.2: Critical tools for future development While our interviews indicated that scientists feel confident that they have the tools to launch new discovery efforts, key improvements could accelerate drug discovery for each disease. Indeed, the Bill & Melinda Gates Foundation launched a $40 million TB Drug Accelerator in 2006 specifically to develop new tools [67]. For malaria and tuberculosis, two needed advances could have tremendous impact: Develop a mouse model capable of maintaining a sustained P. falciparum infection. Rodent malarial species of Plasmodium do not adequately predict results with P. falciparum. A drug designed to act on a P. falciparum target but screened for efficacy against a rodent parasite may exhibit deceptively lower efficacy in the mouse model due to differences in the rodent parasite’s infection cycle, pathology, permeability, and ability to transport drugs across membranes [68], thus generating false negative results. Strains of immunodeficient mice that tolerate grafts of human red blood cells have shown encouraging results as models for P. falciparum infections, but have yet to prove suitable for routine use [69]. A mouse strain that can maintain a P. falciparum infection would be a key asset for malaria drug discovery. Develop an improved model for latent tuberculosis. Most humans infected with M. tuberculosis develop a latent infection in which the organism lies dormant, possibly for years, until reactivated by suppression of the immune system or other poorly understood mechanisms. Ridding the body of a latent infection is possible but requires long treatment times. The biology of latent infection is not understood, but the bacteria appear to be in a different metabolic state from those present in active disease [70]. Researchers place a high priority on finding ways to screen candidate compounds against M. tuberculosis in the latent state. Currently there is no in vitro or animal model that emulates a latent infection. 14 “Mechanism of action” refers to how a drug interacts with its target to produce its pharmacological effect. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 39 Biotechnology companies are expert in identifying and validating new biochemical targets that mediate cell growth and viability and that play key roles in diseases such as cancer and neurological disorders. For small molecule drug targets, early evidence of chemical tractability and dose responsiveness can come from compound screening. This evidence is then confirmed by making potency improvements during lead optimization. Examples of proteins widely employed as targets for drug discovery include proteases (proteins that degrade other proteins), protein kinases (intracellular messengers), ion channels (transmitting molecules across the cell membrane), and farnesyl transferases (cell signaling). Leading drug discovery companies have developed technologies and built tools around specific target classes (see Table 5.1). Certain classes of drug targets, such as kinases and ion channels, have different roles in different cell types. Related targets in different cell types can function in entirely different diseases. This explains why many companies build drug discovery technologies specializing on particular target classes and then launch programs on multiple diseases. For example, one company specializing in kinases attacks multiple types of cancer. Another specializing in ion channels has programs in pain, hypertension, and epilepsy. A company’s specialized technologies for a particular target class could be applied in drug discovery programs against a neglected disease pathogen, where the pathogen shares a target with a chronic disease such as cancer. As summarized in Figure 5.2, significant target class overlap exists between chronic noninfectious diseases and neglected infectious diseases. Moreover, many of the same major target classes are shared between P. falciparum and T. brucei, or among P. falciparum and M. tuberculosis and T. brucei (Figure 5.3). Shared targets include kinases, proteases, protein farnesyl transferases, and phosphodiesterases. Target-specialized drug discovery know-how and targetspecialized compound libraries have already been applied successfully to selecting compounds active against targets in P. falciparum and T. brucei [72]. Table 5.1: Drug Targets Favored by Biotechnology Companies and the Tools Available to Tackle Them Biotechnology Drug Discovery Tools Target class Compound libraries High-throughput screening assays & screens Crystal structures Proteases Yes Yes Yes Proteasome Yes Yes Yes Metabolic enzymes (DHFR, etc) Yes Yes Yes Phosphodiesterases Yes Yes Yes Protein farnesyltransferases Yes Yes Yes Ion channels Yes Yes Models only Kinases Yes Yes Yes Nucleic acid – replication – transcription – purine salvage – pyrimidine salvage – other Yes to all Yes Yes Cytoskeleton Yes Yes Yes G protein-coupled receptors Yes Yes Yes Heat-shock proteins Yes Yes Yes Nuclear receptors Yes Yes Models only 40 Closing the Global Health Innovation Gap Figure 5.2: Target Classes Are Transferable Across Diseases Table 5.2 presents a more detailed compilation of target class overlap between small molecule drug discovery companies and each pathogen. Below, we highlight three major shared target classes: proteases, cyclic nucleotide phosphodiesterases, and protein kinases. Chronic Disease Proteases cleave peptide bonds, breaking down proteins into peptide chains or single amino acids. Drugs on the market that target proteases include Tekturna® used to treat hypertension and Kaletra® and Reyataz®, used to treat HIV. Clinical trials are currently under way to test the efficacy of various protease inhibitors as therapeutics for hepatitis C and osteoporosis. Inside a red blood cell, P. falciparum derives energy and nutrients by breaking down hemoglobin. Hemoglobin breakdown requires several P. falciparum proteases [73]. Among them, a cysteine protease subfamily known as falci- Molecular Target Neglected Disease Cancer Kinases Malaria TB HAT Cardiovascular disease; HIV Proteases Malaria TB HAT Cancer Farnesyl tranferases Malaria HAT Central nervous system diseases Ion channels Malaria Cancer Cytoskeletal proteins HAT Cardiovascular disease; Erectile dysfunction Phosphodiesterases Malaria HAT Figure 5.3: Target Classes Shared by P. falciparum, M. tuberculosis, and T. brucei Cytoskeleton (flagella) Phosphodiesterases Glycosome T. brucei Nucleic acid Proteases (transcription/ translation) Kinases Ion channels P. falciparum Metabolic enzymes Proteasome M. tuberculosis Cell wall synthesis A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 41 pains has been validated and is being pursued as part of a collaboration between MMV and GSK. As of late 2006, these teams were selecting clinical candidates from the falcipain inhibitor programs. The metalloprotease falcilysin is another protease required for hemoglobin breakdown and other functions. Its potential as a P. falciparum target is currently under evaluation. Other proteases have been validated in M. tuberculosis and T. brucei. Cyclic nucleotide phosphodiesterases (PDEs) break the phosphodiester bond found in cyclic nucleotides involved in eukaryotic signal transduction. Inhibitors of the PDE-5 subclass are used as vasodilators to treat pulmonary arterial hypertension and erectile dysfunction (e.g., Viagra®). New inhibitors of different PDEs are being pursued for conditions ranging from depression to inflammation. The T. brucei genome encodes five PDEs. The bloodstream form of T. brucei cannot survive in the absence of two of these enzymes, TbrPDEB1 and TbrPDEB2 [74]. Because the catalytic sites of TbrPDEB1 and TbrPDEB2 are nearly identical, it may be possible to design a single inhibitor of both enzymes. PDEs are also considered validated targets in P. falciparum [75]. Protein kinases are enzymes that transfer a phosphate group from an adenosine triphosphate (ATP) molecule to a protein substrate in a process called phosphoryation. Kinases play fundamental roles in cell division and signal transduction, processes that often malfunction in cancerous cells. Kinase inhibitors hold enormous therapeutic potential for cancer. For example, Gleevec®, an inhibitor of the protein kinase BCR-ABL, has been approved for use in chronic myeloid leukemia and gastrointestinal stromal tumors, and it is being pursued for treatment of a variety of additional cancers. Because of their essential role in cell proliferation, kinases may also be key targets in preventing replication of infectious pathogens. Table 5.2: Validated Targets in Neglected Disease Pathogens for Which the Tools and Expertise of Biotechnology Companies Might Be Leveraged Targets That Have Been Genetically and/or Chemically Validated by Pathogen Target class P. falciparum M. tuberculosis Proteases – Serine – Cysteine – Other Falcipains Falcilysin (metalloprotease) PDF (metalloprotease) T. brucei TbCatb, brucipain mpa; paf; PrcBA Proteasome Metabolic enzymes – Folate metabolism – Fatty acid synthesis – Glycolosis – Other DHFR-TS; dihydropteroate synthase Fab H; FabI (apicoplast) Lactate dehydrogenase Phosphodiesterases PfPDE1 TbrPDEB1; TbrPDEB2 Protein farnesyltransferases PFT TbPFT Ion channels PSAC Kinases PfMrk; PfMap1; PfNek-1; PfPKG PknG Nucleic acid – DNA synthesis – Transcription – Purine salvage – Pyrimidine salvage – Other DNA gyrase (apicoplast) RNA polymerase (apicoplast) PfNT1 Dihydroorotate dehydrogenase DNA gyrase rpoB DHFR-TS FabI Enoyl-ACP reductase (InhA) Malate synthase (glcB) Isocitrate lyase (ICL1/2) Glycosome enzymes Trypanothione reductase Trypanothione synthase Ornithine decarboxylase CRK3, PK4, PK50 ATP synthase (AtpE) CTP synthetase Note: G protein–coupled receptors are not found in P. falciparum, M. tuberculosis, or T. brucei and thus have been omitted from this table. Similarly, nuclear receptors are not relevant to a nonnucleated organism such as M. tuberculosis and have not yet been validated for P. falciparum or T. brucei. Heat-shock proteins also have not been validated for any of these pathogens. 42 Closing the Global Health Innovation Gap All of the genes predicted to encode kinases (“the kinome”) in P. falciparum and T. brucei have been described [76, 77]. For most of these genes, the biology remains to be worked out, and few have been genetically or chemically validated. Nonetheless, kinases involved in cell-cycle control have been chemically or genetically validated for both P. falciparum (PfMrk) [78, 79] and T. brucei (CRK3) [80, 81]. The latter is one of several kinases actively pursued by the Dundee Drug Discovery Initiative [82]. PknG, an M. tuberculosis kinase required for bacterial survival within the host macrophage, has also received attention as a new drug target [83, 84]. Applying target-focused tools and infra structure to neglected disease drug discovery How might the existing tools and infrastructure of biotechnology be used to attack neglected diseases? A particular strength of the biotechnology industry is the diversity of approaches that are utilized to generate new small molecule drugs, including compounds that inhibit a single target class (see Sidebar 5.3). To commence a new drug discovery program, at a minimum, a biotechnology company would require a TPP and well-researched biological targets that can be assessed for chemical tractability. A project is enhanced by availability of recombinant proteins, assays for biochemical high-throughput, or whole-cell screening and structural information. At least three approaches can employ infrastructure and proprietary technologies to produce optimized lead compounds: High-throughput screening against a conserved target Certain pathogen targets have already been validated, where biological function is comparable to that of a human protein of the same target class. Here, a company could apply the full complement of target-specific biotechnology tools. First, the same high-throughput screening assay format for identifying hits and leads for the chronic disease target could be applied to the pathogen target. Second, a target-focused compound library could be used for screening, improving the odds of identifying hits and leads that could be quickly confirmed to be structure dependent and dose responsive. With the hope of rapidly identifying an advanced candidate for proof-of-concept and animal studies, lead compounds generated from other projects might also be tested for inhibiting the pathogen target. High-throughput screening against a conserved target class In other cases, a target class is known to be essential for viability or virulence in a pathogen, but specific targets have yet to be validated. Using a focused compound library, whole-cell screening could be performed to identify compound hits that kill the target pathogen. Chemogenomic approaches15 could then be used to identify the specific protein in the target class bound by the hit compound. With the pathogen protein target in hand, leads could be identified and further optimized. Alternatively, high-throughput screening with a focused compound library could be carried out on a panel of proteins corresponding to a particular target class (e.g., pathogen kinases). Compounds that inhibit a specific target class member and that kill the pathogen in vitro would be selected for further evaluation. High-throughput screening against a novel target class Certain pathogen targets may be biologically validated but do not correspond to families already explored by companies. For example, genes of the apicoplast (an ancient, nonphotosynthetic plastid) in P. falciparum are required for survival but have no homologs in mammalian cells. Yet there are still ways to utilize biotechnology assets against these targets. In contrast to target-specialized companies, companies with generalized discovery platforms have compound libraries that emphasize chemical diversity and drug-like properties over other considerations. A potential disadvantage of drug discovery performed on a novel target is the lack of preexisting assays, structural information, and lead compounds from related target-focused approaches. Furthermore, starting a program on a novel target may require more time and funding than a program based on membership in a well-validated target class. Nonetheless, there are potential advantages in safety and specificity when selecting targets present within organelles or metabolic pathways that are found exclusively in the pathogen because of fewer nonspecific interactions. 15 Chemogenomics is the systematic analysis of chemical-biological interactions, specifically the investigation of classes of compounds (libraries) against families of functionally related proteins. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 43 The case for further exploration Several of the companies we interviewed have investigated applying their platform technologies and proprietary compound libraries to neglected diseases. On their own, or in collaboration with academic researchers, a number have carried out early-discovery efforts. Of the companies we interviewed, nine either had a compound they considered worth testing on a neglected disease or have been in active collaborations with neglected disease researchers. In nearly every case, interest in a neglected disease was driven by target homologies that suggested new utilities for existing compound sets, many of which were synthesized as candidates for chronic disease indications. Unfortunately, most of these efforts were not pursued further because any or all of the following reasons: inability to obtain funding, lack of preclinical pharmacology support, high opportunity costs, or absence of a clear route to commercialization. These initial efforts nonetheless indicate that biotechnology company participation is a problem of incentives, not capabilities. Chapter 6 details the hurdles to biotechnology company involvement in neglected disease drug discovery. We also present ways in which these problems might be overcome. Sidebar 5.3: Harnessing diverse biotechnology solutions A major strength of the biotechnology industry is the diversity of approaches to inhibitor design, even when the inhibitors target the same protein class. For example, protein kinases are enzymes involved in signal transduction through which cell growth, morphology, and movement are regulated. Nine of the 50 companies we examined focus exclusively on protein kinases. Thirty (or 60 percent) of them have at least one kinase program. Approaches used to generate inhibitors include the following: ATP-binding pocket inhibitors. Small molecules that bind to and block access to the ATP-binding domain of a protein kinase serve to turn off its function. Because ATP-binding domains are highly conserved among protein kinases, finding inhibitors with sufficient target specificity has proven daunting, and new approaches are now favored. Allosteric inhibitors. An allosteric site refers to a protein surface feature that when bound by an inhibitor changes the protein’s conformation to become enzymatically inactive. Allosteric sites among kinases are not highly conserved. By selecting for compounds that bind to a target protein kinase’s allosteric site, high levels of specificity can be achieved. Additionally, inhibitors bound to allosteric sites have longer “off rates” than those bound to the ATP-binding site, a characteristic that makes the inhibitor more potent. Fragment approach to inhibitors. Knowing the structure of the kinase of interest, “fragments” of small molecules are tested by computational modeling for the ability to bind specific nooks of the ATP-binding site. Combinations of fragments are then assembled into single molecules, tested for inhibitory effects and co-crystallized with the kinase target to allow their quality of fit within the binding site to be evaluated and improved. Those deemed most promising are modified iteratively until high affinity binding is achieved. Modular approach to inhibitors. This approach relies on linking small molecules that bind independent sites on the kinase, thereby increasing their specificity and avoiding toxicity. Although an individual module may bind a kinase only weakly, once modules are united into a single molecule high binding affinity can be achieved. ATP-binding pocket inhibitors Allosteric inhibitors Discover compounds that bind specifically to the ATP-binding pocket Discover compounds that bind to allosteric sites ATP x ATP Binding Pocket Kinase ATP x Allosteric Site Kinase Fragment approach Modular approach Build compounds with high binding affinity from small chemical fragments Link compounds that bind to adjacent sites ATP x Kinase ATP x Kinase Adjacent Domain Any of the above approaches could be applied to kinase or nonkinase targets identified in P. falciparum, M. tuberculosis, T. brucei, or any other neglected disease pathogen. Depending on the information available, one approach might be significantly favored over others. Importantly, the diversity of approaches developed for kinase inhibitor discovery typifies the diversity of approaches for other target classes. Sources: Company websites including Ambit, Kémia, Plexxikon, and Sunesis 44 Closing the Global Health Innovation Gap Chapter 6: Building a New Discovery Pipeline Although biotechnology companies possess technologies and expertise that could accelerate drug discovery and development for neglected diseases, information, managerial, and financial hurdles have hindered their participation in global health. This chapter explores a range of ways to summon the most experienced and capable innovators; forge partnerships among companies, PDPs, and academia; and fund and manage the most promising drug discovery projects. The Current Landscape Leading public sector organizations have recognized the need to close the innovation gap by increasing effort and investment in drug discovery. PDPs such as the TB Alliance and MMV sponsor several million dollars per year of drug discovery work at major pharmaceutical companies such as GSK and Novartis, along with smaller collaborations with several biotechnology firms [21, 85]. To help build the foundation of biological knowledge and discovery tools available to drug hunters, several public sector initiatives have been launched in the past few years. They include— n The Gates Grand Challenges in Global Health, with $436 million of basic research funding awarded in 2005 [86]; n The $40 million Gates Foundation–sponsored TB Drug Accelerator announced in 2006 [67]; and n The Pathogen Sequencing Unit, part of the £334 million Wellcome Trust Sanger Institute [87]. Academic research institutions have also formed centers of excellence and consortiums to target drug discovery for neglected diseases and bolstered their efforts by key hires from industry [88]. Examples include: n The Tropical Disease Drug Discovery Initiative at the University of Dundee, focused on trypanosomatids; n The Sandler Center at the University of California at San Francisco, focused on parasitic diseases; and n The Consortium for Parasitic Drug Development at the University of North Carolina, focused on trypanosomatids. Additionally, two Seattle-based nonprofit research institutions have dedicated efforts to innovate new drugs and vaccines for neglected diseases. The Infectious Disease Research Institute (IDRI) was founded in 1993 and has multifaceted programs in a number of neglected diseases including TB, Chagas disease, and leishmaniasis. The Seattle Biomedical Research Institute (SBRI) was founded in 1976 and has research efforts under way on numerous bacterial, viral, fungal, and parasitic diseases. In 2007 IDRI and SBRI announced a partnership with Eli Lilly around TB drug discovery [89]. These encouraging initiatives show that the public sector recognizes the innovation gap and is developing ways to address it. But building translational capability in academia is unlikely to be enough to close the innovation gap. Purchasing compound libraries, building drug discovery infrastructure, and hiring the necessary expertise is expensive and time consuming. To fill this gap academic institutions are beginning to “integrate forward,” developing programs in translational research. PDPs are also beginning to “integrate backward,” building preclinical capabilities. However, whether the two “meet in the middle” remains to be seen. More importantly, these public sector initiatives aren’t leveraging the potent capabilities and infrastructure of the biotechnology industry. Hurdles to biotechnology participation In discussions with biotechnology companies, we found a strong desire to tackle the problems of global health. While they must satisfy their obligations to shareholders, many industry leaders are inspired by the chance to make a difference for millions of underserved patients. Biotechnology executives recognize that new models and new incentives will be instrumental to building the pipeline for global health. To engage their companies in the battle against neglected diseases, biotechnology leaders need to address three key hurdles (Figure 6.1): A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 45 n n n Information hurdles. They need to become much more familiar with neglected diseases, potential markets, and prospective partners; Managerial hurdles. They need to build expertise in managing collaborations with prospective partners in the not-for-profit and academic sectors; and Financial hurdles. They need market incentives to invest in R&D and overcome “opportunity cost”—the profit lost by not working on a core business project. Information hurdles A key challenge for bringing biotechnology resources to bear is identifying opportunities and convening collaborators. Biotechnology companies lack expertise in neglected diseases, while academic institutions and PDPs lack deep familiarity with the proprietary tools available in the biotechnology industry. Efforts must be made to educate both sectors and bring these groups together. BVGH is devoted to bridging this information gap, forming coalitions around specific discovery opportunities to build the global health product pipeline. Many attractive collaboration opportunities exist, but they will not happen without diligent efforts to bring decision makers together and illustrate how collaborations can serve their interests. Managerial hurdles Biotechnology companies are particularly concerned about the costs of project management. For a biotechnology company to manage a neglected disease drug discovery project on its own, foreseeable tasks include securing grant funding, managing staff, linking drug discovery efforts with a specific target product profile, and coordinating with academic and PDP collaborators for capabilities not available in-house. Biotechnology company managers are unlikely to have neglected disease expertise. Assembling expertise internally would distract from their core business. To the extent that neglected disease drug discovery projects can be managed externally, these concerns can be relieved. Financial hurdles Financial hurdles for biotechnology companies stem from insufficient market “pull,” lack of excess capital to support discovery R&D, and the opportunity cost of allocating resources to a neglected disease project. Unlike large pharmaceutical companies, biotechnology companies are often cash-constrained and must triage short-term choices in favor of the greatest value to their investors. Resources are often tightly budgeted to support programs that will move rapidly toward approved products for high-value markets. Figure 6.1: Hurdles to the Biotechnology Industry’s Involvement in Neglected Disease Drug Discovery Hurdles Information Hurdle Potential Solution Managerial Financial Companies lack access to and experience with neglected disease science Companies cannot devote management time to non-core activities Companies require market incentive and funding to overcome opportunity costs Establish links between neglected disease-focused academic groups and companies External project management and champions are needed to guide projects through discovery Appropriate financial incentives must be in place Match the right companies to the right science Intellectual property and collaboration templates are needed 46 Closing the Global Health Innovation Gap For diseases affecting the developing world, lack of credible market opportunities and information on viable markets is a significant barrier to entry for innovators. Biotechnology companies’ reliance on pharmaceutical companies and investors to finance their R&D programs is critically tied to the convincing demonstration of a future product’s market viability. In the case of neglected diseases, the limited purchasing power of developing countries and the poor expected return on investment makes attracting such private capital or pharmaceutical partners particularly difficult. the hundreds of millions of dollars, to develop and market these products. These companies are not in business to provide research services in return for cost coverage and a slight profit. More importantly, the cash required for clinical development usually dwarfs what is available through grant support. In fact, biotechnology companies are especially wary of grant cycles at odds with their time requirements for producing results. For example, many companies estimate that lead optimization requires 10–12 chemists for up to three years and over $10 million to generate a development candidate (Figure 6.2). So a grant for lead optimization lasting only one year would not be long enough for the team to make progress. Biotechnology companies consider typical grant cycles (often annual) too short for these projects, so other, longer-term arrangements are needed. Further, direct support (“push funding”—see below) alone will not lead most companies—particularly the most capable innovators—to allocate sufficient resources, typically in Figure 6.2: The Costs of Producing a Single New Drug* 1 Year Screening for Hits 2 3 Lead Identification 4 5 Lead Optimization 6 Preclinical 7 8 Phase I 9 10 Phase II 11 Phase III Clinical Trials 50 45 43 43 Annual Cost in Millions ($) 35 30 25 20 15 15 12 12 10 5 3.3 0.8 3.3 3.3 1.5 0.8 0 $0.8 M $1.6 M $11.6 M $13.1 M $28.1 M $52.1 M ~$138.1 M Cumulative Cost per Program *Excludes the costs of failure Sources: Adams, C.P., and Brantner, V.K. Estimating the cost of new drug development. Health Affairs 25 (2): 420 – 428 (2006) as cited in Parexel’s R&S Statistical Sourcebook 2006/2007 and BVGH/L.E.K. interviews and analysis A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 47 Finally, other costs—particularly opportunity costs— cannot be underestimated. Biotechnology companies operate at capacity, especially with regard to medicinal chemistry. So there are significant costs to reallocating staff for a neglected disease project. These costs consist of direct labor (e.g., chemist and biologist salaries), indirect overhead (e.g., allocation of discovery assets), and opportunity cost. For biotechnology companies to engage in neglected disease drug discovery, a substantial portion of these costs must be addressed by external funding. Engaging the biotechnology industry It is unlikely that biotechnology companies will overcome these hurdles on their own. Their immediate economic concerns keep them too focused on developing drugs for developed-world markets. Only a few dozen of the 1,500 U.S. and European institutionallybacked biotechnology companies are profitable; none of the rest has positive cash flow to support even modest philanthropy. Thus, accessing biotechnology assets for global health product development is most likely to be achieved by new “push” and “pull” financial incentives. Push incentives are direct funding to reduce the risk and cost of R&D. Pull incentives enhance the market to encourage new R&D. Examples of push incentives include: n Grants to fund early-stage R&D, including through the U.S. National Institutes for Health or the UK Medical Research Council. n Tax credits that allow companies to reduce their tax liability by deducting R&D expenditures. Examples of pull incentives include: n Advance Market Commitments that guarantee markets for new medicines in developing countries [90]. n Transferable “priority” vouchers to speed up regulatory review, provided to companies upon approval of a developing-world vaccine or drug. n Willingness of donors, PDPs, or pharmaceutical companies to pay a “risk premium” to license new medicines that have shown proof-of-concept such as phase II efficacy and safety. 48 Closing the Global Health Innovation Gap Models for increasing industry engagement in neglected disease drug discovery We explored several different models for overcoming the hurdles to industry participation in neglected disease drug discovery: subcontracting to biotechnology companies directly, building partnerships, donor-directed portfolio management, and establishing a discovery-focused PDP. Subcontracting to biotechnology companies In selected cases, PDPs have forged new alliances with biotechnology companies, allowing them access to advanced drug discovery technologies and compound libraries that exist nowhere else. An example of this approach is the collaboration launched in 2006 between the TB Alliance and BG Medicine, Inc., to identify novel tuberculosis biomarkers [91]. The advantage of this approach is that PDPs act as “portfolio managers.” They have a strong command of their diseases and can offer biotechnology much-needed guidance on TPPs. Leadership and program management can remain centered on the PDP, minimizing the need for joint development committees or other overarching management structures. The limitation to this approach is that not all PDPs are set up to take full advantage of discovery technologies in industry. In some cases, the formation of drug discovery alliances will require a shift in managerial focus. This is because drug development and drug discovery are very different processes. If PDPs were to seek to integrate upstream into discovery, they would need to add managerial talent with particular experience in managing industrial-scale, small molecule discovery projects. Building partnerships Another model is to form more expansive partnerships among biotechnology companies, PDPs, and academic institutions. Partnerships can maximally leverage biotechnology expertise, proprietary technology, and infrastructure. These partnerships need leadership and operational management to leverage the strengths of each participant. Some discovery efforts can be initiated through biotechPDP or biotech-academia collaborations; others will require the participation of all three. As an example of how academia, PDPs, and biotechnology companies can work together, in 2006, The Broad Institute, MMV, and Genzyme Corporation announced a collaboration to target malaria. The Broad Institute contributes genomics expertise for understanding malaria disease mechanisms. MMV brings expertise in malaria drug development. Genzyme offers small molecule drug discovery capabilities. The collaborators have four early-discovery projects and hope to attract additional resources and funding [92]. New independently generated partnerships might work in a similar fashion. The biotechnology company would rapidly apply its target-based expertise, screening, hit-tolead capabilities, and proprietary compound libraries while taking advantage of the academic center’s disease expertise and biochemical assay systems. The PDP would provide downstream know-how, market knowledge, and access to donors, regulatory information, and the global community. Ownership of compounds, targets, and other intellectual property could be shared or reside with the party taking the lead in the collaboration. Donor-directed portfolio management A third approach is to create management structures within donor organizations or to engage independent portfolio managers funded by donor organizations. Two leading examples for donor-directed portfolio management are the Cystic Fibrosis Foundation Therapeutics, Inc., (CFFT) and the Wellcome Trust (WT). CFFT was created by the Cystic Fibrosis Foundation to fund and manage collaborations with industry to invent and develop new cystic fibrosis therapeutics. CFFT translates basic research from academia into product discovery and development by industry. CFFT identifies opportunities, performs due diligence, negotiates partnerships, and provides product management. Like its parent foundation, CFFT is nonprofit. CFFT R&D funding was over $66 million in 2005, much of which went into early-stage product discovery. CFFT funds provide sufficient incentive for companies to work on what is otherwise an “orphan” disease, where the market is too small to earn a return that competes with disease indications like diabetes or hepatitis C. The Wellcome Trust also funds translational and product discovery work around specific goals and initiatives. WT is as willing to fund R&D in the private sector as it is in academia—what counts is whether the R&D contributes to the goal. An example of a WT initiative is a set of strategic translation awards in Seeding Drug Discovery [93]. This £91 million initiative “to develop drug-like, small molecules will be the springboard for further research and development by the biotechnology and pharmaceutical industry in areas of unmet medical need.” WT evaluates, negotiates, coordinates, and manages these efforts. In these two instances, the foundations decided to be direct investors and coordinators and obtained infrastructure and expert staff for long-term management of their programs. Critically, they have included staff with industry experience and did not exclude private companies as grant recipients. Externally structured, discovery-focused PDPs An alternative, with potentially greater flexibility across multiple diseases, is for donors to support a discoveryfocused PDP. To deploy tens of millions of dollars of neglected disease drug discovery funding investment each year, the community may benefit from funding a PDPlike organization specialized in working across diseases to form new drug discovery coalitions. This portfoliomanagement organization would independently source, negotiate, and manage partnerships with public and private sector participants. This approach would mirror the R&D structure in several pharmaceutical companies, where R&D programs are organized vertically by disease, while drug discovery is organized horizontally and tasked with delivering new lead candidates to the development staff across multiple diseases. Such an approach could be virtual, as adopted by “vertical” PDPs that focus on a single disease such as MMV and the TB Alliance. Or it could focus on one or more centers of excellence with a core group of scientists responsible for collaborations with biotechnology companies and academia and managing key steps in the discovery process for a number of diseases. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 49 A discovery-focused PDP could overcome the key information and managerial hurdles preventing the formation of new discovery partnerships (Figure 6.3). It could provide dedicated project management essential to coordinating efforts involving multiple participants. And it could address the financial hurdles by helping to secure R&D funding and identify potential “hand-offs” to PDPs and large pharmaceutical companies. n n Managerial Capabilities: n Operationally, a discovery-focused PDP will need to assemble the informational, managerial, and financial capabilities and resources needed to establish productive collaborations. n Informational Capabilities: n n Convene Leading Academics: Academic experts will be needed to select drug targets, assay technologies, and tools for pathogen manipulation. Identify Industry Collaborators: Deep knowledge of biotechnology capabilities will be needed to match the right companies with the right academic science and projects. Drive Science Transfer: An ability to guide the process of transferring academic science into biotechnology discovery assets will be needed. Invest in Gaps: Research funding is required to overcome gaps in research tools needed for neglected disease drug discovery. n Project Champion: The discovery-focused PDP will need to function as an external project champion to ensure that biotechnology companies give neglected disease drug discovery collaborations appropriate attention. Provide Project Management: Duties include coordinating grant support, managing staff, and guiding programs toward target product profiles that allow biotechnology companies minimal distraction from their core businesses. Manage Timelines: Grant support must be aligned with realistic timelines for lead identification and optimization programs instead of the annual grant cycles. This will enable biotechnology companies to staff neglected disease discovery programs efficiently. Figure 6.3: Possible Roles for a Discovery-Focused PDP Funding Organizations $$$ Project Management/Coordination Hurdles to Address Coordinate partnerships between neglected disease scientists and biotechnology companies Provide external project management/champions Coordinate hand-offs to PDPs or pharmaceutical companies Provide access to neglected disease expertise Development Candidates Targets Academic Science 50 Closing the Global Health Innovation Gap Biotechnology Companies Product Development Partnerships n n Coordinate Exits with Other PDPs: Preestablished exits of development candidates into PDP portfolios will ensure that biotechnology resources can continue through development. Take Calculated Risks: To fill the pipeline a large portfolio of projects is needed. Failing projects must be quickly winnowed to maximize the overall probability of success of the portfolio. Financial Capabilities: n Provide Funding: The discovery-focused PDP will provide direct financial support to its partnerships. Clearly there are substantial challenges to creating such an organization. But the advantages are impressive— including independence, focus, ability to work with public and private organizations alike, ability to attract talented staff (particularly with industry experience), and flexibility to capitalize on emerging opportunities. Sidebar 6.1: Solving the innovation gap for neglected disease drug discovery: How much will it cost? The discovery programs we are advocating for neglected diseases can take advantage of existing R&D infrastructure in industry, but they will nonetheless incur the variable costs of actually performing the research. Costs for neglected disease drug discovery are likely to be similar to those for developed-world diseases, and they may actually be higher because the specifications for affordability, oral delivery, and thermostability may “raise the bar” for selecting compounds that could enter the clinic. We found that “top down” and “bottom up” analyses yielded similar answers: roughly $40 million per year in discovery R&D funding for each disease to yield a minimum flow of clinical candidates and the potential for a new approved drug every three to five years. In a recent article, Hopkins et al. reckoned that a single discovery program costs on average $20 million to generate a single clinical candidate [94]. For anti-infectives, they estimated attrition rates of 84 percent, meaning that six such programs are needed to generate a single approved drug. A small biotechnology company with a robust discovery platform typically spends $20 million per year on earlystage R&D, and it may have between three and six programs running in parallel. For a developed-world disease such as diabetes, dozens of biotechnology companies will be taking different approaches to the problem. Since R&D success in any one group experiences periods of productivity and drought, success and failure, sustained effort of “two biotechnology company units” of discovery R&D seems the minimum commitment required to smooth out variability in rates of attrition. The advantage of harnessing industry resources is that a large number of screening and hit-generation projects can be undertaken in parallel at low cost to identify the most promising approaches across multiple platforms. We estimate the investment in malaria and tuberculosis therapeutic R&D at roughly $100 million worldwide each. The majority of this investment is in development, with a smaller portion devoted to discovery. If we apply the pharmaceutical industry allocation of 35 to 40 percent of R&D to discovery, this would argue for an additional $50 million investment in discovery R&D for each disease at a minimum. We analyzed in detail the discovery R&D costs of a “model” biotechnology company running three discovery programs in parallel. Each costs a little more than $13 million over a three-year period, yielding a $40 million steadystate run rate. Notably, costs in the earliest stages were under $2.5 million to get to a “lead” molecule, which allows considerable winnowing and optimization before larger commitments are made. Our estimate of discovery spending matches DiMasi et al.’s (2003) estimates [95] of variable costs for discovery to preclinical research. It also matches estimates of discovery spending per IND filed over the past three to five years [27]. Taken together, the evidence supports the idea of highly-focused, tightly-managed programs building to a $40 million per-year investment in drug discovery for each of the neglected diseases. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 51 Chapter 7: Conclusions and Recommendations The biotechnology and pharmaceutical industries have invested billions of dollars in building small molecule drug discovery capabilities. These companies possess target expertise and compound libraries highly applicable to neglected diseases. Therapeutic R&D for neglected diseases will proceed most effectively by enlisting the biopharmaceutical industry’s infrastructure, drug discovery capabilities, and expertise. Engaging the biotechnology industry will accelerate the arrival of better medicines for neglected diseases. The companies best able to meet the challenges of drug discovery for the three neglected diseases selected for this report are those that focus on small molecule drugs and that have advanced novel small molecules into clinical development. Approximately 120 biotechnology companies—of the many that could contribute to global health— are particularly well matched for these criteria. They have discovered and developed some of the most innovative new small molecule therapies, including ones targeting HIV and cancer. Groups in the public sector have succeeded in pushing forward new therapies for neglected disease. Despite their many achievements, an innovation gap remains that limits the translation of academic discoveries in disease biology into new medicines. Unless this gap is closed, neglected disease pipelines will generate far fewer drugs in the long term. Based on experience with antibiotics and anti-virals, we may reasonably expect that drug-resistant pathogens are going to emerge and thus compromise existing medicines. Without more new drugs, many more years will pass before neglected diseases are called neglected no longer and are brought under control. Key findings from our review of select drug discovery companies n Extensive Experience: The companies we examined in depth have impressive accomplishments in launching small molecule drugs and have ongoing discovery and development programs and alliances. n Existing Infrastructure: Billions of dollars in equity financing have allowed these companies to create infrastructure and expertise in small molecule drug discovery that would be prohibitively time consuming and costly to duplicate. n Overlapping Targets and Technologies: Target-based discovery assets are potentially applicable to analogous systems in neglected disease pathogens. n Significant Interest: Biotechnology companies are interested in participating in neglected disease drug discovery to extend the reach of their technologies, establish relationships with larger companies, and contribute to global health. n Obstacles to Participation: Though biotechnology companies are interested in participating in global health campaigns, scientific, managerial, and especially, financial issues prevent them from doing so. Leading biotechnology companies recognize the tremendous unmet needs in global health. Many are seeking ways to participate that are consistent with their business strategies and limited cash resources. They are open to applying their capabilities through R&D collaborations with disease experts in PDPs and academia. Such collaborations will leverage small molecule discovery infrastructure, accelerate innovation, and address the innovation gap in neglected disease drug discovery most efficiently. 52 Closing the Global Health Innovation Gap Recommendations 1. The biotechnology industry’s most capable innovators have an integral role in closing the innovation gap. Biotechnology companies have track records of employing advanced technologies to create new therapeutics that have met with success in human clinical trials. This expertise can and should be applied to neglected diseases. 2. New partnerships are needed to lower barriers for biotechnology companies to invest their resources. Most biotechnology compa- nies are unfamiliar with neglected diseases. To take advantage of their technology platforms, they need to access disease expertise and biochemical assays that are resident in academia, research institutions, and PDPs. R&D collaborations are the best way to combine strengths and increase productivity. 3. Expanded research funding is needed to build an early-stage pipeline. To produce a new, approved therapeutic every three to five years for a single disease, the minimum investment required for new discovery R&D is comparable to the annual funding for two small biotechnology companies—increasing over several years to roughly $40 million per year per disease. This investment will fund several parallel drug discovery programs and accommodate attrition at typical industry rates while allowing surviving programs to enter preclinical development. Among the options: n Independent consortiums of companies, academic labs, and PDPs that work together to transform neglected disease drug targets into optimized lead compounds and preclinical drug candidates. n Direct donor investment in company-led programs with accompanying R&D management and monitoring. n Creation of a discovery PDP that can serve as a “portfolio manager” for new neglected disease discovery programs with a mission of augmenting the pipelines of existing PDPs. Such an organization could efficiently enlist the most experienced innovators; forge partnerships among companies, development-focused PDPs, and academics; and manage and monitor numerous discovery projects. Biotechnology companies could contribute substantially to the discovery and development of new therapeutics for neglected diseases. This document provides a road map for enlisting their capabilities in this fight. By employing existing advanced drug discovery technologies, donor community funds will be used to maximum effect, novel drugs will be developed faster, and more lives will be saved. 4. Effective investment will depend on dedicated portfolio managers. Many of the current participants in global health product development lack deep expertise in managing early-stage drug discovery. The scope of the partnerships and investments we recommend call for project management capabilities that would stretch the current capabilities of any single public sector organization. Dedicated project management to maximize R&D productivity can be infused into PDPs or donor organizations, or it can be built as an independent discovery PDP. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 53 References 1. Sachs, J.D., Helping the World’s Poorest, The Economist. August 14, 1999. 17.Chirac, P., and E. Torreele, Global framework on essential health R&D. 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PLoS Med, 2005. 2(8): p. e210. 89.Eli Lilly and Company, Lilly Not-for-Profit Partnership for TB Early Phase Drug Discovery. 2007 [cited October 19, 2007]; available from: http://newsroom.lilly.com/ReleaseDetail. cfm?ReleaseID=248931. 90.Tremonti, G., Advanced market committments for vaccines: a new tool to fight against disease and poverty, in Report to the G8 Finance Ministers. 2005. 91.BG Medicine, TB Alliance and BG Medicine initiate biomarker discovery program. 2006 [cited September 13, 2007]; available from: http://www.bg-medicine.com/content/ news-center/news/q/id/23. 92.Genzyme. Medicines for Malaria Venture: Genzyme Corporation and the Broad Institute Expand Collaboration to Discover New Drugs for Malaria. 2006 [cited October 23, 2007]; available from: http://www.genzyme.com/corp/media/ HAND_PR.pdf. 93.Wellcome Trust. Strategic Translation Awards in Seeding Drug Discovery. 2007 [cited October 23, 2007]; available from: http://www.wellcome.ac.uk/node2630.html. 94.Hopkins, A.L., M.J. Witty, and S. Nwaka, Mission possible. Nature, 2007. 449(7159): p. 166-9. 95.DiMasi, J.A., R.W. Hansen, and H.G. Grabowski, The price of innovation: new estimates of drug development costs. J Health Econ, 2003. 22(2): p. 151-85. Appendix I. Why Small Molecule Drug Discovery Is a Risky Business As explained earlier in this report, in small molecule drug discovery it is possible to find drugs that can be taken orally and are stable when stored at room temperature. These are key advantages to include in the next generation of drugs for tuberculosis, malaria, and trypanosomal diseases. However, discovering a single new small molecule drug candidate—whatever the disease—is a notoriously lowyield process. Thus, many drug discovery projects must be pursued simultaneously to ensure that any new drug candidates are available for clinical development. In addition to assets, infrastructure, and expertise, the multidisciplinary nature of drug discovery requires time, excellent project management skills, and money. Yet, even if all of these are present in abundance, no single drug discovery program is guaranteed a compound that will achieve IND status and enter clinical trials. The process of small molecule drug discovery To appreciate why most small molecule discovery efforts fail, it is helpful to understand the small molecule discovery process. Researchers begin with a target product profile (TPP), a set of minimum characteristics a new drug must possess to warrant development and use in people. Researchers must possess a deep biological understanding of the disease. They must also have a protein or macromolecule “target” through which the new drug is expected to exert its function. Suitable compound libraries are then “screened” through a battery of in vitro assays to identify a small number of compounds with some hint of activity against the target. Whether the candidate drugs are first identified in vitro by HTS or by structure-based drug design, any compound advancing as a “lead” candidate must then be co-optimized by subsequent chemical structure modifications for as many as 20 or 30 properties that contribute to the TPP. Lead optimization is an extremely complex process in which failure is far more frequent than success. The screening and design processes yield families of compounds related by their structure-activity relationships (SAR). At this point a team of skilled medicinal chemists takes over and synthesizes multiple versions of new but related compounds. Biologists evaluate these compounds for target binding in vitro, providing data that help the chemists sharpen the SAR. Through further rounds of refinement, chemists generate compounds with improved performance against the TPP. Even with powerful computational algorithms that attempt to predict problems with particular compound structures and compound families, iterative cycles of synthesis and screening remain today the only viable method to refine favorable properties and eliminate the undesired ones in search of small molecule drug candidates for in vivo characterization. It is not uncommon for drug discovery teams to sift through hundreds or thousands of compounds in careful in vitro assays—or screen millions in high-throughput mode—to find a very limited number of lead compounds in two or three classes related by SAR. If oral delivery is crucial to the TPP, as it is for most infectious diseases, the degree of difficulty in identifying lead compounds rises dramatically. The human body has multiple layers of defense to resist intrusion by foreign molecules. The body foils drug developers by a host of protective mechanisms. For example, the body may simply not absorb the drug from the stomach or gastrointestinal tract. Or the body may metabolize the drug rapidly. Achieving sufficient and consistent oral bioavailability is a high hurdle for passage to the next stage. The few compound classes nominated for the in vitro medicinal chemistry optimization cycle are now iteratively reoptimized (or more likely, eliminated) by this requirement for an orally bioavailable molecule. A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 57 Only when orally bioavailable candidates are identified can in vivo proof-of-concept studies to validate the biological linkage of the target and the disease be initiated in animals. The few compounds that survive all of these hurdles are thoroughly evaluated in animals for their efficacy and possible toxicity. From the potential candidates that advance through these in vivo studies, usually only a single compound and a backup are nominated for further highly regimented, FDA-mandated IND-enabling work—with no guarantee that any compound will be qualified for subsequent clinical development. The time and manpower required to advance a compound to candidate status is substantial. HTS and lead identification each require two to four full-time scientists working for six to 12 months. Lead optimization is significantly more demanding. A typical program has about 15 to 20 scientists and can last for two to three years, with a 10 to 20 percent chance to find an IND candidate out of the thousands or millions of chemicals evaluated throughout the process. To find a potent, safe, and effective drug candidate for clinical development, drug discovery as practiced today results in a steep “de-selection funnel.” That is, during serial assessment the undesirable properties of proposed hit and lead compounds rapidly reduce the number of candidates under evaluation. Thus, compound attrition rates are very high. Nevertheless, these steps, combined with scientific rigor and luck, transform simple organic chemicals into valuable drugs for the safe and effective treatment of human disease. 58 Closing the Global Health Innovation Gap Appendix II. Snapshots of the Drug Development Pipelines for Malaria, TB, and HAT The drug development pipelines for malaria, TB, and HAT were compiled by examining publicly available data including PDP and company websites and published and unpublished reports. In the early stages of drug discovery, programs are added and dropped rapidly, and thus the “snapshots” below are likely to have changed by the time our report is published. P. falciparum malaria pipeline Drug Discovery Screening for Hits Drug Development Lead Identification PSAC Antagonists (MMV, Broad Institute, NIH / NIAID) PfSub-1 Inhibitor (TDR, Serono) Lead Optimization Clinical OZ Next Generation Isoquine (MMV, Nebraska Univ, Monash Univ, STI) 4(1H)-pyridones Back-ups 4(1H)-pyridone Novartis Institute for Tropical Diseases miniportfolio Falcipains SAR 97276 Dihydrofolate Reductase Inhibitors SAR 116242 Broad Institute/ Genzyme mini-portfolio (MMV, BIOTEC, LSHTM, Monash Univ) (MMV, GSK) (MMV, NITD) (MMV, UT Southwestern, Univ. Washington) PfCDK-1 Inhibitor (TDR, Serono) Artesunate-Mefloquine (DNDi) Chloroproguanil-dapsone (Lapdap™) – Artesunate Ferroquine (Sanofi-Aventis) (MMV, GSK, WHO/TDR, Liverpool Univ) Pediatric Coartem (Sanofi-Aventis) Dihydro-orotate inhibitors (MMV, Broad, Genzyme) Phase III (Jomaa) (MMV, GSK) (MMV, GSK, UCSF) Phase II Trials Fosmidomycin + Clindamycin (MMV, GSK, Liverpool Uni) FAB I (MMV, GSK) Phase I Preclinical (MMV, Novartis) Dihydro-artemisinin-piperaquine (Sanofi-Aventis) (MMV, Sigma Tau, Chongqing Holley, Holleykin Pharma, Oxford Univ, Mahidol Univ) HDAC Inhibitor (TopoTarget, WHO / TDR) Pyronaridine – Artesunate (Pyramax®) Artemisinin (MMV, Univ Iowa, Shin Poong, WHO/TDR) (Amyris/iOWH)) PfGSK3 inhibitor Zithromax + Chloroquine (TDR, Serono) (Pfizer) Tuberculosis pipeline Drug Discovery Screening for Hits Target Identification and screening (AstraZeneca) Target Identification and screening (Novartis Institute for Tropical Disease) Malate Synthase Inhibitors (GSK, Rockefeller Univ, Texas A&M) Drug Development Lead Identification Multifunctional Molecules (TB Alliance, Univ of Auckland, NITD, NIAID) InhA Inhibitors Pleuromutilins (TB Alliance, GSK) (TB Alliance, GSK) Riminophenazines Quinolones (TB Alliance, Institute of Materia Medica, BTTTRI) N-acetyltransferase inhibitors (Summit) Protease Inhibitors Thiolactomycin analogs (Medivir, Queen Mary, Univ of London) Nitroimidazole Analogs (TB Alliance, Cumbre) Proteasome Inhibitors (Cornell Univ) Lead Optimization (NIAID, NIH) Nitrofuranylamides Dihydrolipoamide Acyl (NIAID, Univ Tennessee) transferase Inhibitors (Cornell Univ/NIAID) Phase I Preclinical Trials SQ609 Pyrrole LL-3858 Diarylquinoline FAS 20013 Diamine SQ109 (Sequella) (Lupin) (FASgene) (TB Alliance, KRICT, Yonsei Univ) Dications (Univ of Illinois-Chicaco, Immtech) Bacterial Topoisomerase Inhibitors (TB Alliance, GSK) (Sequella) Phase III TMC207 (Tibotec/Johnson & Johnson) Translocase Inhibitors Gatifloxacin (OFLTUB Consortium) Moxifloxacin (Sankyo, Sequella) PA-824 Nitroimidazole Non-fluorinated quinolones (TB Alliance, Bayer) (TaiGen) (TB Alliance, Chiron, Novartis) Nitroimidazole backup Nitroimidazole OPC-67683 (Otsuka) (Otsuka) Focused Screening (electron transport inhibitors and peptide deformylase inhibitors) Phase II Clinical Oxazolidinones (Pfizer) (TB Alliance, GSK) Promazine analogs (Salisbury Univ) Cell-wall synthesis inhibitors (Colorado State Univ, NIAID) Human African trypansomiasis pipeline Drug Discovery Screening for Hits Drug Development Lead Identification Cysteine Protease Inhibitors Microtubule Inhibitors Trypanothione Reductase Inhibitors Novel Nitroheterocycles Dihydrofolate Reductase Inhibitors Ascofuranone (DNDi/Sandler center) (DNDi/Dundee) Lead Optimization Phase I Preclinical Clinical Nitroimidazoles (DNDi) Phase II Nifurtimox-Eflornithine (DNDi) Phase III Trials DB 289 Pafuramidine maleate (Immtech, UNC consortium) (DNDi) (DNDi) (DNDi) (DNDi/Dundee) Kitasato Screening (DNDi) Screening Program (Genzyme/DNDi) Screening Program (Scynexis) Screening Program (CDRI) Screening Program (TDR, Harvard, Dundee) A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 59 Appendix III. Academic and Company Interviews Academics Matt Berriman William Bishai George Cross Kirk Deitsch Joe DeRisi Alan Fairlamb Mike Ferguson David Fidock Dan Goldberg Keith Gull Luise Krauth-Siegel Sanjeev Krishna Michelle Larsen Pascal Maeser Jim McKerrow John McKinney Carl Nathan Margaret Phillips Pradipsinh Rathod David Roos Philip Rosenthal Eric Rubin David Russell James Sacchettini Thomas Seebeck Clive Shiff Christine Sizemore David Sullivan Juliano Timm Catherine Vilcheze Andy Waters Paul Wyatt Companies Wellcome Trust Sanger Institute Johns Hopkins University Rockefeller University Weill Medical College of Cornell University University of California San Francisco University of Dundee University of Dundee Columbia University Washington University Oxford University University of Heidelberg St. Georges University Albert Einstein College of Medicine University of Bern University of California San Francisco Ecole Polytechnique Fédérale de Lausanne Weill Medical College of Cornell University University of Texas Southwestern University of Washington University of Pennsylvania University of California San Francisco Harvard School of Public Health Cornell University Texas A&M University University of Bern Johns Hopkins School of Public Health National Institutes of Health Johns Hopkins School of Public Health Rockefeller University Albert Einstein College of Medicine Leiden University University of Dundee 60 Closing the Global Health Innovation Gap Achillion Pharmaceuticals Ambit BioSciences Anadys Pharmaceuticals Archemix AstraZeneca ChemoCentryx Cytokinetics Eisai Research Institute Exelixis GlaxoSmithKline (Tres Cantos) Infinity Pharmaceuticals Kémia Locus Pharmaceuticals Metabasis Therapeutics Novartis Institute for Tropical Disease Novocell OSI Pharmaceuticals Pharmacopeia Drug Discovery Plexxikon Replidyne SRI International Sunesis Pharmaceuticals Vertex Pharmaceuticals Vitae Pharmaceuticals Appendix IV. List of 50 Focus Companies Company Location Public/Private 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 ACADIA Pharmaceuticals Achillion Pharmaceuticals Albany Molecular Research Ambit Biosciences Amphora Discovery Corporation Anadys Pharmaceuticals Arena Pharmaceuticals ARIAD Pharmaceuticals ArQule Array BioPharma Astex Therapeutics BioCryst Pharmaceuticals Celgene Corporation Cephalon ChemoCentryx CV Therapeutics Cytokinetics Eisai Research Institute Exelixis Genelabs Technologies Gilead Sciences Icagen Immtech Pharmaceuticals Infinity Pharmaceuticals Kalypsys Kémia Kinex Pharmaceuticals Lexicon Genetics Locus Pharmaceuticals Metabasis Therapeutics Millennium Pharmaceuticals Neurogen Corporation Neuromed Pharmaceuticals Optimer Pharmaceuticals OSI Pharmaceuticals Pharmacopeia Drug Discovery Plexxikon Renovis Replidyne Rexahn Pharmaceuticals Rigel Pharmaceuticals Sequella Sepracor SRI International Sunesis Pharmaceuticals Synta Pharmaceuticals Telik Theravance Vertex Pharmaceuticals Vitae Pharmaceuticals San Diego, CA New Haven, CT Albany, NY San Diego, CA Research Triangle Park, NC San Diego, CA San Diego, CA Cambridge, MA Woburn, MA Boulder, CO Cambridge, UK Birmingham, AL Summit, NJ Philadelphia, PA San Francisco, CA Palo Alto, CA South San Francisco, CA Andover, MA South San Francisco, CA Redwood City, CA Foster City, CA Durham, NC Vernon Hills, IL Cambridge, MA San Diego, CA San Diego, CA Buffalo, NY San Diego, CA Blue Bell, PA La Jolla, CA Cambridge, MA Branford, CT Vancouver, BC, Canada San Diego, CA Melville, NY Cranbury, NJ Berkeley, CA South San Francisco, CA Louisville, CO Rockville, MD South San Francisco, CA Rockville, MD Marlborough, MA Menlo Park, CA San Francisco, CA Lexington, MA Palo Alto, CA South San Francisco, CA Cambridge, MA Fort Washington, PA ACAD ACHN AMRI Private Private ANDS ARNA ARIA ARQL ARRY Private BCRX CELG CEPH Private CVTX CYTK ESALY EXEL GNLB GILD ICGN IMM INFI Private Private Private LEXG Private MBRX MLNM NRGN Private Private OSIP PCOP Private RNVS RDYN RXHN RIGL Private SEPR Private SNSS Private TELK THRX VRTX Private A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 61 About BVGH BIO Ventures for Global Health, a nonprofit organization, is accelerating the development of innovative vaccines, drugs and diagnostics to treat the most devastating diseases of the developing world. Our mission is to harness the biopharmaceutical skills and resources that have transformed medicine in the industrialized world to help save the lives of millions in the developing world. 62 Closing the Global Health Innovation Gap BIO Ventures for Global Health 1225 Eye Street, NW, Suite 1010 Washington, DC 20005 USA Phone: +1 202-312-9260 Fax: +1 443-320-4430 www.bvgh.org Closing the Global Health Innovation Gap BIO Ventures for Global Health Building Biotech Solutions for Diseases of the Developing World Closing the Global Health Innovation Gap A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases BIO Ventures for Global Health