BVGH Therapeutics Innovation Map

Closing the Global Health Innovation Gap
BIO Ventures for Global Health

Building Biotech Solutions for Diseases of the Developing World Closing the Global Health
1225 Eye Street, NW, Suite 1010
Phone: +1 202-312-9260
Fax: +1 443-320-4430
Innovation Gap
Washington, DC 20005 USA www.bvgh.org
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases

Closing the Global Health
Innovation Gap
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:

Washington, DC 20005
Tel: +1 202.312.9260
Fax: +1 443.320.4430
E-mail: info@bvgh.org
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
Figures
Figure 3.1: Drug Discovery and Development— Figure 4.4: The Composition and Tasks of
the Necessary Prelude to New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 17 a Drug Discovery Team. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Figure 3.2: Risks and Benefits of Expanding Figure 4.5: Target Class Focus of 50 Focus Companies. . . . . . . . . 34
Use of Existing Drugs Versus the Creation
of New Chemical Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Figure 5.1: Target Validation and Drug
Discovery Tools Available for P. falciparum,
Figure 3.3: Attrition Rates and Current M. tuberculosis, and T. brucei. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Neglected Disease Pipelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 5.2: Target Classes Are Transferable
Figure 3.4: The Innovation Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Across Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Figure 3.5: Annual R&D Spending by Figure 5.3: Target Classes Shared by
Biotechnology Companies and PDPs. . . . . . . . . . . . . . . . . . . . . . . . . . 23 P. falciparum, M. tuberculosis, and T. brucei. . . . . . . . . . . . . . . . . . . 41
Figure 3.6: Building a Continuum of Players Figure 6.1: Hurdles to the Biotechnology
to Move from Basic Research to Product Registration . . . . . . . . 26 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 6.2: The Costs of Producing a Single New Drug. . . . . . . . . 47
Figure 4.2: Biotechnology Companies Can Figure 6.3: Possible Roles for a Discovery-Focused PDP . . . . . . . 50
Be Segmented by Capabilities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Figure 4.3: The Financial Strength of the

50 Focus Companies: Equity Capital Raised . . . . . . . . . . . . . . . . . . . 31

Tables Sidebars
Table 2.1: initial Assessment of the Need Sidebar 2.1: List of select global health
for New Therapeutics and the Scientific Feasibility product development partnerships (PDPs). . . . . . . . . . . . . . . . . . . . 11
of Creating Them for Key Neglected Diseases. . . . . . . . . . . . . . . . . 13
Sidebar 2.2: Examples of new global health products. . . . . . . . . 11
Table 3.1: Malaria, Tuberculosis, and Human African
Trypanosomiasis. Summary of Disease Characteristics, Sidebar 4.1: Characteristics of small molecule drugs. . . . . . . . . . 27
Pathogen, and Current Standard of Care. . . . . . . . . . . . . . . . . . . . . . 15
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 Sidebar 5.2: Critical tools for future development. . . . . . . . . . . . . 39
Table 3.4: Target Product Profiles for Uncomplicated Sidebar 5.3: Harnessing diverse biotechnology solutions . . . . . 44
P. falciparum Malaria, Active Pulmonary TB,
and Late-stage HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 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
Chapter 1: Executive Summary
Ninety percent of the world’s expenditure on medical Although biotechnology companies are best known
care benefits the richest fifth of the world’s population. for developing protein drugs such as human growth
Technological breakthroughs fueled by billions of dollars hormone and monoclonal antibodies, they are also now
of investment have transformed health care for the affluent, leading innovators in small molecule drugs—the type
yet patients in resource-poor countries cannot afford high- of therapeutic best suited to meet developing-world
quality care. They lack the purchasing power that would needs for oral delivery, thermostability, and affordability.
draw investment in new medicines to treat infectious The challenge is to bring the biotechnology industry’s
diseases that are unknown, or long since eradicated, in discovery assets, know-how, and project management
wealthy countries. capabilities—developed over 30 years and with nearly
$400 billion of equity capital—to the fight against
The devastation caused by these “neglected diseases” has diseases of the developing world.
attracted renewed attention in the past decade, as it’s been
recognized that focused investment and commitment could In this study, BIO Ventures for Global Health (BVGH)
yield powerful new vaccines, drugs, and diagnostics based examined the core capabilities of the biotechnology
on the same technologies that have revolutionized health industry, academia, and the nonprofit entities that focus on
care for the affluent. clinical development of new drugs for neglected diseases.
Based on a preliminary assessment that reviewed areas of
For the first time, several hundred million dollars from significant alignment between biotechnology industry capa-
donors such as the Bill & Melinda Gates Foundation are bilities, basic disease understanding, and unmet medical
being invested annually in important research and develop- need, we focused on three classes of diseases—malaria,
ment (R&D) for diseases such as malaria and tuberculosis. tuberculosis, and trypanosomal diseases (human African
But relatively little of this investment is devoted to the trypanosomiasis, Chagas disease, and leishmaniasis).
discovery of drugs with the potential for providing break-
through therapeutic benefits. As a result, an innovation gap Central to our findings is the transferability of the tech-
is increasingly apparent in the discovery of new medicines nologies used to address cardiovascular disease, neuro-
for neglected diseases. logical disease, and cancer to the infectious diseases of the
developing world caused by parasites and bacteria. Several
This innovation gap stems from insufficient investment families of proteins that have served as principal targets
devoted to early-stage drug discovery, limited public sector for drug discovery for chronic diseases of the industrial-
access to key technologies and drug discovery expertise, ized world are also present in infectious pathogens and can
and the scarcity of capable innovators devoted to creating serve as targets for drug discovery. In principle, this means
new medicines for neglected diseases. that biotechnology companies are in an advantageous posi-
tion to apply their discovery resources and expertise to
Today, product development for neglected diseases is neglected diseases.
mainly carried out in the public and nonprofit sectors,
with for-profit companies serving as partners and subcon- To narrow the scope of our study, we focused on a
tractors in a number of cases. In contrast, the vast majority select group of over 120 companies that have capability,
of new treatments for diseases with markets in the devel- scale, and track records of innovation in small molecule
oped world are created by biotechnology and pharmaceu- discovery that could be highly relevant to neglected disease
tical companies, which together have the expertise and the drug discovery. We further chose to analyze 50 companies
infrastructure to carry discovery and development of prod- in greater depth, including the originators of more than 20
ucts from bench to bedside. small molecule drugs now approved by the FDA.
Key findings
Drug discovery for neglected diseases is hindered nology companies have the speed, flexibility, and persis-
by an “innovation gap.” tence to take leadership roles in attacking new challenges
Despite a revolution in funding for neglected diseases to create new products.
and the evolution of new R&D partnerships, the current
neglected disease pipeline will not fully address key treat- Substantial investment in discovery will be
ment goals (e.g., substantially shortening the duration of required.
certain treatments). The investment in product discovery The pharmaceutical industry typically allocates up to 40
and “translational” research for neglected diseases remains percent of its R&D budget to discovery. Using similar
a fraction of the level necessary to move promising criteria, to build a discovery pipeline that will feed the
discoveries from academic laboratories into commercial existing development infrastructure for diseases such as
settings—far too little to ensure a steady stream of new tuberculosis and malaria will require substantial additional
medicines for neglected diseases. Long-term investments investment. We estimate that a sustained investment of at
in innovation are needed to build a sustainable pipeline least $40 million per year for each disease is required to
of drugs that meet the needs of patients and offer hope of ensure a pipeline that delivers a new, approved therapeutic
alleviating the suffering from these diseases. every three years.
Bringing drug discovery assets built for developed- Significant hurdles hinder biotechnology industry
world diseases to bear on neglected diseases is involvement.
scientifically feasible. Three major hurdles have discouraged many biotech-
For malaria, tuberculosis, and trypanosomal diseases, suffi- nology companies from becoming engaged in global health
cient scientific tools exist for drug discovery R&D efforts product discovery:
to be initiated. Importantly, for many human molecular n Information hurdles. Companies need to become
targets that have received extensive attention from drug much more familiar with neglected diseases,
discovery companies, there are analogous targets in potential markets, and partners.
neglected disease pathogens. This means, in particular, that n Managerial hurdles. They need to build expertise
researchers can employ proprietary compound libraries in managing collaborations with partners in the
used for drug discovery for major diseases for neglected not-for-profit and academic sectors.
disease drug discovery. n Financial hurdles. They need market incentives to
invest in R&D and overcome “opportunity cost”—
Biotechnology companies that focus on small the potential profit lost by not working on a core
molecule drugs and have taken novel small business project.
molecules into clinical development are well
positioned to address the innovation gap. New approaches will be required for effective
Hundreds of biotechnology companies have resources that investment in discovery.
could contribute to the fight against neglected diseases. There is a great need to encourage collaborations between
Many of these are well positioned to take the lead in biotechnology companies with discovery expertise and
developing new drugs, vaccines, or diagnostics to address academic experts with deep understanding of the target
these diseases. For example, many proprietary compound diseases and sophisticated biochemical and molecular tools
libraries used by biotechnology companies for small mole- useful in drug discovery. Such partnerships can lower the
cule drug discovery have been optimized around target barriers to industry involvement. Managerial and financial
classes that are also relevant to neglected diseases. These hurdles must be overcome to attract biotechnology compa-
resources and capabilities would be prohibitively expensive nies to participate in global health initiatives.
to duplicate in the nonprofit sector. Moreover, biotech-

Recommendations
1. The biotechnology industry’s most capable Among the options:

innovators have an integral role in closing n Independent consortiums of companies, academic
the innovation gap. Biotechnology companies have labs, and PDPs that work together to transform
track records of employing advanced technologies to create neglected disease drug targets into optimized lead
new therapeutics that have met with success in human compounds and preclinical drug candidates.
clinical trials. This expertise can and should be applied to n Direct donor investment in company-led
neglected diseases. programs with accompanying R&D management
and monitoring.
2. New partnerships are needed to lower n Creation of a discovery PDP that can serve
barriers for biotechnology companies to as a “portfolio manager” for new neglected
invest their resources. Most biotechnology compa- disease discovery programs with a mission of
nies are unfamiliar with neglected diseases. To take advan- augmenting the pipelines of existing PDPs. Such
tage of their technology platforms, they need to access an organization could efficiently enlist the most
disease expertise and biochemical assays that are resident experienced innovators; forge partnerships among
in academia, research institutions, and product develop- companies, development-focused PDPs, and
ment partnerships (PDPs). R&D collaborations are the best academics; and manage and monitor numerous
way to combine strengths and increase productivity. discovery projects.
3. Expanded research funding is needed to Biotechnology companies could contribute substantially

build an early-stage pipeline. To produce a new, to the discovery and development of new therapeutics for
approved therapeutic every three to five years for a single neglected diseases. This document provides a road map
disease, the minimum investment required for new for enlisting their capabilities in this fight. By employing
discovery R&D is comparable to the annual funding for existing advanced drug discovery technologies, donor
two small biotechnology companies—increasing over community funds will be used to maximum effect, novel
several years to roughly $40 million per year per disease. drugs will be developed faster, and more lives will be saved.
This investment will fund several parallel drug discovery
programs and accommodate attrition at typical industry
rates, while allowing surviving programs to enter preclin-
ical development.
4. Effective investment will depend on dedi-

cated 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 organi-
zation. Dedicated project management to maximize R&D
productivity can be infused into PDPs or donor organiza-
tions, or it can be built as an independent discovery PDP.
Chapter 2: Introduction
The challenge of neglected diseases access to the biotechnology industry’s most advanced
Major advances in biotechnology over the last 30 years have technologies and expertise for discovering and developing
transformed medicine in the industrialized world, but these new medicines.3
innovations have yet to reach the world’s poorest countries,
where 3 billion people live on less than two dollars a day. Today’s medicines are insufficient
A fundamental transformation in commitment to solving
Each year more than 10 million people in the devel- global health problems has occurred during the first
oping world die of infectious diseases such as HIV/AIDS, decade of the 21st century. In 2000, the United Nations
malaria, tuberculosis, diarrheal diseases, and acute lower adopted the Millennium Development Goals (MDGs),
respiratory infections. Millions more suffer from debili- setting forth ambitious health-related objectives: cutting
tating parasitic diseases, which often incapacitate people child mortality by two-thirds, reducing maternal mortality
in their most productive years. The burden of infec- by three-quarters, and reversing the tide of HIV/AIDS,
tious illness falls most heavily on children and pregnant malaria, and other major infectious diseases. In response,
women. In poor countries, the magnitude of suffering governments, foundations, and international nongovern-
caused by infectious diseases makes economic develop- mental organizations (NGOs) in the developed world have
ment nearly impossible [1]. provided billions of dollars to purchase existing vaccines
and drugs for patients in the developing world.
Many of these infectious diseases have earned the label
“neglected”1 because health-care markets in the afflicted The global health crisis demands a comprehensive and
countries are insufficient to attract biopharmaceutical integrated response that begins with faster delivery of
industry2 investment in research and development (R&D). existing drugs, vaccines, and diagnostics to those most in
Over the past decade, a revolution has occurred in public need. While programs to ensure access to current medi-
sector investment combating infectious diseases of the devel- cines can yield substantial benefits, they will not offer
oping world. Governments, multilateral organizations, and complete solutions. Many of the treatments available today
foundations spend billions of dollars purchasing treatments. are decades old and are often limited by problems of drug
Millions more are invested each year in neglected disease R&D. resistance, inadequate safety, and efficacy.
Most of the R&D investment devoted to neglected diseases For example, current treatments for river blindness
is deployed through public-private, not-for-profit, product (onchocerciasis) only kill immature parasitic worms in
development partnerships (PDPs). Since 1996, over a early stages of infection and are ineffective for advanced
dozen PDP organizations have arisen to tackle the develop- disease. The sole therapy for a major form of human
ment of new vaccines, drugs, and diagnostics for devel- African trypanosomiasis is marginally effective, requires
oping-world diseases (see Sidebar 2.1). In addition, several intravenous administration, and is so toxic that it can kill
research institutes, a few large pharmaceutical companies, up to 5 percent of patients. No effective vaccine exists for
and a handful of biotechnology companies initiated their any disease on the World Health Organization’s Special
own programs, in many cases working with PDPs. Programme for Research and Training in Tropical Diseases
(WHO/TDR) list of neglected diseases (see Footnote 1).
The challenge now is to augment these public and private Diagnostics, where they exist, are often impractical for field
sector efforts. What today’s partnerships lack most is 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) International AIDS Vaccine Initiative (IAVI)
Focus: TB vaccine development Focus: HIV vaccine development
Headquarters: Rockville, MD, USA Headquarters: New York, NY, USA
Founded: 1997 Founded: 1996
Drugs for Neglected Diseases Initiative (DNDi) International Partnership in Microbicides (IPM)
Focus: Drug development for malaria and trypanosomal diseases Focus: Microbicide development for HIV prevention
Headquarters: Geneva, Switzerland Headquarters: Silver Spring, MD, USA
Founded: 2003 Founded: 2002
Foundation for Innovative New Diagnostics (FIND) Medicines for Malaria Venture (MMV)
Focus: Diagnostic development for TB, malaria, and human Focus: Malaria drug development
African trypanosomiasis Headquarters: Geneva, Switzerland
Headquarters: Geneva, Switzerland Founded: 1999
Founded: 2003
Malaria Vaccine Initiative (MVI)
Global Alliance for TB Drug Development (TB Alliance) Focus: Malaria vaccine development
Focus: TB drug development Headquarters: Bethesda, MD, USA
Headquarters: New York, NY, USA Founded: 1999 as an independent program within PATH
Founded: 2000
Pediatric Dengue Vaccine Initiative (PDVI)
Human Hookworm Vaccine Initiative (HHVI) Focus: Dengue vaccine development
Focus: Vaccine development for hookworm Headquarters: Seoul, Korea
Headquarters: Washington, DC, USA Founded: 2003
Founded: 2000
Program for Appropriate Technology in Health (PATH)
Institute for OneWorld Health (iOWH) Focus: Development of health technologies
Focus: Drug development for visceral leishmaniasis, malaria, Headquarters: Seattle, WA, USA
and diarrheal diseases Founded: 1977
Headquarters: San Francisco, CA, USA
Founded: 2000
Fortunately, PDPs, research institutes, and a small but

growing cadre of biopharmaceutical companies are
Sidebar 2.2: Examples of new
building a growing development pipeline of promising global health products
products to address neglected diseases. The bulk of R&D
l Paromomycin: A drug to treat visceral leishmaniasis
investment to date—$1.2 billion as of early 2006—flowed (Kala-Azar), developed by the Institute for OneWorld
to treatment and prevention of HIV/AIDS, tuberculosis, Health (iOWH), registered in India in 2006.
and malaria [2]. The remainder is being devoted to other
viral, bacterial, protozoan, and helminth (worm) infections l Rotarix®: Novel rotavirus vaccine, developed by Avant
where new medicines are desperately needed. Immunotherapeutics and licensed to GlaxoSmithKline
(GSK), approved for use in 90 countries since 2004.
Several PDPs, often through outsourcing and partnering, l Pyramax®: Combination therapy (pyronaridine-artesunate)
have assembled substantial clinical development infrastruc- for malaria, developed by Medicines for Malaria Venture
tures. PDPs also manage sophisticated clinical programs in (MMV), currently in phase III clinical trials.
multiple developing countries. Their efforts, and those of a
small number of biopharmaceutical companies, are begin- l RTS,S/ASO2A: Malaria vaccine, developed jointly through
the Malaria Vaccine Initiative (MVI) and GSK, has completed
ning to pay off. New products have succeeded in clinical
phase II trials.
trials, and a few have already been registered for sale in
developing countries (Sidebar 2.2).
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 11
These products offer important opportunities to improve Long-term investments in innovation are needed to build a
standards of care for key neglected diseases, but are just sustainable pipeline of drugs meeting the needs of patients
a start. Continued investment will be required to expand now and into the future. Experience has shown that
the pipeline of products that can keep improving care for returns on pharmaceutical R&D investments are measured
neglected diseases. For example, we need: in decades, not years. Moreover, the lesson from all expe-
n a shorter course of TB therapy that works against rience with treatments for infectious diseases—whether
drug-resistant microbes; it’s antibiotics for streptococcal bacteria or anti-retrovirals
n a safe and affordable treatment for human African (ARVs) for HIV/AIDS—is that the pathogens eventually
trypanosomiasis; develop resistance to drugs. Researchers must constantly
n a diagnostic that distinguishes between malaria fight back by inventing new drugs that kill pathogens
and bacteremia in a feverish child; through novel mechanisms of action.
n a drug that kills adult forms of the many species
of worm, causing such diseases as lymphatic Study approach and objectives
filariasis, that deform and incapacitate millions BIO Ventures for Global Health (BVGH) undertook this
of patients; and study to assess whether the biotechnology industry’s
n new vaccines to prevent millions of deaths diverse technology platforms and expertise can be applied
each year. to inventing products for neglected diseases and, if so,
how. We focused on opportunities and challenges facing
An innovation gap impedes progress development of therapeutics for key neglected diseases:
Achieving the most ambitious public health goals for tuberculosis (TB), malaria, and three diseases caused by
the treatment and prevention of neglected diseases will trypanosomatids4—human African trypanosomiasis (HAT,
require extensive discovery efforts supported by long-term also known as African sleeping sickness), leishmaniasis,
funding. Most of today’s global health product pipeline and Chagas disease. For simplicity’s sake, at several points
in therapeutics, however, focuses on products amenable in this report we use Trypanosoma brucei, the cause of
to rapid clinical development, mainly by repurposing HAT, to represent all trypanosomatids.
known drugs for new uses. Finding new uses for existing
drugs makes sense because it speeds development and We focused on therapeutics in this report because it
makes it possible to reach those in need in the shortest gave us the opportunity to include the largest number of
possible time. Currently, a relatively small portion of the biopharmaceutical companies. The vast majority of inno-
investment in R&D for neglected diseases is directed to vative biopharmaceutical companies develop therapeu-
discovering new chemical entities (NCEs)—that is, novel tics; a smaller number focus on vaccines and diagnostics.
compounds with the potential of providing breakthrough Drugs represent the largest segment of global pharma-
therapeutic benefits. ceutical markets. We selected TB, malaria, and the three
trypanosomal diseases for several reasons: Each is associ-
This report highlights the current innovation gap in the ated with a high disease burden; current treatments have
discovery of new medicines for neglected diseases. The serious limitations; and each has strong scientific founda-
investments in product discovery and “translational” tions upon which new therapeutic R&D might be based
research necessary to move promising discoveries from (see Table 2.1).
academic laboratories into commercial settings are at a very
early stage and are insufficient in scale to ensure a steady We should emphasize that our goal was to be inclusive,
stream of new medicines for neglected diseases. Without not exclusive. Biopharmaceutical companies can clearly
increased effort and investment in discovery research, contribute in many other areas. Future studies can and
bringing neglected diseases under control will be delayed should assess biotechnology innovation in other diseases
by years, perhaps even decades. 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.

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 Pathogen genome sequenced; genetic
time, treatment administration manipulation facile; animal models
of disease
Chagas Disease 0.7 M No treatments available for chronic Pathogen genome sequenced; genetic
form of disease manipulation possible; animal models
of disease
Leishmaniasis 2.1 M Safety, administration, and long pathogen genome(s) sequenced; genetic
treatment time 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 fill it for each of the diseases we evaluated. Chapter 4
researchers focused on TB, malaria, and trypanosomal describes the critical role that the biotechnology industry
diseases (see Appendix III). We aimed to determine the has played in developed-world drug discovery and the
availability of biological and molecular tools for drug wealth of biotechnology industry expertise and infra-
discovery and identify critical bottlenecks. We then evalu- structure that can be applied to neglected disease drug
ated current product pipelines against international public discovery. Chapter 5 evaluates the status of the molecular
health goals and drug target product profiles (TPPs) to tools for TB, malaria, and HAT, and it maps biotech-
determine where new discovery efforts are required for nology industry capabilities against drug targets for the
each disease. three diseases.
To evaluate whether industry has the capability and rele- Applying biotechnology to global health will call for new
vant tools to address the gaps we identified, we selected collaborative models and financial incentives to encourage
50 leading biotechnology companies from the hundreds industry to take on the risk and cost of product devel-
focused on small molecule drug discovery. These compa- opment. This will require vision, new partnerships,
nies were chosen for their discovery capabilities in small risk-taking, innovative business strategies, and financial
molecule therapeutics, the scale of their discovery efforts, commitment. Chapter 6 explores these issues and proposes
and their track records of bringing NCEs into the clinic. several approaches to investing in new global health R&D.
These are some of the most experienced companies in Chapter 7 outlines our conclusions and recommendations.
small molecule drug discovery today. They are listed in
Appendix IV, and their capabilities are described further The obstacles to developing new drugs for neglected
in Chapter 4. diseases are formidable. But they are not insurmountable.
If the worldwide health-care community can make the
This report makes the case that there is a compelling role same progress against malaria, tuberculosis, and trypano-
for the biopharmaceutical industry in building the global somal diseases that it has in the past 20 years against
health product pipeline and shortening the critical R&D cancer, diabetes, and cardiovascular disease, we can look
timelines on the way to achieving that goal. Chapter 3 forward to millions of lives saved and a better world for
defines the innovation gap and what may be needed to us all.
Chapter 3: The Innovation Gap in Discovering
New Therapeutics for Neglected Diseases
Creating innovative pharmaceutical products is a urged. Artemisinin-based combination therapies (ACTs)
complex process that typically takes 10 to 15 years. have proven especially efficacious. Artemisinin, a structur-
Donor funding and the emergence of product develop- ally complex natural product, is comparatively expensive
ment partnerships has led to an unprecedented number to manufacture, which, until recently, precluded the use of
of late-stage candidate medicines in the pipeline for ACTs in many impoverished countries.
neglected diseases. R&D efforts at the drug discovery
stage, however, are insufficient to ensure a continuous Tuberculosis. One-third of the global population—more
flow of products entering clinical development. This than 2 billion people—harbors a latent or asymptomatic
innovation gap results from insufficient investment, infection by Mycobacterium tuberculosis, the bacterium
limited access to key technologies and drug discovery causing tuberculosis (TB). About 10 percent of those
expertise, and difficulties in assembling the collabora- infected will develop active TB at some point during their
tions necessary to transform a laboratory discovery lifetime, translating into nearly 9 million cases of active
into an investigational new drug. Failure to address disease and more than 2 million deaths annually. In immu-
the innovation gap will impede the creation of the next nocompromised populations, such as those with HIV, rates
generation of treatments for malaria, tuberculosis, and of active TB are extremely high. Worldwide, TB is now the
trypanosomal diseases. leading cause of death among AIDS patients [6].
New drugs for old diseases First-line treatment for active TB consists of two or four
Many of the available medicines for neglected diseases are antibiotic drugs taken in combination for a minimum
outdated, impractical, insufficiently efficacious, or subject of six to nine months. The duration of the regimen,
to pathogen resistance and unacceptable toxicities [3-5]. combined with the medications’ toxicities, causes many
New medicines are urgently needed for tuberculosis, all patients to fail to complete the full course of treatment
diseases caused by protozoan parasites, and many of the [7]. This, in turn, has hampered TB control programs and
helminth (worm) infections. fueled the proliferation of antibiotic-resistant M. tubercu-
losis strains. Recently, extensively drug-resistant TB (XDR-
This study focuses on the need for new drugs for malaria, TB) has entered communities with high HIV prevalence
tuberculosis, and trypanosomal diseases. Each disease is and is killing people at alarming rates [8, 9].
summarized below and in Table 3.1, along with the status
and limitations of today’s treatments. Trypanosomal diseases. Three major classes of
trypanosomal diseases affect humans: human African
Malaria. More than 40 percent of the world’s population trypanosomiasis (HAT), Chagas disease, and leishmaniasis.
is at risk for malaria, and up to 500 million people develop n HAT (also referred to as African sleeping sickness)
the disease each year. Malaria results from infections by is found only in sub-Saharan Africa, where 60
parasitic protozoa from the genus Plasmodium. Young million people are at risk for the disease. Each
children and pregnant women, especially those living in year, there are up to 300,000 cases, resulting in
sub-Saharan Africa where the more virulent Plasmodium nearly 50,000 deaths.
falciparum parasite is dominant, are most vulnerable to n Chagas disease is endemic in rural areas in South
malaria and account for the majority of the 1 million and Central America, placing an estimated 25
deaths estimated to occur annually. million at risk. In total, as many as 9 million
people may be infected with the Chagas parasite.
Commonly used antimalarials are increasingly ineffec- Annually, 14,000 deaths result from Chagas
tive due to widespread drug resistance. To combat the cardiomyopathy associated with the chronic form
emergence of resistance to the drugs remaining in the of the disease and often occurring 10 to 20 years
antimalarial arsenal, use of combination therapies has been after initial infection.

Table 3.1: Malaria, Tuberculosis, and Human African Trypanosomiasis: Summary Of Disease Characteristics,
Pathogen, and Current Standard of Care
Disease Epidemiology Pathogen Current Standard of Care
Deaths Cases Population Other (launch year): Limitations
per Year per Year at Risk
Malaria > 1 million 300-500 40% of global Children and Plasmodium Chloroquine (1945): resistance
A parasitic disease transmitted million population pregnant species;
by Anopheles mosquitoes. Primaquine (1948): safety
women
Malaria is categorized as either P. falciparum Fansidar (1961): resistance
are most
uncomplicated (fever, chills, is the most
body aches, nausea, headache, susceptible Mefloquine (1984): resistance, safety
deadly
vomiting, and diarrhea) or severe
Artemisinin (1994): cost, compliance,
(anemia, acute respiratory distress
Good Manufacturing Practice
syndrome, coma, and death).
Atovaquone/proguanil (1999): cost
TB 2 million 9 million Pandemic; Immuno- Mycobacterium All first-line treatments have issues
A bacterial disease that most (active TB) 2 billion are compromised tuberculosis concerning resistance, toxicity, and
commonly affects the lungs. In infected with populations treatment length (6-9 months):
otherwise healthy individuals, are at
latent TB. Rifampicin (1963)
most infections are latent and
highest risk
asymptomatic. About 10% of those Ethambutol (1962)
infected develop active pulmonary
disease; symptoms include a cough Streptomycin (1955)
lasting more than two weeks, Pyrazinamide (1954)
coughing up blood, fatigue, fever,
chills, night sweats, and weight and Isoniazid (1952)
appetite loss.
HAT 50,000 Up to 60 million; Trypanosoma Pentamidine (1941): lacks oral formulation,
A parasitic disease transmitted 300,000 (sub-Saharan brucei side effects, early-stage specific, most
by tsetse flies. HAT progresses Africa) (subspecies effective against T. b. gambiense
from fever and fatigue (early-stage
gambiense Suramin (1921): lacks oral formulation,
disease) to severe neurological
and side effects, early-stage specific, first-line
conditions (late-stage or chronic
rhodesiense) treatment against T. b. rhodesiense
disease). Untreated HAT is fatal.
Melarsoprol (1949): toxicity, resistance
Eflornithine (1980): toxicity, administration,
spectrum of activity, supply, cost, only
effective against T. b. gambiense
Chagas disease 14,000 750,000 25 million; 8-9 million Trypanosoma Chronic disease - no treatments available
A parasitic disease that over time (Latin are currently cruzi
Acute disease -
causes damage to the nervous America and infected Nifurtimox (1960): resistance, safety,
system, digestive tract, and the
Caribbean) efficacy
heart. The disease is contracted via
the feces of an infected Reduviid bug. Benznidazole (1970s): resistance, safety,
efficacy
Leishmaniasis >50,000 1.5-2 million 350 million 12 million ~20 Leishmania Visceral leishmaniasis:
A collection of parasitic diseases are currently species
Miltefosine (2003): safety
transmitted by the Phlebotomine infected
sandfly that affects the skin, Paromomycin (2006): delivery
mucosa, or internal organs,
resulting in severe disfigurement, Pentosam (1944), Amphotericin B (1950s),
disability or death. 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 HAT, Chagas disease, and all forms of leishmaniasis are
are cutaneous, mucosal, and visceral forms. caused by divergent species of single-celled protozoa called
Worldwide, about 350 million people are at risk trypanosomatids. These pathogens share many unusual
for leishmaniasis. Cutaneous and mucosal forms molecular and biochemical pathways, but their infectious
cause severe disfigurement and disability. The cycles and target tissues for infection are very different.
visceral form is fatal if untreated. An estimated 12 While there is precedent that a treatment designed for one
million people are infected with leishmania, and pathogen may have efficacy toward another [5, 10], it is
each year there are over 50,000 deaths. likely that drug discovery and development will mostly
proceed independently for different species. For simplicity’s Drug discovery refers to the earliest stages of generating
sake, at several points in this report we use Trypanosoma an actual product. It begins with the difficult process of
brucei, the cause of HAT, to represent the entire class. translating findings from basic research into candidate
molecules with the potential to treat disease. Researchers
Problems associated with existing drugs for trypanosomal organize their work around a target product profile
diseases include lack of efficacy, drug resistance, long (TPP), essentially a list of minimum characteristics a drug
treatment duration, availability, expense, and safety. For must possess to warrant development and use in people.
instance, melarsoprol, the only treatment for HAT caused “Small molecule” drug discovery is a chemistry-intensive
by one subspecies of T. brucei, is so toxic that it kills up process in which a library of thousands or even millions
to 5 percent of those who receive it [11]. There are no of compounds is screened for molecules with drug-
drugs to treat the chronic form of Chagas disease. Visceral like activity potentially meeting TPP requirements. The
leishmaniasis treated with paromomycin requires 21 days compounds identified by screening, often called “hits,” are
of injections. An orally available alternative, miltefosine, is then refined for other essential drug-like properties into
unsafe for pregnant women. “leads.” A lead is a compound that interacts with accept-
able potency and selectivity with a cellular “target” macro-
The drug development process molecule such as a protein.
To understand the serious challenges presented by
today’s global health drug pipeline, we must first under- For an infectious disease, the target is usually a macro-
stand the process of creating a new drug. More complex molecule belonging to the pathogen, and ideally the
and time-consuming than nearly any other commercial interaction between the drug and its target kills the
endeavor, pharmaceutical R&D requires technological pathogen and cures the disease. In an iterative process,
and scientific expertise, teamwork, leadership, risk-taking, lead compounds are optimized and retested for improved
time—and most of all, money. The steps of the process activity, specificity, potency, and safety. A more detailed
are commonly broken into three phases: basic research discussion of the intricacies of the small molecule drug
that establishes biological knowledge of disease causality discovery process is presented in Appendix I. There is no
and creates tools for R&D; discovery, the innovative steps hard-and-fast point where the iterative process of drug
by which new therapeutic compounds are identified and discovery ends.
evaluated; and development, or testing first in animals
of small numbers of compounds winnowed from the Drug development is most simply defined as the point at
discovery steps, leading to a single, promising candidate which an optimized lead compound with good efficacy
compound to evaluate for therapeutic efficacy and safety in animal models and acceptable toxicity and pharmaco-
in human clinical trials. kinetic5 properties is selected for preclinical evaluation
[12]. Once a “preclinical candidate” has been chosen, it
Basic research refers to the scientific exploration of disease must pass a rigorous series of tests designed to ensure
and, in the case of infectious diseases, the pathogens that safety in animals and provide persuasive indications
cause them. The goal of most basic research is to develop of efficacy. With a successful preclinical compound in
a molecular, genetic, and biochemical understanding of hand, researchers may then apply to the U.S. Food and
disease pathology in the hope that this knowledge will Drug Administration (FDA) for investigational new drug
lead to treatments and cures. Developing this knowledge (IND) status, which permits the compound to be tested
requires an extensive set of tools for research. The process in humans. The IND candidate’s safety, dosing, and effi-
of inventing research tools is in itself another component cacy in humans are then established by clinical trials.
of basic research. 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).

Figure 3.1: Drug Discovery and Development—the Necessary Prelude to New Drugs
Drug Discovery Drug Development
Screening Lead Lead Optimization Preclinical Phase I Phase II Phase III Registration
for Hits Identification
Clinical Trials
3-6 years 1 year 6-7 years 1 year
are approved by regulatory authorities such as the FDA or investment since 1999 [2]. Although certain large pharma-
European Medicines Agency (EMEA) and registered in the ceutical companies, academic centers, and biotechnology
countries in which they will be sold. companies have begun to participate, the driving forces for
therapeutic R&D in global health have been PDPs [21].
Together, projects in discovery and development make
up the product “pipeline.” As illustrated in Figure 3.1, PDPs are not-for-profit organizations funded and championed
the process of discovering and developing drugs requires by the donor community6 to develop novel vaccines, drugs,
an average of 10–15 years [13, 14]. Although the failure and diagnostics for specific neglected diseases. Like many for-
rate is greatest at the earliest stages of discovery, prod- profit biopharmaceutical companies, PDPs drive preclinical
ucts can fail at any point. Indeed, high rates of attrition and clinical development of new product portfolios, picking
partially explain why the process of inventing a drug takes and choosing which products to advance through the pipe-
so long. According to the Pharmaceutical Research and line, including which to launch or terminate. In contrast to
Manufacturers of America (PhRMA), for every 5,000–10,000 for-profit companies, many PDPs are “virtual” organizations
compounds that enter the pipeline, only one becomes a with comparatively small staffs and no laboratories of their
registered product [14]. Thus, because of attrition, the vast own. Most, if not all, of the projects in their portfolios are
majority of compounds that enter drug discovery and devel- carried out by partners, including researchers in academic
opment will never progress to success in clinical trials [15]. institutions, contract research organizations (CROs), and
large pharmaceutical companies. The larger PDPs oversee
New players build the therapeutics and coordinate projects occurring all over the globe.
pipeline for neglected diseases
From 1975 to 2004, out of 1,556 new drugs approved by Four leading PDPs focus on therapeutics for malaria, TB,
the FDA, EMEA, and other government authorities, only 21 and trypanosomal diseases:
were registered for tuberculosis, malaria, and other neglected n The Medicines for Malaria Venture (MMV)
diseases [16, 17]. This oft-cited statistic reflects the lack promotes new antimalarials.
of incentives for biopharmaceutical companies to invest in n The Global Alliance for TB Drug Development (TB
products for which there are insufficient paying markets. Alliance) focuses exclusively on drug development
for tuberculosis.
In 2006 alone, U.S. pharmaceutical and biotechnology n The Drugs for Neglected Disease Initiative (DNDi)
companies invested over $55 billion of their own resources creates new drugs to treat trypanosomal diseases
to invent medicines for diseases of the developed world and malaria.
[18]. Yet, they directed only a fraction of that sum—we n The Institute for OneWorld Health (iOWH)
estimate based on two recent studies less than $100 concentrates on leishmaniasis, malaria, and
million—for R&D aimed at two of the world’s biggest diarrheal diseases.
killers, malaria and tuberculosis [19, 20].
All four are mostly virtual and work extensively with
To remedy this imbalance, over the past decade new public nonprofit and for-profit partners to conduct discovery and
sector R&D efforts have arisen to build a pipeline of new development. By supporting PDPs, donors have created
products for neglected diseases, with over $1.2 billion of centers of expertise for each disease area.
6 We use the term “donor community” to refer to governments, nonprofit organizations, and foundations.
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) Existing (new use) iOWH
Phase III (East Africa) 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 Malaria Phase III Existing (new combination therapy) MMV

(Lapdap™)-artesunate
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 Malaria Phase III Existing (new combination therapy) MMV

(Pyramax®)
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.

Evaluation of neglected disease Tables 3.2 and 3.3 show these classifications for products
drug pipelines currently in clinical trials.
Eager to show early results in bringing new treatments
to afflicted populations, PDPs initially focused on testing Figure 3.2 compares risks and benefits of expanding uses
existing drugs registered for other diseases against the for existing drugs versus creating NCEs. A key advantage
target pathogens. These efforts have borne fruit, with two of using existing drugs is that often they have extensive
products launched (paromomycin and artesunate-amodia- records of safety in humans and do not require years
quine) and eight additional products in clinical trials and millions of dollars to establish safety in treating
(Table 3.2). Through the efforts of industry and various neglected diseases. NCEs, on the other hand, are much
consortiums, several other promising compounds or riskier to invent than expanding the use of existing
combination therapies are also in clinical trials (Table 3.3). drugs. But with risks come benefits. NCEs targeted for
A snapshot of the current therapeutic pipelines for malaria, potency, specificity, and lack of toxicity have greater
TB, and HAT is presented in Appendix II. potential to provide breakthrough therapeutic benefits
within a wide safety margin. Thus, in the long run,
Products in neglected disease drug pipelines can substantial improvement over existing treatments will
be divided into require discovering NCEs.
n existing drugs being evaluated for new
indications,
n drugs in new formulations,
n novel fixed-dose combinations, or
n new chemical entities (NCEs).
Figure 3.2: Risks and Benefits of Expanding Use of Existing Drugs Versus the Creation of New Chemical Entities
Requirements for effective drugs The World Health Organization (WHO), via the Stop TB
for neglected diseases partnership and TDR, has drawn together the views of
Any new drug emerging from the pipeline for neglected leading scientists in global health into a set of ambitious
diseases must be safe, inexpensive to manufacture, prac- goals for discovering new treatments for tuberculosis,
tical to administer, stable in harsh climates, potent against malaria, HAT, and other neglected diseases [12, 24]. Table
resistant strains, and effective within time frames compa- 3.5 summarizes these goals. New medicines that fulfill
rable to or better than existing products. In addition, these objectives might halt and even reverse the spread of
as illustrated in Table 3.4, each disease has a specific, these diseases.
minimum TPP that a new product must meet [22, 23].
Table 3.4: Target Product Profiles for Uncomplicated P. falciparum Malaria, Active Pulmonary TB, and Late-stage HAT
Necessary Desirable P. falciparum TB HAT

malaria
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.

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
HAT Efficacy against all stages of disease and all subspecies Goal unlikely to be met
Sources: WHO/TDR, DNDi, MMV, TB Alliance, and Stop TB Partnership
The activity and safety of the drugs now in development lack of credible screening hits, failure to optimize efficacy
will be fully apparent only upon completion of clinical versus toxicity, lack of oral bioavailability, and failure in
trials. But it is clear already that these drugs will not meet animal proof-of-concept models. Project failure rates before
some of the ambitious goals in Table 3.5, such as short- identifying an IND candidate are routinely over 75 percent.
ening the duration of TB treatment to two months or less Subsequent attrition due to clinical failures, safety concerns,
[25], reducing malaria treatment to a single, curative dose, and market forces reduces the success rate to less than 5
and developing a treatment effective against all stages of percent, sometimes only 1 to 2 percent. Thus, a credible
HAT. For these advances, a new generation of therapeutics effort to develop a new drug in the biopharmaceutical industry
will be required. requires substantial numbers of discovery projects—enough to
ensure that a product with the desired TPP will emerge from
An innovation gap impedes creation the pipeline.
of the next generation of drugs
As the current generation of drug candidates advances The pipeline of clinical-stage programs for malaria, TB,
toward clinical success and registration, or toward clinical and HAT is expected to yield several new products in
failure and abandonment, a new generation of drug candi- the next few years [21]. However, as Figure 3.3 shows,
dates must follow that offers the promise of achieving more a major disparity exists between early-stage pipelines of
ambitious goals. Similar to drug development for cancer these diseases and the profile of a typical industry-driven
and diabetes, neglected disease drug development pipe- program for a disease with an established market. For
lines require “high-quality” discovery programs7 backed instance, our analysis found that there are five, six, and
by substantial, sustained investment as occurs when the one discovery projects in the lead optimization stage
biopharmaceutical industry tackles diseases such as cancer for malaria, TB, and HAT, respectively. Assuming that
or diabetes. the average industry project failure rates will also apply
to neglected disease projects, these numbers are far shy
For instance, a major biopharmaceutical company intent of the 20 projects typically required to yield a single
on developing a new oral treatment for a chronic disease new drug. Indeed, for all of the neglected diseases we
market such as heart disease would explore 10 to 20 examined, none has a drug discovery effort sufficient to
targets generated by genomics and biochemistry, and ensure that the next generation of candidate compounds
advance five to 10 targets in parallel into high-throughput will be ready to enter clinical development in the coming
screening. Each project would initially screen thousands years. This observation has also been noted by others
to millions of compounds. Most of these projects will [26]. This deficiency, or innovation gap, restricts the
fail because of myriad interrelated reasons: for example, flow of new, approved medicines for neglected diseases
inability to express the target protein and develop an assay, (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.
Figure 3.3: Attrition Rates and Current Neglected Disease Pipelines
100.0
100 Out of 100 programs entering the Expected program
screening phase of discovery, on survival rate
90 average 1.3 drugs will successfully
reach the market 12–14 years later
Number of Programs Entering Each Phase
80 Malaria
of Drug Discovery and Development
70 TB
Innovation Gap
HAT
60
50
40
30.0
30
19.5
20
10.7
10 5.8 1.9
4.0 1.3
1.3
0
Phase Screening Lead Lead Preclinical Phase I Phase II Phase III Registration Approved
for Hits Identification Optimization
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
Limited
5 Clinical Candidates Clinical
Candidates
1 Approved Novel Drugs

Drug Rarely Approved

Causes of the innovation gap While the upper limits of the proportion of their R&D
The innovation gap results from insufficient investment investments devoted to drug discovery is similar, the
devoted to early-stage drug discovery, limited access to key absolute level of PDP investment in drug discovery is low
technologies and drug discovery expertise, and difficulties compared with commercial discovery efforts. Depending
in assembling the collaborations necessary to transform a on the size of the discovery team, drug discovery compa-
laboratory discovery into an IND. We explore these prob- nies typically spend between $2 million and $4 million per
lems in detail below. year per preclinical lead optimization project [27]. Even if
a hypothetical PDP had a $50 million budget, 30 percent
Insufficient investment in discovery still represents only $15 million, which will support a
The cost of clinical development is high—estimated in the pipeline of only three to six early-stage projects to advance
hundreds of millions of dollars for the cumulative successes lead compounds to IND candidate stage. Current PDP
and failures required to bring a single new drug to market investments are far less than this.
in the developed world. The discovery stage of this process
also requires substantial investments of time and money to Among the biotechnology companies we examined for
n create an initial population of biologically active this report, “discovery-only” and “early-development”
molecules; companies8 spend a median of $20.9 million and $30.8
n optimize them through multiple iterations of million per year, respectively, on research that does not
medicinal chemistry and pharmacologic assays; and include clinical trial activities. This is substantially more
n select a small number for further development. than the hypothetical PDP defined previously (Figure 3.5).
Companies typically view their levels of investment as the
Industry studies show that innovative pharmaceutical and minimum to maintain a discovery team and generate an
large biotechnology companies typically spend between 35 IND drug candidate at least every other year.
and 40 percent of their R&D budget on discovery [27].
The need for this level of investment stems from the diffi-
culties of finding a compound that meets all the pharma-
cologic criteria required for proceeding into development.
Figure 3.5: Annual R&D Spending by Biotechnology
Typically, thousands of compounds are intensely evaluated Companies and PDPs
for two to four years before a clinical candidate is selected.
Indeed, most discovery programs fail before an IND Median Annual R&D Spending
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. 35
30
By contrast, PDPs have focused smaller proportions of
Millions of Dollars
their R&D investments on drug discovery, although they 25

recognize the need to build sustainable pipelines and have
20
continually supported work on new compounds. Based on
publicly available information [28-30], these partnerships 15
have only been able to devote between 15 and 30 percent
5
of their funds to discovery, with MMV and the TB Alliance
putting the greatest investments into discovery. PDPs have 0
increased their discovery program productivity by partnering arly-Development
E Discovery-Only Hypothetical PDP
with large pharmaceutical companies that make matching Company Company
in-kind contributions of manpower and resources. 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.
Access to technology and expertise and limited Publicly available compound libraries, on the other hand,
scale of operations are largely limited to diversity libraries obtained from
The technological platforms, assets, and expertise neces- commercial sources. Many academic research facilities have
sary to transform biological findings into NCEs are well assembled libraries from commercial sources, but few if any
established (see Chapter 4). Biotechnology and phar- compare with those available in industry. The most well-
maceutical companies engaged in drug discovery have constructed and diverse public library is a new collection of
purchased or synthesized large compound libraries. They over 100,000 small molecules accessible through the NIH
have assembled capabilities in advanced technologies such Molecular Libraries Screening Center Network (MLSCN).9
as high-throughput screening, X-ray crystallography, and
computational modeling. They have teams of scientists With a few exceptions, publicly available libraries do
with expertise in assay development, medicinal chemistry, not have the target-class focus common to proprietary,
and pharmacology. purpose-built libraries in biotechnology and pharmaceutical
companies. Commercial libraries are based almost solely
Academic centers and individual investigators carrying on structural novelty, much like the early combinatorial
out neglected disease research have identified compelling libraries used by industry, as opposed to relevance to the
new targets for therapeutic intervention [26, 31, 32]. targets of interest. Screening large numbers of such unbiased
For the most part, however, they lack the tools available compounds against a target may generate hits, but hit rates
to industry to extend their research into drug discovery. are extremely low (less than 1 in 1,000) and can be expected
Even with the advent of academic- and government-based to identify a distracting number of false positives [35].
high-throughput drug screening (HTS) initiatives such as
the NIH Roadmap for Medical Research [33], advances Although these concerns limit the utility of publicly
in neglected disease biology are not adequately matched available libraries, two trends may make it possible for
with the tools and expertise that lead to the discovery of public sector researchers to avoid some of these pitfalls.
NCEs [34]. First, there are now commercial sources of target-focused
libraries. These libraries offer much higher yields when
In interviews with academic leaders in malaria, tubercu- screened against members of a target family. Second, it
losis, and trypanosomal diseases (for list, see Appendix is possible and cost-effective to engage chemistry CROs,
III), we found they face three key obstacles in progressing many of which are offshore, to design certain types of
beyond generating hits through small molecule screening: custom compound libraries. Nonetheless, the public sector
first, limited access to the most advanced drug discovery still does not have access to the breadth of target-focused
technology and compound libraries; second, lack of drug libraries available to industry—a reality that limits the
discovery experience and expertise; and third, insufficient types of NCEs that can emerge from a neglected disease
scale of operations. drug discovery campaign.
Limited access to the best compound libraries Limited access to discovery infrastructure and
Compound libraries are collections of organic chemicals chemistry expertise
assembled by purchase or custom synthesis for repeated In recent years, high-throughput screening centers—facili-
screening in multiple biological assays. An industrial ties allowing chemical compounds to be tested for activity
compound library is organized around a biological target against putative or established drug targets in high-
class, drug-like properties, or chemical structural diversity. throughput mode—have been installed at universities and
A company’s organized, selected, and annotated compound public research institutes all over the world. These centers
library is a core, proprietary asset. 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.

[23, 36]. To capitalize on the potential value of their own Current joint industry-PDP efforts provide a good model
technology, many academic institutions now vie to estab- for future collaborations, but the number of projects being
lish themselves in drug discovery by creating “translational pursued in these programs is far from sufficient to ensure
research” centers. These initiatives have facilitated target a robust pipeline for any of the neglected diseases. In the
validation and hit generation, but they represent only part biopharmaceutical industry, the limited discovery research
of the infrastructure required to transform an academic under way for neglected diseases mostly takes place in
laboratory into a true drug discovery facility. Without three companies: GSK, Novartis, and AstraZeneca.10
industry expertise, resources, and scale, such efforts are Two of these programs are partnered with MMV and TB
unlikely to be efficient generators of NCEs that can be Alliance.
entered into commercial development. This limitation
holds true as well for academic translational research initia- Building a continuum of players
tives for neglected diseases. The innovation gap is not only a problem of investment,
access to infrastructure, technology, and expertise. It is
Converting hits to lead compounds is an iterative, also a problem of recruiting organizations experienced in
chemistry-intensive process requiring expertise in different aspects of product development that together
analytic, synthetic, and medicinal chemistry. For can ensure that the fruits of R&D flow efficiently from the
academic biologists and biochemists pursuing drug laboratory into the clinic, and then to the patient’s bedside.
discovery, accessing chemists—particularly those with
medicinal chemistry expertise—requires collabora- For diseases with a developed-world market, such a
tion with academic chemists sharing an interest in the system of collaborating organizations has been in place
biological target or disease. Because of the expense and for many years. It begins with commercially viable ideas
long timelines associated with lead-optimization medic- and inventions created in academia and research institu-
inal chemistry, and the high expected failure rate, it can tions. Biotechnology and pharmaceutical companies then
be challenging to identify and engage academic groups license these innovations, where industrial scientists,
with organic chemistry resources essential to optimize experienced in translating basic science into nascent prod-
leads into true drug candidates. ucts, undertake drug discovery. R&D typically concludes
with completion of clinical and regulatory activities by
Insufficient Scale the biotechnology industry innovator or a large pharma-
Many of the organizations working on neglected disease ceutical company that may license the product once it
drug discovery are limited by the scale of their efforts. shows persuasive evidence of preclinical or clinical efficacy.
For example, TDR reports that its medicinal chemistry Biotechnology companies often partner with multinational
network devoted to tropical diseases consists of 11 pharmaceutical companies that have the financial resources
postdoctoral fellows scattered in eight organizations all to carry out phase II and phase III clinical trials and handle
over the world to address all of their programs [23]. In regulatory applications for approval to enter the market-
contrast, even the smallest drug discovery companies have place on a worldwide scale.
coordinated teams of at least eight in-house or contract
chemists per project [27]. Additionally, few universities Unfortunately, this well-worn path in the private sector
possess the instrumentation and expertise required for has yet to evolve fully for global health product develop-
high-throughput assay development, X-ray crystallog- ment (Figure 3.6). Opportunities for collaboration and
raphy, computational modeling, and in vitro pharmacoki- technology transfer that exist for developed-world diseases
netics and toxicology studies—all of which are essential have, in many cases, not materialized for neglected diseases
tools in drug discovery. 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.
Figure 3.6: Building a Continuum of Players to Move from Basic Research to Product Registration
Diseases with a paying market
Academia and
Research Biotechnology Companies Multinational Pharmaceutical Companies
Institutions
Basic Screening Lead Lead Preclinical Phase I Phase II Phase III Registration
Research for Hits Identification Optimization
CLINICAL TRIALS
NEGLECTED DISEASES
Multinational Pharmaceutical Companies
Academia and
Research Innovation
Institutions 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 If not addressed soon, the innovation gap could delay
have developed tools and technologies that might be put for years, and potentially decades, victory over neglected
to work in drug discovery. But the options for transfer- diseases. Moreover, these efforts need to be sustained;
ring their findings to industry are limited, in part because no new drug, no matter how powerful, can forever
an appropriate structure for licensing arrangements that evade the development of drug resistance. Researchers
may not generate revenue has yet to be established. As a must constantly fight back with drugs that have new
result, organizations lack sufficient incentives to overcome mechanisms of action.
barriers to forming partnerships and moving neglected
disease product development forward [34]. It is essential that neglected disease pipelines include
large numbers of high-quality discovery programs to
Closing the innovation gap ensure continuing improvements in care. The innovation
Achieving the ambitious goals for treatment of tubercu- gap cannot be closed with money alone. We must also
losis, malaria, and human African trypanosomiasis will do a better job aligning the efforts of basic researchers
entail extensive drug discovery efforts requiring long- with biotechnology drug discovery tools and expertise—
term commitment and funding that does not exist today. described in detail in the next chapter.

Chapter 4: Harnessing Discovery Resources
Addressing the innovation gap in neglected disease The biotechnology industry has been built with over
therapeutics requires access to small molecule discovery $377 billion of equity capital [37, 39] and hundreds of
capabilities. The biotechnology industry has evolved from billions of dollars more in partnership financing from
having an early focus on protein-based therapeutics to large pharmaceutical companies. Indeed, between 1998
becoming leading innovators of small molecule drugs. and 2006, nearly 200 discovery alliances were forged each
Today, biotechnology companies supply large pharma- year between biotechnology companies and pharmaceutical
ceutical companies with novel small molecule drug candi- companies [27]. In 2006, public biotechnology companies
dates for clinical development. Biotechnology companies had estimated revenues of $82 billion and another $47
with successful track records in small molecule discovery billion of income from partnering and financing deals
and development could play a similar role in building the [39]. By the end of 2006, the combined market capital-
neglected disease drug pipeline. In this chapter, we assess ization of publicly traded biotechnology companies was
their infrastructure and skills; in the next chapter, we look $490 billion, a sum exceeding the valuation of the top
at how their resources are applicable to neglected diseases. five U.S. pharmaceutical companies [39].
The biotechnology industry The emerging role of biotechnology

In wealthy countries, drugs are invented, developed, in small molecule discovery
tested, registered, and marketed by pharmaceutical and Until the early 1990s, biotechnology companies used
biotechnology companies. The pharmaceutical industry their drug discovery technologies primarily to develop
evolved from chemical companies founded in the late large-molecule biologics—therapeutically active proteins
1800s and early 1900s and is now dominated by about 20 such as hormones and monoclonal antibodies. Early
large, “innovative” companies that develop new drugs. The product successes included erythropoietin (EPO), human
biotechnology industry is much younger. It originated in growth hormone (hGH), and tissue plasminogen activator
academic research laboratories following the invention of (tPA). These products were created by cloning human
recombinant DNA technology in the mid-1970s. Through genes through recombinant DNA technologies, expressing
three decades of technology innovation and investment, it the genes in cell culture, and scaling up manufacture of
has grown to approximately 5,000 companies worldwide the proteins. In the early days, biotechnology compa-
[37], of which we estimate 1,500 in the United States and nies did not compete with the pharmaceutical industry
Europe are financed with institutional investment.11 in discovering small molecule drugs (see Sidebar 4.1).
Instead, pharmaceutical companies dominated small
The first generation of public biotechnology companies molecule discovery through their enormous manpower
was launched in the early 1980s. These companies focused and historical expertise in synthetic, medicinal, and
on making “large molecule” protein drugs, often referred process-scale chemistry.
to as “biologics” because they were produced from living
cells using recombinant DNA technology. Initially, biotech- Sidebar 4.1: Characteristics of small
nology companies had neither the financial resources nor molecule drugs
the capabilities to develop their own drugs and depended A small molecule drug is either a natural product or a synthetic
on large pharmaceutical companies to develop and organic compound made by chemical synthesis. It is not a
commercialize their discoveries. 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
Today, the biotechnology industry rivals the global pharma-
bonds, and intermediate hydrophobicity [40]. To synthesize
ceutical industry in size, scope, and capabilities. Over 250 small molecule drugs, medicinal chemists typically make
therapies and vaccines that originated in the biotechnology analogs of core structures (scaffolds) and alter side chains to
industry have been approved by regulatory authorities [38]. improve specificity and efficacy while lowering toxicity.
11 “Institutional” investment refers to commercial public and private equity investors.
Over the past decade and a half, industry’s landscape percent of the new medicines approved by the FDA origi-
changed dramatically. Biotechnology companies recog- nated from biotechnology company R&D [27, 42]. In
nized the increasing demand for treatments using small early 2007, nearly two-thirds of the small molecule drug
molecules, especially for orally administered drugs against candidates in clinical trials originated in biotechnology
chronic diseases. Taking advantage of a revolution in companies (Figure 4.1). By this measure, the biotech-
miniaturization, discovery technologies, and vast increases nology industry has overtaken large pharmaceutical
in throughput in screening small molecules for drug companies and assumed the leading role in innovation of
activity, biotechnology companies became leading origina- small molecule drugs.
tors of small molecule drugs.
Large pharmaceutical companies have traditionally devoted
This change is critical to whether biotechnology can significant resources to making drug analogs (modified
contribute to developing new drugs for neglected diseases. versions of known compounds) or creating new drugs
This is because most large molecule biologics (excluding that act on previously validated drug targets. A defining
vaccines) are produced in small quantities, are compara- characteristic of biotechnology companies has been their
tively expensive (in many cases extremely expensive), must willingness to take on risk and engage in innovation, and
be stored in the cold, and are delivered only by injection. thus the biotechnology industry has taken a different
The profile of most drugs envisioned for the developing approach. Capitalizing on breakthroughs in understanding
world demands the opposite: large quantities produced at of the biochemistry of disease and technical advances such
very low cost, heat stability, and oral delivery. Only small as genomics and proteomics, biotechnology companies
molecule drugs typically achieve this profile. developed technologies for screening compound libraries
for activity against novel molecular targets or new target
The biotechnology industry has achieved therapeutic classes, such as cell receptors or intracellular messengers
success with small molecule anti-infectives, anticancer that regulate biochemical processes involved in disease.
agents, and cardiovascular disease drugs. As of 2005, These technologies are competitive with the drug discovery
the top 10 small molecule drugs originating in biotech- capabilities of pharmaceutical companies, and they
nology had sales totaling $7.5 billion. More than half of routinely enable screening millions of compounds against a
the drugs that originated in biotechnology companies and new biological target in a matter of weeks [35, 43].
received regulatory approval in 2004–2006 were small
molecules [41]. Between 1998 and 2006, more than 25 Biotechnology companies focused on drug discovery can
be segmented by capabilities. As summarized in Figure
Figure 4.1: The Origins of Small Molecule Drugs in Clinical 4.2, companies can be classified as fully integrated, early
Trials (January 2007) development, or discovery only:
n Many larger, mature biotechnology companies
600 have fully integrated discovery and development
Small Molecule Drugs in Clinical Development
512 capabilities. They can advance lead compounds

500
emerging from their in-house discovery programs
through preclinical development and into the clinic
400
346 without needing outside development expertise.
300 n Early-development companies are smaller and
younger than fully integrated companies. They
Originating
200 161 from large possess strong discovery platforms that they
pharmaceutical have used to identify lead compounds. Their
companies
100 capabilities support IND filing, and they have
Originating
from advanced compounds through early preclinical
0 biotechnology
Phase I Phase II Phase III
development. To drive clinical development, these
companies
Source: PharmaProjects
companies must partner with larger organizations.

Figure 4.2: Biotechnology Companies Can Be Segmented by Capabilities
Basic Target Target Screening Lead Lead Preclinical Phase I Phase II Phase III
Research Identification Validation for Hits Identification Optimization
Examples: • OSI Pharmaceuticals

Fully Integrated • Exelixis
• Vertex
• Gilead
Early Development Examples: • Pharmacopeia

• Kalypsys
Discovery Only Core Discovery Offering Examples: • Amphora

• Kémia
• Locus
Well-developed
Less well-developed
n Discovery-only companies are typically young and develop platform technologies, vaccines, drugs and diag-
privately held. They have some of the most novel nostics, not to mention agricultural, environmental, and
drug technology platforms. Lacking in-house industrial products. To concentrate on the companies
preclinical capabilities, they contract with CROs potentially most relevant to closing the drug discovery
and partner with larger companies to advance innovation gap for select diseases, we winnowed a list
drug candidates through preclinical development of over 1,500 U.S. and European companies12 down to
and into IND status. approximately 120 that: (a) focus on small molecule drugs,
(b) have significant discovery programs, (c) have succeeded
Small molecule innovation in the in taking new compounds into human clinical trials, and
biotechnology industry (d) have sufficient scale to pursue multiple programs with
Given the risk and high attrition rate of drug discovery, at least some vertical integration (see Sidebar 4.2). To
biotechnology companies typically aim to develop truly refine our analysis, we analyzed in depth 50 representative
novel products for high-impact therapeutic markets. companies. These companies are listed in Appendix IV and
Hence, few apply their skills to neglected diseases. But are summarized as a group in Table 4.1.
if markets and incentives were available, would the
Table 4.1: Summary of 50 Focus Companies
infrastructure of the industry be applicable to neglected
diseases? Would companies be in a position to undertake Approved drugs originating from focus companies 23
discovery projects against unfamiliar pathogens?
Programs in active clinical development (Jan 2007) 121
Programs in discovery and preclinical development (Jan 2007) >400

The diversity of biotechnology businesses bewilders even
Equity capital raised since inception $20 billion
those steeped in the industry. Biotechnology companies
12 We elected to focus on U.S. and European biotechnology companies because they represent the most innovative companies.
The companies we examined closely have collectively on a scientific foundation in cellular biochemistry. At least
raised over $20 billion in public equity capital and as important—and even harder to import or build from
received billions more in partnering revenues from collabo- scratch—is their drug discovery expertise. Companies
rators. Their financial strength is also concentrated: just have assembled highly experienced teams of biologists,
over half the $20 billion was raised by the five largest structural biologists, pharmacologists, and chemists. Their
companies (Figure 4.3). skills are indispensable to “lead optimization,” the itera-
tive process of synthesizing and testing compounds for
The resources of the biotechnology industry potency, efficacy, and low toxicity.
Through interviews with executive and scientific manage-
ment of many companies in our representative set, we Biotechnology industry resources: Infrastructure
found that the industry possesses three key resources for Companies have used their equity and partnering revenues
discovering new drugs for neglected diseases: infrastruc- to build their infrastructure and develop their proprietary
ture, technological assets, and expertise. technologies (Table 4.2). To compete with the pharmaceu-
tical industry in small molecule discovery and development,
Biotechnology companies have invested heavily in early-stage biotechnology companies had to innovate. Most
high-throughput compound screening facilities, X-ray biotechnology companies were founded upon a single tech-
crystallography, computational modeling, and other infra- nological insight and then focused on a therapeutic applica-
structure to support drug discovery programs. Foremost tion of the technology. Subsequent partnering or outright
among many companies’ technological assets are the sale of the technology funded further drug discovery
combination of highly evolved compound libraries used programs. Most companies invest $100 million to $250
in drug screening and proprietary assay technologies built 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
1,519 More than 1,500 biotechnology companies are focused on

Total Biotechnology Industry
Companies therapeutics
1,008
Small Molecule Therapeutic Focus 1,000 focus on small molecule therapeutics
Companies
733 700 are pursuing new small molecules

Chemistry-based Discovery Capabilities
Companies
162 160 have the scale to support new programs

Scale
Companies
123 Over 120 have a track record of taking new drugs into the clinic
Development Experience
Companies
50 Focus Companies We chose a sample of 50 companies to analyze

A competitive clinical pipeline with potential to produce Table 4.2: The Assets and Infrastructure
a portfolio of marketed drugs demands constant invest- Used in Drug Discovery
ment in mid- and late-stage discovery, preclinical develop-
Animal study capabilities
ment, and clinical development capabilities. Biotechnology
Assay development: Cloning and expression of proteins
companies eventually need the same technologies and
skills resident in any pharmaceutical company, the major Chemistry instrumentation (e.g., nuclear magnetic resonance,
high performance liquid chromatography, mass spectrometry)
differences being only focus and scale. So biotechnology
Chemoinformatics
companies hire pharmaceutical industry veterans, expand
facilities, and license or purchase established pharmaceu- Compound libraries
tical assets. To reach this level of maturity, with multiple Compound storage and retrieval systems
compounds in clinical development, likely represents more Computational modeling (for structure-based design)
than half a billion dollars in total investment. High throughput screening robotics
In vitro pharmacokinetic (ADME) and toxicology assays

Biotechnology industry resources: Compound
Purification, fractionation, and identification equipment
libraries
X-ray crystallography
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
Figure 4.3: The Financial Strength of the 50 Focus companies: Equity Capital Raised
Equity Capital Invested in the 50 Focus Companies Equity Capital Invested in Select Smaller
Companies within Sample
25 250
Median of all 50 companies

20 200
Millions of Dollars Invested
Billions of Dollars Invested
15 150
10 100
5 50
0 0
m nce
s or ls tex g 45 al ta st y any ys
niu rac tica Ver inin Tot Syn cry Arra Alb yps
Mil
len d Scie Sep a ceu m a Bio Kal
a rm Re
Gile Pha
OSI
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
compounds. There are no definitive rules on what makes An important advantage of developing highly focused
a “good” compound library, but certain characteristics libraries is that screens once requiring a few million
dictated in part by a compound’s backbone, or “scaffold,” compounds, many of which were unassociated with any
have been proposed as predictive of orally available small biological activity, can now be performed with about
molecule drugs [40]. 100,000 compounds, winnowed down by computer algo-
rithms to represent a chosen attribute (function, shape, or
Biotechnology companies have taken many approaches target class). Highly focused libraries save time and money.
to building compound libraries. A diversity library, as They, and their associated computational modeling tools,
its name implies, aims to capture a broad array of drug- provide potentially unique starting points for medicinal
like molecules without selecting any particular target chemistry and lead optimization—and are critical to accel-
or scaffolds. This type of library can be employed in a erating drug discovery and development for any disease.
wide range of drug discovery programs. A focused library
strives for just the opposite: its compounds are biased The majority of our 50 focus companies have been
by structure or function in favor of interaction with a successful in discovering and developing novel small
specific target class. Because of the effort and inven- molecule drugs and clinical candidates. Each company
tiveness required to develop a refined and annotated generally possesses a mix of diversity and focused libraries.
collection of compounds, compound libraries are among Proprietary compound libraries that have yielded lead
drug discovery companies’ most important and closely compounds are likely to be of increasing value because
guarded assets. of the inherent drug-like qualities of the compounds
Figure 4.4: The Composition and Tasks of a Drug Discovery Team
Exploratory Discovery Lead Identification Lead Optimization Preclinical
Description Biologists are needed for Biologists are needed for Biologists and Biologists and
target biology and assay screening and follow up pharmacologists are needed pharmacologists are needed
Candidate selection
development (cloning and for pharmacokinetic (ADME/ for in vitro IND-directed

Chemists are needed for hit
expression) tox) assessment of analogs toxicity studies
characterization
Chemists are needed Chemists are needed for Chemists are needed for
Computationalists are needed
for compound library medicinal chemistry and process chemistry and
for structure-based design
development analoging formulation
Structural biologists and Computationalists are CROs may provide

computationalists are needed needed for structure-based additional animal capacity
for X-ray crystallography and design
target modeling
Representative Staff
Biologists and
Pharmacologists
Chemists
Structural Biologists/
Computationalists
Outsourced
Chemists Biologists and Pharmacologists

and constant compound data annotation from screening exploration has been carried out. Beyond the value of the
campaigns. But no matter how well constructed and anno- specific contents of given compound libraries and anno-
tated, any library’s value rests in its repeated success in tations stored in databases, companies benefit from the
yielding tools for in vitro proof-of-concept experiments and collective knowledge of those who created and used the
hits for lead optimization. companies’ technologies.
Unfortunately, the industry’s compound libraries have At successful biotechnology companies, the convergence of
rarely been mined for hits and leads against targets relevant focus and expertise almost always augments the next level
to global health. For neglected diseases, specific natural of development, where knowing how to develop drugs and
products (and small collections of such compounds) have knowing which drugs not to develop are equally impor-
historically been the main source of new lead compounds. tant. Constant pipeline triage is instrumental to working
But things have changed. Today, genomics technologies quickly and within budget constraints. For example, our
have identified molecular targets specific to neglected 50 focus companies have collectively discontinued more
disease pathogens. This is of tremendous importance. It than 700 internal discovery programs [27]. Moreover,
means that screening compound libraries using either pipeline triage can accelerate project timelines to IND
phenotypic or target-based screens should significantly and result in more focused clinical trials. Combining this
expedite neglected disease drug discovery programs. discipline with the inherent value of the company’s R&D
infrastructure and proprietary assets continuously creates
Biotechnology industry resources: Expertise opportunities for evaluation and action.
As biotechnology companies evolved into leaders in small
molecule discovery, they built teams with scientific exper- Biotechnology industry resources: Target focus
tise in many disciplines, including basic biology, structural Companies focused on small molecule drug discovery are
biology, pharmacology, and analytic, synthetic, and medic- typically thought of in terms of the diseases they tackle.
inal chemistry. The composition of a typical drug discovery In fact, many are organized not around a disease but
team at each stage of a project is summarized in Figure around specialized molecular targets that may underlie
4.4. Although the mixture of skills changes over the course mechanisms of several unrelated diseases. Their targets
of a project, advancing to lead optimization frequently are typically members of an extended target family,
requires a dozen or more medicinal chemists, making such as G protein–coupled receptors (GPCRs) (Arena
chemistry expertise integral to success. Our 50 focus Pharmaceuticals), kinases (OSI Pharmaceuticals, Exelixis,
companies report employing between 20 and 50 medicinal Ambit BioSciences), ion channels (Neuromed), and
chemists each, either on staff or outsourced to CROs often phosphodiesterases (PDEs) (Plexxikon) (Figure 4.5).
located in India or China. Breakthrough drugs have been found in all these classes
across a range of therapeutic indications, from the kinase
Of those companies we examined, most have been in inhibitor Gleevec® for treating chronic myelogenous
operation for more than 10 years. By assembling industry leukemia, to PDE-5 inhibitors like Viagra® for cardiovas-
veterans and motivated younger scientists into small, cular function and erectile dysfunction.
highly focused teams, biotechnology companies build
cohesive discovery-driven cultures and increase exper- Target expertise is critical for a company’s competitive posi-
tise in the specific areas of interest. Discovery teams in a tion. Concentrated expertise, technology, and intellectual
successful company are likely to become internationally property are why pharmaceutical companies seek commer-
recognized leaders in their particular area. This special cial partnerships with biotechnology companies to build
expertise is valuable to the company in ongoing efforts their pipelines. Target expertise can result in a continual
to build a pipeline of projects, and it also adds valuable source of compounds spanning many therapeutic areas,
corporate memory. For example, many companies have simply because specific members of the target family have
“legacy programs,” in which extensive medicinal chemistry been associated with different disease pathologies. A target-
Figure 4.5: Target Class Focus of 50 Focus Companies
Cytoskeleton Host response
General discovery Proteases/Metabolic GPCRs

enzymes
SRI International
CV Therapeutics
Kinases Nucleic acid Ion channels
ChemoCentryx
Pharmacopeia
Cytokinetics
Theravance
Millennium
Neuromed
Metabasis
Replidyne
Neurogen
Plexxikon
Cephalon
Genelabs
Amphora
Immtech
Sepracor
Kalypsys
Achillion
Sequella
BioCryst
Optimer
Celgene
Renovis
Lexicon
Sunesis
Exelixis
Rexahn
Infinity
ACADIA
Anadys
ArQule
Icagen
Vertex
Gilead
Kémia
Ambit
Arena
Locus
Synta
Kinex
Astex
Array
Ariad
Vitae
Rigel
Eisai
Telik
OSI
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 ≥50% of Portfolio 10–50% of Portfolio <10% of Portfolio
Source: PharmaProjects
based approach allows companies to attack different diseases Can biotechnology industry drug
by attacking distinct proteins within a single target class. discovery technologies be adapted
Often the same compound libraries and similar biochemical to neglected diseases?
assays can be used to tackle entirely different diseases. Clearly, there are important questions to address. Can
drug discovery tools be shared? Is the overlap among drug
The classic example of how a library developed for one targets between noninfectious diseases like diabetes and
disease was applied to another involved compounds origi- many cancers and developing-world pathogens more than
nally made to inhibit the human enzyme renin, an aspartyl superficial? How relevant to drug discovery for neglected
protease implicated in hypertension. These libraries were diseases are shared molecular structures? How can we
enlisted in drug discovery for HIV in the urgent early years harness the tools of the biotechnology industry that are
of the pandemic. Screening of these very same compounds so effective in developing new therapies for the affluent to
against the HIV aspartyl protease provided the first lead develop new therapies for the poor?
compounds against the viral target and yielded such
breakthrough drugs as saquinavir (Fortovase®), indinavir In the remaining chapters, we will examine the scientific
(Crixivan®) and many more protease inhibitors in broad rationale for extending biotechnology companies’ capa-
clinical use today. This example, repeated often in the bilities to neglected diseases, the hurdles that stand in
last 20 years, provides a clear road map for target-based the way, and new models for collaboration between the
drug discovery, regardless of the disease. The very same biotechnology industry, academic organizations, and PDPs.
approach can generate drugs for neglected diseases.

Chapter 5: Mapping Biotechnology
Capabilities to Neglected Diseases
Biotechnology companies have brought many innovative The choice of diseases . . .
small molecule drugs from the test tube to the clinic. But Malaria, TB, and the trypanosomal diseases have been
does their expertise—built around cancer, cardiovas- studied for more than a century, and much is known
cular disease, and other conditions that afflict the aging about the basic biology of the pathogens that cause them
population of wealthy nations—offer hope for neglected [44-47]. Scientists in academia and at research institutes
diseases? The universality of biochemical mechanisms have suggested that disease understanding per se is not
and adaptability of tools for drug discovery strongly limiting, and they have developed tools and assays that
suggest that the answer is yes. The unique biology of support drug discovery. But they also caution that each
infectious disease–causing pathogens, however, creates pathogen has unusual features that complicate drug
distinct hurdles that will require new solutions by drug discovery [5, 48-50].
discovery scientists.
TB is caused by a single species of bacterium,
Essential tools for drug discovery Mycobacterium tuberculosis. In contrast, malaria and
As Chapter 4 explains, general drug discovery infrastruc- trypanosomal diseases are caused by several species of
ture and skill sets resident in industry can play a critical
role in creating drugs for neglected diseases. But scientists Sidebar 5.1: The tool kit for modern
in drug discovery companies embarking on a discovery drug discovery
program for a neglected disease also need key pathogen- Guided by the target product profile (TPP), drug discovery
specific tools: scientists know what biochemical and pharmacologic hurdles
n A comprehensive understanding of the disease their candidate compounds must overcome. For rapid progress,
process at molecular and cellular levels; discovering new drug candidates for neglected diseases
n Biochemical, cellular, and in vivo assays to requires the following:
evaluate the efficacy, pharmacology, and toxicity

Understanding of biochemical pathways of infectious
of candidate compounds (see Sidebar 5.1); and pathogens. Drug discovery is much more likely to succeed if
n Validated targets against which to screen the target pathways are understood. It is much more likely to
promising therapeutic compounds. produce unintended side effects if screening is done in a “black
box” of unknown biochemical activity.
Our analysis explored whether malaria, tuberculosis (TB),
Genomic information. A fully sequenced and annotated
and human African trypanosomiasis (HAT) can be added
pathogen genome allows researchers to predict pathogen
to the list of diseases that can be tackled by small molecule gene function, greatly facilitating target identification.
drug discovery companies. To answer this question, we
first assessed the state of the art of neglected disease drug Genetic tools. To “genetically validate” a target molecule
discovery tools. Specifically, we asked whether neglected requires tools that enable researchers to test if a gene is
disease researchers have created bioinformatic and genetic essential for virulence, pathogenesis, or viability.
tools, biochemical assays, and animal disease models

Discovery tools. Such tools include recombinant target protein
that can be combined with the target-specific screening expression, high-resolution protein crystal structure, and
systems found in leading small molecule drug discovery biochemical or whole-cell assays.
companies. We also looked for target overlap between P.
falciparum, M. tuberculosis, and T. brucei, the pathogens that Animal disease models. Screening small molecules for in vivo
cause malaria, TB, and HAT, respectively, and the diseases pharmaceutical activity is a prerequisite to further preclinical
and clinical development. Animal models give an initial
on which leading biotechnology companies currently focus
indication of the efficacy one hopes to see in humans, along
their efforts. with indications of toxicity, pharmacokinetics, drug half-life,
and unanticipated side effects.
protozoan parasites. In order to examine specific opportu- much less effective than for bacteria with doubling times
nities within protozoan diseases, we limited our analysis to on the order of minutes. Furthermore, the thick, waxy
P. falciparum (malaria) and T. brucei (HAT). surface coat of M. tuberculosis is not at all like a mamma-
lian cell membrane and is an impossible barrier for many
Malaria is caused by four species of Plasmodium parasites, drug-like molecules to cross. In addition, due to a poorly
each with its own unique biology and pathology. Nearly all understood phenomenon known as “persistence,” a frac-
efforts to invent new malaria drugs, however, are directed tion of M. tuberculosis in an individual with active disease
at P. falciparum, the deadliest and best understood species can survive in the presence of currently available drugs for
and the most common throughout Africa. months [51].
Leishmaniasis, Chagas disease, and HAT are caused by T. brucei. T. brucei hides in privileged spaces, where it
divergent species of protozoa (called trypanosomatids) with can be difficult for drugs to reach. In late-stage disease,
unique life cycles and insect vectors. Leishmaniasis is not a the parasite leaves the bloodstream and enters the central
single disease. It exists in visceral, cutaneous, and mucosal nervous system and brain. For a drug to be effective in
forms and is caused by more than 20 separate Leishmania this stage, it must be able to cross the blood-brain barrier
species. Although Leishmania, T. cruzi (the pathogen that (BBB), a gradient mechanism that normally serves to
causes Chagas disease), and T. brucei evolved from a protect the brain from most chemicals circulating in the
common ancestor, and therefore share many molecular blood. Designing a drug capable of crossing the blood-
and biochemical pathways, their infection cycles and the brain barrier (BBB) without any associated toxicities pres-
tissues they target are very different. We focused our anal- ents an enormous challenge.
ysis on T. brucei because the set of research tools available
for its study are better developed than for any other type of Drug discovery tools for neglected diseases:
trypanosomatid. The state of the art
Several factors have primed M. tuberculosis, P. falciparum,
. . . and their challenges and T. brucei for major therapeutic advances:
P. falciparum. The life cycle of P. falciparum is extraor- n Their genomes have been sequenced and annotated;
dinarily complex. The parasite targets several tissue types n Genetic tools have been developed to validate
and shifts between living freely in the blood and entering potential drug targets; and
and inhabiting the host’s cells. The parasite undergoes n Animal models of infection exist, making it
radical changes in morphology and metabolism as it passes possible to test the ability of compounds to kill
through these stages. Drug discovery in P. falciparum, pathogens in vivo.
however, is effectively restricted to the red blood cell or
erythrocytic stage of its life cycle—the stage responsible Each of these topics is described in more detail below.
for the symptoms of uncomplicated malaria—because only
this stage of the parasite can be cultured in the labora- The importance of genomic information
tory. Laboratory culture is not routine for the forms of for target identification
the parasite that infect the liver or for those that survive The revolution in DNA sequencing and bioinformatics,
ingestion by mosquitoes and complete the transmission along with order-of-magnitude increases in speed and
cycle. These obstacles make developing a drug that relieves reductions in cost, has made it possible to sequence the
symptoms and also prevents infection and transmission genomes of dozens of infectious microbes. Beginning with
much more difficult. the M. tuberculosis genome in 1998 [52], scientists have
reported fully sequenced and annotated genomes for P.
M. tuberculosis. Even under optimal laboratory condi- falciparum [53], T. brucei, [54] and closely related organ-
tions, M. tuberculosis grows extremely slowly (a doubling isms [55-58]. Pathogen-specific genomic information is
time of about 24 hours). As a result, antibiotics that accessible through a variety of publicly available databases
disrupt processes required for rapid growth are rendered (see Figure 5.1) [59-61].

The availability of genomic information is important for Conditional knock-outs are especially important for testing
drug discovery for several reasons. First, it greatly facili- if a gene is essential to the pathogen when the pathogen
tates correlations between pathogenicity and specific genes. infects a laboratory animal. This may reveal whether a
It also allows researchers to identify genes that, based gene’s function is required to maintain a chronic infection.
on their known or predicted function, are potential drug In recent years, a tool known as RNA interference (RNAi/
targets. Finally, it has led to the routine application of siRNA) has proven to be a rapid way of testing whether a
molecular and recombinant techniques that may reveal gene is essential in many eukaryotes,13 including the human
more about a pathogen’s potential vulnerabilities to drugs. infective form of T. brucei [62]. This technique does not
For example, with a pathogen genome sequence in hand, a disrupt the gene, but inhibits expression of the protein that
researcher has all the information necessary to manipulate the gene encodes. Unfortunately, RNAi cannot function
the pathogen genetically and to make pathogen proteins in P. falciparum because the pathogen lacks key enzymes
to determine protein crystal structure and to develop a required to generate interfering RNAs. Likewise, RNAi is
biochemical assay. not relevant to a bacterium like M. tuberculosis.
Target validation depends on genetic tools A genetically validated target proves useful only if it is
Target validation is the determination of whether a gene shown to be “druggable”: not only is the enzyme integral
encoding a pathogen protein is essential to the viability or to the disease process, but it can also be inhibited through
virulence of the pathogen. That is, can the pathogen survive specific binding with small molecules. For reasons such as
under laboratory culture or infect an animal when a gene’s functional obscurity or redundancy, physical inaccessibility,
function is lost? If a parasite with a mutation in a specific or even the shape and size of a unique binding site (or lack
gene dies, is severely weakened, or cannot maintain an thereof), many potential drug targets prove undruggable.
infection, scientists may decide to design a drug to inhibit
the function of the gene product to yield a similar outcome. The importance of mouse models in
target validation
For a neglected disease pathogen, most validated targets Researchers depend on animal models of infectious disease
will be proteins or protein complexes. Inhibition of the to identify and validate potential drug targets. Mouse
activity of these proteins with an effective small molecule models are most often used in early-stage drug discovery
drug will cause the pathogen either to stop growing or die. because large numbers of experiments can be conducted
Historically, most antibiotics have interfered with pathogen at comparatively low cost to predict effects in humans.
“housekeeping functions” such as DNA replication, RNA Researchers can test if a target that has been genetically
transcription, protein translation, or cell wall synthesis. validated in vitro is also required to initiate or maintain an
Thus, pathogen genes involved in these processes continue infection in animals. A mouse model allows compounds
to be viewed as potential drug targets. identified on the basis of in vitro activity (for example,
compounds identified for inhibiting a target pathogen
Several techniques can test if a gene is essential for protein in test tube experiments) to be tested for the ability
viability. The most straightforward is to “knock out,” or to prevent infection or cure an infected animal.
permanently disrupt the target gene, thereby eliminating
the production of the protein it ordinarily encodes. This M. tuberculosis and T. brucei can be grown in mice with
genetic engineering technique has become routine for relative ease. For T. brucei, mouse models exist that
P. falciparum, M. tuberculosis, and T. brucei [48, 62, 63]. mimic both acute and chronic stages of disease, making
There are, however, technical limitations associated with it possible to evaluate compounds for their ability to clear
gene knock-outs. To overcome them, M. tuberculosis and both types of infection. The latter is especially important
T. brucei researchers developed methods of “condition- because for a drug to cure chronic infections, it must
ally” knocking out gene function [64, 65]. That is, they are cross the BBB. The chronic-infection mouse model allows
able to turn off a gene’s expression temporarily and then researchers to test compounds for ability to kill T. brucei
observe if the organism remains viable. that have entered the central nervous system.
13 A eukaryote is most simply defined as an organism containing a nucleus.
In contrast to M. tuberculosis and T. brucei, P. falciparum routine, but does require later confirmation because at the
cannot normally survive in mice. Instead, the rodent amino acid level P. berghei and P. falciparum proteins share
malaria parasite P. berghei is commonly used as an imper- on average just over 60 percent sequence identity [55]. In
fect substitute for infected animal studies. Establishing that instances where the structure of the P. falciparum target
a compound effective at killing P. falciparum in culture differs substantially from that in P. berghei, the P. berghei
will kill P. berghei in a mouse via the homologous target is 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
Basic Research: Target Screening: Target Validation Lead Identification Lead Optimization
Identification
Genome: sequenced and Gene knock-outs: increasingly Whole-cell screening: Primate disease models
P. falciparum
annotated; comparative routine (erythrocytic stage only) routine for erythrocytic available
genomics possible with other stage; assay for DNA
Conditional gene knock-outs: P. falciparum does not
human and rodent species of replication
in development normally grow in rodents;
Plasmodium
new immunocompromised
Transposon mutagenesis:
Key databases: and ‘humanized’ mouse
possible
– www.plasmodb.org models emerging
– tdrtargets.org RNAi: no
The rodent malarial parasite
Erythrocytic-stage parasite Gene microarrays: available P. berghei is frequently used
can be grown in culture in place of P. falciparum;
Proteomics: extensive
allelic replacement can be
Safety: BSL2 laboratory
Crystal structures: not extensive used to generate improved
P. berghei
Genome: sequenced and Gene knock-outs: routine Whole-cell screening: Animal models: mouse for
M. tuberculosis
annotated; comparative routine under a variety of acute and chronic disease;

Conditional gene knock-outs: conditions; assay for growth
genomics possible with guinea pig, rabbit, and
possible
Bacille Camille Guérin (BCG), primate models also available
For safety reasons,
M. smegmatis, M. leprae Transposon mutagenesis: M. smegmatis is commonly No animal model for
routine used as a substitute for
Key databases: latent disease
– genolist.pasteur.fr/TubercuList/ RNAi: not relevant M. tuberculosis
– webhost.nts.jhu.edu/target/
Gene microarrays: available
Can be grown on solid media,
Crystal structures: extensive
in liquid culture, or in animal
and freely available
models
- TB structural genomics
Safety: requires BSL3 laboratory consortium:
www.doe-mbi.ucla.edu
Genome: sequenced and Gene knock-outs: routine Whole-cell screening: Animal models: mouse
T. brucei
annotated; comparative routine; assay for for acute and chronic (late-
Conditional gene knock-outs:
genomics possible with ATP production stage) forms of disease
routine
Leishmania sp. and T. cruzi
RNAi: routine
Key databases:
– www.genedb.org/genedb/tryp/ Gene microarrays: available,
– tdrtargets.org but polycistronic transcription
limits usefulness
Bloodstream stage parasite
can be grown in culture or Proteomics: limited
in rodents
Crystal structures: limited
Safety: BSL1 for standard
lab strain
Well-developed tools Less well-developed tools

[66]. Such a transgenic organism would be predicted to The search for validated targets
more closely mimic P. falciparum than normal P. berghei. Most of today’s standard treatments for diseases such as TB
and HAT are over 40 years old [5, 71] and have severe limi-
Additional drug discovery tools for tations in potency, safety, and resistance profiles. Many of
neglected diseases these drugs were discovered serendipitously or by traditional
Modern drug discovery is supplemented by a variety of screening of drug compounds against whole organisms in
technologies that require specific molecular information or vitro. While some traditional screening techniques are still
reagents. These technologies include the following: useful, modern biotechnology now enables drug hunters to
n Recombinant target proteins. Screening campaigns hone in on specific molecular targets in pathogenic microbes
typically require that the target protein be cloned, and understand from the start the mechanism of action.14
expressed, and purified. The protein can then be used This approach significantly improves the likelihood of iden-
in high-throughput-screening biochemical assays. tifying compounds that are highly potent and specific to the
n High-resolution crystal structures. Protein crystals target and potentially safe and efficacious.
made of highly purified target protein and then
subjected to X-ray diffraction provide researchers
Sidebar 5.2: Critical tools for future development
with structural information useful in designing and
refining small molecule inhibitors by computational While our interviews indicated that scientists feel confident
that they have the tools to launch new discovery efforts,
modeling. Co-crystallization of an inhibitor bound
key improvements could accelerate drug discovery for each
to the target protein aids lead optimization by disease. Indeed, the Bill & Melinda Gates Foundation launched
providing additional high-resolution information on a $40 million TB Drug Accelerator in 2006 specifically to develop
where the drug binds its target. new tools [67]. For malaria and tuberculosis, two needed
n Biochemical or whole-cell assays. An assay suitable advances could have tremendous impact:
for screening thousands of compounds needs to
Develop a mouse model capable of maintaining a sustained P.
be simple and highly reproducible. In many cases
falciparum infection. Rodent malarial species of Plasmodium do
it is useful to screen compounds against whole not adequately predict results with P. falciparum. A drug designed
organisms using medium-throughput in vitro assays to act on a P. falciparum target but screened for efficacy against
to test if the compound inhibits pathogen growth. a rodent parasite may exhibit deceptively lower efficacy in the
mouse model due to differences in the rodent parasite’s infection
Figure 5.1 provides an overview of many of the tools avail- cycle, pathology, permeability, and ability to transport drugs
across membranes [68], thus generating false negative results.
able for P. falciparum, M. tuberculosis, and T. brucei.
Strains of immunodeficient mice that tolerate grafts of human
red blood cells have shown encouraging results as models
Drug discovery tools for neglected for P. falciparum infections, but have yet to prove suitable for
diseases: Conclusions routine use [69]. A mouse strain that can maintain a P. falciparum
Our interviews with scientists in academia and biotech- infection would be a key asset for malaria drug discovery.
nology companies strongly suggest that modern tech-
Develop an improved model for latent tuberculosis. Most
niques of drug discovery are readily applicable to neglected
humans infected with M. tuberculosis develop a latent
diseases. In every case, the neglected disease knowledge base infection in which the organism lies dormant, possibly for
and early discovery work, from genomics to assay develop- years, until reactivated by suppression of the immune system
ment, meet or exceed biopharmaceutical industry standards or other poorly understood mechanisms. Ridding the body
for initiating a discovery project. Moreover, these discovery of a latent infection is possible but requires long treatment
assets in many cases are of sufficiently high quality to initiate times. The biology of latent infection is not understood, but the
bacteria appear to be in a different metabolic state from those
high-throughput screening (HTS) projects to search for
present in active disease [70]. Researchers place a high priority
lead candidates or structure-based drug design projects. on finding ways to screen candidate compounds against M.
More work, however, is still needed on target validation tuberculosis in the latent state. Currently there is no in vitro or
and animal models for neglected diseases (see Sidebar 5.2). 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.
Biotechnology companies are expert in identifying and particular target classes and then launch programs on
validating new biochemical targets that mediate cell growth multiple diseases. For example, one company special-
and viability and that play key roles in diseases such as izing in kinases attacks multiple types of cancer. Another
cancer and neurological disorders. For small molecule drug specializing in ion channels has programs in pain, hyper-
targets, early evidence of chemical tractability and dose tension, and epilepsy.
responsiveness can come from compound screening. This
evidence is then confirmed by making potency improve- A company’s specialized technologies for a particular target
ments during lead optimization. Examples of proteins class could be applied in drug discovery programs against
widely employed as targets for drug discovery include a neglected disease pathogen, where the pathogen shares
proteases (proteins that degrade other proteins), protein a target with a chronic disease such as cancer. As summa-
kinases (intracellular messengers), ion channels (transmit- rized in Figure 5.2, significant target class overlap exists
ting molecules across the cell membrane), and farnesyl between chronic noninfectious diseases and neglected
transferases (cell signaling). Leading drug discovery infectious diseases. Moreover, many of the same major
companies have developed technologies and built tools target classes are shared between P. falciparum and T.
around specific target classes (see Table 5.1). brucei, or among P. falciparum and M. tuberculosis and T.
brucei (Figure 5.3). Shared targets include kinases, prote-
Certain classes of drug targets, such as kinases and ion ases, protein farnesyl transferases, and phosphodiesterases.
channels, have different roles in different cell types. Target-specialized drug discovery know-how and target-
Related targets in different cell types can function in specialized compound libraries have already been applied
entirely different diseases. This explains why many compa- successfully to selecting compounds active against targets
nies build drug discovery technologies specializing on 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 Yes Yes Yes

(DHFR, etc)
Phosphodiesterases Yes Yes Yes
Protein farnesyltransferases Yes Yes Yes
Ion channels Yes Yes Models only
Kinases Yes Yes Yes
Nucleic acid Yes to all Yes Yes

– replication
– transcription
– purine salvage
– pyrimidine salvage
– other
Cytoskeleton Yes Yes Yes
G protein-coupled receptors Yes Yes Yes
Heat-shock proteins Yes Yes Yes
Nuclear receptors Yes Yes Models only

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
Chronic Disease Molecular Target Neglected Disease
companies and each pathogen. Below, we highlight three
major shared target classes: proteases, cyclic nucleotide
Malaria
phosphodiesterases, and protein kinases. Cancer Kinases TB
HAT
Proteases cleave peptide bonds, breaking down proteins Cardiovascular Malaria

disease; Proteases TB
into peptide chains or single amino acids. Drugs on the HIV HAT
market that target proteases include Tekturna® used to
treat hypertension and Kaletra® and Reyataz®, used to Malaria
Cancer Farnesyl tranferases HAT
treat HIV. Clinical trials are currently under way to test the
efficacy of various protease inhibitors as therapeutics for Central nervous Ion channels Malaria
system diseases
hepatitis C and osteoporosis.
Cancer Cytoskeletal proteins HAT
Inside a red blood cell, P. falciparum derives energy and
Cardiovascular Malaria
nutrients by breaking down hemoglobin. Hemoglobin disease; Phosphodiesterases
Erectile HAT
breakdown requires several P. falciparum proteases [73]. dysfunction
Among them, a cysteine protease subfamily known as falci-
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 Proteasome
P. falciparum Metabolic M. tuberculosis

enzymes
Cell wall
synthesis
pains has been validated and is being pursued as part of these enzymes, TbrPDEB1 and TbrPDEB2 [74]. Because
a collaboration between MMV and GSK. As of late 2006, the catalytic sites of TbrPDEB1 and TbrPDEB2 are nearly
these teams were selecting clinical candidates from the identical, it may be possible to design a single inhibitor of
falcipain inhibitor programs. The metalloprotease falcilysin both enzymes. PDEs are also considered validated targets
is another protease required for hemoglobin breakdown in P. falciparum [75].
and other functions. Its potential as a P. falciparum target
is currently under evaluation. Other proteases have been Protein kinases are enzymes that transfer a phosphate
validated in M. tuberculosis and T. brucei. group from an adenosine triphosphate (ATP) molecule to
a protein substrate in a process called phosphoryation.
Cyclic nucleotide phosphodiesterases (PDEs) break Kinases play fundamental roles in cell division and signal
the phosphodiester bond found in cyclic nucleotides transduction, processes that often malfunction in cancerous
involved in eukaryotic signal transduction. Inhibitors of the cells. Kinase inhibitors hold enormous therapeutic poten-
PDE-5 subclass are used as vasodilators to treat pulmonary tial for cancer. For example, Gleevec®, an inhibitor of
arterial hypertension and erectile dysfunction (e.g., Viagra®). the protein kinase BCR-ABL, has been approved for use
New inhibitors of different PDEs are being pursued for in chronic myeloid leukemia and gastrointestinal stromal
conditions ranging from depression to inflammation. tumors, and it is being pursued for treatment of a variety
of additional cancers. Because of their essential role in cell
The T. brucei genome encodes five PDEs. The bloodstream proliferation, kinases may also be key targets in preventing
form of T. brucei cannot survive in the absence of two of 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 T. brucei
Proteases
– Serine
– Cysteine Falcipains TbCatb, brucipain
– Other Falcilysin (metalloprotease) PDF (metalloprotease)
Proteasome mpa; paf; PrcBA
Metabolic enzymes
– Folate metabolism DHFR-TS; dihydropteroate synthase DHFR-TS
– Fatty acid synthesis Fab H; FabI (apicoplast) FabI Enoyl-ACP reductase (InhA)
– Glycolosis Lactate dehydrogenase Glycosome enzymes
– Other Malate synthase (glcB) Trypanothione reductase
Isocitrate lyase (ICL1/2) Trypanothione synthase
Ornithine decarboxylase
Phosphodiesterases PfPDE1 TbrPDEB1; TbrPDEB2
Protein farnesyltransferases PFT TbPFT
Ion channels PSAC
Kinases PfMrk; PfMap1; PfNek-1; PfPKG PknG CRK3, PK4, PK50
Nucleic acid
– DNA synthesis DNA gyrase (apicoplast) DNA gyrase
– Transcription RNA polymerase (apicoplast) rpoB
– Purine salvage PfNT1
– Pyrimidine salvage Dihydroorotate dehydrogenase ATP synthase (AtpE)
– Other 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 recep-
tors 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.

All of the genes predicted to encode kinases (“the kinome”) High-throughput screening against
in P. falciparum and T. brucei have been described [76, 77]. a conserved target class
For most of these genes, the biology remains to be worked In other cases, a target class is known to be essential
out, and few have been genetically or chemically validated. for viability or virulence in a pathogen, but specific
Nonetheless, kinases involved in cell-cycle control have been targets have yet to be validated. Using a focused
chemically or genetically validated for both P. falciparum compound library, whole-cell screening could be
(PfMrk) [78, 79] and T. brucei (CRK3) [80, 81]. The latter is performed to identify compound hits that kill the
one of several kinases actively pursued by the Dundee Drug target pathogen. Chemogenomic approaches15 could
Discovery Initiative [82]. PknG, an M. tuberculosis kinase then be used to identify the specific protein in the
required for bacterial survival within the host macrophage, target class bound by the hit compound. With the
has also received attention as a new drug target [83, 84]. pathogen protein target in hand, leads could be
identified and further optimized. Alternatively,
Applying target-focused tools and infra high-throughput screening with a focused compound
structure to neglected disease drug discovery library could be carried out on a panel of proteins
How might the existing tools and infrastructure of corresponding to a particular target class (e.g.,
biotechnology be used to attack neglected diseases? A pathogen kinases). Compounds that inhibit a specific
particular strength of the biotechnology industry is the target class member and that kill the pathogen in vitro
diversity of approaches that are utilized to generate new would be selected for further evaluation.
small molecule drugs, including compounds that inhibit a
single target class (see Sidebar 5.3). To commence a new High-throughput screening against
drug discovery program, at a minimum, a biotechnology a novel target class
company would require a TPP and well-researched biolog- Certain pathogen targets may be biologically validated
ical targets that can be assessed for chemical tractability. A but do not correspond to families already explored
project is enhanced by availability of recombinant proteins, by companies. For example, genes of the apicoplast
assays for biochemical high-throughput, or whole-cell (an ancient, nonphotosynthetic plastid) in P. falciparum
screening and structural information. At least three are required for survival but have no homologs in
approaches can employ infrastructure and proprietary mammalian cells. Yet there are still ways to utilize
technologies to produce optimized lead compounds: biotechnology assets against these targets. In contrast to
target-specialized companies, companies with general-
High-throughput screening against ized discovery platforms have compound libraries that
a conserved target emphasize chemical diversity and drug-like properties
Certain pathogen targets have already been validated, over other considerations.
where biological function is comparable to that of a human
protein of the same target class. Here, a company could A potential disadvantage of drug discovery performed
apply the full complement of target-specific biotechnology on a novel target is the lack of preexisting assays,
tools. First, the same high-throughput screening assay structural information, and lead compounds from
format for identifying hits and leads for the chronic disease related target-focused approaches. Furthermore, starting
target could be applied to the pathogen target. Second, a program on a novel target may require more time
a target-focused compound library could be used for and funding than a program based on membership
screening, improving the odds of identifying hits and leads in a well-validated target class. Nonetheless, there are
that could be quickly confirmed to be structure dependent potential advantages in safety and specificity when
and dose responsive. With the hope of rapidly identifying selecting targets present within organelles or metabolic
an advanced candidate for proof-of-concept and animal pathways that are found exclusively in the pathogen
studies, lead compounds generated from other projects because of fewer nonspecific interactions.
might also be tested for inhibiting the pathogen target.
15 Chemogenomics is the systematic analysis of chemical-biological interactions, specifically the investigation of classes of compounds (libraries)
against families of functionally related proteins.
The case for further exploration Unfortunately, most of these efforts were not pursued
Several of the companies we interviewed have investi- further because any or all of the following reasons: inability
gated applying their platform technologies and propri- to obtain funding, lack of preclinical pharmacology
etary compound libraries to neglected diseases. On their support, high opportunity costs, or absence of a clear route
own, or in collaboration with academic researchers, a to commercialization. These initial efforts nonetheless indi-
number have carried out early-discovery efforts. Of the cate that biotechnology company participation is a problem
companies we interviewed, nine either had a compound of incentives, not capabilities.
they considered worth testing on a neglected disease
or have been in active collaborations with neglected Chapter 6 details the hurdles to biotechnology company
disease researchers. In nearly every case, interest in involvement in neglected disease drug discovery. We also
a neglected disease was driven by target homologies present ways in which these problems might be overcome.
that suggested new utilities for existing compound
sets, many of which were synthesized as candidates for
chronic disease indications.
Sidebar 5.3: Harnessing diverse biotechnology solutions

A major strength of the biotechnology industry is the diversity Modular approach to inhibitors. This approach relies on linking
of approaches to inhibitor design, even when the inhibitors small molecules that bind independent sites on the kinase,
target the same protein class. For example, protein kinases are thereby increasing their specificity and avoiding toxicity.
enzymes involved in signal transduction through which cell Although an individual module may bind a kinase only weakly,
growth, morphology, and movement are regulated. Nine of the once modules are united into a single molecule high binding
50 companies we examined focus exclusively on protein kinases. affinity can be achieved.
Thirty (or 60 percent) of them have at least one kinase program.
Approaches used to generate inhibitors include the following: ATP Binding
ATP Pocket
ATP-binding Discover compounds
x
ATP-binding pocket inhibitors. Small molecules that bind to pocket inhibitors that bind specifically
to the ATP-binding
and block access to the ATP-binding domain of a protein kinase Kinase
pocket
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 Allosteric Discover compounds ATP
Allosteric
approaches are now favored. inhibitors that bind to x Site
allosteric sites
Kinase
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. Build compounds
Fragment ATP
Allosteric sites among kinases are not highly conserved. By approach with high binding x
selecting for compounds that bind to a target protein kinase’s affinity from small
allosteric site, high levels of specificity can be achieved. chemical fragments
Kinase
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. Modular Link compounds that ATP
approach bind to adjacent sites x
Fragment approach to inhibitors. Knowing the structure of the
kinase of interest, “fragments” of small molecules are tested by Kinase
computational modeling for the ability to bind specific nooks
Adjacent Domain
of the ATP-binding site. Combinations of fragments are then
assembled into single molecules, tested for inhibitory effects Any of the above approaches could be applied to kinase or nonkinase targets
identified in P. falciparum, M. tuberculosis, T. brucei, or any other neglect-
and co-crystallized with the kinase target to allow their quality
ed disease pathogen. Depending on the information available, one approach
of fit within the binding site to be evaluated and improved. might be significantly favored over others. Importantly, the diversity of
Those deemed most promising are modified iteratively until approaches developed for kinase inhibitor discovery typifies the diversity of
high affinity binding is achieved. approaches for other target classes.
Sources: Company websites including Ambit, Kémia, Plexxikon, and Sunesis

Chapter 6: Building a New Discovery Pipeline
Although biotechnology companies possess technologies Additionally, two Seattle-based nonprofit research institu-
and expertise that could accelerate drug discovery and tions have dedicated efforts to innovate new drugs and
development for neglected diseases, information, mana- vaccines for neglected diseases. The Infectious Disease
gerial, and financial hurdles have hindered their partici- Research Institute (IDRI) was founded in 1993 and has
pation in global health. This chapter explores a range multifaceted programs in a number of neglected diseases
of ways to summon the most experienced and capable including TB, Chagas disease, and leishmaniasis. The
innovators; forge partnerships among companies, PDPs, Seattle Biomedical Research Institute (SBRI) was founded
and academia; and fund and manage the most promising in 1976 and has research efforts under way on numerous
drug discovery projects. bacterial, viral, fungal, and parasitic diseases. In 2007 IDRI
and SBRI announced a partnership with Eli Lilly around
The Current Landscape TB drug discovery [89].
Leading public sector organizations have recognized the
need to close the innovation gap by increasing effort These encouraging initiatives show that the public sector
and investment in drug discovery. PDPs such as the TB recognizes the innovation gap and is developing ways to
Alliance and MMV sponsor several million dollars per year address it. But building translational capability in academia
of drug discovery work at major pharmaceutical companies is unlikely to be enough to close the innovation gap.
such as GSK and Novartis, along with smaller collabora- Purchasing compound libraries, building drug discovery
tions with several biotechnology firms [21, 85]. infrastructure, and hiring the necessary expertise is expen-
sive and time consuming.
To help build the foundation of biological knowledge and
discovery tools available to drug hunters, several public To fill this gap academic institutions are beginning to
sector initiatives have been launched in the past few years. “integrate forward,” developing programs in translational
They include— research. PDPs are also beginning to “integrate back-
n The Gates Grand Challenges in Global Health, ward,” building preclinical capabilities. However, whether
with $436 million of basic research funding the two “meet in the middle” remains to be seen. More
awarded in 2005 [86]; importantly, these public sector initiatives aren’t lever-
n The $40 million Gates Foundation–sponsored TB aging the potent capabilities and infrastructure of the
Drug Accelerator announced in 2006 [67]; and biotechnology industry.
n The Pathogen Sequencing Unit, part of the £334
million Wellcome Trust Sanger Institute [87]. Hurdles to biotechnology participation
In discussions with biotechnology companies, we found
Academic research institutions have also formed centers a strong desire to tackle the problems of global health.
of excellence and consortiums to target drug discovery for While they must satisfy their obligations to shareholders,
neglected diseases and bolstered their efforts by key hires many industry leaders are inspired by the chance to
from industry [88]. Examples include: make a difference for millions of underserved patients.
n The Tropical Disease Drug Discovery Initiative Biotechnology executives recognize that new models and
at the University of Dundee, focused on new incentives will be instrumental to building the pipe-
trypanosomatids; line for global health.
n The Sandler Center at the University of California
at San Francisco, focused on parasitic diseases; and To engage their companies in the battle against neglected
n The Consortium for Parasitic Drug Development diseases, biotechnology leaders need to address three key
at the University of North Carolina, focused on hurdles (Figure 6.1):
trypanosomatids.
n Information hurdles. They need to become much Managerial hurdles
more familiar with neglected diseases, potential Biotechnology companies are particularly concerned about
markets, and prospective partners; the costs of project management. For a biotechnology
n Managerial hurdles. They need to build expertise in company to manage a neglected disease drug discovery
managing collaborations with prospective partners project on its own, foreseeable tasks include securing
in the not-for-profit and academic sectors; and grant funding, managing staff, linking drug discovery
n Financial hurdles. They need market incentives to invest efforts with a specific target product profile, and coor-
in R&D and overcome “opportunity cost”—the profit dinating with academic and PDP collaborators for capa-
lost by not working on a core business project. bilities not available in-house. Biotechnology company
managers are unlikely to have neglected disease exper-
Information hurdles tise. Assembling expertise internally would distract from
A key challenge for bringing biotechnology resources to their core business. To the extent that neglected disease
bear is identifying opportunities and convening collabora- drug discovery projects can be managed externally, these
tors. Biotechnology companies lack expertise in neglected concerns can be relieved.
diseases, while academic institutions and PDPs lack deep
familiarity with the proprietary tools available in the Financial hurdles
biotechnology industry. Efforts must be made to educate Financial hurdles for biotechnology companies stem from
both sectors and bring these groups together. insufficient market “pull,” lack of excess capital to support
discovery R&D, and the opportunity cost of allocating
BVGH is devoted to bridging this information gap, forming resources to a neglected disease project. Unlike large phar-
coalitions around specific discovery opportunities to build maceutical companies, biotechnology companies are often
the global health product pipeline. Many attractive collabo- cash-constrained and must triage short-term choices in
ration opportunities exist, but they will not happen without favor of the greatest value to their investors. Resources are
diligent efforts to bring decision makers together and illus- often tightly budgeted to support programs that will move
trate how collaborations can serve their interests. 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 Managerial Financial
Hurdle Companies lack access Companies cannot devote Companies require market
to and experience with management time to incentive and funding to
neglected disease science non-core activities overcome opportunity costs
Establish links between External project Appropriate financial

Potential
neglected disease-focused management and champions incentives must be in place
Solution
academic groups and are needed to guide projects
companies through discovery
Match the right companies Intellectual property and

to the right science collaboration templates are
needed

For diseases affecting the developing world, lack of cred- the hundreds of millions of dollars, to develop and market
ible market opportunities and information on viable these products. These companies are not in business to
markets is a significant barrier to entry for innovators. provide research services in return for cost coverage and a
Biotechnology companies’ reliance on pharmaceutical slight profit. More importantly, the cash required for clinical
companies and investors to finance their R&D programs development usually dwarfs what is available through grant
is critically tied to the convincing demonstration of a support. In fact, biotechnology companies are especially
future product’s market viability. In the case of neglected wary of grant cycles at odds with their time requirements for
diseases, the limited purchasing power of developing coun- producing results. For example, many companies estimate
tries and the poor expected return on investment makes that lead optimization requires 10–12 chemists for up to
attracting such private capital or pharmaceutical partners three years and over $10 million to generate a development
particularly difficult. candidate (Figure 6.2). So a grant for lead optimization
lasting only one year would not be long enough for the team
Further, direct support (“push funding”—see below) alone to make progress. Biotechnology companies consider typical
will not lead most companies—particularly the most capable grant cycles (often annual) too short for these projects, so
innovators—to allocate sufficient resources, typically in other, longer-term arrangements are needed.
Figure 6.2: The Costs of Producing a Single New Drug*
Year 1 2 3 4 5 6 7 8 9 10 11
Screening Lead
Lead Optimization Preclinical Phase I Phase II Phase III
Clinical Trials
50
45 43 43
35
Annual Cost in Millions ($)
30
25
20
15 15
12 12
10
5
3.3 3.3 3.3
0.8 0.8 1.5
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
Finally, other costs—particularly opportunity costs— Models for increasing industry engagement
cannot be underestimated. Biotechnology companies in neglected disease drug discovery
operate at capacity, especially with regard to medicinal We explored several different models for overcoming the
chemistry. So there are significant costs to reallocating staff hurdles to industry participation in neglected disease drug
for a neglected disease project. These costs consist of direct discovery: subcontracting to biotechnology companies
labor (e.g., chemist and biologist salaries), indirect over- directly, building partnerships, donor-directed portfolio
head (e.g., allocation of discovery assets), and opportunity management, and establishing a discovery-focused PDP.
cost. For biotechnology companies to engage in neglected
disease drug discovery, a substantial portion of these costs Subcontracting to biotechnology companies
must be addressed by external funding. In selected cases, PDPs have forged new alliances with
biotechnology companies, allowing them access to
Engaging the biotechnology industry advanced drug discovery technologies and compound
It is unlikely that biotechnology companies will over- libraries that exist nowhere else. An example of this
come these hurdles on their own. Their immediate approach is the collaboration launched in 2006 between
economic concerns keep them too focused on devel- the TB Alliance and BG Medicine, Inc., to identify novel
oping drugs for developed-world markets. Only a few tuberculosis biomarkers [91].
dozen of the 1,500 U.S. and European institutionally-
backed biotechnology companies are profitable; none of The advantage of this approach is that PDPs act as “portfolio
the rest has positive cash flow to support even modest managers.” They have a strong command of their diseases
philanthropy. Thus, accessing biotechnology assets for and can offer biotechnology much-needed guidance on TPPs.
global health product development is most likely to be Leadership and program management can remain centered
achieved by new “push” and “pull” financial incentives. on the PDP, minimizing the need for joint development
Push incentives are direct funding to reduce the risk committees or other overarching management structures.
and cost of R&D. Pull incentives enhance the market to
encourage new R&D. The limitation to this approach is that not all PDPs are
set up to take full advantage of discovery technologies in
Examples of push incentives include: industry. In some cases, the formation of drug discovery
n Grants to fund early-stage R&D, including alliances will require a shift in managerial focus. This is
through the U.S. National Institutes for Health or because drug development and drug discovery are very
the UK Medical Research Council. different processes. If PDPs were to seek to integrate
n Tax credits that allow companies to reduce their upstream into discovery, they would need to add manage-
tax liability by deducting R&D expenditures. rial talent with particular experience in managing indus-
trial-scale, small molecule discovery projects.
Examples of pull incentives include:
n Advance Market Commitments that guarantee Building partnerships
markets for new medicines in developing Another model is to form more expansive partnerships
countries [90]. among biotechnology companies, PDPs, and academic
n Transferable “priority” vouchers to speed up institutions. Partnerships can maximally leverage biotech-
regulatory review, provided to companies upon nology expertise, proprietary technology, and infrastruc-
approval of a developing-world vaccine or drug. ture. These partnerships need leadership and operational
n Willingness of donors, PDPs, or pharmaceutical management to leverage the strengths of each participant.
companies to pay a “risk premium” to license new Some discovery efforts can be initiated through biotech-
medicines that have shown proof-of-concept such PDP or biotech-academia collaborations; others will require
as phase II efficacy and safety. the participation of all three.

As an example of how academia, PDPs, and biotechnology The Wellcome Trust also funds translational and product
companies can work together, in 2006, The Broad Institute, discovery work around specific goals and initiatives. WT
MMV, and Genzyme Corporation announced a collaboration is as willing to fund R&D in the private sector as it is in
to target malaria. The Broad Institute contributes genomics academia—what counts is whether the R&D contributes
expertise for understanding malaria disease mechanisms. to the goal. An example of a WT initiative is a set of stra-
MMV brings expertise in malaria drug development. tegic translation awards in Seeding Drug Discovery [93].
Genzyme offers small molecule drug discovery capabilities. This £91 million initiative “to develop drug-like, small
The collaborators have four early-discovery projects and molecules will be the springboard for further research and
hope to attract additional resources and funding [92]. development by the biotechnology and pharmaceutical
industry in areas of unmet medical need.” WT evaluates,
New independently generated partnerships might work negotiates, coordinates, and manages these efforts.
in a similar fashion. The biotechnology company would
rapidly apply its target-based expertise, screening, hit-to- In these two instances, the foundations decided to be direct
lead capabilities, and proprietary compound libraries while investors and coordinators and obtained infrastructure and
taking advantage of the academic center’s disease expertise expert staff for long-term management of their programs.
and biochemical assay systems. The PDP would provide Critically, they have included staff with industry experience
downstream know-how, market knowledge, and access to and did not exclude private companies as grant recipients.
donors, regulatory information, and the global community.
Ownership of compounds, targets, and other intellectual Externally structured, discovery-focused PDPs
property could be shared or reside with the party taking An alternative, with potentially greater flexibility across
the lead in the collaboration. multiple diseases, is for donors to support a discovery-
focused PDP. To deploy tens of millions of dollars of
Donor-directed portfolio management neglected disease drug discovery funding investment each
A third approach is to create management structures year, the community may benefit from funding a PDP-
within donor organizations or to engage independent like organization specialized in working across diseases
portfolio managers funded by donor organizations. Two to form new drug discovery coalitions. This portfolio-
leading examples for donor-directed portfolio manage- management organization would independently source,
ment are the Cystic Fibrosis Foundation Therapeutics, negotiate, and manage partnerships with public and
Inc., (CFFT) and the Wellcome Trust (WT). CFFT private sector participants.
was created by the Cystic Fibrosis Foundation to fund
and manage collaborations with industry to invent and This approach would mirror the R&D structure in several
develop new cystic fibrosis therapeutics. CFFT translates pharmaceutical companies, where R&D programs are
basic research from academia into product discovery and organized vertically by disease, while drug discovery is
development by industry. CFFT identifies opportuni- organized horizontally and tasked with delivering new
ties, performs due diligence, negotiates partnerships, and lead candidates to the development staff across multiple
provides product management. Like its parent foundation, diseases.
CFFT is nonprofit.
Such an approach could be virtual, as adopted by “vertical”
CFFT R&D funding was over $66 million in 2005, much PDPs that focus on a single disease such as MMV and the
of which went into early-stage product discovery. CFFT TB Alliance. Or it could focus on one or more centers of
funds provide sufficient incentive for companies to work excellence with a core group of scientists responsible for
on what is otherwise an “orphan” disease, where the collaborations with biotechnology companies and academia
market is too small to earn a return that competes with and managing key steps in the discovery process for a
disease indications like diabetes or hepatitis C. number of diseases.
A discovery-focused PDP could overcome the key informa- n Drive Science Transfer: An ability to guide the
tion and managerial hurdles preventing the formation of process of transferring academic science into
new discovery partnerships (Figure 6.3). It could provide biotechnology discovery assets will be needed.
dedicated project management essential to coordinating n Invest in Gaps: Research funding is required
efforts involving multiple participants. And it could to overcome gaps in research tools needed for
address the financial hurdles by helping to secure R&D neglected disease drug discovery.
funding and identify potential “hand-offs” to PDPs and
large pharmaceutical companies. Managerial Capabilities:
n Project Champion: The discovery-focused PDP will
Operationally, a discovery-focused PDP will need to need to function as an external project champion
assemble the informational, managerial, and financial to ensure that biotechnology companies give
capabilities and resources needed to establish productive neglected disease drug discovery collaborations
collaborations. appropriate attention.
n Provide Project Management: Duties include
Informational Capabilities: coordinating grant support, managing staff, and
n Convene Leading Academics: Academic experts guiding programs toward target product profiles
will be needed to select drug targets, assay that allow biotechnology companies minimal
technologies, and tools for pathogen manipulation. distraction from their core businesses.
n Identify Industry Collaborators: Deep knowledge of n Manage Timelines: Grant support must be aligned
biotechnology capabilities will be needed to match with realistic timelines for lead identification and
the right companies with the right academic optimization programs instead of the annual grant
science and projects. 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
Coordinate partnerships Provide external project Coordinate hand-offs

between neglected disease management/champions to PDPs or
Hurdles to Address scientists and biotechnology pharmaceutical
companies companies
Provide access to
neglected disease
expertise
Development
Targets Candidates
Product
Academic Science Biotechnology Companies Development
Partnerships

n Coordinate Exits with Other PDPs: Preestablished Financial Capabilities:
exits of development candidates into PDP n Provide Funding: The discovery-focused PDP will
portfolios will ensure that biotechnology resources provide direct financial support to its partnerships.
can continue through development.
n Take Calculated Risks: To fill the pipeline a large Clearly there are substantial challenges to creating such
portfolio of projects is needed. Failing projects an organization. But the advantages are impressive—
must be quickly winnowed to maximize the including independence, focus, ability to work with public
overall probability of success of the portfolio. 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 early-
stage 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 steady-
state 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.
Chapter 7: Conclusions and Recommendations
The biotechnology and pharmaceutical industries have The companies best able to meet the challenges of drug
invested billions of dollars in building small molecule discovery for the three neglected diseases selected for this
drug discovery capabilities. These companies possess report are those that focus on small molecule drugs and
target expertise and compound libraries highly appli- that have advanced novel small molecules into clinical
cable to neglected diseases. Therapeutic R&D for development. Approximately 120 biotechnology compa-
neglected diseases will proceed most effectively by nies—of the many that could contribute to global health—
enlisting the biopharmaceutical industry’s infrastruc- are particularly well matched for these criteria. They have
ture, drug discovery capabilities, and expertise. Engaging discovered and developed some of the most innovative
the biotechnology industry will accelerate the arrival of new small molecule therapies, including ones targeting
better medicines for neglected diseases. HIV and cancer.
Groups in the public sector have succeeded in pushing Key findings from our review of select drug
forward new therapies for neglected disease. Despite their discovery companies
many achievements, an innovation gap remains that limits n Extensive Experience: The companies we examined
the translation of academic discoveries in disease biology in depth have impressive accomplishments
into new medicines. Unless this gap is closed, neglected in launching small molecule drugs and have
disease pipelines will generate far fewer drugs in the long ongoing discovery and development programs
term. Based on experience with antibiotics and anti-virals, and alliances.
we may reasonably expect that drug-resistant pathogens n Existing Infrastructure: Billions of dollars in equity
are going to emerge and thus compromise existing medi- financing have allowed these companies to create
cines. Without more new drugs, many more years will pass infrastructure and expertise in small molecule
before neglected diseases are called neglected no longer drug discovery that would be prohibitively time
and are brought under control. consuming and costly to duplicate.
n Overlapping Targets and Technologies: Target-based
Leading biotechnology companies recognize the tremen- discovery assets are potentially applicable to
dous unmet needs in global health. Many are seeking ways analogous systems in neglected disease pathogens.
to participate that are consistent with their business strate- n Significant Interest: Biotechnology companies are
gies and limited cash resources. They are open to applying interested in participating in neglected disease
their capabilities through R&D collaborations with disease drug discovery to extend the reach of their
experts in PDPs and academia. Such collaborations will technologies, establish relationships with larger
leverage small molecule discovery infrastructure, accelerate companies, and contribute to global health.
innovation, and address the innovation gap in neglected n Obstacles to Participation: Though biotechnology
disease drug discovery most efficiently. companies are interested in participating in global
health campaigns, scientific, managerial, and
especially, financial issues prevent them from
doing so.

Recommendations Among the options:
n Independent consortiums of companies, academic
1. The biotechnology industry’s most capable labs, and PDPs that work together to transform
innovators have an integral role in closing neglected disease drug targets into optimized lead
the innovation gap. Biotechnology companies have compounds and preclinical drug candidates.
track records of employing advanced technologies to create n Direct donor investment in company-led
new therapeutics that have met with success in human programs with accompanying R&D management
clinical trials. This expertise can and should be applied to and monitoring.
neglected diseases. n Creation of a discovery PDP that can serve
as a “portfolio manager” for new neglected
2. New partnerships are needed to lower disease discovery programs with a mission of
barriers for biotechnology companies to augmenting the pipelines of existing PDPs. Such
invest their resources. Most biotechnology compa- an organization could efficiently enlist the most
nies are unfamiliar with neglected diseases. To take advan- experienced innovators; forge partnerships among
tage of their technology platforms, they need to access companies, development-focused PDPs, and
disease expertise and biochemical assays that are resi- academics; and manage and monitor numerous
dent in academia, research institutions, and PDPs. R&D discovery projects.
collaborations are the best way to combine strengths and
increase productivity. Biotechnology companies could contribute substantially
to the discovery and development of new therapeutics for
3. Expanded research funding is needed to neglected diseases. This document provides a road map
build an early-stage pipeline. To produce a new, for enlisting their capabilities in this fight. By employing
approved therapeutic every three to five years for a single existing advanced drug discovery technologies, donor
disease, the minimum investment required for new community funds will be used to maximum effect, novel
discovery R&D is comparable to the annual funding for drugs will be developed faster, and more lives will be saved.
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.
4. Effective investment will depend on dedi-

cated 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 organi-
zation. Dedicated project management to maximize R&D
productivity can be infused into PDPs or donor organiza-
tions, or it can be built as an independent discovery PDP.
References
1. Sachs, J.D., Helping the World’s Poorest, The Economist. 17. Chirac, P., and E. Torreele, Global framework on essential
August 14, 1999. health R&D. Lancet, 2006. 367(9522): p. 1560-1.
2. Cohen, J., Global health. The new world of global health. 18. PhRMA. R&D spending by U.S. Biopharmaceutical
Science, 2006. 311(5758): p. 162-7. Companies Reaches a Record $55.2 Billion in 2006. 2007;
[cited September 5, 2007]; available from: http://www.phrma.
3. Harries, A.D., and C. Dye, Tuberculosis. Ann Trop Med
org/news_room/press_releases/r%26d_spending_by_u.s._
Parasitol, 2006. 100(5-6): p. 415-31.
biopharmaceutical_companies_reaches_a_record_%2455.2_
4. Baird, J.K., Effectiveness of antimalarial drugs. N Engl J billion_in_2006/.
Med, 2005. 352(15): p. 1565-77.
19. Malaria Research & Development Alliance, Malaria Research
5. Fairlamb, A.H., Chemotherapy of human African & Development: An Assessment of Global Investment. 2005.
trypanosomiasis: current and future prospects. Trends Parasitol,
20. Feurer, C., Tuberculosis Research & Development: A Critical
2003. 19(11): p. 488-94.
Analysis, J. Syed, M. Harrington, and B. Huff, Editors. 2006.
6. Centers for Disease Control and Prevention. The Deadly
21. Moran, M., A breakthrough in R&D for neglected diseases:
Intersection between TB and HIV. 1999; [cited September 5,
new ways to get the drugs we need. PLoS Med, 2005. 2(9): p.
2007]; available from: http://www.cdc.gov/hiv/resources/
e302.
factsheets/hivtb.htm.
22. Medicines for Malaria Venture, Product Profiles for
7. Munro, S.A., et al., Patient adherence to tuberculosis
Antimalarial Drugs. 2006. p. 1-8.
treatment: a systematic review of qualitative research. PLoS
Med, 2007. 4(7): p. e238. 23. Nwaka, S., and A. Hudson, Innovative lead discovery
strategies for tropical diseases. Nat Rev Drug Discov, 2006.
8. Gandhi, N.R., et al., Extensively drug-resistant tuberculosis
5(11): p. 941-55.
as a cause of death in patients co-infected with tuberculosis and
HIV in a rural area of South Africa. Lancet, 2006. 368(9547): 24. The Working Group on new TB drugs, Strategic Plan: Stop TB
p. 1575-80. Partnership Working Group on New TB Drugs. 2006.
9. Dorman, S.E., and R.E. Chaisson, From magic bullets back 25. Harper, C., Tuberculosis, a neglected opportunity? Nat Med,
to the magic mountain: the rise of extensively drug-resistant 2007. 13(3): p. 309-12.
tuberculosis. Nat Med, 2007. 13(3): p. 295-8.
26. Casenghi, M., Development of new drugs for TB
10. Pecoul, B., New drugs for neglected diseases: from pipeline chemotherapy: analysis of the current pipeline. 2006, Campaign
to patients. PLoS Med, 2004. 1(1): p. e6. for Access to Essential Medicines: Medecins Sans Frontieres.
11. Pepin, J., and F. Milord, The treatment of human African 27. L.E.K Consulting, 2007.
trypanosomiasis. Adv Parasitol, 1994. 33: p. 1-47.
28. Medicines for Malaria Venture, Annual Reports. 2001-2006.
12. UNICEF/UNDP/World Bank/WHO Special Programme for
29. Drugs for Neglected Diseases Initiative, Report of
Research & Training in Tropical Diseases (TDR), Drug Discovery
Independent Auditors: Financial Statements. 2005.
and Drug Development. March 2004.
30. Global Alliance for TB Drug Development, Annual Report.
13. GAO, New Drug Development: Science, Business, Regulatory,
2005-2006.
and Intellectual Property Issues Cited as Hampering Drug
Development Efforts, U.S.G.A. Office, Editor. 2006. p. 1-52. 31. Ridley, R.G., Medical need, scientific opportunity and the drive
for antimalarial drugs. Nature, 2002. 415(6872): p. 686-93.
14. PhRMA, Drug Discovery and Development: Understanding the
R&D Process. 2007. [cited October 28, 2007]; available from 32. Renslo, A.R., and J.H. McKerrow, Drug discovery and
http://www.phrma.org/files/RD%20Brochure%20022307.pdf. development for neglected parasitic diseases. Nat Chem Biol,
2006. 2(12): p. 701-10.
15. Duyk, G., Attrition and translation. Science, 2003.
302(5645): p. 603-5. 33. Austin, C.P., et al., NIH Molecular Libraries Initiative.
Science, 2004. 306(5699): p. 1138-9.
16. Trouiller, P., et al., Drugs for neglected diseases: a failure
of the market and a public health failure? Trop Med Int Health, 34. Butler, D., Lost in translation. Nature, 2007. 449(7159):
2001. 6(11): p. 945-51. p. 158-9.

35. Stockwell, B.R., Exploring biology with small organic 52. Cole, S.T., et al., Deciphering the biology of Mycobacterium
molecules. Nature, 2004. 432(7019): p. 846-54. tuberculosis from the complete genome sequence. Nature,
1998. 393(6685): p. 537-44.
36. Anonymous, The academic pursuit of screening. Nat Chem
Biol, 2007. 3(8): p. 433. 53. Gardner, M.J., et al., Genome sequence of the human
malaria parasite Plasmodium falciparum. Nature, 2002.
37. Burrill & Company, Biotech 2006: Life Sciences: A Changing
419(6906): p. 498-511.
Prescription. 2006.
54. Berriman, M., et al., The genome of the African trypanosome
38. BIO. Approved Biotechnology Drugs [cited August 22,
Trypanosoma brucei. Science, 2005. 309(5733): p. 416-22.
2007]; available from: http://bio.org/speeches/pubs/er/
approveddrugs.asp. 55. Hall, N., et al., A comprehensive survey of the Plasmodium
life cycle by genomic, transcriptomic, and proteomic analyses.
39. Burrill & Company, Biotech 2007. 2007.
Science, 2005. 307(5706): p. 82-6.
40. Lipinski, C.A., et al., Experimental and computational
56. El-Sayed, N.M., et al., The genome sequence of
approaches to estimate solubility and permeability in drug
Trypanosoma cruzi, etiologic agent of Chagas disease. Science,
discovery and development settings. Adv Drug Deliv Rev, 2001.
2005. 309(5733): p. 409-15.
46(1-3): p. 3-26.
57. Ivens, A.C., et al., The genome of the kinetoplastid parasite,
41. Van Brunt, J., Banner Year for Biotech Drugs. Signals
Leishmania major. Science, 2005. 309(5733): p. 436-42.
Magazine. March 13, 2007.
58. Peacock, C.S., et al., Comparative genomic analysis of three
42. Kneller, R., The origins of new drugs. Nat Biotechnol, 2005.
Leishmania species that cause diverse human disease. Nat
23(5): p. 529-30.
Genet, 2007. 39(7): p. 839-47.
43. Fox, S., et al., High-throughput screening: update on
59. Anonymous. TubercuList [cited September 5, 2007];
practices and success. J Biomol Screen, 2006. 11(7): p. 864-9.
available from: http://genolist.pasteur.fr/TubercuList/.
44. Greenwood, B.M., et al., Malaria. Lancet, 2005.
60. Wellcome Trust Sanger Institute [cited September 4,
365(9469): p. 1487-98.
2007]; available from: http://www.sanger.ac.uk/Projects/
45. Smith, I., Mycobacterium tuberculosis pathogenesis and Pathogens/.
molecular determinants of virulence. Clin Microbiol Rev, 2003.
61. Stoeckert, C.J., Jr., et al., PlasmoDB v5: new looks, new
16(3): p. 463-96.
genomes. Trends Parasitol, 2006. 22(12): p. 543-6.
46. Fevre, E.M., et al., Human African trypanosomiasis:
62. Beverley, S.M., Protozomics: trypanosomatid parasite
Epidemiology and control. Adv Parasitol, 2006. 61: p. 167-221.
genetics comes of age. Nat Rev Genet, 2003. 4(1): p. 11-9.
47. Seed, J.R., African trypanosomiasis research: 100 years
63. Murry, J.P., and E.J. Rubin, New genetic approaches shed
of progress, but questions and problems still remain. Int J
light on TB virulence. Trends Microbiol, 2005. 13(8): p. 366-72.
Parasitol, 2001. 31(5-6): p. 434-42.
64. Ehrt, S., et al., Controlling gene expression in mycobacteria
48. Balu, B., and J.H. Adams, Advancements in transfection
with anhydrotetracycline and Tet repressor. Nucleic Acids Res,
technologies for Plasmodium. Int J Parasitol, 2007. 37(1):
2005. 33(2): p. e21.
p. 1-10.
65. Wirtz, E., et al., A tightly regulated inducible expression
49. Brun, R., and O. Balmer, New developments in human
system for conditional gene knock-outs and dominant-negative
African trypanosomiasis. Curr Opin Infect Dis, 2006. 19(5): p.
genetics in Trypanosoma brucei. Mol Biochem Parasitol, 1999.
415-20.
99(1): p. 89-101.
50. Balganesh, T.S., V. Balasubramanian, and S.A. Kumar, Drug
66. Waters, A.P., Personal communication. 2007.
discovery for tuberculosis: bottlenecks and path forward. Current
Science, 2004. 86(1): p. 167-76. 67. Kaufmann, S.H., and S.K. Parida, Changing funding patterns
in tuberculosis. Nat Med, 2007. 13(3): p. 299-303.
51. Zhang, Y., K. Post-Martens, and S. Denkin, New drug
candidates and therapeutic targets for tuberculosis therapy. 68. Staines, H.M., J.C. Ellory, and K. Chibale, The new
Drug Discov Today, 2006. 11(1-2): p. 21-7. permeability pathways: targets and selective routes for the
development of new antimalarial agents. Comb Chem High
Throughput Screen, 2005. 8(1): p. 81-8.
69. Moreno, A., et al., Plasmodium falciparum-infected mice: 84. Scherr, N., et al., Structural basis for the specific inhibition
more than a tour de force. Trends Parasitol, 2007. 23(6): p. of protein kinase G, a virulence factor of Mycobacterium
254-9. tuberculosis. Proc Natl Acad Sci U S A, 2007. 104(29): p.
12151-6.
70. Gomez, J.E., and J.D. McKinney, M. tuberculosis
persistence, latency, and drug tolerance. Tuberculosis (Edinb), 85. Herrling, P., Experiments in social responsibility. Nature,
2004. 84(1-2): p. 29-44. 2006. 439(7074): p. 267-8.
71. Duncan, K., Progress in TB drug development and what is 86. Bill & Melinda Gates Foundation, Grand Challenges in Global
still needed. Tuberculosis (Edinb), 2003. 83(1-3): p. 201-7. Health Initiative Selects 43 Groundbreaking Research Projects
for More Than $436 Million in Funding. 2005 [cited September
72. Sabry, J., Personal communication. 2007.
13, 2007]; available from: http://www.gatesfoundation.
73. Rosenthal, P.J., Antimalarial drug discovery: old and new org/GlobalHealth/BreakthroughScience/GrandChallenges/
approaches. J Exp Biol, 2003. 206(Pt 21): p. 3735-44. Announcements/Announce-050627.htm.
74. Oberholzer, M., et al., The Trypanosoma brucei cAMP 87. SiliconFen Business Report, TheDirectory. 2006
phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar [cited September 13, 2007]; available from: http://www.
enzymes that are essential for parasite virulence. FASEB J, siliconfenbusiness.com/viewcomp.php?id=123.
2007. 21(3): p. 720-31.
88. McKerrow, J.H., Designing drugs for parasitic diseases of the
75. Yuasa, K., et al., PfPDE1, a novel cGMP-specific developing world. PLoS Med, 2005. 2(8): p. e210.
phosphodiesterase from the human malaria parasite Plasmodium
89. Eli Lilly and Company, Lilly Not-for-Profit Partnership for TB
falciparum. Biochem J, 2005. 392(Pt 1): p. 221-9.
Early Phase Drug Discovery. 2007 [cited October 19, 2007];
76. Ward, P., et al., Protein kinases of the human malaria available from: http://newsroom.lilly.com/ReleaseDetail.
parasite Plasmodium falciparum: the kinome of a divergent cfm?ReleaseID=248931.
eukaryote. BMC Genomics, 2004. 5(1): p. 79.
90. Tremonti, G., Advanced market committments for vaccines:
77. Naula, C., M. Parsons, and J.C. Mottram, Protein kinases as a new tool to fight against disease and poverty, in Report to the
drug targets in trypanosomes and Leishmania. Biochim Biophys G8 Finance Ministers. 2005.
Acta, 2005. 1754(1-2): p. 151-9.
91. BG Medicine, TB Alliance and BG Medicine initiate
78. Waters, N.C., and J.A. Geyer, Cyclin-dependent protein biomarker discovery program. 2006 [cited September 13,
kinases as therapeutic drug targets for antimalarial drug 2007]; available from: http://www.bg-medicine.com/content/
development. Expert Opin Ther Targets, 2003. 7(1): p. 7-17. news-center/news/q/id/23.
79. Woodard, C.L., et al., Evaluation of broad spectrum protein 92. Genzyme. Medicines for Malaria Venture: Genzyme
kinase inhibitors to probe the architecture of the malarial cyclin Corporation and the Broad Institute Expand Collaboration to
dependent protein kinase Pfmrk. Bioorg Med Chem Lett, 2007. Discover New Drugs for Malaria. 2006 [cited October 23,
17(17): p. 4961-6. 2007]; available from: http://www.genzyme.com/corp/media/
HAND_PR.pdf.
80. Tu, X., and C.C. Wang, The involvement of two cdc2-related
kinases (CRKs) in Trypanosoma brucei cell cycle regulation 93. Wellcome Trust. Strategic Translation Awards in Seeding
and the distinctive stage-specific phenotypes caused by CRK3 Drug Discovery. 2007 [cited October 23, 2007]; available from:
depletion. J Biol Chem, 2004. 279(19): p. 20519-28. http://www.wellcome.ac.uk/node2630.html.
81. Hammarton, T.C., J.C. Mottram, and C. Doerig, The cell 94. Hopkins, A.L., M.J. Witty, and S. Nwaka, Mission possible.
cycle of parasitic protozoa: potential for chemotherapeutic Nature, 2007. 449(7159): p. 166-9.
exploitation. Prog Cell Cycle Res, 2003. 5: p. 91-101.
95. DiMasi, J.A., R.W. Hansen, and H.G. Grabowski, The price
82. Ferguson, M.A., Personal communication. 2007. of innovation: new estimates of drug development costs. J Health
Econ, 2003. 22(2): p. 151-85.
83. Walburger, A., et al., Protein kinase G from pathogenic
mycobacteria promotes survival within macrophages. Science,
2004. 304(5678): p. 1800-4.

Appendix I. Why Small Molecule Drug Discovery
Is a Risky Business
As explained earlier in this report, in small molecule drug The screening and design processes yield families of
discovery it is possible to find drugs that can be taken orally compounds related by their structure-activity relationships
and are stable when stored at room temperature. These are (SAR). At this point a team of skilled medicinal chemists
key advantages to include in the next generation of drugs for takes over and synthesizes multiple versions of new but
tuberculosis, malaria, and trypanosomal diseases. related compounds. Biologists evaluate these compounds
for target binding in vitro, providing data that help the
However, discovering a single new small molecule drug chemists sharpen the SAR. Through further rounds of
candidate—whatever the disease—is a notoriously low- refinement, chemists generate compounds with improved
yield process. Thus, many drug discovery projects must performance against the TPP.
be pursued simultaneously to ensure that any new drug
candidates are available for clinical development. In addi- Even with powerful computational algorithms that
tion to assets, infrastructure, and expertise, the multidis- attempt to predict problems with particular compound
ciplinary nature of drug discovery requires time, excellent structures and compound families, iterative cycles of
project management skills, and money. Yet, even if all of synthesis and screening remain today the only viable
these are present in abundance, no single drug discovery method to refine favorable properties and eliminate the
program is guaranteed a compound that will achieve IND undesired ones in search of small molecule drug candi-
status and enter clinical trials. dates for in vivo characterization. It is not uncommon for
drug discovery teams to sift through hundreds or thou-
The process of small molecule sands of compounds in careful in vitro assays—or screen
drug discovery millions in high-throughput mode—to find a very limited
To appreciate why most small molecule discovery efforts number of lead compounds in two or three classes related
fail, it is helpful to understand the small molecule by SAR.
discovery process. Researchers begin with a target product
profile (TPP), a set of minimum characteristics a new drug If oral delivery is crucial to the TPP, as it is for most
must possess to warrant development and use in people. infectious diseases, the degree of difficulty in identifying
Researchers must possess a deep biological understanding lead compounds rises dramatically. The human body has
of the disease. They must also have a protein or macro- multiple layers of defense to resist intrusion by foreign
molecule “target” through which the new drug is expected molecules. The body foils drug developers by a host of
to exert its function. Suitable compound libraries are then protective mechanisms. For example, the body may simply
“screened” through a battery of in vitro assays to identify not absorb the drug from the stomach or gastrointes-
a small number of compounds with some hint of activity tinal tract. Or the body may metabolize the drug rapidly.
against the target. Whether the candidate drugs are first Achieving sufficient and consistent oral bioavailability
identified in vitro by HTS or by structure-based drug is a high hurdle for passage to the next stage. The few
design, any compound advancing as a “lead” candidate compound classes nominated for the in vitro medicinal
must then be co-optimized by subsequent chemical struc- chemistry optimization cycle are now iteratively reopti-
ture modifications for as many as 20 or 30 properties that mized (or more likely, eliminated) by this requirement for
contribute to the TPP. Lead optimization is an extremely an orally bioavailable molecule.
complex process in which failure is far more frequent than
success.
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 subse-
quent clinical development.
The time and manpower required to advance a compound

to candidate status is substantial. HTS and lead identifica-
tion 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.

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
Screening Lead Lead Optimization Preclinical Phase I Phase II Phase III

Clinical Trials
PSAC Antagonists PfSub-1 OZ Next Generation Isoquine Fosmidomycin + Artesunate-Mefloquine
(MMV, Broad Institute, Inhibitor (MMV, Nebraska Univ, Monash (MMV, GSK, Clindamycin (DNDi)
NIH / NIAID) (TDR, Serono) Univ, STI) Liverpool Uni) (Jomaa) Chloroproguanil-dapsone
FAB I 4(1H)-pyridones Back-ups 4(1H)-pyridone Ferroquine (Lapdap™) – Artesunate
(MMV, GSK) (MMV, GSK) (MMV, GSK) (Sanofi-Aventis) (MMV, GSK, WHO/TDR, Liverpool Univ)
Novartis Institute for Falcipains SAR 97276 Pediatric Coartem
Tropical Diseases mini- (MMV, GSK, UCSF) (Sanofi-Aventis) (MMV, Novartis)
portfolio Dihydrofolate Reductase SAR 116242 Dihydro-artemisinin-piperaquine
(MMV, NITD) Inhibitors (Sanofi-Aventis) (MMV, Sigma Tau, Chongqing Holley,
Broad Institute/ (MMV, BIOTEC, LSHTM, Monash Univ) HDAC Inhibitor Holleykin Pharma, Oxford Univ,
Genzyme mini-portfolio (TopoTarget, Mahidol Univ)
Dihydro-orotate inhibitors
(MMV, Broad, Genzyme) (MMV, UT Southwestern, Univ. WHO / TDR) Pyronaridine – Artesunate
PfCDK-1 Inhibitor Washington) Artemisinin (Pyramax®)
(TDR, Serono) (Amyris/iOWH)) (MMV, Univ Iowa, Shin Poong,
WHO/TDR)
PfGSK3 inhibitor
(TDR, Serono) Zithromax + Chloroquine
(Pfizer)
Tuberculosis pipeline

Clinical Trials
Target Identification Multifunctional Nitroimidazole Analogs SQ609 Pyrrole LL-3858 Diarylquinoline Gatifloxacin
and screening Molecules (TB Alliance, Univ of Auckland, (Sequella) (Lupin) TMC207 (OFLTUB Consortium)
(AstraZeneca) (TB Alliance, Cumbre) NITD, NIAID) (Tibotec/Johnson &
FAS 20013 Diamine SQ109
Target Identification InhA Inhibitors Pleuromutilins (FASgene) (Sequella) Johnson)
and screening (TB Alliance, GSK) (TB Alliance, GSK)
Translocase
(Novartis Institute for Quinolones Moxifloxacin
Riminophenazines Inhibitors (TB Alliance, Bayer)
Tropical Disease) (TB Alliance, Institute (TB Alliance, KRICT, Yonsei Univ) (Sankyo, Sequella) PA-824
Malate Synthase of Materia Medica, Dications
BTTTRI)
Non-fluorinated Nitroimidazole
Inhibitors (Univ of Illinois-Chicaco, quinolones (TB Alliance, Chiron,
(GSK, Rockefeller Univ, N-acetyltransferase Immtech) (TaiGen) Novartis)
Texas A&M) inhibitors Bacterial Topoisomerase Nitroimidazole Nitroimidazole
Proteasome Inhibitors (Summit) Inhibitors backup OPC-67683
(Cornell Univ) Thiolactomycin (TB Alliance, GSK) (Otsuka)
(Otsuka)
Protease Inhibitors analogs Focused Screening Oxazolidinones
(Medivir, Queen Mary, (NIAID, NIH) (electron transport inhibitors (Pfizer)
Univ of London)
Nitrofuranylamides and peptide deformylase
Dihydrolipoamide Acyl (NIAID, Univ inhibitors)
transferase Inhibitors Tennessee) (TB Alliance, GSK)
(Cornell Univ/NIAID)
Promazine analogs
(Salisbury Univ)
Cell-wall synthesis
inhibitors
(Colorado State Univ, NIAID)
Human African trypansomiasis pipeline


Clinical Trials
Cysteine Protease Microtubule Nitroimidazoles Nifurtimox-Eflornithine DB 289 Pafuramidine maleate
Inhibitors Inhibitors (DNDi) (DNDi) (Immtech, UNC consortium)
(DNDi/Sandler center) (DNDi)
Trypanothione Novel Nitrohetero-
Reductase Inhibitors cycles
(DNDi/Dundee) (DNDi)
Dihydrofolate Ascofuranone
Reductase Inhibitors (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 Companies
Matt Berriman Wellcome Trust Sanger Institute Achillion Pharmaceuticals
William Bishai Johns Hopkins University Ambit BioSciences
George Cross Rockefeller University Anadys Pharmaceuticals
Kirk Deitsch Weill Medical College of Cornell University Archemix
Joe DeRisi University of California San Francisco AstraZeneca
Alan Fairlamb University of Dundee ChemoCentryx
Mike Ferguson University of Dundee Cytokinetics
David Fidock Columbia University Eisai Research Institute
Dan Goldberg Washington University Exelixis
Keith Gull Oxford University GlaxoSmithKline (Tres Cantos)
Luise Krauth-Siegel University of Heidelberg Infinity Pharmaceuticals
Sanjeev Krishna St. Georges University Kémia
Michelle Larsen Albert Einstein College of Medicine Locus Pharmaceuticals
Pascal Maeser University of Bern Metabasis Therapeutics
Jim McKerrow University of California San Francisco Novartis Institute for Tropical Disease
John McKinney Ecole Polytechnique Fédérale de Lausanne Novocell
Carl Nathan Weill Medical College of Cornell University OSI Pharmaceuticals
Margaret Phillips University of Texas Southwestern Pharmacopeia Drug Discovery
Pradipsinh Rathod University of Washington Plexxikon
David Roos University of Pennsylvania Replidyne
Philip Rosenthal University of California San Francisco SRI International
Eric Rubin Harvard School of Public Health Sunesis Pharmaceuticals
David Russell Cornell University Vertex Pharmaceuticals
James Sacchettini Texas A&M University Vitae Pharmaceuticals
Thomas Seebeck University of Bern
Clive Shiff Johns Hopkins School of Public Health
Christine Sizemore National Institutes of Health
David Sullivan Johns Hopkins School of Public Health
Juliano Timm Rockefeller University
Catherine Vilcheze Albert Einstein College of Medicine
Andy Waters Leiden University
Paul Wyatt University of Dundee

Appendix IV. List of 50 Focus Companies
Company Location Public/Private
1 ACADIA Pharmaceuticals San Diego, CA ACAD

2 Achillion Pharmaceuticals New Haven, CT ACHN
3 Albany Molecular Research Albany, NY AMRI
4 Ambit Biosciences San Diego, CA Private
5 Amphora Discovery Corporation Research Triangle Park, NC Private
6 Anadys Pharmaceuticals San Diego, CA ANDS
7 Arena Pharmaceuticals San Diego, CA ARNA
8 ARIAD Pharmaceuticals Cambridge, MA ARIA
9 ArQule Woburn, MA ARQL
10 Array BioPharma Boulder, CO ARRY
11 Astex Therapeutics Cambridge, UK Private
12 BioCryst Pharmaceuticals Birmingham, AL BCRX
13 Celgene Corporation Summit, NJ CELG
14 Cephalon Philadelphia, PA CEPH
15 ChemoCentryx San Francisco, CA Private
16 CV Therapeutics Palo Alto, CA CVTX
17 Cytokinetics South San Francisco, CA CYTK
18 Eisai Research Institute Andover, MA ESALY
19 Exelixis South San Francisco, CA EXEL
20 Genelabs Technologies Redwood City, CA GNLB
21 Gilead Sciences Foster City, CA GILD
22 Icagen Durham, NC ICGN
23 Immtech Pharmaceuticals Vernon Hills, IL IMM
24 Infinity Pharmaceuticals Cambridge, MA INFI
25 Kalypsys San Diego, CA Private
26 Kémia San Diego, CA Private
27 Kinex Pharmaceuticals Buffalo, NY Private
28 Lexicon Genetics San Diego, CA LEXG
29 Locus Pharmaceuticals Blue Bell, PA Private
30 Metabasis Therapeutics La Jolla, CA MBRX
31 Millennium Pharmaceuticals Cambridge, MA MLNM
32 Neurogen Corporation Branford, CT NRGN
33 Neuromed Pharmaceuticals Vancouver, BC, Canada Private
34 Optimer Pharmaceuticals San Diego, CA Private
35 OSI Pharmaceuticals Melville, NY OSIP
36 Pharmacopeia Drug Discovery Cranbury, NJ PCOP
37 Plexxikon Berkeley, CA Private
38 Renovis South San Francisco, CA RNVS
39 Replidyne Louisville, CO RDYN
40 Rexahn Pharmaceuticals Rockville, MD RXHN
41 Rigel Pharmaceuticals South San Francisco, CA RIGL
42 Sequella Rockville, MD Private
43 Sepracor Marlborough, MA SEPR
44 SRI International Menlo Park, CA Private
45 Sunesis Pharmaceuticals San Francisco, CA SNSS
46 Synta Pharmaceuticals Lexington, MA Private
47 Telik Palo Alto, CA TELK
48 Theravance South San Francisco, CA THRX
49 Vertex Pharmaceuticals Cambridge, MA VRTX
50 Vitae Pharmaceuticals Fort Washington, PA Private
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.

Building Biotech Solutions for Diseases of the Developing World Closing the Global Health
Phone: +1 202-312-9260
Fax: +1 443-320-4430
Innovation Gap
Washington, DC 20005 USA www.bvgh.org

BVGH Therapeutics Innovation Map

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

BVGH Therapeutics Innovation Map

Uploaded by

Copyright:

Available Formats

Closing the Global Health Innovation Gap

BIO Ventures for Global Health

BIO Ventures for Global Health

Copyright© 2007 BIO Ventures for Global Health.

This report was written by Joanna E. Lowell with contributions from

BIO Ventures for Global Health

Design and layout by Bussolati Associates.

List of Tables and Sidebars. . . . . . . . . . . . . . . . . . . . . . . . . 5

Chapter 1: Executive Summary. . . . . . . . . . . . . . . . . . . . . 7

Chapter 3: The Innovation Gap in Discovering

Chapter 4: Harnessing Discovery Resources. . . . . . . . . . . 27

Chapter 5: Mapping Biotechnology

Chapter 6: Building a New Discovery Pipeline. . . . . . . . . 45

Chapter 7: Conclusions and Recommendations. . . . . . . . 52

Appendix I: Why Small Molecule

Appendix II: Snapshots of the Drug Development

Appendix III: Academic and Company Interviewees . . . . 60

Appendix IV: List of 50 Focus Companies . . . . . . . . . . . 61

Figure 4.3: The Financial Strength of the

 Closing the Global Health Innovation Gap

Table 4.1: Summary of 50 Focus Companies . . . . . . . . . . . . . . . . . . 29

Table 4.2: The Assets and Infrastructure

Table 5.1: Drug Targets Favored by Biotechnology

Table 5.2: Validated Targets in Neglected Disease

 Closing the Global Health Innovation Gap

1. The biotechnology industry’s most capable Among the options:

3. Expanded research funding is needed to Biotechnology companies could contribute substantially

4. Effective investment will depend on dedi-

10 Closing the Global Health Innovation Gap

Fortunately, PDPs, research institutes, and a small but

12 Closing the Global Health Innovation Gap

Malaria 46.4 M Resistance Pathogen genome sequenced; genetic

14 Closing the Global Health Innovation Gap

16 Closing the Global Health Innovation Gap

Drug Discovery Drug Development

Product Disease* Development Stage Drug Type PDP Sponsor

Artesunate-mefloquine Malaria Phase III Existing (new combination therapy) MMV

Cholorproguanil-dapsone Malaria Phase III Existing (new combination therapy) MMV

Pyronaridine-artesunate 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

Table 3.3: Biopharmaceutical and Consortium-Based Drugs in Clinical Trials

Product Disease Development Stage Drug Type Sponsor

Ferroquine Malaria Phase II NCE* Sanofi-Aventis

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

*New chemical entity

18 Closing the Global Health Innovation Gap

Necessary Desirable P. falciparum TB HAT

Low capacity to generate resistant organisms

Effective against drug-resistant strains

No cross resistance with other drugs

Short dosing duration

Safe in pregnant women—no adverse effects on fetus

Inexpensive manufacturing to ensure low cost

Stability in tropical climate—no special storage considerations

Efficacy against multiple disease stages

Efficacy against all important species or sub-species of the pathogen

Evaluate for use in combination with other drugs

Pharmacokinetics and dynamics compatible with dosing regimen

Closing the Global Health Innovation Gap

Closing the Global Health Innovation Gap

Examples: • OSI Pharmaceuticals