Closing the Global Health Innovation Gap

Transcription

BIO Ventures for Global Health
1225 Eye Street, NW, Suite 1010
Washington, DC 20005 USA
Phone: +1 202-312-9260
Fax: +1 443-320-4430
www.bvgh.org
Building Biotech Solutions for Diseases of the Developing World
Closing the Global Health
Innovation Gap
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases
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: [email protected]
Web: www.bvgh.org
The full text of this report is also available online at the BVGH website:
http://www.bvgh.org/documents/InnovationMap.pdf
Cover Image by J. Mainquist, courtesy of NIH’s National Human Genome Research Institute.
The Kalypsys suite of ultra-high throughput robotic technologies can screen the biological
activity of more than one million chemical compounds per day.
Design and layout by Bussolati Associates.
Illustrations for Figures 3.4 and 3.6 by Jennifer Fairman.
Contents
List of Select Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . 3
List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
List of Tables and Sidebars. . . . . . . . . . . . . . . . . . . . . . . . . 5
Chapter 1: Executive Summary. . . . . . . . . . . . . . . . . . . . . 7
Chapter 2: Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . 10
Chapter 3: The Innovation Gap in Discovering
New Therapeutics for Neglected Diseases . . . . . . . . . . . . 14
Chapter 4: Harnessing Discovery Resources. . . . . . . . . . . 27
Chapter 5: Mapping Biotechnology
Capabilities to Neglected Diseases . . . . . . . . . . . . . . . . . . 35
Chapter 6: Building a New Discovery Pipeline. . . . . . . . . 45
Chapter 7: Conclusions and Recommendations. . . . . . . . 52
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Appendix I: Why Small Molecule
Drug Discovery Is a Risky Business . . . . . . . . . . . . . . . . . 57
Appendix II: Snapshots of the Drug Development
Pipelines for Malaria, TB, and HAT. . . . . . . . . . . . . . . . . 59
Appendix III: Academic and Company Interviewees . . . . 60
Appendix IV: List of 50 Focus Companies . . . . . . . . . . . 61
About BVGH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Select Abbreviations
ACT. . . . . . . . . . artemisinin-based combination therapy
ADME . . . . . . . . absorption, distribution, metabolism, and excretion
ARV. . . . . . . . . . anti-retroviral
ATP . . . . . . . . . . adenosine triphosphate
BBB . . . . . . . . . . blood-brain barrier
BVGH . . . . . . . . BIO Ventures for Global Health
CRO. . . . . . . . . . contract research organization
DALY. . . . . . . . . disability-adjusted life year
DNDi. . . . . . . . . Drugs for Neglected Diseases Initiative
EMEA. . . . . . . . . European Medicines Agency
FDA. . . . . . . . . . United States Food and Drug Administration
GPCR. . . . . . . . . G protein–coupled receptor
HAT. . . . . . . . . . human African trypanosomiasis
hGH. . . . . . . . . . human growth hormone
HTS. . . . . . . . . . high-throughput screening
IDRI. . . . . . . . . . Infectious Disease Research Institute
iOWH . . . . . . . . Institute for OneWorld Health
IND. . . . . . . . . . investigational new drug
MDGs. . . . . . . . . Millennium Development Goals
MLSCN . . . . . . . Molecular Libraries Screening Center Network
MMV. . . . . . . . . Medicines for Malaria Venture
NCE. . . . . . . . . . new chemical entity
NGO . . . . . . . . . nongovernmental organization
NIH. . . . . . . . . . United States National Institutes of Health
PDE. . . . . . . . . . phosphodiesterase
PDP. . . . . . . . . . product development partnership
R&D. . . . . . . . . . research and development
SAR . . . . . . . . . . structure-activity relationship
SBRI. . . . . . . . . . Seattle Biomedical Research Institute
TB . . . . . . . . . . . tuberculosis
TB Alliance. . . . . Global Alliance for TB Drug Development
TDR. . . . . . . . . . Special Programme for Research and Training in Tropical Diseases
TPP . . . . . . . . . . target product profile
WHO. . . . . . . . . World Health Organization
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Figures
Figure 3.1: Drug Discovery and Development—
the Necessary Prelude to New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 4.4: The Composition and Tasks of
a Drug Discovery Team. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Figure 3.2: Risks and Benefits of Expanding
Use of Existing Drugs Versus the Creation
of New Chemical Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure 4.5: Target Class Focus of 50 Focus Companies. . . . . . . . . 34
Figure 3.3: Attrition Rates and Current
Neglected Disease Pipelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 5.1: Target Validation and Drug
Discovery Tools Available for P. falciparum,
M. tuberculosis, and T. brucei. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Figure 3.4: The Innovation Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 5.2: Target Classes Are Transferable
Across Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Figure 3.5: Annual R&D Spending by
Biotechnology Companies and PDPs. . . . . . . . . . . . . . . . . . . . . . . . . . 23
Figure 5.3: Target Classes Shared by
P. falciparum, M. tuberculosis, and T. brucei. . . . . . . . . . . . . . . . . . . 41
Figure 3.6: Building a Continuum of Players
to Move from Basic Research to Product Registration . . . . . . . . 26
Figure 6.1: Hurdles to the Biotechnology
Industry’s Involvement in Neglected
Disease Drug Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Figure 4.1: The Origins of Small Molecule
Drugs in Clinical Trials (January 2007). . . . . . . . . . . . . . . . . . . . . . . . . 28
Figure 4.2: Biotechnology Companies Can
Be Segmented by Capabilities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Figure 4.3: The Financial Strength of the
50 Focus Companies: Equity Capital Raised . . . . . . . . . . . . . . . . . . . 31
Figure 6.2: The Costs of Producing a Single New Drug. . . . . . . . . 47
Figure 6.3: Possible Roles for a Discovery-Focused PDP . . . . . . . 50
Tables
Sidebars
Table 2.1: initial Assessment of the Need
for New Therapeutics and the Scientific Feasibility
of Creating Them for Key Neglected Diseases. . . . . . . . . . . . . . . . . 13
Sidebar 2.1: List of select global health
product development partnerships (PDPs). . . . . . . . . . . . . . . . . . . . 11
Sidebar 2.2: Examples of new global health products. . . . . . . . . 11
Table 3.1: Malaria, Tuberculosis, and Human African
Trypanosomiasis. Summary of Disease Characteristics,
Pathogen, and Current Standard of Care. . . . . . . . . . . . . . . . . . . . . . 15
Sidebar 4.1: Characteristics of small molecule drugs. . . . . . . . . . 27
Sidebar 4.2: Company selection process . . . . . . . . . . . . . . . . . . . . . . 30
Table 3.2: PDP Drugs Registered or in Clinical Trials . . . . . . . . . . . 18
Sidebar 5.1: The tool kit for modern drug discovery. . . . . . . . . . . 35
Table 3.3: Biopharmaceutical and
Consortium-Based Drugs in Clinical Trials. . . . . . . . . . . . . . . . . . . . . 18
Table 3.4: Target Product Profiles for Uncomplicated
P. falciparum Malaria, Active Pulmonary TB,
and Late-stage HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
Sidebar 5.2: Critical tools for future development. . . . . . . . . . . . . 39
Sidebar 5.3: Harnessing diverse biotechnology solutions . . . . . 44
Sidebar 6.1: Solving the innovation gap for neglected
disease drug discovery: How much will it cost? . . . . . . . . . . . . . . . 51
Table 3.5: Treatment Goals for Malaria, TB, and HAT . . . . . . . . . . 21
Table 4.1: Summary of 50 Focus Companies . . . . . . . . . . . . . . . . . . 29
Table 4.2: The Assets and Infrastructure
Used in Drug Discovery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Table 5.1: Drug Targets Favored by Biotechnology
Companies and the Tools Available to Tackle Them. . . . . . . . . . . 40
Table 5.2: Validated Targets in Neglected Disease
Pathogens for Which the Tools and Expertise
of Biotechnology Companies Might Be Leveraged . . . . . . . . . . . . 42
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Chapter 1: Executive Summary
Ninety percent of the world’s expenditure on medical
care benefits the richest fifth of the world’s population.
Technological breakthroughs fueled by billions of dollars
of investment have transformed health care for the affluent,
yet patients in resource-poor countries cannot afford highquality care. They lack the purchasing power that would
draw investment in new medicines to treat infectious
diseases that are unknown, or long since eradicated, in
wealthy countries.
The devastation caused by these “neglected diseases” has
attracted renewed attention in the past decade, as it’s been
recognized that focused investment and commitment could
yield powerful new vaccines, drugs, and diagnostics based
on the same technologies that have revolutionized health
care for the affluent.
For the first time, several hundred million dollars from
donors such as the Bill & Melinda Gates Foundation are
being invested annually in important research and development (R&D) for diseases such as malaria and tuberculosis.
But relatively little of this investment is devoted to the
discovery of drugs with the potential for providing breakthrough therapeutic benefits. As a result, an innovation gap
is increasingly apparent in the discovery of new medicines
for neglected diseases.
This innovation gap stems from insufficient investment
devoted to early-stage drug discovery, limited public sector
access to key technologies and drug discovery expertise,
and the scarcity of capable innovators devoted to creating
new medicines for neglected diseases.
Today, product development for neglected diseases is
mainly carried out in the public and nonprofit sectors,
with for-profit companies serving as partners and subcontractors in a number of cases. In contrast, the vast majority
of new treatments for diseases with markets in the developed world are created by biotechnology and pharmaceutical companies, which together have the expertise and the
infrastructure to carry discovery and development of products from bench to bedside.
Although biotechnology companies are best known
for developing protein drugs such as human growth
hormone and monoclonal antibodies, they are also now
leading innovators in small molecule drugs—the type
of therapeutic best suited to meet developing-world
needs for oral delivery, thermostability, and affordability.
The challenge is to bring the biotechnology industry’s
discovery assets, know-how, and project management
capabilities—developed over 30 years and with nearly
$400 billion of equity capital—to the fight against
diseases of the developing world.
In this study, BIO Ventures for Global Health (BVGH)
examined the core capabilities of the biotechnology
industry, academia, and the nonprofit entities that focus on
clinical development of new drugs for neglected diseases.
Based on a preliminary assessment that reviewed areas of
significant alignment between biotechnology industry capabilities, basic disease understanding, and unmet medical
need, we focused on three classes of diseases—malaria,
tuberculosis, and trypanosomal diseases (human African
trypanosomiasis, Chagas disease, and leishmaniasis).
Central to our findings is the transferability of the technologies used to address cardiovascular disease, neurological disease, and cancer to the infectious diseases of the
developing world caused by parasites and bacteria. Several
families of proteins that have served as principal targets
for drug discovery for chronic diseases of the industrialized world are also present in infectious pathogens and can
serve as targets for drug discovery. In principle, this means
that biotechnology companies are in an advantageous position to apply their discovery resources and expertise to
neglected diseases.
To narrow the scope of our study, we focused on a
select group of over 120 companies that have capability,
scale, and track records of innovation in small molecule
discovery that could be highly relevant to neglected disease
drug discovery. We further chose to analyze 50 companies
in greater depth, including the originators of more than 20
small molecule drugs now approved by the FDA.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Key findings
Drug discovery for neglected diseases is hindered
by an “innovation gap.”
Despite a revolution in funding for neglected diseases
and the evolution of new R&D partnerships, the current
neglected disease pipeline will not fully address key treatment goals (e.g., substantially shortening the duration of
certain treatments). The investment in product discovery
and “translational” research for neglected diseases remains
a fraction of the level necessary to move promising
discoveries from academic laboratories into commercial
settings—far too little to ensure a steady stream of new
medicines for neglected diseases. Long-term investments
in innovation are needed to build a sustainable pipeline
of drugs that meet the needs of patients and offer hope of
alleviating the suffering from these diseases.
Bringing drug discovery assets built for developedworld diseases to bear on neglected diseases is
scientifically feasible.
For malaria, tuberculosis, and trypanosomal diseases, sufficient scientific tools exist for drug discovery R&D efforts
to be initiated. Importantly, for many human molecular
targets that have received extensive attention from drug
discovery companies, there are analogous targets in
neglected disease pathogens. This means, in particular, that
researchers can employ proprietary compound libraries
used for drug discovery for major diseases for neglected
disease drug discovery.
Biotechnology companies that focus on small
molecule drugs and have taken novel small
molecules into clinical development are well
positioned to address the innovation gap.
Hundreds of biotechnology companies have resources that
could contribute to the fight against neglected diseases.
Many of these are well positioned to take the lead in
developing new drugs, vaccines, or diagnostics to address
these diseases. For example, many proprietary compound
libraries used by biotechnology companies for small molecule drug discovery have been optimized around target
classes that are also relevant to neglected diseases. These
resources and capabilities would be prohibitively expensive
to duplicate in the nonprofit sector. Moreover, biotech-
nology companies have the speed, flexibility, and persistence to take leadership roles in attacking new challenges
to create new products.
Substantial investment in discovery will be
required.
The pharmaceutical industry typically allocates up to 40
percent of its R&D budget to discovery. Using similar
criteria, to build a discovery pipeline that will feed the
existing development infrastructure for diseases such as
tuberculosis and malaria will require substantial additional
investment. We estimate that a sustained investment of at
least $40 million per year for each disease is required to
ensure a pipeline that delivers a new, approved therapeutic
every three years.
Significant hurdles hinder biotechnology industry
involvement.
Three major hurdles have discouraged many biotechnology companies from becoming engaged in global health
product discovery:
n Information hurdles. Companies need to become
much more familiar with neglected diseases,
potential markets, and partners.
n Managerial hurdles. They need to build expertise
in managing collaborations with partners in the
not-for-profit and academic sectors.
n Financial hurdles. They need market incentives to
invest in R&D and overcome “opportunity cost”—
the potential profit lost by not working on a core
business project.
New approaches will be required for effective
investment in discovery.
There is a great need to encourage collaborations between
biotechnology companies with discovery expertise and
academic experts with deep understanding of the target
diseases and sophisticated biochemical and molecular tools
useful in drug discovery. Such partnerships can lower the
barriers to industry involvement. Managerial and financial
hurdles must be overcome to attract biotechnology companies to participate in global health initiatives.
Recommendations
1. The biotechnology industry’s most capable
innovators have an integral role in closing
the innovation gap. Biotechnology companies have
track records of employing advanced technologies to create
new therapeutics that have met with success in human
clinical trials. This expertise can and should be applied to
neglected diseases.
2. New partnerships are needed to lower
barriers for biotechnology companies to
invest their resources. Most biotechnology compa-
nies are unfamiliar with neglected diseases. To take advantage of their technology platforms, they need to access
disease expertise and biochemical assays that are resident
in academia, research institutions, and product development partnerships (PDPs). R&D collaborations are the best
way to combine strengths and increase productivity.
3. Expanded research funding is needed to
build an early-stage pipeline. To produce a new,
approved therapeutic every three to five years for a single
disease, the minimum investment required for new
discovery R&D is comparable to the annual funding for
two small biotechnology companies—increasing over
several years to roughly $40 million per year per disease.
This investment will fund several parallel drug discovery
programs and accommodate attrition at typical industry
rates, while allowing surviving programs to enter preclinical development.
Among the options:
n Independent consortiums of companies, academic
labs, and PDPs that work together to transform
neglected disease drug targets into optimized lead
compounds and preclinical drug candidates.
n Direct donor investment in company-led
programs with accompanying R&D management
and monitoring.
n Creation of a discovery PDP that can serve
as a “portfolio manager” for new neglected
disease discovery programs with a mission of
augmenting the pipelines of existing PDPs. Such
an organization could efficiently enlist the most
experienced innovators; forge partnerships among
companies, development-focused PDPs, and
academics; and manage and monitor numerous
discovery projects.
Biotechnology companies could contribute substantially
to the discovery and development of new therapeutics for
neglected diseases. This document provides a road map
for enlisting their capabilities in this fight. By employing
existing advanced drug discovery technologies, donor
community funds will be used to maximum effect, novel
drugs will be developed faster, and more lives will be saved.
4. Effective investment will depend on dedicated portfolio managers. Many of the current
participants in global health product development lack
deep expertise in managing early-stage drug discovery. The
scope of the partnerships and investments we recommend
call for project management capabilities that would stretch
the current capabilities of any single public sector organization. Dedicated project management to maximize R&D
productivity can be infused into PDPs or donor organizations, or it can be built as an independent discovery PDP.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases Chapter 2: Introduction
The challenge of neglected diseases
Major advances in biotechnology over the last 30 years have
transformed medicine in the industrialized world, but these
innovations have yet to reach the world’s poorest countries,
where 3 billion people live on less than two dollars a day.
Each year more than 10 million people in the developing world die of infectious diseases such as HIV/AIDS,
malaria, tuberculosis, diarrheal diseases, and acute lower
respiratory infections. Millions more suffer from debilitating parasitic diseases, which often incapacitate people
in their most productive years. The burden of infectious illness falls most heavily on children and pregnant
women. In poor countries, the magnitude of suffering
caused by infectious diseases makes economic development nearly impossible [1].
Many of these infectious diseases have earned the label
“neglected”1 because health-care markets in the afflicted
countries are insufficient to attract biopharmaceutical
industry2 investment in research and development (R&D).
Over the past decade, a revolution has occurred in public
sector investment combating infectious diseases of the developing world. Governments, multilateral organizations, and
foundations spend billions of dollars purchasing treatments.
Millions more are invested each year in neglected disease R&D.
Most of the R&D investment devoted to neglected diseases
is deployed through public-private, not-for-profit, product
development partnerships (PDPs). Since 1996, over a
dozen PDP organizations have arisen to tackle the development of new vaccines, drugs, and diagnostics for developing-world diseases (see Sidebar 2.1). In addition, several
research institutes, a few large pharmaceutical companies,
and a handful of biotechnology companies initiated their
own programs, in many cases working with PDPs.
The challenge now is to augment these public and private
sector efforts. What today’s partnerships lack most is
access to the biotechnology industry’s most advanced
technologies and expertise for discovering and developing
new medicines.3
Today’s medicines are insufficient
A fundamental transformation in commitment to solving
global health problems has occurred during the first
decade of the 21st century. In 2000, the United Nations
adopted the Millennium Development Goals (MDGs),
setting forth ambitious health-related objectives: cutting
child mortality by two-thirds, reducing maternal mortality
by three-quarters, and reversing the tide of HIV/AIDS,
malaria, and other major infectious diseases. In response,
governments, foundations, and international nongovernmental organizations (NGOs) in the developed world have
provided billions of dollars to purchase existing vaccines
and drugs for patients in the developing world.
The global health crisis demands a comprehensive and
integrated response that begins with faster delivery of
existing drugs, vaccines, and diagnostics to those most in
need. While programs to ensure access to current medicines can yield substantial benefits, they will not offer
complete solutions. Many of the treatments available today
are decades old and are often limited by problems of drug
resistance, inadequate safety, and efficacy.
For example, current treatments for river blindness
(onchocerciasis) only kill immature parasitic worms in
early stages of infection and are ineffective for advanced
disease. The sole therapy for a major form of human
African trypanosomiasis is marginally effective, requires
intravenous administration, and is so toxic that it can kill
up to 5 percent of patients. No effective vaccine exists for
any disease on the World Health Organization’s Special
Programme for Research and Training in Tropical Diseases
(WHO/TDR) list of neglected diseases (see Footnote 1).
Diagnostics, where they exist, are often impractical for field
use in the developing world.
1 The 10 critical “neglected diseases” as defined by the WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR) are
African trypanosomiasis, Chagas disease, dengue, leishmaniasis, leprosy, lymphatic filariasis, malaria, onchocerciasis (river blindness), schistosomiasis,
and tuberculosis. Other major killers include diarrheal diseases and lower respiratory tract infections. Although HIV disproportionately affects the
developing world, it is not considered a neglected disease because billions of dollars are going into product development for the developed world.
2 For the purpose of this report, the “biopharmaceutical industry” comprises the 20 large, innovative pharmaceutical companies and the biotechnology industry.
3 The term “medicine” is used here to encompass vaccines, drugs, and diagnostics.
10 Closing the Global Health Innovation Gap
Sidebar 2.1: List of select global health product development partnerships (PDPs)
Aeras Global TB Vaccine Foundation (Aeras)
Focus: TB vaccine development
Headquarters: Rockville, MD, USA
Founded: 1997
International AIDS Vaccine Initiative (IAVI)
Focus: HIV vaccine development
Headquarters: New York, NY, USA
Founded: 1996
Drugs for Neglected Diseases Initiative (DNDi)
Focus: Drug development for malaria and trypanosomal diseases
Headquarters: Geneva, Switzerland
Founded: 2003
International Partnership in Microbicides (IPM)
Focus: Microbicide development for HIV prevention
Headquarters: Silver Spring, MD, USA
Founded: 2002
Foundation for Innovative New Diagnostics (FIND)
Focus: Diagnostic development for TB, malaria, and human
African trypanosomiasis
Founded: 2003
Medicines for Malaria Venture (MMV)
Focus: Malaria drug development
Founded: 1999
Global Alliance for TB Drug Development (TB Alliance)
Focus: TB drug development
Headquarters: New York, NY, USA
Founded: 2000
Malaria Vaccine Initiative (MVI)
Focus: Malaria vaccine development
Headquarters: Bethesda, MD, USA
Founded: 1999 as an independent program within PATH
Pediatric Dengue Vaccine Initiative (PDVI)
Focus: Dengue vaccine development
Headquarters: Seoul, Korea
Founded: 2003
Human Hookworm Vaccine Initiative (HHVI)
Focus: Vaccine development for hookworm
Headquarters: Washington, DC, USA
Founded: 2000
Institute for OneWorld Health (iOWH)
Focus: Drug development for visceral leishmaniasis, malaria,
and diarrheal diseases
Headquarters: San Francisco, CA, USA
Founded: 2000
Fortunately, PDPs, research institutes, and a small but
growing cadre of biopharmaceutical companies are
building a growing development pipeline of promising
products to address neglected diseases. The bulk of R&D
investment to date—$1.2 billion as of early 2006—flowed
to treatment and prevention of HIV/AIDS, tuberculosis,
and malaria [2]. The remainder is being devoted to other
viral, bacterial, protozoan, and helminth (worm) infections
where new medicines are desperately needed.
Several PDPs, often through outsourcing and partnering,
have assembled substantial clinical development infrastructures. PDPs also manage sophisticated clinical programs in
multiple developing countries. Their efforts, and those of a
small number of biopharmaceutical companies, are beginning to pay off. New products have succeeded in clinical
trials, and a few have already been registered for sale in
developing countries (Sidebar 2.2). Program for Appropriate Technology in Health (PATH)
Focus: Development of health technologies
Headquarters: Seattle, WA, USA
Founded: 1977
Sidebar 2.2: Examples of new
global health products
l
Paromomycin: A drug to treat visceral leishmaniasis
(Kala-Azar), developed by the Institute for OneWorld
Health (iOWH), registered in India in 2006.
l
Rotarix®: Novel rotavirus vaccine, developed by Avant
Immunotherapeutics and licensed to GlaxoSmithKline
(GSK), approved for use in 90 countries since 2004.
l
Pyramax®: Combination therapy (pyronaridine-artesunate)
for malaria, developed by Medicines for Malaria Venture
(MMV), currently in phase III clinical trials.
l
RTS,S/ASO2A: Malaria vaccine, developed jointly through
the Malaria Vaccine Initiative (MVI) and GSK, has completed
phase II trials.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 11
These products offer important opportunities to improve
standards of care for key neglected diseases, but are just
a start. Continued investment will be required to expand
the pipeline of products that can keep improving care for
neglected diseases. For example, we need:
n a shorter course of TB therapy that works against
drug-resistant microbes;
n a safe and affordable treatment for human African
trypanosomiasis;
n a diagnostic that distinguishes between malaria
and bacteremia in a feverish child;
n a drug that kills adult forms of the many species
of worm, causing such diseases as lymphatic
filariasis, that deform and incapacitate millions
of patients; and
n new vaccines to prevent millions of deaths
each year.
An innovation gap impedes progress
Achieving the most ambitious public health goals for
the treatment and prevention of neglected diseases will
require extensive discovery efforts supported by long-term
funding. Most of today’s global health product pipeline
in therapeutics, however, focuses on products amenable
to rapid clinical development, mainly by repurposing
known drugs for new uses. Finding new uses for existing
drugs makes sense because it speeds development and
makes it possible to reach those in need in the shortest
possible time. Currently, a relatively small portion of the
investment in R&D for neglected diseases is directed to
discovering new chemical entities (NCEs)—that is, novel
compounds with the potential of providing breakthrough
therapeutic benefits.
This report highlights the current innovation gap in the
discovery of new medicines for neglected diseases. The
investments in product discovery and “translational”
research necessary to move promising discoveries from
academic laboratories into commercial settings are at a very
early stage and are insufficient in scale to ensure a steady
stream of new medicines for neglected diseases. Without
increased effort and investment in discovery research,
bringing neglected diseases under control will be delayed
by years, perhaps even decades.
Long-term investments in innovation are needed to build a
sustainable pipeline of drugs meeting the needs of patients
now and into the future. Experience has shown that
returns on pharmaceutical R&D investments are measured
in decades, not years. Moreover, the lesson from all experience with treatments for infectious diseases—whether
it’s antibiotics for streptococcal bacteria or anti-retrovirals
(ARVs) for HIV/AIDS—is that the pathogens eventually
develop resistance to drugs. Researchers must constantly
fight back by inventing new drugs that kill pathogens
through novel mechanisms of action.
Study approach and objectives
BIO Ventures for Global Health (BVGH) undertook this
study to assess whether the biotechnology industry’s
diverse technology platforms and expertise can be applied
to inventing products for neglected diseases and, if so,
how. We focused on opportunities and challenges facing
development of therapeutics for key neglected diseases:
tuberculosis (TB), malaria, and three diseases caused by
trypanosomatids4—human African trypanosomiasis (HAT,
also known as African sleeping sickness), leishmaniasis,
and Chagas disease. For simplicity’s sake, at several points
in this report we use Trypanosoma brucei, the cause of
HAT, to represent all trypanosomatids.
We focused on therapeutics in this report because it
gave us the opportunity to include the largest number of
biopharmaceutical companies. The vast majority of innovative biopharmaceutical companies develop therapeutics; a smaller number focus on vaccines and diagnostics.
Drugs represent the largest segment of global pharmaceutical markets. We selected TB, malaria, and the three
trypanosomal diseases for several reasons: Each is associated with a high disease burden; current treatments have
serious limitations; and each has strong scientific foundations upon which new therapeutic R&D might be based
(see Table 2.1).
We should emphasize that our goal was to be inclusive,
not exclusive. Biopharmaceutical companies can clearly
contribute in many other areas. Future studies can and
should assess biotechnology innovation in other diseases
and interventions, including diagnostics and vaccines.
4 Trypanosomatids are flagellated, parasitic protozoa (single-celled eukaryotic organisms) with complex life cycles during which they alternate
between vertebrate hosts and insect vectors.
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
manipulation possible; primate models
of disease
HAT
1.5 M
Safety, efficacy, resistance, long treatment
time, treatment administration
manipulation facile; animal models
of disease
Chagas Disease
0.7 M
No treatments available for chronic
form of disease
of disease
Leishmaniasis
2.1 M
Safety, administration, and long
treatment time
pathogen genome(s) sequenced; genetic
of disease
*One disability adjusted life year (DALY) is equivalent to one year of healthy life lost.
Source of DALY information: WHO/TDR.
We began our analysis by interviewing academic
researchers focused on TB, malaria, and trypanosomal
diseases (see Appendix III). We aimed to determine the
availability of biological and molecular tools for drug
discovery and identify critical bottlenecks. We then evaluated current product pipelines against international public
health goals and drug target product profiles (TPPs) to
determine where new discovery efforts are required for
each disease.
fill it for each of the diseases we evaluated. Chapter 4
describes the critical role that the biotechnology industry
has played in developed-world drug discovery and the
wealth of biotechnology industry expertise and infrastructure that can be applied to neglected disease drug
discovery. Chapter 5 evaluates the status of the molecular
tools for TB, malaria, and HAT, and it maps biotechnology industry capabilities against drug targets for the
three diseases.
To evaluate whether industry has the capability and relevant tools to address the gaps we identified, we selected
50 leading biotechnology companies from the hundreds
focused on small molecule drug discovery. These companies were chosen for their discovery capabilities in small
molecule therapeutics, the scale of their discovery efforts,
and their track records of bringing NCEs into the clinic.
These are some of the most experienced companies in
small molecule drug discovery today. They are listed in
Appendix IV, and their capabilities are described further
in Chapter 4.
Applying biotechnology to global health will call for new
collaborative models and financial incentives to encourage
industry to take on the risk and cost of product development. This will require vision, new partnerships,
risk-taking, innovative business strategies, and financial
commitment. Chapter 6 explores these issues and proposes
several approaches to investing in new global health R&D.
Chapter 7 outlines our conclusions and recommendations.
This report makes the case that there is a compelling role
for the biopharmaceutical industry in building the global
health product pipeline and shortening the critical R&D
timelines on the way to achieving that goal. Chapter 3
defines the innovation gap and what may be needed to
The obstacles to developing new drugs for neglected
diseases are formidable. But they are not insurmountable.
If the worldwide health-care community can make the
same progress against malaria, tuberculosis, and trypanosomal diseases that it has in the past 20 years against
cancer, diabetes, and cardiovascular disease, we can look
forward to millions of lives saved and a better world for
us all.
Chapter 3: The Innovation Gap in Discovering
New Therapeutics for Neglected Diseases
Creating innovative pharmaceutical products is a
complex process that typically takes 10 to 15 years.
Donor funding and the emergence of product development partnerships has led to an unprecedented number
of late-stage candidate medicines in the pipeline for
neglected diseases. R&D efforts at the drug discovery
stage, however, are insufficient to ensure a continuous
flow of products entering clinical development. This
innovation gap results from insufficient investment,
limited access to key technologies and drug discovery
expertise, and difficulties in assembling the collaborations necessary to transform a laboratory discovery
into an investigational new drug. Failure to address
the innovation gap will impede the creation of the next
generation of treatments for malaria, tuberculosis, and
trypanosomal diseases.
urged. Artemisinin-based combination therapies (ACTs)
have proven especially efficacious. Artemisinin, a structurally complex natural product, is comparatively expensive
to manufacture, which, until recently, precluded the use of
ACTs in many impoverished countries.
New drugs for old diseases
Many of the available medicines for neglected diseases are
outdated, impractical, insufficiently efficacious, or subject
to pathogen resistance and unacceptable toxicities [3-5].
New medicines are urgently needed for tuberculosis, all
diseases caused by protozoan parasites, and many of the
helminth (worm) infections.
First-line treatment for active TB consists of two or four
antibiotic drugs taken in combination for a minimum
of six to nine months. The duration of the regimen,
combined with the medications’ toxicities, causes many
patients to fail to complete the full course of treatment
[7]. This, in turn, has hampered TB control programs and
fueled the proliferation of antibiotic-resistant M. tuberculosis strains. Recently, extensively drug-resistant TB (XDRTB) has entered communities with high HIV prevalence
and is killing people at alarming rates [8, 9].
This study focuses on the need for new drugs for malaria,
tuberculosis, and trypanosomal diseases. Each disease is
summarized below and in Table 3.1, along with the status
and limitations of today’s treatments.
Malaria. More than 40 percent of the world’s population
is at risk for malaria, and up to 500 million people develop
the disease each year. Malaria results from infections by
parasitic protozoa from the genus Plasmodium. Young
children and pregnant women, especially those living in
sub-Saharan Africa where the more virulent Plasmodium
falciparum parasite is dominant, are most vulnerable to
malaria and account for the majority of the 1 million
deaths estimated to occur annually.
Commonly used antimalarials are increasingly ineffective due to widespread drug resistance. To combat the
emergence of resistance to the drugs remaining in the
antimalarial arsenal, use of combination therapies has been
Tuberculosis. One-third of the global population—more
than 2 billion people—harbors a latent or asymptomatic
infection by Mycobacterium tuberculosis, the bacterium
causing tuberculosis (TB). About 10 percent of those
infected will develop active TB at some point during their
lifetime, translating into nearly 9 million cases of active
disease and more than 2 million deaths annually. In immunocompromised populations, such as those with HIV, rates
of active TB are extremely high. Worldwide, TB is now the
leading cause of death among AIDS patients [6].
Trypanosomal diseases. Three major classes of
trypanosomal diseases affect humans: human African
trypanosomiasis (HAT), Chagas disease, and leishmaniasis.
n HAT (also referred to as African sleeping sickness)
is found only in sub-Saharan Africa, where 60
million people are at risk for the disease. Each
year, there are up to 300,000 cases, resulting in
nearly 50,000 deaths.
n Chagas disease is endemic in rural areas in South
and Central America, placing an estimated 25
million at risk. In total, as many as 9 million
people may be infected with the Chagas parasite.
Annually, 14,000 deaths result from Chagas
cardiomyopathy associated with the chronic form
of the disease and often occurring 10 to 20 years
after initial infection.
Table 3.1: Malaria, Tuberculosis, and Human African Trypanosomiasis: Summary Of Disease Characteristics,
Pathogen, and Current Standard of Care
Disease
Malaria
A parasitic disease transmitted
by Anopheles mosquitoes.
Malaria is categorized as either
uncomplicated (fever, chills,
body aches, nausea, headache,
vomiting, and diarrhea) or severe
(anemia, acute respiratory distress
syndrome, coma, and death).
Deaths
per Year
> 1 million
Epidemiology Pathogen
Cases Population Other
per Year
at Risk
300-500
40% of global Children and Plasmodium
million
population
pregnant
species;
women
P. falciparum
are most
is the most
susceptible
deadly
Current Standard of Care
(launch year): Limitations
Chloroquine (1945): resistance
Primaquine (1948): safety
Fansidar (1961): resistance
Mefloquine (1984): resistance, safety
Artemisinin (1994): cost, compliance,
Good Manufacturing Practice
Atovaquone/proguanil (1999): cost
TB
A bacterial disease that most
commonly affects the lungs. In
otherwise healthy individuals,
most infections are latent and
asymptomatic. About 10% of those
infected develop active pulmonary
disease; symptoms include a cough
lasting more than two weeks,
coughing up blood, fatigue, fever,
chills, night sweats, and weight and
appetite loss.
2 million
HAT
A parasitic disease transmitted
by tsetse flies. HAT progresses
from fever and fatigue (early-stage
disease) to severe neurological
conditions (late-stage or chronic
disease). Untreated HAT is fatal.
50,000
9 million
(active TB)
Immuno- Mycobacterium
Pandemic;
2 billion are compromised tuberculosis
infected with populations
are at
latent TB.
highest risk
All first-line treatments have issues
concerning resistance, toxicity, and
treatment length (6-9 months):
Rifampicin (1963)
Ethambutol (1962)
Streptomycin (1955)
Pyrazinamide (1954)
Isoniazid (1952)
Up to
300,000
60 million;
(sub-Saharan
Africa)
Trypanosoma
brucei
(subspecies
gambiense
and
rhodesiense)
Pentamidine (1941): lacks oral formulation,
side effects, early-stage specific, most
effective against T. b. gambiense
Suramin (1921): lacks oral formulation,
side effects, early-stage specific, first-line
treatment against T. b. rhodesiense
Melarsoprol (1949): toxicity, resistance
Eflornithine (1980): toxicity, administration,
spectrum of activity, supply, cost, only
effective against T. b. gambiense
Chagas disease
A parasitic disease that over time
causes damage to the nervous
system, digestive tract, and the
heart. The disease is contracted via
the feces of an infected Reduviid bug.
14,000
Leishmaniasis
A collection of parasitic diseases
transmitted by the Phlebotomine
sandfly that affects the skin,
mucosa, or internal organs,
resulting in severe disfigurement,
disability or death.
>50,000
750,000
8-9 million Trypanosoma
25 million;
are currently
cruzi
(Latin
infected
America and
Caribbean)
Chronic disease - no treatments available
Acute disease Nifurtimox (1960): resistance, safety,
efficacy
Benznidazole (1970s): resistance, safety,
efficacy
1.5-2 million
350 million
12 million ~20 Leishmania Visceral leishmaniasis:
species
are currently
Miltefosine (2003): safety
infected
Paromomycin (2006): delivery
Pentosam (1944), Amphotericin B (1950s),
Ketoconazole (1980s), Pentamidine (1941),
and antimony-containing compounds:
resistance, efficacy
Sources: WHO/TDR and Hotez, P.J., et al., Control of neglected tropical diseases. N Engl J Med, 2007. 357(10): p. 1018-27.
n
Leishmaniasis is a collection of diseases; there
are cutaneous, mucosal, and visceral forms.
Worldwide, about 350 million people are at risk
for leishmaniasis. Cutaneous and mucosal forms
cause severe disfigurement and disability. The
visceral form is fatal if untreated. An estimated 12
million people are infected with leishmania, and
each year there are over 50,000 deaths.
HAT, Chagas disease, and all forms of leishmaniasis are
caused by divergent species of single-celled protozoa called
trypanosomatids. These pathogens share many unusual
molecular and biochemical pathways, but their infectious
cycles and target tissues for infection are very different.
While there is precedent that a treatment designed for one
pathogen may have efficacy toward another [5, 10], it is
likely that drug discovery and development will mostly
proceed independently for different species. For simplicity’s
sake, at several points in this report we use Trypanosoma
brucei, the cause of HAT, to represent the entire class.
Problems associated with existing drugs for trypanosomal
diseases include lack of efficacy, drug resistance, long
treatment duration, availability, expense, and safety. For
instance, melarsoprol, the only treatment for HAT caused
by one subspecies of T. brucei, is so toxic that it kills up
to 5 percent of those who receive it [11]. There are no
drugs to treat the chronic form of Chagas disease. Visceral
leishmaniasis treated with paromomycin requires 21 days
of injections. An orally available alternative, miltefosine, is
unsafe for pregnant women.
The drug development process
To understand the serious challenges presented by
today’s global health drug pipeline, we must first understand the process of creating a new drug. More complex
and time-consuming than nearly any other commercial
endeavor, pharmaceutical R&D requires technological
and scientific expertise, teamwork, leadership, risk-taking,
time—and most of all, money. The steps of the process
are commonly broken into three phases: basic research
that establishes biological knowledge of disease causality
and creates tools for R&D; discovery, the innovative steps
by which new therapeutic compounds are identified and
evaluated; and development, or testing first in animals
of small numbers of compounds winnowed from the
discovery steps, leading to a single, promising candidate
compound to evaluate for therapeutic efficacy and safety
in human clinical trials.
Basic research refers to the scientific exploration of disease
and, in the case of infectious diseases, the pathogens that
cause them. The goal of most basic research is to develop
a molecular, genetic, and biochemical understanding of
disease pathology in the hope that this knowledge will
lead to treatments and cures. Developing this knowledge
requires an extensive set of tools for research. The process
of inventing research tools is in itself another component
of basic research.
Drug discovery refers to the earliest stages of generating
an actual product. It begins with the difficult process of
translating findings from basic research into candidate
molecules with the potential to treat disease. Researchers
organize their work around a target product profile
(TPP), essentially a list of minimum characteristics a drug
must possess to warrant development and use in people.
“Small molecule” drug discovery is a chemistry-intensive
process in which a library of thousands or even millions
of compounds is screened for molecules with druglike activity potentially meeting TPP requirements. The
compounds identified by screening, often called “hits,” are
then refined for other essential drug-like properties into
“leads.” A lead is a compound that interacts with acceptable potency and selectivity with a cellular “target” macromolecule such as a protein.
For an infectious disease, the target is usually a macromolecule belonging to the pathogen, and ideally the
interaction between the drug and its target kills the
pathogen and cures the disease. In an iterative process,
lead compounds are optimized and retested for improved
activity, specificity, potency, and safety. A more detailed
discussion of the intricacies of the small molecule drug
discovery process is presented in Appendix I. There is no
hard-and-fast point where the iterative process of drug
discovery ends.
Drug development is most simply defined as the point at
which an optimized lead compound with good efficacy
in animal models and acceptable toxicity and pharmacokinetic5 properties is selected for preclinical evaluation
[12]. Once a “preclinical candidate” has been chosen, it
must pass a rigorous series of tests designed to ensure
safety in animals and provide persuasive indications
of efficacy. With a successful preclinical compound in
hand, researchers may then apply to the U.S. Food and
Drug Administration (FDA) for investigational new drug
(IND) status, which permits the compound to be tested
in humans. The IND candidate’s safety, dosing, and efficacy in humans are then established by clinical trials.
Products with demonstrated efficacy and safety in humans
5 “Pharmacokinetics” refers to the study of how an externally administered agent behaves in animals or humans—“what the body does to a drug.”
Routinely examined pharmacokinetic properties of a drug are its absorption, distribution, metabolism, excretion, and toxicological properties
(ADME/Tox).
Figure 3.1: Drug Discovery and Development—the Necessary Prelude to New Drugs
Drug Development
Drug Discovery
Screening
for Hits
Lead
Identification
3-6 years
Lead Optimization
Preclinical
Phase I
Clinical
1 year
are approved by regulatory authorities such as the FDA or
European Medicines Agency (EMEA) and registered in the
countries in which they will be sold.
Together, projects in discovery and development make
up the product “pipeline.” As illustrated in Figure 3.1,
the process of discovering and developing drugs requires
an average of 10–15 years [13, 14]. Although the failure
rate is greatest at the earliest stages of discovery, products can fail at any point. Indeed, high rates of attrition
partially explain why the process of inventing a drug takes
so long. According to the Pharmaceutical Research and
Manufacturers of America (PhRMA), for every 5,000–10,000
compounds that enter the pipeline, only one becomes a
registered product [14]. Thus, because of attrition, the vast
majority of compounds that enter drug discovery and development will never progress to success in clinical trials [15].
New players build the therapeutics
pipeline for neglected diseases
From 1975 to 2004, out of 1,556 new drugs approved by
the FDA, EMEA, and other government authorities, only 21
were registered for tuberculosis, malaria, and other neglected
diseases [16, 17]. This oft-cited statistic reflects the lack
of incentives for biopharmaceutical companies to invest in
products for which there are insufficient paying markets.
In 2006 alone, U.S. pharmaceutical and biotechnology
companies invested over $55 billion of their own resources
to invent medicines for diseases of the developed world
[18]. Yet, they directed only a fraction of that sum—we
estimate based on two recent studies less than $100
million—for R&D aimed at two of the world’s biggest
killers, malaria and tuberculosis [19, 20].
To remedy this imbalance, over the past decade new public
sector R&D efforts have arisen to build a pipeline of new
products for neglected diseases, with over $1.2 billion of
Phase II
Phase III
Registration
Trials
6-7 years
1 year
investment since 1999 [2]. Although certain large pharmaceutical companies, academic centers, and biotechnology
companies have begun to participate, the driving forces for
therapeutic R&D in global health have been PDPs [21].
PDPs are not-for-profit organizations funded and championed
by the donor community6 to develop novel vaccines, drugs,
and diagnostics for specific neglected diseases. Like many forprofit biopharmaceutical companies, PDPs drive preclinical
and clinical development of new product portfolios, picking
and choosing which products to advance through the pipeline, including which to launch or terminate. In contrast to
for-profit companies, many PDPs are “virtual” organizations
with comparatively small staffs and no laboratories of their
own. Most, if not all, of the projects in their portfolios are
carried out by partners, including researchers in academic
institutions, contract research organizations (CROs), and
large pharmaceutical companies. The larger PDPs oversee
and coordinate projects occurring all over the globe.
Four leading PDPs focus on therapeutics for malaria, TB,
and trypanosomal diseases:
n The Medicines for Malaria Venture (MMV)
promotes new antimalarials.
n The Global Alliance for TB Drug Development (TB
Alliance) focuses exclusively on drug development
for tuberculosis.
n The Drugs for Neglected Disease Initiative (DNDi)
creates new drugs to treat trypanosomal diseases
and malaria.
n The Institute for OneWorld Health (iOWH)
concentrates on leishmaniasis, malaria, and
diarrheal diseases.
All four are mostly virtual and work extensively with
nonprofit and for-profit partners to conduct discovery and
development. By supporting PDPs, donors have created
centers of expertise for each disease area.
6 We use the term “donor community” to refer to governments, nonprofit organizations, and foundations.
Table 3.2: PDP Drugs Registered or in Clinical Trials
Product
Disease*
Development Stage
Drug Type
PDP Sponsor
Paromomycin
Visceral leishmaniasis Registered in 2006 (India)
Phase III (East Africa)
Existing (new use)
iOWH
DNDi
Artesunate-amodiaquine
Malaria
Registered in 2007 (Morocco) Existing (new combination therapy)
DNDi
Artesunate-mefloquine
Malaria
Phase III
Existing (new combination therapy)
MMV
Cholorproguanil-dapsone
(Lapdap™)-artesunate
Malaria
Phase III
MMV
Coartem® dispersible tablet
Malaria
Phase III
New formulation of existing combination therapy MMV
Dihydroartemisinin-piperaquine Malaria
Phase III
MMV
Pyronaridine-artesunate
(Pyramax®)
Malaria
Phase III
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
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
Pfizer
Ferroquine
Malaria
Phase II
NCE*
Sanofi-Aventis
Fosmidomycin-clindamycin
Malaria
Phase II
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
drug pipelines
Eager to show early results in bringing new treatments
to afflicted populations, PDPs initially focused on testing
existing drugs registered for other diseases against the
target pathogens. These efforts have borne fruit, with two
products launched (paromomycin and artesunate-amodiaquine) and eight additional products in clinical trials
(Table 3.2). Through the efforts of industry and various
consortiums, several other promising compounds or
combination therapies are also in clinical trials (Table 3.3).
A snapshot of the current therapeutic pipelines for malaria,
TB, and HAT is presented in Appendix II.
Products in neglected disease drug pipelines can
be divided into
n existing drugs being evaluated for new
indications,
n drugs in new formulations,
n novel fixed-dose combinations, or
n new chemical entities (NCEs).
Tables 3.2 and 3.3 show these classifications for products
currently in clinical trials.
Figure 3.2 compares risks and benefits of expanding uses
for existing drugs versus creating NCEs. A key advantage
of using existing drugs is that often they have extensive
records of safety in humans and do not require years
and millions of dollars to establish safety in treating
neglected diseases. NCEs, on the other hand, are much
riskier to invent than expanding the use of existing
drugs. But with risks come benefits. NCEs targeted for
potency, specificity, and lack of toxicity have greater
potential to provide breakthrough therapeutic benefits
within a wide safety margin. Thus, in the long run,
substantial improvement over existing treatments will
require discovering NCEs.
Figure 3.2: Risks and Benefits of Expanding Use of Existing Drugs Versus the Creation of New Chemical Entities
Requirements for effective drugs
for neglected diseases
Any new drug emerging from the pipeline for neglected
diseases must be safe, inexpensive to manufacture, practical to administer, stable in harsh climates, potent against
resistant strains, and effective within time frames comparable to or better than existing products. In addition,
as illustrated in Table 3.4, each disease has a specific,
minimum TPP that a new product must meet [22, 23].
The World Health Organization (WHO), via the Stop TB
partnership and TDR, has drawn together the views of
leading scientists in global health into a set of ambitious
goals for discovering new treatments for tuberculosis,
malaria, HAT, and other neglected diseases [12, 24]. Table
3.5 summarizes these goals. New medicines that fulfill
these objectives might halt and even reverse the spread of
these diseases.
Table 3.4: Target Product Profiles for Uncomplicated P. falciparum Malaria, Active Pulmonary TB, and Late-stage HAT
Necessary
Desirable
P. falciparum
malaria
TB
Resistance
Low capacity to generate resistant organisms
Effective against drug-resistant strains
No cross resistance with other drugs
Dosing
Oral formulation
Short dosing duration
Fast acting
Pediatric formulation
Safety
Safe/low toxicity
Safe in pregnant women—no adverse effects on fetus
Manufacturing
Inexpensive manufacturing to ensure low cost
Stability in tropical climate—no special storage considerations
Broad Spectrum
Efficacy against multiple disease stages
Efficacy against all important species or sub-species of the pathogen
Combination Use
Evaluate for use in combination with other drugs
Pharmacokinetics and dynamics compatible with dosing regimen
No adverse interactions with anti-retrovirals (ARVs)
Other
Ability to cross blood-brain barrier
Sources: DNDi, MMV, TB Alliance, and Nwaka, S., and A. Hudson, Innovative lead discovery strategies for tropical diseases.
Nat Rev Drug Discov, 2006. 5(11): p. 941-55.
HAT
Table 3.5: Treatment Goals for Malaria, TB, and HAT
Disease
Goal
Ability of drugs in development to meet goal
Malaria
Single-dose curative treatment
Goal unlikely to be met
TB
Reduce treatment time to 2 months or less
Shorten therapy of latent disease
Unknown
Efficacy against all stages of disease and all subspecies
HAT
Sources: WHO/TDR, DNDi, MMV, TB Alliance, and Stop TB Partnership
The activity and safety of the drugs now in development
will be fully apparent only upon completion of clinical
trials. But it is clear already that these drugs will not meet
some of the ambitious goals in Table 3.5, such as shortening the duration of TB treatment to two months or less
[25], reducing malaria treatment to a single, curative dose,
and developing a treatment effective against all stages of
HAT. For these advances, a new generation of therapeutics
will be required.
An innovation gap impedes creation
of the next generation of drugs
As the current generation of drug candidates advances
toward clinical success and registration, or toward clinical
failure and abandonment, a new generation of drug candidates must follow that offers the promise of achieving more
ambitious goals. Similar to drug development for cancer
and diabetes, neglected disease drug development pipelines require “high-quality” discovery programs7 backed
by substantial, sustained investment as occurs when the
biopharmaceutical industry tackles diseases such as cancer
or diabetes.
For instance, a major biopharmaceutical company intent
on developing a new oral treatment for a chronic disease
market such as heart disease would explore 10 to 20
targets generated by genomics and biochemistry, and
advance five to 10 targets in parallel into high-throughput
screening. Each project would initially screen thousands
to millions of compounds. Most of these projects will
fail because of myriad interrelated reasons: for example,
inability to express the target protein and develop an assay,
lack of credible screening hits, failure to optimize efficacy
versus toxicity, lack of oral bioavailability, and failure in
animal proof-of-concept models. Project failure rates before
identifying an IND candidate are routinely over 75 percent.
Subsequent attrition due to clinical failures, safety concerns,
and market forces reduces the success rate to less than 5
percent, sometimes only 1 to 2 percent. Thus, a credible
effort to develop a new drug in the biopharmaceutical industry
requires substantial numbers of discovery projects—enough to
ensure that a product with the desired TPP will emerge from
the pipeline.
The pipeline of clinical-stage programs for malaria, TB,
and HAT is expected to yield several new products in
the next few years [21]. However, as Figure 3.3 shows,
a major disparity exists between early-stage pipelines of
these diseases and the profile of a typical industry-driven
program for a disease with an established market. For
instance, our analysis found that there are five, six, and
one discovery projects in the lead optimization stage
for malaria, TB, and HAT, respectively. Assuming that
the average industry project failure rates will also apply
to neglected disease projects, these numbers are far shy
of the 20 projects typically required to yield a single
new drug. Indeed, for all of the neglected diseases we
examined, none has a drug discovery effort sufficient to
ensure that the next generation of candidate compounds
will be ready to enter clinical development in the coming
years. This observation has also been noted by others
[26]. This deficiency, or innovation gap, restricts the
flow of new, approved medicines for neglected diseases
(Figure 3.4).
7 A high-quality program is defined as having the following characteristics: 1) a solid molecular target associated with disease pathology, validated
by genomics, molecular biology, cellular systems, and animal pharmacology; 2) a druggable target—one where a small molecule drug would exert
a positive therapeutic effect; 3) creating new compositions-of-matter that have the desired effect or improve upon known compounds, with low or
no side effects; 4) the ability to manufacture the drug at reasonable cost for desired benefit; 5) the ability to get a clear clinical answer in a defined
population quickly; and 6) a clearly defined path to regulatory approval.
Figure 3.3: Attrition Rates and Current Neglected Disease Pipelines
100.0
100
Out of 100 programs entering the
screening phase of discovery, on
average 1.3 drugs will successfully
reach the market 12–14 years later
Number of Programs Entering Each Phase
of Drug Discovery and Development
90
Expected program
survival rate
Malaria
80
TB
70
Innovation Gap
HAT
60
50
40
30.0
30
19.5
20
10.7
10
Phase
0
Screening
for Hits
Lead
Identification
Lead
Optimization
Preclinical
5.8
4.0
Phase I
Phase II
1.9
Phase III
1.3
Registration
Sources : MMV, DNDi, TB Alliance, PharmaProjects, and BVGH/L.E.K. analysis
Figure 3.4: The Innovation Gap
Developed World Disease Drug Development
Neglected Disease Drug Development
Thousands of Potential Gene Targets
Thousands of Potential Gene Targets
Hundreds of Validated Targets
Dozens of Validated Targets
Tens of Chemical Leads
Few Chemical Leads
8 - 10 Preclinical Candidates
Few Preclinical
Candidates
5 Clinical Candidates
Limited
Clinical
Candidates
1 Approved
Drug
Novel Drugs
Rarely Approved
1.3
Approved
Insufficient investment in discovery
The cost of clinical development is high—estimated in the
hundreds of millions of dollars for the cumulative successes
and failures required to bring a single new drug to market
in the developed world. The discovery stage of this process
also requires substantial investments of time and money to
n create an initial population of biologically active
molecules;
n optimize them through multiple iterations of
medicinal chemistry and pharmacologic assays; and
n select a small number for further development.
Industry studies show that innovative pharmaceutical and
large biotechnology companies typically spend between 35
and 40 percent of their R&D budget on discovery [27].
The need for this level of investment stems from the difficulties of finding a compound that meets all the pharmacologic criteria required for proceeding into development.
Typically, thousands of compounds are intensely evaluated
for two to four years before a clinical candidate is selected.
Indeed, most discovery programs fail before an IND
application can be filed to initiate clinical trials. It is not
an exaggeration to say that the likelihood that any single
compound will reach the clinic is vanishingly small.
By contrast, PDPs have focused smaller proportions of
their R&D investments on drug discovery, although they
recognize the need to build sustainable pipelines and have
continually supported work on new compounds. Based on
publicly available information [28-30], these partnerships
have only been able to devote between 15 and 30 percent
of their funds to discovery, with MMV and the TB Alliance
putting the greatest investments into discovery. PDPs have
increased their discovery program productivity by partnering
with large pharmaceutical companies that make matching
in-kind contributions of manpower and resources.
While the upper limits of the proportion of their R&D
investments devoted to drug discovery is similar, the
absolute level of PDP investment in drug discovery is low
compared with commercial discovery efforts. Depending
on the size of the discovery team, drug discovery companies typically spend between $2 million and $4 million per
year per preclinical lead optimization project [27]. Even if
a hypothetical PDP had a $50 million budget, 30 percent
still represents only $15 million, which will support a
pipeline of only three to six early-stage projects to advance
lead compounds to IND candidate stage. Current PDP
investments are far less than this.
Among the biotechnology companies we examined for
this report, “discovery-only” and “early-development”
companies8 spend a median of $20.9 million and $30.8
million per year, respectively, on research that does not
include clinical trial activities. This is substantially more
than the hypothetical PDP defined previously (Figure 3.5).
Companies typically view their levels of investment as the
minimum to maintain a discovery team and generate an
IND drug candidate at least every other year.
Figure 3.5: Annual R&D Spending by Biotechnology
Companies and PDPs
Median Annual R&D Spending
35
30
Millions of Dollars
Causes of the innovation gap
The innovation gap results from insufficient investment
devoted to early-stage drug discovery, limited access to key
technologies and drug discovery expertise, and difficulties
in assembling the collaborations necessary to transform a
laboratory discovery into an IND. We explore these problems in detail below.
25
20
15
5
0
arly-Development
E
Company
Discovery-Only
Company
Hypothetical PDP
Sources: Company SEC Filings and BVGH/L.E.K analysis
8 Discovery-only companies are defined as those capable of screening for hits and generating leads and optimized lead compounds. Few carry out
preclinical work except on a contract basis. Early-development companies possess comparable capabilities to discovery-only companies, but they can
also carry out preclinical work and phase I clinical trials.
Access to technology and expertise and limited
scale of operations
The technological platforms, assets, and expertise necessary to transform biological findings into NCEs are well
established (see Chapter 4). Biotechnology and pharmaceutical companies engaged in drug discovery have
purchased or synthesized large compound libraries. They
have assembled capabilities in advanced technologies such
as high-throughput screening, X-ray crystallography, and
computational modeling. They have teams of scientists
with expertise in assay development, medicinal chemistry,
and pharmacology.
Academic centers and individual investigators carrying
out neglected disease research have identified compelling
new targets for therapeutic intervention [26, 31, 32].
For the most part, however, they lack the tools available
to industry to extend their research into drug discovery.
Even with the advent of academic- and government-based
high-throughput drug screening (HTS) initiatives such as
the NIH Roadmap for Medical Research [33], advances
in neglected disease biology are not adequately matched
with the tools and expertise that lead to the discovery of
NCEs [34].
In interviews with academic leaders in malaria, tuberculosis, and trypanosomal diseases (for list, see Appendix
III), we found they face three key obstacles in progressing
beyond generating hits through small molecule screening:
first, limited access to the most advanced drug discovery
technology and compound libraries; second, lack of drug
discovery experience and expertise; and third, insufficient
scale of operations.
Limited access to the best compound libraries
Compound libraries are collections of organic chemicals
assembled by purchase or custom synthesis for repeated
screening in multiple biological assays. An industrial
compound library is organized around a biological target
class, drug-like properties, or chemical structural diversity.
A company’s organized, selected, and annotated compound
library is a core, proprietary asset.
Publicly available compound libraries, on the other hand,
are largely limited to diversity libraries obtained from
commercial sources. Many academic research facilities have
assembled libraries from commercial sources, but few if any
compare with those available in industry. The most wellconstructed and diverse public library is a new collection of
over 100,000 small molecules accessible through the NIH
Molecular Libraries Screening Center Network (MLSCN).9
With a few exceptions, publicly available libraries do
not have the target-class focus common to proprietary,
purpose-built libraries in biotechnology and pharmaceutical
companies. Commercial libraries are based almost solely
on structural novelty, much like the early combinatorial
libraries used by industry, as opposed to relevance to the
targets of interest. Screening large numbers of such unbiased
compounds against a target may generate hits, but hit rates
are extremely low (less than 1 in 1,000) and can be expected
to identify a distracting number of false positives [35].
Although these concerns limit the utility of publicly
available libraries, two trends may make it possible for
public sector researchers to avoid some of these pitfalls.
First, there are now commercial sources of target-focused
libraries. These libraries offer much higher yields when
screened against members of a target family. Second, it
is possible and cost-effective to engage chemistry CROs,
many of which are offshore, to design certain types of
custom compound libraries. Nonetheless, the public sector
still does not have access to the breadth of target-focused
libraries available to industry—a reality that limits the
types of NCEs that can emerge from a neglected disease
drug discovery campaign.
Limited access to discovery infrastructure and
chemistry expertise
In recent years, high-throughput screening centers—facilities allowing chemical compounds to be tested for activity
against putative or established drug targets in highthroughput mode—have been installed at universities and
public research institutes all over the world. These centers
are particularly abundant in North America and Europe
9 MLSCN is an NIH-funded consortium that provides the following: high-throughput screening (HTS) to identify compounds active in
target- and phenotype-based assays; medicinal chemistry to transform hits into tool compounds; and deposition of screening data into
a freely accessible public database. See Austin, C.P., et al., NIH Molecular Libraries Initiative. Science, 2004. 306(5699): p. 1138-9.
[23, 36]. To capitalize on the potential value of their own
technology, many academic institutions now vie to establish themselves in drug discovery by creating “translational
research” centers. These initiatives have facilitated target
validation and hit generation, but they represent only part
of the infrastructure required to transform an academic
laboratory into a true drug discovery facility. Without
industry expertise, resources, and scale, such efforts are
unlikely to be efficient generators of NCEs that can be
entered into commercial development. This limitation
holds true as well for academic translational research initiatives for neglected diseases.
Converting hits to lead compounds is an iterative,
chemistry-intensive process requiring expertise in
analytic, synthetic, and medicinal chemistry. For
academic biologists and biochemists pursuing drug
discovery, accessing chemists—particularly those with
medicinal chemistry expertise—requires collaboration with academic chemists sharing an interest in the
biological target or disease. Because of the expense and
long timelines associated with lead-optimization medicinal chemistry, and the high expected failure rate, it can
be challenging to identify and engage academic groups
with organic chemistry resources essential to optimize
leads into true drug candidates.
Insufficient Scale
Many of the organizations working on neglected disease
drug discovery are limited by the scale of their efforts.
For example, TDR reports that its medicinal chemistry
network devoted to tropical diseases consists of 11
postdoctoral fellows scattered in eight organizations all
over the world to address all of their programs [23]. In
contrast, even the smallest drug discovery companies have
coordinated teams of at least eight in-house or contract
chemists per project [27]. Additionally, few universities
possess the instrumentation and expertise required for
high-throughput assay development, X-ray crystallography, computational modeling, and in vitro pharmacokinetics and toxicology studies—all of which are essential
tools in drug discovery.
Current joint industry-PDP efforts provide a good model
for future collaborations, but the number of projects being
pursued in these programs is far from sufficient to ensure
a robust pipeline for any of the neglected diseases. In the
biopharmaceutical industry, the limited discovery research
under way for neglected diseases mostly takes place in
three companies: GSK, Novartis, and AstraZeneca.10
Two of these programs are partnered with MMV and TB
Alliance.
Building a continuum of players
The innovation gap is not only a problem of investment,
access to infrastructure, technology, and expertise. It is
also a problem of recruiting organizations experienced in
different aspects of product development that together
can ensure that the fruits of R&D flow efficiently from the
laboratory into the clinic, and then to the patient’s bedside.
For diseases with a developed-world market, such a
system of collaborating organizations has been in place
for many years. It begins with commercially viable ideas
and inventions created in academia and research institutions. Biotechnology and pharmaceutical companies then
license these innovations, where industrial scientists,
experienced in translating basic science into nascent products, undertake drug discovery. R&D typically concludes
with completion of clinical and regulatory activities by
the biotechnology industry innovator or a large pharmaceutical company that may license the product once it
shows persuasive evidence of preclinical or clinical efficacy.
Biotechnology companies often partner with multinational
pharmaceutical companies that have the financial resources
to carry out phase II and phase III clinical trials and handle
regulatory applications for approval to enter the marketplace on a worldwide scale.
Unfortunately, this well-worn path in the private sector
has yet to evolve fully for global health product development (Figure 3.6). Opportunities for collaboration and
technology transfer that exist for developed-world diseases
have, in many cases, not materialized for neglected diseases
due to a lack of market-based incentives.
10 GSK’s Diseases of the Developing World program in Tres Cantos, Spain; the Novartis Institute for Tropical Diseases (NITD) in Singapore;
AstraZeneca’s TB Research Programme in Bangalore, India.
Figure 3.6: Building a Continuum of Players to Move from Basic Research to Product Registration
Diseases with a paying market
Academia and
Research
Institutions
Basic
Research
Multinational Pharmaceutical Companies
Biotechnology Companies
Screening
for Hits
Lead
Identification
Lead
Optimization
Preclinical Phase I
Phase II
Phase III
Registration
CLINICAL TRIALS
NEGLECTED DISEASES
Multinational Pharmaceutical Companies
Academia and
Research
Institutions
Innovation
Gap
Product Development Partnerships
Legend: Neglected disease R&D lacks the continuum of players and handoffs that has evolved for developed-world diseases.
Many academics pursuing neglected disease research
have developed tools and technologies that might be put
to work in drug discovery. But the options for transferring their findings to industry are limited, in part because
an appropriate structure for licensing arrangements that
may not generate revenue has yet to be established. As a
result, organizations lack sufficient incentives to overcome
barriers to forming partnerships and moving neglected
disease product development forward [34].
Closing the innovation gap
Achieving the ambitious goals for treatment of tuberculosis, malaria, and human African trypanosomiasis will
entail extensive drug discovery efforts requiring longterm commitment and funding that does not exist today.
If not addressed soon, the innovation gap could delay
for years, and potentially decades, victory over neglected
diseases. Moreover, these efforts need to be sustained;
no new drug, no matter how powerful, can forever
evade the development of drug resistance. Researchers
must constantly fight back with drugs that have new
mechanisms of action.
It is essential that neglected disease pipelines include
large numbers of high-quality discovery programs to
ensure continuing improvements in care. The innovation
gap cannot be closed with money alone. We must also
do a better job aligning the efforts of basic researchers
with biotechnology drug discovery tools and expertise—
described in detail in the next chapter.
Chapter 4: Harnessing Discovery Resources
Addressing the innovation gap in neglected disease
therapeutics requires access to small molecule discovery
capabilities. The biotechnology industry has evolved from
having an early focus on protein-based therapeutics to
becoming leading innovators of small molecule drugs.
Today, biotechnology companies supply large pharmaceutical companies with novel small molecule drug candidates for clinical development. Biotechnology companies
with successful track records in small molecule discovery
and development could play a similar role in building the
neglected disease drug pipeline. In this chapter, we assess
their infrastructure and skills; in the next chapter, we look
at how their resources are applicable to neglected diseases.
The biotechnology industry has been built with over
$377 billion of equity capital [37, 39] and hundreds of
billions of dollars more in partnership financing from
large pharmaceutical companies. Indeed, between 1998
and 2006, nearly 200 discovery alliances were forged each
year between biotechnology companies and pharmaceutical
companies [27]. In 2006, public biotechnology companies
had estimated revenues of $82 billion and another $47
billion of income from partnering and financing deals
[39]. By the end of 2006, the combined market capitalization of publicly traded biotechnology companies was
$490 billion, a sum exceeding the valuation of the top
five U.S. pharmaceutical companies [39].
The biotechnology industry
In wealthy countries, drugs are invented, developed,
tested, registered, and marketed by pharmaceutical and
biotechnology companies. The pharmaceutical industry
evolved from chemical companies founded in the late
1800s and early 1900s and is now dominated by about 20
large, “innovative” companies that develop new drugs. The
biotechnology industry is much younger. It originated in
academic research laboratories following the invention of
recombinant DNA technology in the mid-1970s. Through
three decades of technology innovation and investment, it
has grown to approximately 5,000 companies worldwide
[37], of which we estimate 1,500 in the United States and
Europe are financed with institutional investment.11
The emerging role of biotechnology
in small molecule discovery
Until the early 1990s, biotechnology companies used
their drug discovery technologies primarily to develop
large-molecule biologics—therapeutically active proteins
such as hormones and monoclonal antibodies. Early
product successes included erythropoietin (EPO), human
growth hormone (hGH), and tissue plasminogen activator
(tPA). These products were created by cloning human
genes through recombinant DNA technologies, expressing
the genes in cell culture, and scaling up manufacture of
the proteins. In the early days, biotechnology companies did not compete with the pharmaceutical industry
in discovering small molecule drugs (see Sidebar 4.1).
Instead, pharmaceutical companies dominated small
molecule discovery through their enormous manpower
and historical expertise in synthetic, medicinal, and
process-scale chemistry.
The first generation of public biotechnology companies
was launched in the early 1980s. These companies focused
on making “large molecule” protein drugs, often referred
to as “biologics” because they were produced from living
cells using recombinant DNA technology. Initially, biotechnology companies had neither the financial resources nor
the capabilities to develop their own drugs and depended
on large pharmaceutical companies to develop and
commercialize their discoveries.
Today, the biotechnology industry rivals the global pharmaceutical industry in size, scope, and capabilities. Over 250
therapies and vaccines that originated in the biotechnology
industry have been approved by regulatory authorities [38].
Sidebar 4.1: Characteristics of small
molecule drugs
A small molecule drug is either a natural product or a synthetic
organic compound made by chemical synthesis. It is not a
protein. In general, compounds suitable as orally available,
small molecule drugs have low molecular weight (typically less
than 500 daltons), limited ability to form and accept hydrogen
bonds, and intermediate hydrophobicity [40]. To synthesize
small molecule drugs, medicinal chemists typically make
analogs of core structures (scaffolds) and alter side chains to
improve specificity and efficacy while lowering toxicity.
11 “Institutional” investment refers to commercial public and private equity investors.
Over the past decade and a half, industry’s landscape
changed dramatically. Biotechnology companies recognized the increasing demand for treatments using small
molecules, especially for orally administered drugs against
chronic diseases. Taking advantage of a revolution in
miniaturization, discovery technologies, and vast increases
in throughput in screening small molecules for drug
activity, biotechnology companies became leading originators of small molecule drugs.
This change is critical to whether biotechnology can
contribute to developing new drugs for neglected diseases.
This is because most large molecule biologics (excluding
vaccines) are produced in small quantities, are comparatively expensive (in many cases extremely expensive), must
be stored in the cold, and are delivered only by injection.
The profile of most drugs envisioned for the developing
world demands the opposite: large quantities produced at
very low cost, heat stability, and oral delivery. Only small
molecule drugs typically achieve this profile.
The biotechnology industry has achieved therapeutic
success with small molecule anti-infectives, anticancer
agents, and cardiovascular disease drugs. As of 2005,
the top 10 small molecule drugs originating in biotechnology had sales totaling $7.5 billion. More than half of
the drugs that originated in biotechnology companies and
received regulatory approval in 2004–2006 were small
molecules [41]. Between 1998 and 2006, more than 25
Small Molecule Drugs in Clinical Development
Figure 4.1: The Origins of Small Molecule Drugs in Clinical
Trials (January 2007)
600
512
500
400
346
300
200
161
100
0
Phase I
Phase II
Phase III
Source: PharmaProjects
Originating
from large
pharmaceutical
companies
Originating
from
biotechnology
companies
percent of the new medicines approved by the FDA originated from biotechnology company R&D [27, 42]. In
early 2007, nearly two-thirds of the small molecule drug
candidates in clinical trials originated in biotechnology
companies (Figure 4.1). By this measure, the biotechnology industry has overtaken large pharmaceutical
companies and assumed the leading role in innovation of
small molecule drugs.
Large pharmaceutical companies have traditionally devoted
significant resources to making drug analogs (modified
versions of known compounds) or creating new drugs
that act on previously validated drug targets. A defining
characteristic of biotechnology companies has been their
willingness to take on risk and engage in innovation, and
thus the biotechnology industry has taken a different
approach. Capitalizing on breakthroughs in understanding
of the biochemistry of disease and technical advances such
as genomics and proteomics, biotechnology companies
developed technologies for screening compound libraries
for activity against novel molecular targets or new target
classes, such as cell receptors or intracellular messengers
that regulate biochemical processes involved in disease.
These technologies are competitive with the drug discovery
capabilities of pharmaceutical companies, and they
routinely enable screening millions of compounds against a
new biological target in a matter of weeks [35, 43].
Biotechnology companies focused on drug discovery can
be segmented by capabilities. As summarized in Figure
4.2, companies can be classified as fully integrated, early
development, or discovery only:
n Many larger, mature biotechnology companies
have fully integrated discovery and development
capabilities. They can advance lead compounds
emerging from their in-house discovery programs
through preclinical development and into the clinic
without needing outside development expertise.
n Early-development companies are smaller and
younger than fully integrated companies. They
possess strong discovery platforms that they
have used to identify lead compounds. Their
capabilities support IND filing, and they have
advanced compounds through early preclinical
development. To drive clinical development, these
companies must partner with larger organizations.
Figure 4.2: Biotechnology Companies Can Be Segmented by Capabilities
Basic
Research
Target
Target
Identification Validation
Screening
for Hits
Lead
Lead
Identification Optimization
Phase I
Phase II
Phase III
Examples: • OSI Pharmaceuticals
• Exelixis
• Vertex
• Gilead
Fully Integrated
Examples: • Pharmacopeia
• Kalypsys
Early Development
Discovery Only
Preclinical
Core Discovery Offering
Examples: • Amphora
• Kémia
• Locus
Well-developed
Less well-developed
n
Discovery-only companies are typically young and
privately held. They have some of the most novel
drug technology platforms. Lacking in-house
preclinical capabilities, they contract with CROs
and partner with larger companies to advance
drug candidates through preclinical development
and into IND status.
Small molecule innovation in the
biotechnology industry
Given the risk and high attrition rate of drug discovery,
biotechnology companies typically aim to develop truly
novel products for high-impact therapeutic markets.
Hence, few apply their skills to neglected diseases. But
if markets and incentives were available, would the
infrastructure of the industry be applicable to neglected
diseases? Would companies be in a position to undertake
discovery projects against unfamiliar pathogens?
The diversity of biotechnology businesses bewilders even
those steeped in the industry. Biotechnology companies
develop platform technologies, vaccines, drugs and diagnostics, not to mention agricultural, environmental, and
industrial products. To concentrate on the companies
potentially most relevant to closing the drug discovery
innovation gap for select diseases, we winnowed a list
of over 1,500 U.S. and European companies12 down to
approximately 120 that: (a) focus on small molecule drugs,
(b) have significant discovery programs, (c) have succeeded
in taking new compounds into human clinical trials, and
(d) have sufficient scale to pursue multiple programs with
at least some vertical integration (see Sidebar 4.2). To
refine our analysis, we analyzed in depth 50 representative
companies. These companies are listed in Appendix IV and
are summarized as a group in Table 4.1.
Table 4.1: Summary of 50 Focus Companies
Approved drugs originating from focus companies
23
Programs in active clinical development (Jan 2007)
121
Programs in discovery and preclinical development (Jan 2007) >400
Equity capital raised since inception
$20 billion
12 We elected to focus on U.S. and European biotechnology companies because they represent the most innovative companies.
The companies we examined closely have collectively
raised over $20 billion in public equity capital and
received billions more in partnering revenues from collaborators. Their financial strength is also concentrated: just
over half the $20 billion was raised by the five largest
companies (Figure 4.3).
The resources of the biotechnology industry
Through interviews with executive and scientific management of many companies in our representative set, we
found that the industry possesses three key resources for
discovering new drugs for neglected diseases: infrastructure, technological assets, and expertise.
Biotechnology companies have invested heavily in
high-throughput compound screening facilities, X-ray
crystallography, computational modeling, and other infrastructure to support drug discovery programs. Foremost
among many companies’ technological assets are the
combination of highly evolved compound libraries used
in drug screening and proprietary assay technologies built
on a scientific foundation in cellular biochemistry. At least
as important—and even harder to import or build from
scratch—is their drug discovery expertise. Companies
have assembled highly experienced teams of biologists,
structural biologists, pharmacologists, and chemists. Their
skills are indispensable to “lead optimization,” the iterative process of synthesizing and testing compounds for
potency, efficacy, and low toxicity.
Biotechnology industry resources: Infrastructure
Companies have used their equity and partnering revenues
to build their infrastructure and develop their proprietary
technologies (Table 4.2). To compete with the pharmaceutical industry in small molecule discovery and development,
early-stage biotechnology companies had to innovate. Most
biotechnology companies were founded upon a single technological insight and then focused on a therapeutic application of the technology. Subsequent partnering or outright
sale of the technology funded further drug discovery
programs. Most companies invest $100 million to $250
million to reach this point in early-stage development.
Sidebar 4.2: Company selection process
Many biotechnology companies have the potential to contribute to small molecule drug discovery for neglected diseases. For the
purpose of this study, we chose to focus on a small subset of these companies that have the infrastructure, scale, and experience
to undertake a substantial new discovery R&D program. We began with approximately 1,500 U.S. and European biotechnology
companies focused on human therapeutics and applied successive “filters” to select a representative sample. About 1,000 of these
firms concentrate on small molecule therapeutics as opposed to therapeutic proteins. Of these, 700 are originators that create
new compounds rather than reformulating existing active molecules. Of these, about 160 have scale and capital sufficient to
support diversified drug discovery programs—typically, they have at least 50–80 discovery scientists and spend more than $20
million per year on R&D. Of these 160 companies, 123 companies had a track record of advancing compounds into human clinical
development. We further reduced this list to a sample of 50 companies to analyze in greater depth.
Company Filter Description
Total Biotechnology Industry
1,519
Companies
More than 1,500 biotechnology companies are focused on
therapeutics
Small Molecule Therapeutic Focus
1,008
Companies
1,000 focus on small molecule therapeutics
Chemistry-based Discovery Capabilities
733
Companies
700 are pursuing new small molecules
Scale
162
Companies
160 have the scale to support new programs
Development Experience
123
Companies
Over 120 have a track record of taking new drugs into the clinic
50 Focus Companies
We chose a sample of 50 companies to analyze
A competitive clinical pipeline with potential to produce
a portfolio of marketed drugs demands constant investment in mid- and late-stage discovery, preclinical development, and clinical development capabilities. Biotechnology
companies eventually need the same technologies and
skills resident in any pharmaceutical company, the major
differences being only focus and scale. So biotechnology
companies hire pharmaceutical industry veterans, expand
facilities, and license or purchase established pharmaceutical assets. To reach this level of maturity, with multiple
compounds in clinical development, likely represents more
than half a billion dollars in total investment.
Table 4.2: The Assets and Infrastructure
Used in Drug Discovery
Animal study capabilities
Assay development: Cloning and expression of proteins
Chemistry instrumentation (e.g., nuclear magnetic resonance,
high performance liquid chromatography, mass spectrometry)
Chemoinformatics
Compound libraries
Compound storage and retrieval systems
Computational modeling (for structure-based design)
High throughput screening robotics
In vitro pharmacokinetic (ADME) and toxicology assays
Biotechnology industry resources: Compound
libraries
Purification, fractionation, and identification equipment
A key requirement of most small molecule drug discovery
programs is a proprietary compound library that can be
screened for drug activity. Although a high-quality library
cannot ensure the success of a discovery program, the
converse nearly always holds—a library composed of
inferior chemical matter is unlikely to yield promising lead
X-ray crystallography
Figure 4.3: The Financial Strength of the 50 Focus companies: Equity Capital Raised
Equity Capital Invested in Select Smaller
Companies within Sample
25
250
20
200
Millions of Dollars Invested
Billions of Dollars Invested
Equity Capital Invested in the 50 Focus Companies
15
10
5
Median of all 50 companies
150
100
50
0
0
s
ls
m
or
tex
g 45
nce
niu
rac
tica
Ver
inin
len
Scie
Sep
ceu
a
a
d
m
Mil
a
rm
Re
Gile
Pha
OSI
al
Tot
ta
Syn
st
cry
Bio
y
Arra
any
Alb
ys
yps
Kal
Note: Equity capital invested based on additional paid in capital, capital surplus, and proceeds from venture rounds
Sources: Company SEC filings, VentureXpert, and BVGH/L.E.K. analysis
compounds. There are no definitive rules on what makes
a “good” compound library, but certain characteristics
dictated in part by a compound’s backbone, or “scaffold,”
have been proposed as predictive of orally available small
molecule drugs [40].
Biotechnology companies have taken many approaches
to building compound libraries. A diversity library, as
its name implies, aims to capture a broad array of druglike molecules without selecting any particular target
or scaffolds. This type of library can be employed in a
wide range of drug discovery programs. A focused library
strives for just the opposite: its compounds are biased
by structure or function in favor of interaction with a
specific target class. Because of the effort and inventiveness required to develop a refined and annotated
collection of compounds, compound libraries are among
drug discovery companies’ most important and closely
guarded assets.
An important advantage of developing highly focused
libraries is that screens once requiring a few million
compounds, many of which were unassociated with any
biological activity, can now be performed with about
100,000 compounds, winnowed down by computer algorithms to represent a chosen attribute (function, shape, or
target class). Highly focused libraries save time and money.
They, and their associated computational modeling tools,
provide potentially unique starting points for medicinal
chemistry and lead optimization—and are critical to accelerating drug discovery and development for any disease.
The majority of our 50 focus companies have been
successful in discovering and developing novel small
molecule drugs and clinical candidates. Each company
generally possesses a mix of diversity and focused libraries.
Proprietary compound libraries that have yielded lead
compounds are likely to be of increasing value because
of the inherent drug-like qualities of the compounds
Figure 4.4: The Composition and Tasks of a Drug Discovery Team
Exploratory Discovery
Description
Chemists are needed
for compound library
development
Structural biologists and
computationalists are needed
for X-ray crystallography and
target modeling
Biologists are needed for
screening and follow up
Chemists are needed for hit
characterization
Computationalists are needed
for structure-based design
Lead Optimization
Biologists and
pharmacologists are needed
for pharmacokinetic (ADME/
tox) assessment of analogs
Chemists are needed for
medicinal chemistry and
analoging
Computationalists are
needed for structure-based
design
Preclinical
Candidate selection
Biologists are needed for
target biology and assay
development (cloning and
expression)
Lead Identification
Biologists and
pharmacologists are needed
for in vitro IND-directed
toxicity studies
Chemists are needed for
process chemistry and
formulation
CROs may provide
additional animal capacity
Representative Staff
Biologists and
Pharmacologists
Chemists
Structural Biologists/
Computationalists
Outsourced
Chemists
Biologists and Pharmacologists
and constant compound data annotation from screening
campaigns. But no matter how well constructed and annotated, any library’s value rests in its repeated success in
yielding tools for in vitro proof-of-concept experiments and
hits for lead optimization.
exploration has been carried out. Beyond the value of the
specific contents of given compound libraries and annotations stored in databases, companies benefit from the
collective knowledge of those who created and used the
companies’ technologies.
Unfortunately, the industry’s compound libraries have
rarely been mined for hits and leads against targets relevant
to global health. For neglected diseases, specific natural
products (and small collections of such compounds) have
historically been the main source of new lead compounds.
But things have changed. Today, genomics technologies
have identified molecular targets specific to neglected
disease pathogens. This is of tremendous importance. It
means that screening compound libraries using either
phenotypic or target-based screens should significantly
expedite neglected disease drug discovery programs.
At successful biotechnology companies, the convergence of
focus and expertise almost always augments the next level
of development, where knowing how to develop drugs and
knowing which drugs not to develop are equally important. Constant pipeline triage is instrumental to working
quickly and within budget constraints. For example, our
50 focus companies have collectively discontinued more
than 700 internal discovery programs [27]. Moreover,
pipeline triage can accelerate project timelines to IND
and result in more focused clinical trials. Combining this
discipline with the inherent value of the company’s R&D
infrastructure and proprietary assets continuously creates
opportunities for evaluation and action.
Biotechnology industry resources: Expertise
As biotechnology companies evolved into leaders in small
molecule discovery, they built teams with scientific expertise in many disciplines, including basic biology, structural
biology, pharmacology, and analytic, synthetic, and medicinal chemistry. The composition of a typical drug discovery
team at each stage of a project is summarized in Figure
4.4. Although the mixture of skills changes over the course
of a project, advancing to lead optimization frequently
requires a dozen or more medicinal chemists, making
chemistry expertise integral to success. Our 50 focus
companies report employing between 20 and 50 medicinal
chemists each, either on staff or outsourced to CROs often
located in India or China.
Of those companies we examined, most have been in
operation for more than 10 years. By assembling industry
veterans and motivated younger scientists into small,
highly focused teams, biotechnology companies build
cohesive discovery-driven cultures and increase expertise in the specific areas of interest. Discovery teams in a
successful company are likely to become internationally
recognized leaders in their particular area. This special
expertise is valuable to the company in ongoing efforts
to build a pipeline of projects, and it also adds valuable
corporate memory. For example, many companies have
“legacy programs,” in which extensive medicinal chemistry
Biotechnology industry resources: Target focus
Companies focused on small molecule drug discovery are
typically thought of in terms of the diseases they tackle.
In fact, many are organized not around a disease but
around specialized molecular targets that may underlie
mechanisms of several unrelated diseases. Their targets
are typically members of an extended target family,
such as G protein–coupled receptors (GPCRs) (Arena
Pharmaceuticals), kinases (OSI Pharmaceuticals, Exelixis,
Ambit BioSciences), ion channels (Neuromed), and
phosphodiesterases (PDEs) (Plexxikon) (Figure 4.5).
Breakthrough drugs have been found in all these classes
across a range of therapeutic indications, from the kinase
inhibitor Gleevec® for treating chronic myelogenous
leukemia, to PDE-5 inhibitors like Viagra® for cardiovascular function and erectile dysfunction.
Target expertise is critical for a company’s competitive position. Concentrated expertise, technology, and intellectual
property are why pharmaceutical companies seek commercial partnerships with biotechnology companies to build
their pipelines. Target expertise can result in a continual
source of compounds spanning many therapeutic areas,
simply because specific members of the target family have
been associated with different disease pathologies. A target-
Figure 4.5: Target Class Focus of 50 Focus Companies
Host response
Cytoskeleton
General discovery
Proteases/Metabolic
enzymes
Nucleic acid
GPCRs
Plexxikon
Exelixis
Sunesis
OSI
Cephalon
Infinity
Millennium
Eisai
Locus
Kalypsys
Vertex
Telik
Metabasis
Pharmacopeia
SRI International
Synta
ArQule
Celgene
Astex
Ambit
Ariad
Kinex
Amphora
Array
Kémia
Rexahn
Rigel
Cytokinetics
Vitae
Immtech
Sequella
Optimer
Replidyne
Achillion
Genelabs
Gilead
BioCryst
Anadys
ChemoCentryx
ACADIA
Arena
Sepracor
CV Therapeutics
Neurogen
Theravance
Neuromed
Icagen
Renovis
Lexicon
Kinases
Ion channels
Kinases
Proteases
Metabolic enzymes
Nucleic acid synthesis
Cytoskeleton
Host response
Proteasomes
Phosphodiesterases
Nuclear receptors
GPCRs
Heat shock proteins
Ion channels
Note: Albany Molecular is not listed because it is a drug
discovery CRO and does not have internal programs
Source: PharmaProjects
based approach allows companies to attack different diseases
by attacking distinct proteins within a single target class.
Often the same compound libraries and similar biochemical
assays can be used to tackle entirely different diseases.
The classic example of how a library developed for one
disease was applied to another involved compounds originally made to inhibit the human enzyme renin, an aspartyl
protease implicated in hypertension. These libraries were
enlisted in drug discovery for HIV in the urgent early years
of the pandemic. Screening of these very same compounds
against the HIV aspartyl protease provided the first lead
compounds against the viral target and yielded such
breakthrough drugs as saquinavir (Fortovase®), indinavir
(Crixivan®) and many more protease inhibitors in broad
clinical use today. This example, repeated often in the
last 20 years, provides a clear road map for target-based
drug discovery, regardless of the disease. The very same
approach can generate drugs for neglected diseases.
≥50% of Portfolio
10–50% of Portfolio
<10% of Portfolio
Can biotechnology industry drug
discovery technologies be adapted
to neglected diseases?
Clearly, there are important questions to address. Can
drug discovery tools be shared? Is the overlap among drug
targets between noninfectious diseases like diabetes and
many cancers and developing-world pathogens more than
superficial? How relevant to drug discovery for neglected
diseases are shared molecular structures? How can we
harness the tools of the biotechnology industry that are
so effective in developing new therapies for the affluent to
develop new therapies for the poor?
In the remaining chapters, we will examine the scientific
rationale for extending biotechnology companies’ capabilities to neglected diseases, the hurdles that stand in
the way, and new models for collaboration between the
biotechnology industry, academic organizations, and PDPs.
Chapter 5: Mapping Biotechnology
Capabilities to Neglected Diseases
Biotechnology companies have brought many innovative
small molecule drugs from the test tube to the clinic. But
does their expertise—built around cancer, cardiovascular disease, and other conditions that afflict the aging
population of wealthy nations—offer hope for neglected
diseases? The universality of biochemical mechanisms
and adaptability of tools for drug discovery strongly
suggest that the answer is yes. The unique biology of
infectious disease–causing pathogens, however, creates
distinct hurdles that will require new solutions by drug
discovery scientists.
Essential tools for drug discovery
As Chapter 4 explains, general drug discovery infrastructure and skill sets resident in industry can play a critical
role in creating drugs for neglected diseases. But scientists
in drug discovery companies embarking on a discovery
program for a neglected disease also need key pathogenspecific tools:
n A comprehensive understanding of the disease
process at molecular and cellular levels;
n Biochemical, cellular, and in vivo assays to
evaluate the efficacy, pharmacology, and toxicity
of candidate compounds (see Sidebar 5.1); and
n Validated targets against which to screen
promising therapeutic compounds.
Our analysis explored whether malaria, tuberculosis (TB),
and human African trypanosomiasis (HAT) can be added
to the list of diseases that can be tackled by small molecule
drug discovery companies. To answer this question, we
first assessed the state of the art of neglected disease drug
discovery tools. Specifically, we asked whether neglected
disease researchers have created bioinformatic and genetic
tools, biochemical assays, and animal disease models
that can be combined with the target-specific screening
systems found in leading small molecule drug discovery
companies. We also looked for target overlap between P.
falciparum, M. tuberculosis, and T. brucei, the pathogens that
cause malaria, TB, and HAT, respectively, and the diseases
on which leading biotechnology companies currently focus
their efforts.
The choice of diseases . . .
Malaria, TB, and the trypanosomal diseases have been
studied for more than a century, and much is known
about the basic biology of the pathogens that cause them
[44-47]. Scientists in academia and at research institutes
have suggested that disease understanding per se is not
limiting, and they have developed tools and assays that
support drug discovery. But they also caution that each
pathogen has unusual features that complicate drug
discovery [5, 48-50].
TB is caused by a single species of bacterium,
Mycobacterium tuberculosis. In contrast, malaria and
trypanosomal diseases are caused by several species of
Sidebar 5.1: The tool kit for modern
drug discovery
Guided by the target product profile (TPP), drug discovery
scientists know what biochemical and pharmacologic hurdles
their candidate compounds must overcome. For rapid progress,
discovering new drug candidates for neglected diseases
requires the following:
Understanding of biochemical pathways of infectious
pathogens. Drug discovery is much more likely to succeed if
the target pathways are understood. It is much more likely to
produce unintended side effects if screening is done in a “black
box” of unknown biochemical activity.
Genomic information. A fully sequenced and annotated
pathogen genome allows researchers to predict pathogen
gene function, greatly facilitating target identification.
Genetic tools. To “genetically validate” a target molecule
requires tools that enable researchers to test if a gene is
essential for virulence, pathogenesis, or viability.
Discovery tools. Such tools include recombinant target protein
expression, high-resolution protein crystal structure, and
biochemical or whole-cell assays.
Animal disease models. Screening small molecules for in vivo
pharmaceutical activity is a prerequisite to further preclinical
and clinical development. Animal models give an initial
indication of the efficacy one hopes to see in humans, along
with indications of toxicity, pharmacokinetics, drug half-life,
and unanticipated side effects.
protozoan parasites. In order to examine specific opportunities within protozoan diseases, we limited our analysis to
P. falciparum (malaria) and T. brucei (HAT).
Malaria is caused by four species of Plasmodium parasites,
each with its own unique biology and pathology. Nearly all
efforts to invent new malaria drugs, however, are directed
at P. falciparum, the deadliest and best understood species
and the most common throughout Africa.
Leishmaniasis, Chagas disease, and HAT are caused by
divergent species of protozoa (called trypanosomatids) with
unique life cycles and insect vectors. Leishmaniasis is not a
single disease. It exists in visceral, cutaneous, and mucosal
forms and is caused by more than 20 separate Leishmania
species. Although Leishmania, T. cruzi (the pathogen that
causes Chagas disease), and T. brucei evolved from a
common ancestor, and therefore share many molecular
and biochemical pathways, their infection cycles and the
tissues they target are very different. We focused our analysis on T. brucei because the set of research tools available
for its study are better developed than for any other type of
trypanosomatid.
. . . and their challenges
P. falciparum. The life cycle of P. falciparum is extraordinarily complex. The parasite targets several tissue types
and shifts between living freely in the blood and entering
and inhabiting the host’s cells. The parasite undergoes
radical changes in morphology and metabolism as it passes
through these stages. Drug discovery in P. falciparum,
however, is effectively restricted to the red blood cell or
erythrocytic stage of its life cycle—the stage responsible
for the symptoms of uncomplicated malaria—because only
this stage of the parasite can be cultured in the laboratory. Laboratory culture is not routine for the forms of
the parasite that infect the liver or for those that survive
ingestion by mosquitoes and complete the transmission
cycle. These obstacles make developing a drug that relieves
symptoms and also prevents infection and transmission
much more difficult.
M. tuberculosis. Even under optimal laboratory condi-
tions, M. tuberculosis grows extremely slowly (a doubling
time of about 24 hours). As a result, antibiotics that
disrupt processes required for rapid growth are rendered
much less effective than for bacteria with doubling times
on the order of minutes. Furthermore, the thick, waxy
surface coat of M. tuberculosis is not at all like a mammalian cell membrane and is an impossible barrier for many
drug-like molecules to cross. In addition, due to a poorly
understood phenomenon known as “persistence,” a fraction of M. tuberculosis in an individual with active disease
can survive in the presence of currently available drugs for
months [51].
T. brucei. T. brucei hides in privileged spaces, where it
can be difficult for drugs to reach. In late-stage disease,
the parasite leaves the bloodstream and enters the central
nervous system and brain. For a drug to be effective in
this stage, it must be able to cross the blood-brain barrier
(BBB), a gradient mechanism that normally serves to
protect the brain from most chemicals circulating in the
blood. Designing a drug capable of crossing the bloodbrain barrier (BBB) without any associated toxicities presents an enormous challenge.
Drug discovery tools for neglected diseases:
The state of the art
Several factors have primed M. tuberculosis, P. falciparum,
and T. brucei for major therapeutic advances:
n Their genomes have been sequenced and annotated;
n Genetic tools have been developed to validate
potential drug targets; and
n Animal models of infection exist, making it
possible to test the ability of compounds to kill
pathogens in vivo.
Each of these topics is described in more detail below.
The importance of genomic information
for target identification
The revolution in DNA sequencing and bioinformatics,
along with order-of-magnitude increases in speed and
reductions in cost, has made it possible to sequence the
genomes of dozens of infectious microbes. Beginning with
the M. tuberculosis genome in 1998 [52], scientists have
reported fully sequenced and annotated genomes for P.
falciparum [53], T. brucei, [54] and closely related organisms [55-58]. Pathogen-specific genomic information is
accessible through a variety of publicly available databases
(see Figure 5.1) [59-61].
The availability of genomic information is important for
drug discovery for several reasons. First, it greatly facilitates correlations between pathogenicity and specific genes.
It also allows researchers to identify genes that, based
on their known or predicted function, are potential drug
targets. Finally, it has led to the routine application of
molecular and recombinant techniques that may reveal
more about a pathogen’s potential vulnerabilities to drugs.
For example, with a pathogen genome sequence in hand, a
researcher has all the information necessary to manipulate
the pathogen genetically and to make pathogen proteins
to determine protein crystal structure and to develop a
biochemical assay.
Conditional knock-outs are especially important for testing
if a gene is essential to the pathogen when the pathogen
infects a laboratory animal. This may reveal whether a
gene’s function is required to maintain a chronic infection.
In recent years, a tool known as RNA interference (RNAi/
siRNA) has proven to be a rapid way of testing whether a
gene is essential in many eukaryotes,13 including the human
infective form of T. brucei [62]. This technique does not
disrupt the gene, but inhibits expression of the protein that
the gene encodes. Unfortunately, RNAi cannot function
in P. falciparum because the pathogen lacks key enzymes
required to generate interfering RNAs. Likewise, RNAi is
not relevant to a bacterium like M. tuberculosis.
Target validation depends on genetic tools
Target validation is the determination of whether a gene
encoding a pathogen protein is essential to the viability or
virulence of the pathogen. That is, can the pathogen survive
under laboratory culture or infect an animal when a gene’s
function is lost? If a parasite with a mutation in a specific
gene dies, is severely weakened, or cannot maintain an
infection, scientists may decide to design a drug to inhibit
the function of the gene product to yield a similar outcome.
A genetically validated target proves useful only if it is
shown to be “druggable”: not only is the enzyme integral
to the disease process, but it can also be inhibited through
specific binding with small molecules. For reasons such as
functional obscurity or redundancy, physical inaccessibility,
or even the shape and size of a unique binding site (or lack
thereof), many potential drug targets prove undruggable.
For a neglected disease pathogen, most validated targets
will be proteins or protein complexes. Inhibition of the
activity of these proteins with an effective small molecule
drug will cause the pathogen either to stop growing or die.
Historically, most antibiotics have interfered with pathogen
“housekeeping functions” such as DNA replication, RNA
transcription, protein translation, or cell wall synthesis.
Thus, pathogen genes involved in these processes continue
to be viewed as potential drug targets.
Several techniques can test if a gene is essential for
viability. The most straightforward is to “knock out,” or
permanently disrupt the target gene, thereby eliminating
the production of the protein it ordinarily encodes. This
genetic engineering technique has become routine for
P. falciparum, M. tuberculosis, and T. brucei [48, 62, 63].
There are, however, technical limitations associated with
gene knock-outs. To overcome them, M. tuberculosis and
T. brucei researchers developed methods of “conditionally” knocking out gene function [64, 65]. That is, they are
able to turn off a gene’s expression temporarily and then
observe if the organism remains viable.
The importance of mouse models in
target validation
Researchers depend on animal models of infectious disease
to identify and validate potential drug targets. Mouse
models are most often used in early-stage drug discovery
because large numbers of experiments can be conducted
at comparatively low cost to predict effects in humans.
Researchers can test if a target that has been genetically
validated in vitro is also required to initiate or maintain an
infection in animals. A mouse model allows compounds
identified on the basis of in vitro activity (for example,
compounds identified for inhibiting a target pathogen
protein in test tube experiments) to be tested for the ability
to prevent infection or cure an infected animal.
M. tuberculosis and T. brucei can be grown in mice with
relative ease. For T. brucei, mouse models exist that
mimic both acute and chronic stages of disease, making
it possible to evaluate compounds for their ability to clear
both types of infection. The latter is especially important
because for a drug to cure chronic infections, it must
cross the BBB. The chronic-infection mouse model allows
researchers to test compounds for ability to kill T. brucei
that have entered the central nervous system.
13 A eukaryote is most simply defined as an organism containing a nucleus.
In contrast to M. tuberculosis and T. brucei, P. falciparum
cannot normally survive in mice. Instead, the rodent
malaria parasite P. berghei is commonly used as an imperfect substitute for infected animal studies. Establishing that
a compound effective at killing P. falciparum in culture
will kill P. berghei in a mouse via the homologous target is
routine, but does require later confirmation because at the
amino acid level P. berghei and P. falciparum proteins share
on average just over 60 percent sequence identity [55]. In
instances where the structure of the P. falciparum target
differs substantially from that in P. berghei, the P. berghei
gene can be replaced with the relevant P. falciparum gene
Figure 5.1: Target Validation and Drug Discovery Tools Available for P. falciparum, M. tuberculosis, and T. brucei
P. falciparum
Basic Research: Target
Identification
Genome: sequenced and
annotated; comparative
genomics possible with other
human and rodent species of
Plasmodium
Conditional gene knock-outs:
in development
Safety: BSL2 laboratory
Proteomics: extensive
Key databases:
– genolist.pasteur.fr/TubercuList/
– webhost.nts.jhu.edu/target/
Can be grown on solid media,
in liquid culture, or in animal
models
Safety: requires BSL3 laboratory
genomics possible with
Leishmania sp. and T. cruzi
Key databases:
– www.genedb.org/genedb/tryp/
– tdrtargets.org
Bloodstream stage parasite
can be grown in culture or
in rodents
Gene knock-outs: routine
possible
Transposon mutagenesis:
routine
RNAi: not relevant
Lead Optimization
Primate disease models
available
P. falciparum does not
normally grow in rodents;
new immunocompromised
and ‘humanized’ mouse
models emerging
The rodent malarial parasite
P. berghei is frequently used
in place of P. falciparum;
allelic replacement can be
used to generate improved
P. berghei
Gene microarrays: available
Crystal structures: not extensive
genomics possible with
Bacille Camille Guérin (BCG),
M. smegmatis, M. leprae
Whole-cell screening:
routine under a variety of
conditions; assay for growth
For safety reasons,
M. smegmatis is commonly
used as a substitute for
M. tuberculosis
Animal models: mouse for
acute and chronic disease;
guinea pig, rabbit, and
primate models also available
No animal model for
latent disease
Gene microarrays: available
Crystal structures: extensive
and freely available
- TB structural genomics
consortium:
www.doe-mbi.ucla.edu
Gene knock-outs: routine
routine
RNAi: routine
Gene microarrays: available,
but polycistronic transcription
limits usefulness
Proteomics: limited
Crystal structures: limited
Safety: BSL1 for standard
lab strain
Well-developed tools
routine for erythrocytic
stage; assay for DNA
replication
RNAi: no
Erythrocytic-stage parasite
can be grown in culture
M. tuberculosis
Gene knock-outs: increasingly
routine (erythrocytic stage only)
Lead Identification
Transposon mutagenesis:
possible
Key databases:
– www.plasmodb.org
– tdrtargets.org
T. brucei
Screening: Target Validation
Less well-developed tools
routine; assay for
ATP production
Animal models: mouse
for acute and chronic (latestage) forms of disease
[66]. Such a transgenic organism would be predicted to
more closely mimic P. falciparum than normal P. berghei.
Additional drug discovery tools for
neglected diseases
Modern drug discovery is supplemented by a variety of
technologies that require specific molecular information or
reagents. These technologies include the following:
n Recombinant target proteins. Screening campaigns
typically require that the target protein be cloned,
expressed, and purified. The protein can then be used
in high-throughput-screening biochemical assays.
n High-resolution crystal structures. Protein crystals
made of highly purified target protein and then
subjected to X-ray diffraction provide researchers
with structural information useful in designing and
refining small molecule inhibitors by computational
modeling. Co-crystallization of an inhibitor bound
to the target protein aids lead optimization by
providing additional high-resolution information on
where the drug binds its target.
n Biochemical or whole-cell assays. An assay suitable
for screening thousands of compounds needs to
be simple and highly reproducible. In many cases
it is useful to screen compounds against whole
organisms using medium-throughput in vitro assays
to test if the compound inhibits pathogen growth.
Figure 5.1 provides an overview of many of the tools available for P. falciparum, M. tuberculosis, and T. brucei.
Drug discovery tools for neglected
diseases: Conclusions
Our interviews with scientists in academia and biotechnology companies strongly suggest that modern techniques of drug discovery are readily applicable to neglected
diseases. In every case, the neglected disease knowledge base
and early discovery work, from genomics to assay development, meet or exceed biopharmaceutical industry standards
for initiating a discovery project. Moreover, these discovery
assets in many cases are of sufficiently high quality to initiate
high-throughput screening (HTS) projects to search for
lead candidates or structure-based drug design projects.
More work, however, is still needed on target validation
and animal models for neglected diseases (see Sidebar 5.2).
The search for validated targets
Most of today’s standard treatments for diseases such as TB
and HAT are over 40 years old [5, 71] and have severe limitations in potency, safety, and resistance profiles. Many of
these drugs were discovered serendipitously or by traditional
screening of drug compounds against whole organisms in
vitro. While some traditional screening techniques are still
useful, modern biotechnology now enables drug hunters to
hone in on specific molecular targets in pathogenic microbes
and understand from the start the mechanism of action.14
This approach significantly improves the likelihood of identifying compounds that are highly potent and specific to the
target and potentially safe and efficacious.
Sidebar 5.2: Critical tools for future development
While our interviews indicated that scientists feel confident
that they have the tools to launch new discovery efforts,
key improvements could accelerate drug discovery for each
disease. Indeed, the Bill & Melinda Gates Foundation launched
a $40 million TB Drug Accelerator in 2006 specifically to develop
new tools [67]. For malaria and tuberculosis, two needed
advances could have tremendous impact:
Develop a mouse model capable of maintaining a sustained P.
falciparum infection. Rodent malarial species of Plasmodium do
not adequately predict results with P. falciparum. A drug designed
to act on a P. falciparum target but screened for efficacy against
a rodent parasite may exhibit deceptively lower efficacy in the
mouse model due to differences in the rodent parasite’s infection
cycle, pathology, permeability, and ability to transport drugs
across membranes [68], thus generating false negative results.
Strains of immunodeficient mice that tolerate grafts of human
red blood cells have shown encouraging results as models
for P. falciparum infections, but have yet to prove suitable for
routine use [69]. A mouse strain that can maintain a P. falciparum
infection would be a key asset for malaria drug discovery.
Develop an improved model for latent tuberculosis. Most
humans infected with M. tuberculosis develop a latent
infection in which the organism lies dormant, possibly for
years, until reactivated by suppression of the immune system
or other poorly understood mechanisms. Ridding the body
of a latent infection is possible but requires long treatment
times. The biology of latent infection is not understood, but the
bacteria appear to be in a different metabolic state from those
present in active disease [70]. Researchers place a high priority
on finding ways to screen candidate compounds against M.
tuberculosis in the latent state. Currently there is no in vitro or
animal model that emulates a latent infection.
14 “Mechanism of action” refers to how a drug interacts with its target to produce its pharmacological effect.
Biotechnology companies are expert in identifying and
validating new biochemical targets that mediate cell growth
and viability and that play key roles in diseases such as
cancer and neurological disorders. For small molecule drug
targets, early evidence of chemical tractability and dose
responsiveness can come from compound screening. This
evidence is then confirmed by making potency improvements during lead optimization. Examples of proteins
widely employed as targets for drug discovery include
proteases (proteins that degrade other proteins), protein
kinases (intracellular messengers), ion channels (transmitting molecules across the cell membrane), and farnesyl
transferases (cell signaling). Leading drug discovery
companies have developed technologies and built tools
around specific target classes (see Table 5.1).
Certain classes of drug targets, such as kinases and ion
channels, have different roles in different cell types.
Related targets in different cell types can function in
entirely different diseases. This explains why many companies build drug discovery technologies specializing on
particular target classes and then launch programs on
multiple diseases. For example, one company specializing in kinases attacks multiple types of cancer. Another
specializing in ion channels has programs in pain, hypertension, and epilepsy.
A company’s specialized technologies for a particular target
class could be applied in drug discovery programs against
a neglected disease pathogen, where the pathogen shares
a target with a chronic disease such as cancer. As summarized in Figure 5.2, significant target class overlap exists
between chronic noninfectious diseases and neglected
infectious diseases. Moreover, many of the same major
target classes are shared between P. falciparum and T.
brucei, or among P. falciparum and M. tuberculosis and T.
brucei (Figure 5.3). Shared targets include kinases, proteases, protein farnesyl transferases, and phosphodiesterases.
Target-specialized drug discovery know-how and targetspecialized compound libraries have already been applied
successfully to selecting compounds active against targets
in P. falciparum and T. brucei [72].
Table 5.1: Drug Targets Favored by Biotechnology Companies and the Tools Available to Tackle Them
Biotechnology Drug Discovery Tools
Target class
Compound libraries
High-throughput screening assays & screens
Crystal structures
Proteases
Yes
Yes
Yes
Proteasome
Yes
Yes
Yes
Metabolic enzymes
(DHFR, etc)
Yes
Yes
Yes
Phosphodiesterases
Yes
Yes
Yes
Protein farnesyltransferases
Yes
Yes
Yes
Ion channels
Yes
Yes
Models only
Kinases
Yes
Yes
Yes
Nucleic acid
– replication
– transcription
– purine salvage
– pyrimidine salvage
– other
Yes to all
Yes
Yes
Cytoskeleton
Yes
Yes
Yes
G protein-coupled receptors
Yes
Yes
Yes
Heat-shock proteins
Yes
Yes
Yes
Nuclear receptors
Yes
Yes
Models only
Figure 5.2: Target Classes Are Transferable Across Diseases
Table 5.2 presents a more detailed compilation of target
class overlap between small molecule drug discovery
companies and each pathogen. Below, we highlight three
major shared target classes: proteases, cyclic nucleotide
phosphodiesterases, and protein kinases.
Chronic Disease
Proteases cleave peptide bonds, breaking down proteins
into peptide chains or single amino acids. Drugs on the
market that target proteases include Tekturna® used to
treat hypertension and Kaletra® and Reyataz®, used to
treat HIV. Clinical trials are currently under way to test the
efficacy of various protease inhibitors as therapeutics for
hepatitis C and osteoporosis.
Inside a red blood cell, P. falciparum derives energy and
nutrients by breaking down hemoglobin. Hemoglobin
breakdown requires several P. falciparum proteases [73].
Among them, a cysteine protease subfamily known as falci-
Molecular Target
Neglected Disease
Cancer
Kinases
Malaria
TB
HAT
Cardiovascular
disease;
HIV
Proteases
Malaria
TB
HAT
Cancer
Farnesyl tranferases
Malaria
HAT
Central nervous
system diseases
Ion channels
Malaria
Cancer
Cytoskeletal proteins
HAT
Cardiovascular
disease;
Erectile
dysfunction
Phosphodiesterases
Malaria
HAT
Figure 5.3: Target Classes Shared by P. falciparum, M. tuberculosis, and T. brucei
Cytoskeleton
(flagella)
Phosphodiesterases
Glycosome
T. brucei
Nucleic
acid
Proteases
(transcription/
translation)
Kinases
Ion channels
P. falciparum
Metabolic
enzymes
Proteasome
M. tuberculosis
Cell wall
synthesis
pains has been validated and is being pursued as part of
a collaboration between MMV and GSK. As of late 2006,
these teams were selecting clinical candidates from the
falcipain inhibitor programs. The metalloprotease falcilysin
is another protease required for hemoglobin breakdown
and other functions. Its potential as a P. falciparum target
is currently under evaluation. Other proteases have been
validated in M. tuberculosis and T. brucei.
Cyclic nucleotide phosphodiesterases (PDEs) break
the phosphodiester bond found in cyclic nucleotides
involved in eukaryotic signal transduction. Inhibitors of the
PDE-5 subclass are used as vasodilators to treat pulmonary
arterial hypertension and erectile dysfunction (e.g., Viagra®).
New inhibitors of different PDEs are being pursued for
conditions ranging from depression to inflammation.
The T. brucei genome encodes five PDEs. The bloodstream
form of T. brucei cannot survive in the absence of two of
these enzymes, TbrPDEB1 and TbrPDEB2 [74]. Because
the catalytic sites of TbrPDEB1 and TbrPDEB2 are nearly
identical, it may be possible to design a single inhibitor of
both enzymes. PDEs are also considered validated targets
in P. falciparum [75].
Protein kinases are enzymes that transfer a phosphate
group from an adenosine triphosphate (ATP) molecule to
a protein substrate in a process called phosphoryation.
Kinases play fundamental roles in cell division and signal
transduction, processes that often malfunction in cancerous
cells. Kinase inhibitors hold enormous therapeutic potential for cancer. For example, Gleevec®, an inhibitor of
the protein kinase BCR-ABL, has been approved for use
in chronic myeloid leukemia and gastrointestinal stromal
tumors, and it is being pursued for treatment of a variety
of additional cancers. Because of their essential role in cell
proliferation, kinases may also be key targets in preventing
replication of infectious pathogens.
Table 5.2: Validated Targets in Neglected Disease Pathogens for Which the Tools and Expertise of Biotechnology Companies
Might Be Leveraged
Targets That Have Been Genetically and/or Chemically Validated by Pathogen
Target class
P. falciparum
M. tuberculosis
Proteases
– Serine
– Cysteine
– Other
Falcipains
Falcilysin (metalloprotease)
PDF (metalloprotease)
T. brucei
TbCatb, brucipain
mpa; paf; PrcBA
Proteasome
Metabolic enzymes
– Folate metabolism
– Fatty acid synthesis
– Glycolosis
– Other
DHFR-TS; dihydropteroate synthase
Fab H; FabI (apicoplast)
Lactate dehydrogenase
Phosphodiesterases
PfPDE1
TbrPDEB1; TbrPDEB2
Protein farnesyltransferases
PFT
TbPFT
Ion channels
PSAC
Kinases
PfMrk; PfMap1; PfNek-1; PfPKG
PknG
Nucleic acid
– DNA synthesis
– Transcription
– Purine salvage
– Pyrimidine salvage
– Other
DNA gyrase (apicoplast)
RNA polymerase (apicoplast)
PfNT1
Dihydroorotate dehydrogenase
DNA gyrase
rpoB
DHFR-TS
FabI Enoyl-ACP reductase (InhA)
Malate synthase (glcB)
Isocitrate lyase (ICL1/2)
Glycosome enzymes
Trypanothione reductase
Trypanothione synthase
Ornithine decarboxylase
CRK3, PK4, PK50
ATP synthase (AtpE)
CTP synthetase
Note: G protein–coupled receptors are not found in P. falciparum, M. tuberculosis, or T. brucei and thus have been omitted from this table. Similarly, nuclear receptors are not relevant to a nonnucleated organism such as M. tuberculosis and have not yet been validated for P. falciparum or T. brucei. Heat-shock proteins also
have not been validated for any of these pathogens.
All of the genes predicted to encode kinases (“the kinome”)
in P. falciparum and T. brucei have been described [76, 77].
For most of these genes, the biology remains to be worked
out, and few have been genetically or chemically validated.
Nonetheless, kinases involved in cell-cycle control have been
chemically or genetically validated for both P. falciparum
(PfMrk) [78, 79] and T. brucei (CRK3) [80, 81]. The latter is
one of several kinases actively pursued by the Dundee Drug
Discovery Initiative [82]. PknG, an M. tuberculosis kinase
required for bacterial survival within the host macrophage,
has also received attention as a new drug target [83, 84].
Applying target-focused tools and infra
structure to neglected disease drug discovery
How might the existing tools and infrastructure of
biotechnology be used to attack neglected diseases? A
particular strength of the biotechnology industry is the
diversity of approaches that are utilized to generate new
small molecule drugs, including compounds that inhibit a
single target class (see Sidebar 5.3). To commence a new
drug discovery program, at a minimum, a biotechnology
company would require a TPP and well-researched biological targets that can be assessed for chemical tractability. A
project is enhanced by availability of recombinant proteins,
assays for biochemical high-throughput, or whole-cell
screening and structural information. At least three
approaches can employ infrastructure and proprietary
technologies to produce optimized lead compounds:
High-throughput screening against
a conserved target
Certain pathogen targets have already been validated,
where biological function is comparable to that of a human
protein of the same target class. Here, a company could
apply the full complement of target-specific biotechnology
tools. First, the same high-throughput screening assay
format for identifying hits and leads for the chronic disease
target could be applied to the pathogen target. Second,
a target-focused compound library could be used for
screening, improving the odds of identifying hits and leads
that could be quickly confirmed to be structure dependent
and dose responsive. With the hope of rapidly identifying
an advanced candidate for proof-of-concept and animal
studies, lead compounds generated from other projects
might also be tested for inhibiting the pathogen target.
a conserved target class
In other cases, a target class is known to be essential
for viability or virulence in a pathogen, but specific
targets have yet to be validated. Using a focused
compound library, whole-cell screening could be
performed to identify compound hits that kill the
target pathogen. Chemogenomic approaches15 could
then be used to identify the specific protein in the
target class bound by the hit compound. With the
pathogen protein target in hand, leads could be
identified and further optimized. Alternatively,
high-throughput screening with a focused compound
library could be carried out on a panel of proteins
corresponding to a particular target class (e.g.,
pathogen kinases). Compounds that inhibit a specific
target class member and that kill the pathogen in vitro
would be selected for further evaluation.
a novel target class
Certain pathogen targets may be biologically validated
but do not correspond to families already explored
by companies. For example, genes of the apicoplast
(an ancient, nonphotosynthetic plastid) in P. falciparum
are required for survival but have no homologs in
mammalian cells. Yet there are still ways to utilize
biotechnology assets against these targets. In contrast to
target-specialized companies, companies with generalized discovery platforms have compound libraries that
emphasize chemical diversity and drug-like properties
over other considerations.
A potential disadvantage of drug discovery performed
on a novel target is the lack of preexisting assays,
structural information, and lead compounds from
related target-focused approaches. Furthermore, starting
a program on a novel target may require more time
and funding than a program based on membership
in a well-validated target class. Nonetheless, there are
potential advantages in safety and specificity when
selecting targets present within organelles or metabolic
pathways that are found exclusively in the pathogen
because of fewer nonspecific interactions.
15 Chemogenomics is the systematic analysis of chemical-biological interactions, specifically the investigation of classes of compounds (libraries)
against families of functionally related proteins.
The case for further exploration
Several of the companies we interviewed have investigated applying their platform technologies and proprietary compound libraries to neglected diseases. On their
own, or in collaboration with academic researchers, a
number have carried out early-discovery efforts. Of the
companies we interviewed, nine either had a compound
they considered worth testing on a neglected disease
or have been in active collaborations with neglected
disease researchers. In nearly every case, interest in
a neglected disease was driven by target homologies
that suggested new utilities for existing compound
sets, many of which were synthesized as candidates for
chronic disease indications.
Unfortunately, most of these efforts were not pursued
further because any or all of the following reasons: inability
to obtain funding, lack of preclinical pharmacology
support, high opportunity costs, or absence of a clear route
to commercialization. These initial efforts nonetheless indicate that biotechnology company participation is a problem
of incentives, not capabilities.
Chapter 6 details the hurdles to biotechnology company
involvement in neglected disease drug discovery. We also
present ways in which these problems might be overcome.
Sidebar 5.3: Harnessing diverse biotechnology solutions
A major strength of the biotechnology industry is the diversity
of approaches to inhibitor design, even when the inhibitors
target the same protein class. For example, protein kinases are
enzymes involved in signal transduction through which cell
growth, morphology, and movement are regulated. Nine of the
50 companies we examined focus exclusively on protein kinases.
Thirty (or 60 percent) of them have at least one kinase program.
Approaches used to generate inhibitors include the following:
ATP-binding pocket inhibitors. Small molecules that bind to
and block access to the ATP-binding domain of a protein kinase
serve to turn off its function. Because ATP-binding domains
are highly conserved among protein kinases, finding inhibitors
with sufficient target specificity has proven daunting, and new
approaches are now favored.
Allosteric inhibitors. An allosteric site refers to a protein
surface feature that when bound by an inhibitor changes the
protein’s conformation to become enzymatically inactive.
Allosteric sites among kinases are not highly conserved. By
selecting for compounds that bind to a target protein kinase’s
allosteric site, high levels of specificity can be achieved.
Additionally, inhibitors bound to allosteric sites have longer
“off rates” than those bound to the ATP-binding site, a
characteristic that makes the inhibitor more potent.
Fragment approach to inhibitors. Knowing the structure of the
kinase of interest, “fragments” of small molecules are tested by
computational modeling for the ability to bind specific nooks
of the ATP-binding site. Combinations of fragments are then
assembled into single molecules, tested for inhibitory effects
and co-crystallized with the kinase target to allow their quality
of fit within the binding site to be evaluated and improved.
Those deemed most promising are modified iteratively until
high affinity binding is achieved.
Modular approach to inhibitors. This approach relies on linking
small molecules that bind independent sites on the kinase,
thereby increasing their specificity and avoiding toxicity.
Although an individual module may bind a kinase only weakly,
once modules are united into a single molecule high binding
affinity can be achieved.
ATP-binding
pocket inhibitors
Allosteric
inhibitors
Discover compounds
that bind specifically
to the ATP-binding
pocket
Discover compounds
that bind to
allosteric sites
ATP
x
ATP Binding
Pocket
Kinase
ATP
x
Allosteric
Site
Kinase
Fragment
approach
Modular
approach
Build compounds
with high binding
affinity from small
chemical fragments
Link compounds that
bind to adjacent sites
ATP
x
Kinase
ATP
x
Kinase
Adjacent Domain
Any of the above approaches could be applied to kinase or nonkinase targets
identified in P. falciparum, M. tuberculosis, T. brucei, or any other neglected disease pathogen. Depending on the information available, one approach
might be significantly favored over others. Importantly, the diversity of
approaches developed for kinase inhibitor discovery typifies the diversity of
approaches for other target classes.
Sources: Company websites including Ambit, Kémia, Plexxikon, and Sunesis
Chapter 6: Building a New Discovery Pipeline
Although biotechnology companies possess technologies
and expertise that could accelerate drug discovery and
development for neglected diseases, information, managerial, and financial hurdles have hindered their participation in global health. This chapter explores a range
of ways to summon the most experienced and capable
innovators; forge partnerships among companies, PDPs,
and academia; and fund and manage the most promising
drug discovery projects.
The Current Landscape
Leading public sector organizations have recognized the
need to close the innovation gap by increasing effort
and investment in drug discovery. PDPs such as the TB
Alliance and MMV sponsor several million dollars per year
of drug discovery work at major pharmaceutical companies
such as GSK and Novartis, along with smaller collaborations with several biotechnology firms [21, 85].
To help build the foundation of biological knowledge and
discovery tools available to drug hunters, several public
sector initiatives have been launched in the past few years.
They include—
n The Gates Grand Challenges in Global Health,
with $436 million of basic research funding
awarded in 2005 [86];
n The $40 million Gates Foundation–sponsored TB
Drug Accelerator announced in 2006 [67]; and
n The Pathogen Sequencing Unit, part of the £334
million Wellcome Trust Sanger Institute [87].
Academic research institutions have also formed centers
of excellence and consortiums to target drug discovery for
neglected diseases and bolstered their efforts by key hires
from industry [88]. Examples include:
n The Tropical Disease Drug Discovery Initiative
at the University of Dundee, focused on
trypanosomatids;
n The Sandler Center at the University of California
at San Francisco, focused on parasitic diseases; and
n The Consortium for Parasitic Drug Development
at the University of North Carolina, focused on
trypanosomatids.
Additionally, two Seattle-based nonprofit research institutions have dedicated efforts to innovate new drugs and
vaccines for neglected diseases. The Infectious Disease
Research Institute (IDRI) was founded in 1993 and has
multifaceted programs in a number of neglected diseases
including TB, Chagas disease, and leishmaniasis. The
Seattle Biomedical Research Institute (SBRI) was founded
in 1976 and has research efforts under way on numerous
bacterial, viral, fungal, and parasitic diseases. In 2007 IDRI
and SBRI announced a partnership with Eli Lilly around
TB drug discovery [89].
These encouraging initiatives show that the public sector
recognizes the innovation gap and is developing ways to
address it. But building translational capability in academia
is unlikely to be enough to close the innovation gap.
Purchasing compound libraries, building drug discovery
infrastructure, and hiring the necessary expertise is expensive and time consuming.
To fill this gap academic institutions are beginning to
“integrate forward,” developing programs in translational
research. PDPs are also beginning to “integrate backward,” building preclinical capabilities. However, whether
the two “meet in the middle” remains to be seen. More
importantly, these public sector initiatives aren’t leveraging the potent capabilities and infrastructure of the
biotechnology industry.
Hurdles to biotechnology participation
In discussions with biotechnology companies, we found
a strong desire to tackle the problems of global health.
While they must satisfy their obligations to shareholders,
many industry leaders are inspired by the chance to
make a difference for millions of underserved patients.
Biotechnology executives recognize that new models and
new incentives will be instrumental to building the pipeline for global health.
To engage their companies in the battle against neglected
diseases, biotechnology leaders need to address three key
hurdles (Figure 6.1):
n
n
n
Information hurdles. They need to become much
more familiar with neglected diseases, potential
markets, and prospective partners;
Managerial hurdles. They need to build expertise in
managing collaborations with prospective partners
in the not-for-profit and academic sectors; and
Financial hurdles. They need market incentives to invest
in R&D and overcome “opportunity cost”—the profit
lost by not working on a core business project.
Information hurdles
A key challenge for bringing biotechnology resources to
bear is identifying opportunities and convening collaborators. Biotechnology companies lack expertise in neglected
diseases, while academic institutions and PDPs lack deep
familiarity with the proprietary tools available in the
biotechnology industry. Efforts must be made to educate
both sectors and bring these groups together.
BVGH is devoted to bridging this information gap, forming
coalitions around specific discovery opportunities to build
the global health product pipeline. Many attractive collaboration opportunities exist, but they will not happen without
diligent efforts to bring decision makers together and illustrate how collaborations can serve their interests.
Managerial hurdles
Biotechnology companies are particularly concerned about
the costs of project management. For a biotechnology
company to manage a neglected disease drug discovery
project on its own, foreseeable tasks include securing
grant funding, managing staff, linking drug discovery
efforts with a specific target product profile, and coordinating with academic and PDP collaborators for capabilities not available in-house. Biotechnology company
managers are unlikely to have neglected disease expertise. Assembling expertise internally would distract from
their core business. To the extent that neglected disease
drug discovery projects can be managed externally, these
concerns can be relieved.
Financial hurdles
Financial hurdles for biotechnology companies stem from
insufficient market “pull,” lack of excess capital to support
discovery R&D, and the opportunity cost of allocating
resources to a neglected disease project. Unlike large pharmaceutical companies, biotechnology companies are often
cash-constrained and must triage short-term choices in
favor of the greatest value to their investors. Resources are
often tightly budgeted to support programs that will move
rapidly toward approved products for high-value markets.
Figure 6.1: Hurdles to the Biotechnology Industry’s Involvement in Neglected Disease Drug Discovery
Hurdles
Information
Hurdle
Potential
Solution
Managerial
Financial
Companies lack access
to and experience with
neglected disease science
Companies cannot devote
management time to
non-core activities
Companies require market
incentive and funding to
overcome opportunity costs
Establish links between
neglected disease-focused
academic groups and
companies
External project
management and champions
are needed to guide projects
through discovery
Appropriate financial
incentives must be in place
Match the right companies
to the right science
Intellectual property and
collaboration templates are
needed
For diseases affecting the developing world, lack of credible market opportunities and information on viable
markets is a significant barrier to entry for innovators.
Biotechnology companies’ reliance on pharmaceutical
companies and investors to finance their R&D programs
is critically tied to the convincing demonstration of a
future product’s market viability. In the case of neglected
diseases, the limited purchasing power of developing countries and the poor expected return on investment makes
attracting such private capital or pharmaceutical partners
particularly difficult.
the hundreds of millions of dollars, to develop and market
these products. These companies are not in business to
provide research services in return for cost coverage and a
slight profit. More importantly, the cash required for clinical
development usually dwarfs what is available through grant
support. In fact, biotechnology companies are especially
wary of grant cycles at odds with their time requirements for
producing results. For example, many companies estimate
that lead optimization requires 10–12 chemists for up to
three years and over $10 million to generate a development
candidate (Figure 6.2). So a grant for lead optimization
lasting only one year would not be long enough for the team
to make progress. Biotechnology companies consider typical
grant cycles (often annual) too short for these projects, so
other, longer-term arrangements are needed.
Further, direct support (“push funding”—see below) alone
will not lead most companies—particularly the most capable
innovators—to allocate sufficient resources, typically in
Figure 6.2: The Costs of Producing a Single New Drug*
1
Year
Screening
for Hits
2
3
Lead
Identification
4
5
Lead Optimization
6
Preclinical
7
8
Phase I
9
10
Phase II
11
Phase III
Clinical Trials
50
45
43
43
Annual Cost in Millions ($)
35
30
25
20
15
15
12
12
10
5
3.3
0.8
3.3
3.3
1.5
0.8
0
$0.8 M
$1.6 M
$11.6 M
$13.1 M
$28.1 M
$52.1 M
~$138.1 M
Cumulative Cost per Program
*Excludes the costs of failure
Sources: Adams, C.P., and Brantner, V.K. Estimating the cost of new drug development. Health Affairs 25 (2): 420 – 428 (2006)
as cited in Parexel’s R&S Statistical Sourcebook 2006/2007 and BVGH/L.E.K. interviews and analysis
Finally, other costs—particularly opportunity costs—
cannot be underestimated. Biotechnology companies
operate at capacity, especially with regard to medicinal
chemistry. So there are significant costs to reallocating staff
for a neglected disease project. These costs consist of direct
labor (e.g., chemist and biologist salaries), indirect overhead (e.g., allocation of discovery assets), and opportunity
cost. For biotechnology companies to engage in neglected
disease drug discovery, a substantial portion of these costs
must be addressed by external funding.
Engaging the biotechnology industry
It is unlikely that biotechnology companies will overcome these hurdles on their own. Their immediate
economic concerns keep them too focused on developing drugs for developed-world markets. Only a few
dozen of the 1,500 U.S. and European institutionallybacked biotechnology companies are profitable; none of
the rest has positive cash flow to support even modest
philanthropy. Thus, accessing biotechnology assets for
global health product development is most likely to be
achieved by new “push” and “pull” financial incentives.
Push incentives are direct funding to reduce the risk
and cost of R&D. Pull incentives enhance the market to
encourage new R&D.
Examples of push incentives include:
n Grants to fund early-stage R&D, including
through the U.S. National Institutes for Health or
the UK Medical Research Council.
n Tax credits that allow companies to reduce their
tax liability by deducting R&D expenditures.
Examples of pull incentives include:
n Advance Market Commitments that guarantee
markets for new medicines in developing
countries [90].
n Transferable “priority” vouchers to speed up
regulatory review, provided to companies upon
approval of a developing-world vaccine or drug.
n Willingness of donors, PDPs, or pharmaceutical
companies to pay a “risk premium” to license new
medicines that have shown proof-of-concept such
as phase II efficacy and safety.
Models for increasing industry engagement
in neglected disease drug discovery
We explored several different models for overcoming the
hurdles to industry participation in neglected disease drug
discovery: subcontracting to biotechnology companies
directly, building partnerships, donor-directed portfolio
management, and establishing a discovery-focused PDP.
Subcontracting to biotechnology companies
In selected cases, PDPs have forged new alliances with
biotechnology companies, allowing them access to
advanced drug discovery technologies and compound
libraries that exist nowhere else. An example of this
approach is the collaboration launched in 2006 between
the TB Alliance and BG Medicine, Inc., to identify novel
tuberculosis biomarkers [91].
The advantage of this approach is that PDPs act as “portfolio
managers.” They have a strong command of their diseases
and can offer biotechnology much-needed guidance on TPPs.
Leadership and program management can remain centered
on the PDP, minimizing the need for joint development
committees or other overarching management structures.
The limitation to this approach is that not all PDPs are
set up to take full advantage of discovery technologies in
industry. In some cases, the formation of drug discovery
alliances will require a shift in managerial focus. This is
because drug development and drug discovery are very
different processes. If PDPs were to seek to integrate
upstream into discovery, they would need to add managerial talent with particular experience in managing industrial-scale, small molecule discovery projects.
Building partnerships
Another model is to form more expansive partnerships
among biotechnology companies, PDPs, and academic
institutions. Partnerships can maximally leverage biotechnology expertise, proprietary technology, and infrastructure. These partnerships need leadership and operational
management to leverage the strengths of each participant.
Some discovery efforts can be initiated through biotechPDP or biotech-academia collaborations; others will require
the participation of all three.
As an example of how academia, PDPs, and biotechnology
companies can work together, in 2006, The Broad Institute,
MMV, and Genzyme Corporation announced a collaboration
to target malaria. The Broad Institute contributes genomics
expertise for understanding malaria disease mechanisms.
MMV brings expertise in malaria drug development.
Genzyme offers small molecule drug discovery capabilities.
The collaborators have four early-discovery projects and
hope to attract additional resources and funding [92].
New independently generated partnerships might work
in a similar fashion. The biotechnology company would
rapidly apply its target-based expertise, screening, hit-tolead capabilities, and proprietary compound libraries while
taking advantage of the academic center’s disease expertise
and biochemical assay systems. The PDP would provide
downstream know-how, market knowledge, and access to
donors, regulatory information, and the global community.
Ownership of compounds, targets, and other intellectual
property could be shared or reside with the party taking
the lead in the collaboration.
Donor-directed portfolio management
A third approach is to create management structures
within donor organizations or to engage independent
portfolio managers funded by donor organizations. Two
leading examples for donor-directed portfolio management are the Cystic Fibrosis Foundation Therapeutics,
Inc., (CFFT) and the Wellcome Trust (WT). CFFT
was created by the Cystic Fibrosis Foundation to fund
and manage collaborations with industry to invent and
develop new cystic fibrosis therapeutics. CFFT translates
basic research from academia into product discovery and
development by industry. CFFT identifies opportunities, performs due diligence, negotiates partnerships, and
provides product management. Like its parent foundation,
CFFT is nonprofit.
CFFT R&D funding was over $66 million in 2005, much
of which went into early-stage product discovery. CFFT
funds provide sufficient incentive for companies to work
on what is otherwise an “orphan” disease, where the
market is too small to earn a return that competes with
disease indications like diabetes or hepatitis C.
The Wellcome Trust also funds translational and product
discovery work around specific goals and initiatives. WT
is as willing to fund R&D in the private sector as it is in
academia—what counts is whether the R&D contributes
to the goal. An example of a WT initiative is a set of strategic translation awards in Seeding Drug Discovery [93].
This £91 million initiative “to develop drug-like, small
molecules will be the springboard for further research and
development by the biotechnology and pharmaceutical
industry in areas of unmet medical need.” WT evaluates,
negotiates, coordinates, and manages these efforts.
In these two instances, the foundations decided to be direct
investors and coordinators and obtained infrastructure and
expert staff for long-term management of their programs.
Critically, they have included staff with industry experience
and did not exclude private companies as grant recipients.
Externally structured, discovery-focused PDPs
An alternative, with potentially greater flexibility across
multiple diseases, is for donors to support a discoveryfocused PDP. To deploy tens of millions of dollars of
neglected disease drug discovery funding investment each
year, the community may benefit from funding a PDPlike organization specialized in working across diseases
to form new drug discovery coalitions. This portfoliomanagement organization would independently source,
negotiate, and manage partnerships with public and
private sector participants.
This approach would mirror the R&D structure in several
pharmaceutical companies, where R&D programs are
organized vertically by disease, while drug discovery is
organized horizontally and tasked with delivering new
lead candidates to the development staff across multiple
diseases.
Such an approach could be virtual, as adopted by “vertical”
PDPs that focus on a single disease such as MMV and the
TB Alliance. Or it could focus on one or more centers of
excellence with a core group of scientists responsible for
collaborations with biotechnology companies and academia
and managing key steps in the discovery process for a
number of diseases.
A discovery-focused PDP could overcome the key information and managerial hurdles preventing the formation of
new discovery partnerships (Figure 6.3). It could provide
dedicated project management essential to coordinating
efforts involving multiple participants. And it could
address the financial hurdles by helping to secure R&D
funding and identify potential “hand-offs” to PDPs and
large pharmaceutical companies.
n
n
Managerial Capabilities:
n
Operationally, a discovery-focused PDP will need to
assemble the informational, managerial, and financial
capabilities and resources needed to establish productive
collaborations.
n
Informational Capabilities:
n
n
Convene Leading Academics: Academic experts
will be needed to select drug targets, assay
technologies, and tools for pathogen manipulation.
Identify Industry Collaborators: Deep knowledge of
biotechnology capabilities will be needed to match
the right companies with the right academic
science and projects.
Drive Science Transfer: An ability to guide the
process of transferring academic science into
biotechnology discovery assets will be needed.
Invest in Gaps: Research funding is required
to overcome gaps in research tools needed for
neglected disease drug discovery.
n
Project Champion: The discovery-focused PDP will
need to function as an external project champion
to ensure that biotechnology companies give
neglected disease drug discovery collaborations
appropriate attention.
Provide Project Management: Duties include
coordinating grant support, managing staff, and
guiding programs toward target product profiles
that allow biotechnology companies minimal
distraction from their core businesses.
Manage Timelines: Grant support must be aligned
with realistic timelines for lead identification and
optimization programs instead of the annual grant
cycles. This will enable biotechnology companies to
staff neglected disease discovery programs efficiently.
Figure 6.3: Possible Roles for a Discovery-Focused PDP
Funding Organizations
$$$
Project Management/Coordination
Hurdles to Address
Coordinate partnerships
between neglected disease
scientists and biotechnology
companies
Provide external project
management/champions
Coordinate hand-offs
to PDPs or
pharmaceutical
companies
Provide access to
neglected disease
expertise
Development
Candidates
Targets
Academic Science
Biotechnology Companies
Product
Development
Partnerships
n
n
Coordinate Exits with Other PDPs: Preestablished
exits of development candidates into PDP
portfolios will ensure that biotechnology resources
can continue through development.
Take Calculated Risks: To fill the pipeline a large
portfolio of projects is needed. Failing projects
must be quickly winnowed to maximize the
overall probability of success of the portfolio.
Financial Capabilities:
n
Provide Funding: The discovery-focused PDP will
provide direct financial support to its partnerships.
Clearly there are substantial challenges to creating such
an organization. But the advantages are impressive—
including independence, focus, ability to work with public
and private organizations alike, ability to attract talented
staff (particularly with industry experience), and flexibility
to capitalize on emerging opportunities.
Sidebar 6.1: Solving the innovation gap for neglected disease drug discovery:
How much will it cost?
The discovery programs we are advocating for neglected diseases can take advantage of existing R&D infrastructure
in industry, but they will nonetheless incur the variable costs of actually performing the research. Costs for neglected
disease drug discovery are likely to be similar to those for developed-world diseases, and they may actually be
higher because the specifications for affordability, oral delivery, and thermostability may “raise the bar” for selecting
compounds that could enter the clinic.
We found that “top down” and “bottom up” analyses yielded similar answers: roughly $40 million per year in discovery
R&D funding for each disease to yield a minimum flow of clinical candidates and the potential for a new approved
drug every three to five years.
In a recent article, Hopkins et al. reckoned that a single discovery program costs on average $20 million to generate a
single clinical candidate [94]. For anti-infectives, they estimated attrition rates of 84 percent, meaning that six such
programs are needed to generate a single approved drug.
A small biotechnology company with a robust discovery platform typically spends $20 million per year on earlystage R&D, and it may have between three and six programs running in parallel. For a developed-world disease such
as diabetes, dozens of biotechnology companies will be taking different approaches to the problem. Since R&D
success in any one group experiences periods of productivity and drought, success and failure, sustained effort of
“two biotechnology company units” of discovery R&D seems the minimum commitment required to smooth out
variability in rates of attrition. The advantage of harnessing industry resources is that a large number of screening and
hit-generation projects can be undertaken in parallel at low cost to identify the most promising approaches across
multiple platforms.
We estimate the investment in malaria and tuberculosis therapeutic R&D at roughly $100 million worldwide each.
The majority of this investment is in development, with a smaller portion devoted to discovery. If we apply the
pharmaceutical industry allocation of 35 to 40 percent of R&D to discovery, this would argue for an additional $50
million investment in discovery R&D for each disease at a minimum.
We analyzed in detail the discovery R&D costs of a “model” biotechnology company running three discovery
programs in parallel. Each costs a little more than $13 million over a three-year period, yielding a $40 million steadystate run rate. Notably, costs in the earliest stages were under $2.5 million to get to a “lead” molecule, which allows
considerable winnowing and optimization before larger commitments are made. Our estimate of discovery spending
matches DiMasi et al.’s (2003) estimates [95] of variable costs for discovery to preclinical research. It also matches
estimates of discovery spending per IND filed over the past three to five years [27].
Taken together, the evidence supports the idea of highly-focused, tightly-managed programs building to a $40 million
per-year investment in drug discovery for each of the neglected diseases.
Chapter 7: Conclusions and Recommendations
The biotechnology and pharmaceutical industries have
invested billions of dollars in building small molecule
drug discovery capabilities. These companies possess
target expertise and compound libraries highly applicable to neglected diseases. Therapeutic R&D for
neglected diseases will proceed most effectively by
enlisting the biopharmaceutical industry’s infrastructure, drug discovery capabilities, and expertise. Engaging
the biotechnology industry will accelerate the arrival of
better medicines for neglected diseases.
The companies best able to meet the challenges of drug
discovery for the three neglected diseases selected for this
report are those that focus on small molecule drugs and
that have advanced novel small molecules into clinical
development. Approximately 120 biotechnology companies—of the many that could contribute to global health—
are particularly well matched for these criteria. They have
discovered and developed some of the most innovative
new small molecule therapies, including ones targeting
HIV and cancer.
Groups in the public sector have succeeded in pushing
forward new therapies for neglected disease. Despite their
many achievements, an innovation gap remains that limits
the translation of academic discoveries in disease biology
into new medicines. Unless this gap is closed, neglected
disease pipelines will generate far fewer drugs in the long
term. Based on experience with antibiotics and anti-virals,
we may reasonably expect that drug-resistant pathogens
are going to emerge and thus compromise existing medicines. Without more new drugs, many more years will pass
before neglected diseases are called neglected no longer
and are brought under control.
Key findings from our review of select drug
discovery companies
n Extensive Experience: The companies we examined
in depth have impressive accomplishments
in launching small molecule drugs and have
ongoing discovery and development programs
and alliances.
n Existing Infrastructure: Billions of dollars in equity
financing have allowed these companies to create
infrastructure and expertise in small molecule
drug discovery that would be prohibitively time
consuming and costly to duplicate.
n Overlapping Targets and Technologies: Target-based
discovery assets are potentially applicable to
analogous systems in neglected disease pathogens.
n Significant Interest: Biotechnology companies are
interested in participating in neglected disease
drug discovery to extend the reach of their
technologies, establish relationships with larger
companies, and contribute to global health.
n Obstacles to Participation: Though biotechnology
companies are interested in participating in global
health campaigns, scientific, managerial, and
especially, financial issues prevent them from
doing so.
Leading biotechnology companies recognize the tremendous unmet needs in global health. Many are seeking ways
to participate that are consistent with their business strategies and limited cash resources. They are open to applying
their capabilities through R&D collaborations with disease
experts in PDPs and academia. Such collaborations will
leverage small molecule discovery infrastructure, accelerate
innovation, and address the innovation gap in neglected
disease drug discovery most efficiently.
Recommendations
1. The biotechnology industry’s most capable
innovators have an integral role in closing
the innovation gap. Biotechnology companies have
track records of employing advanced technologies to create
new therapeutics that have met with success in human
clinical trials. This expertise can and should be applied to
neglected diseases.
2. New partnerships are needed to lower
barriers for biotechnology companies to
invest their resources. Most biotechnology compa-
nies are unfamiliar with neglected diseases. To take advantage of their technology platforms, they need to access
disease expertise and biochemical assays that are resident in academia, research institutions, and PDPs. R&D
collaborations are the best way to combine strengths and
increase productivity.
3. Expanded research funding is needed to
build an early-stage pipeline. To produce a new,
approved therapeutic every three to five years for a single
disease, the minimum investment required for new
discovery R&D is comparable to the annual funding for
two small biotechnology companies—increasing over
several years to roughly $40 million per year per disease.
This investment will fund several parallel drug discovery
programs and accommodate attrition at typical industry
rates while allowing surviving programs to enter preclinical
development.
Among the options:
n Independent consortiums of companies, academic
labs, and PDPs that work together to transform
neglected disease drug targets into optimized lead
compounds and preclinical drug candidates.
n Direct donor investment in company-led
programs with accompanying R&D management
and monitoring.
n Creation of a discovery PDP that can serve
as a “portfolio manager” for new neglected
disease discovery programs with a mission of
augmenting the pipelines of existing PDPs. Such
an organization could efficiently enlist the most
experienced innovators; forge partnerships among
companies, development-focused PDPs, and
academics; and manage and monitor numerous
discovery projects.
Biotechnology companies could contribute substantially
to the discovery and development of new therapeutics for
neglected diseases. This document provides a road map
for enlisting their capabilities in this fight. By employing
existing advanced drug discovery technologies, donor
community funds will be used to maximum effect, novel
drugs will be developed faster, and more lives will be saved.
4. Effective investment will depend on dedicated portfolio managers. Many of the current
participants in global health product development lack
deep expertise in managing early-stage drug discovery. The
scope of the partnerships and investments we recommend
call for project management capabilities that would stretch
the current capabilities of any single public sector organization. Dedicated project management to maximize R&D
productivity can be infused into PDPs or donor organizations, or it can be built as an independent discovery PDP.
References
1. Sachs, J.D., Helping the World’s Poorest, The Economist.
August 14, 1999.
17.Chirac, P., and E. Torreele, Global framework on essential
health R&D. Lancet, 2006. 367(9522): p. 1560-1.
2. Cohen, J., Global health. The new world of global health.
Science, 2006. 311(5758): p. 162-7.
18.PhRMA. R&D spending by U.S. Biopharmaceutical
Companies Reaches a Record $55.2 Billion in 2006. 2007;
[cited September 5, 2007]; available from: http://www.phrma.
org/news_room/press_releases/r%26d_spending_by_u.s._
biopharmaceutical_companies_reaches_a_record_%2455.2_
billion_in_2006/.
3. Harries, A.D., and C. Dye, Tuberculosis. Ann Trop Med
Parasitol, 2006. 100(5-6): p. 415-31.
4. Baird, J.K., Effectiveness of antimalarial drugs. N Engl J
Med, 2005. 352(15): p. 1565-77.
5. Fairlamb, A.H., Chemotherapy of human African
trypanosomiasis: current and future prospects. Trends Parasitol,
2003. 19(11): p. 488-94.
6. Centers for Disease Control and Prevention. The Deadly
Intersection between TB and HIV. 1999; [cited September 5,
2007]; available from: http://www.cdc.gov/hiv/resources/
factsheets/hivtb.htm.
7. Munro, S.A., et al., Patient adherence to tuberculosis
treatment: a systematic review of qualitative research. PLoS
Med, 2007. 4(7): p. e238.
8. Gandhi, N.R., et al., Extensively drug-resistant tuberculosis
as a cause of death in patients co-infected with tuberculosis and
HIV in a rural area of South Africa. Lancet, 2006. 368(9547):
p. 1575-80.
9. Dorman, S.E., and R.E. Chaisson, From magic bullets back
to the magic mountain: the rise of extensively drug-resistant
tuberculosis. Nat Med, 2007. 13(3): p. 295-8.
10.Pecoul, B., New drugs for neglected diseases: from pipeline
to patients. PLoS Med, 2004. 1(1): p. e6.
11.Pepin, J., and F. Milord, The treatment of human African
trypanosomiasis. Adv Parasitol, 1994. 33: p. 1-47.
12.UNICEF/UNDP/World Bank/WHO Special Programme for
Research & Training in Tropical Diseases (TDR), Drug Discovery
and Drug Development. March 2004.
13.GAO, New Drug Development: Science, Business, Regulatory,
and Intellectual Property Issues Cited as Hampering Drug
Development Efforts, U.S.G.A. Office, Editor. 2006. p. 1-52.
14.PhRMA, Drug Discovery and Development: Understanding the
R&D Process. 2007. [cited October 28, 2007]; available from
http://www.phrma.org/files/RD%20Brochure%20022307.pdf.
15.Duyk, G., Attrition and translation. Science, 2003.
302(5645): p. 603-5.
16.Trouiller, P., et al., Drugs for neglected diseases: a failure
of the market and a public health failure? Trop Med Int Health,
2001. 6(11): p. 945-51.
19.Malaria Research & Development Alliance, Malaria Research
& Development: An Assessment of Global Investment. 2005.
20.Feurer, C., Tuberculosis Research & Development: A Critical
Analysis, J. Syed, M. Harrington, and B. Huff, Editors. 2006.
21.Moran, M., A breakthrough in R&D for neglected diseases:
new ways to get the drugs we need. PLoS Med, 2005. 2(9): p.
e302.
22.Medicines for Malaria Venture, Product Profiles for
Antimalarial Drugs. 2006. p. 1-8.
23.Nwaka, S., and A. Hudson, Innovative lead discovery
strategies for tropical diseases. Nat Rev Drug Discov, 2006.
5(11): p. 941-55.
24.The Working Group on new TB drugs, Strategic Plan: Stop TB
Partnership Working Group on New TB Drugs. 2006.
25.Harper, C., Tuberculosis, a neglected opportunity? Nat Med,
2007. 13(3): p. 309-12.
26.Casenghi, M., Development of new drugs for TB
chemotherapy: analysis of the current pipeline. 2006, Campaign
for Access to Essential Medicines: Medecins Sans Frontieres.
27.L.E.K Consulting, 2007.
28.Medicines for Malaria Venture, Annual Reports. 2001-2006.
29.Drugs for Neglected Diseases Initiative, Report of
Independent Auditors: Financial Statements. 2005.
30.Global Alliance for TB Drug Development, Annual Report.
2005-2006.
31.Ridley, R.G., Medical need, scientific opportunity and the drive
for antimalarial drugs. Nature, 2002. 415(6872): p. 686-93.
32.Renslo, A.R., and J.H. McKerrow, Drug discovery and
development for neglected parasitic diseases. Nat Chem Biol,
2006. 2(12): p. 701-10.
33.Austin, C.P., et al., NIH Molecular Libraries Initiative.
Science, 2004. 306(5699): p. 1138-9.
34.Butler, D., Lost in translation. Nature, 2007. 449(7159):
p. 158-9.
35.Stockwell, B.R., Exploring biology with small organic
molecules. Nature, 2004. 432(7019): p. 846-54.
36.Anonymous, The academic pursuit of screening. Nat Chem
Biol, 2007. 3(8): p. 433.
37.Burrill & Company, Biotech 2006: Life Sciences: A Changing
Prescription. 2006.
38.BIO. Approved Biotechnology Drugs [cited August 22,
2007]; available from: http://bio.org/speeches/pubs/er/
approveddrugs.asp.
39.Burrill & Company, Biotech 2007. 2007.
40.Lipinski, C.A., et al., Experimental and computational
approaches to estimate solubility and permeability in drug
discovery and development settings. Adv Drug Deliv Rev, 2001.
46(1-3): p. 3-26.
41.Van Brunt, J., Banner Year for Biotech Drugs. Signals
Magazine. March 13, 2007.
42.Kneller, R., The origins of new drugs. Nat Biotechnol, 2005.
23(5): p. 529-30.
43.Fox, S., et al., High-throughput screening: update on
practices and success. J Biomol Screen, 2006. 11(7): p. 864-9.
44.Greenwood, B.M., et al., Malaria. Lancet, 2005.
365(9469): p. 1487-98.
45.Smith, I., Mycobacterium tuberculosis pathogenesis and
molecular determinants of virulence. Clin Microbiol Rev, 2003.
16(3): p. 463-96.
46.Fevre, E.M., et al., Human African trypanosomiasis:
Epidemiology and control. Adv Parasitol, 2006. 61: p. 167-221.
47.Seed, J.R., African trypanosomiasis research: 100 years
of progress, but questions and problems still remain. Int J
Parasitol, 2001. 31(5-6): p. 434-42.
48.Balu, B., and J.H. Adams, Advancements in transfection
technologies for Plasmodium. Int J Parasitol, 2007. 37(1): p. 1-10.
49.Brun, R., and O. Balmer, New developments in human
African trypanosomiasis. Curr Opin Infect Dis, 2006. 19(5): p.
415-20.
50.Balganesh, T.S., V. Balasubramanian, and S.A. Kumar, Drug
discovery for tuberculosis: bottlenecks and path forward. Current
Science, 2004. 86(1): p. 167-76.
51.Zhang, Y., K. Post-Martens, and S. Denkin, New drug
candidates and therapeutic targets for tuberculosis therapy.
Drug Discov Today, 2006. 11(1-2): p. 21-7.
52.Cole, S.T., et al., Deciphering the biology of Mycobacterium
tuberculosis from the complete genome sequence. Nature,
1998. 393(6685): p. 537-44.
53.Gardner, M.J., et al., Genome sequence of the human
malaria parasite Plasmodium falciparum. Nature, 2002.
419(6906): p. 498-511.
54.Berriman, M., et al., The genome of the African trypanosome
Trypanosoma brucei. Science, 2005. 309(5733): p. 416-22.
55.Hall, N., et al., A comprehensive survey of the Plasmodium
life cycle by genomic, transcriptomic, and proteomic analyses.
Science, 2005. 307(5706): p. 82-6.
56.El-Sayed, N.M., et al., The genome sequence of
Trypanosoma cruzi, etiologic agent of Chagas disease. Science,
2005. 309(5733): p. 409-15.
57.Ivens, A.C., et al., The genome of the kinetoplastid parasite,
Leishmania major. Science, 2005. 309(5733): p. 436-42.
58.Peacock, C.S., et al., Comparative genomic analysis of three
Leishmania species that cause diverse human disease. Nat
Genet, 2007. 39(7): p. 839-47.
59.Anonymous. TubercuList [cited September 5, 2007];
available from: http://genolist.pasteur.fr/TubercuList/.
60.Wellcome Trust Sanger Institute [cited September 4,
2007]; available from: http://www.sanger.ac.uk/Projects/
Pathogens/.
61.Stoeckert, C.J., Jr., et al., PlasmoDB v5: new looks, new
genomes. Trends Parasitol, 2006. 22(12): p. 543-6.
62.Beverley, S.M., Protozomics: trypanosomatid parasite
genetics comes of age. Nat Rev Genet, 2003. 4(1): p. 11-9.
63.Murry, J.P., and E.J. Rubin, New genetic approaches shed
light on TB virulence. Trends Microbiol, 2005. 13(8): p. 366-72.
64.Ehrt, S., et al., Controlling gene expression in mycobacteria
with anhydrotetracycline and Tet repressor. Nucleic Acids Res,
2005. 33(2): p. e21.
65.Wirtz, E., et al., A tightly regulated inducible expression
system for conditional gene knock-outs and dominant-negative
genetics in Trypanosoma brucei. Mol Biochem Parasitol, 1999.
99(1): p. 89-101.
66.Waters, A.P., Personal communication. 2007.
67.Kaufmann, S.H., and S.K. Parida, Changing funding patterns
in tuberculosis. Nat Med, 2007. 13(3): p. 299-303.
68.Staines, H.M., J.C. Ellory, and K. Chibale, The new
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:
more than a tour de force. Trends Parasitol, 2007. 23(6): p.
254-9.
70.Gomez, J.E., and J.D. McKinney, M. tuberculosis
persistence, latency, and drug tolerance. Tuberculosis (Edinb),
2004. 84(1-2): p. 29-44.
71.Duncan, K., Progress in TB drug development and what is
still needed. Tuberculosis (Edinb), 2003. 83(1-3): p. 201-7.
72.Sabry, J., Personal communication. 2007.
73.Rosenthal, P.J., Antimalarial drug discovery: old and new
approaches. J Exp Biol, 2003. 206(Pt 21): p. 3735-44.
74.Oberholzer, M., et al., The Trypanosoma brucei cAMP
phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar
enzymes that are essential for parasite virulence. FASEB J,
2007. 21(3): p. 720-31.
75.Yuasa, K., et al., PfPDE1, a novel cGMP-specific
phosphodiesterase from the human malaria parasite Plasmodium
falciparum. Biochem J, 2005. 392(Pt 1): p. 221-9.
76.Ward, P., et al., Protein kinases of the human malaria
parasite Plasmodium falciparum: the kinome of a divergent
eukaryote. BMC Genomics, 2004. 5(1): p. 79.
77.Naula, C., M. Parsons, and J.C. Mottram, Protein kinases as
drug targets in trypanosomes and Leishmania. Biochim Biophys
Acta, 2005. 1754(1-2): p. 151-9.
78.Waters, N.C., and J.A. Geyer, Cyclin-dependent protein
kinases as therapeutic drug targets for antimalarial drug
development. Expert Opin Ther Targets, 2003. 7(1): p. 7-17.
79.Woodard, C.L., et al., Evaluation of broad spectrum protein
kinase inhibitors to probe the architecture of the malarial cyclin
dependent protein kinase Pfmrk. Bioorg Med Chem Lett, 2007.
17(17): p. 4961-6.
80.Tu, X., and C.C. Wang, The involvement of two cdc2-related
kinases (CRKs) in Trypanosoma brucei cell cycle regulation
and the distinctive stage-specific phenotypes caused by CRK3
depletion. J Biol Chem, 2004. 279(19): p. 20519-28.
81.Hammarton, T.C., J.C. Mottram, and C. Doerig, The cell
cycle of parasitic protozoa: potential for chemotherapeutic
exploitation. Prog Cell Cycle Res, 2003. 5: p. 91-101.
82.Ferguson, M.A., Personal communication. 2007.
83.Walburger, A., et al., Protein kinase G from pathogenic
mycobacteria promotes survival within macrophages. Science,
2004. 304(5678): p. 1800-4.
84.Scherr, N., et al., Structural basis for the specific inhibition
of protein kinase G, a virulence factor of Mycobacterium
tuberculosis. Proc Natl Acad Sci U S A, 2007. 104(29): p.
12151-6.
85.Herrling, P., Experiments in social responsibility. Nature,
2006. 439(7074): p. 267-8.
86.Bill & Melinda Gates Foundation, Grand Challenges in Global
Health Initiative Selects 43 Groundbreaking Research Projects
for More Than $436 Million in Funding. 2005 [cited September
13, 2007]; available from: http://www.gatesfoundation.
org/GlobalHealth/BreakthroughScience/GrandChallenges/
Announcements/Announce-050627.htm.
87.SiliconFen Business Report, TheDirectory. 2006
[cited September 13, 2007]; available from: http://www.
siliconfenbusiness.com/viewcomp.php?id=123.
88.McKerrow, J.H., Designing drugs for parasitic diseases of the
developing world. PLoS Med, 2005. 2(8): p. e210.
89.Eli Lilly and Company, Lilly Not-for-Profit Partnership for TB
Early Phase Drug Discovery. 2007 [cited October 19, 2007];
available from: http://newsroom.lilly.com/ReleaseDetail.
cfm?ReleaseID=248931.
90.Tremonti, G., Advanced market committments for vaccines:
a new tool to fight against disease and poverty, in Report to the
G8 Finance Ministers. 2005.
91.BG Medicine, TB Alliance and BG Medicine initiate
biomarker discovery program. 2006 [cited September 13,
2007]; available from: http://www.bg-medicine.com/content/
news-center/news/q/id/23.
92.Genzyme. Medicines for Malaria Venture: Genzyme
Corporation and the Broad Institute Expand Collaboration to
Discover New Drugs for Malaria. 2006 [cited October 23,
2007]; available from: http://www.genzyme.com/corp/media/
HAND_PR.pdf.
93.Wellcome Trust. Strategic Translation Awards in Seeding
Drug Discovery. 2007 [cited October 23, 2007]; available from:
http://www.wellcome.ac.uk/node2630.html.
94.Hopkins, A.L., M.J. Witty, and S. Nwaka, Mission possible.
Nature, 2007. 449(7159): p. 166-9.
95.DiMasi, J.A., R.W. Hansen, and H.G. Grabowski, The price
of innovation: new estimates of drug development costs. J Health
Econ, 2003. 22(2): p. 151-85.
Appendix I. Why Small Molecule Drug Discovery
Is a Risky Business
As explained earlier in this report, in small molecule drug
discovery it is possible to find drugs that can be taken orally
and are stable when stored at room temperature. These are
key advantages to include in the next generation of drugs for
tuberculosis, malaria, and trypanosomal diseases.
However, discovering a single new small molecule drug
candidate—whatever the disease—is a notoriously lowyield process. Thus, many drug discovery projects must
be pursued simultaneously to ensure that any new drug
candidates are available for clinical development. In addition to assets, infrastructure, and expertise, the multidisciplinary nature of drug discovery requires time, excellent
project management skills, and money. Yet, even if all of
these are present in abundance, no single drug discovery
program is guaranteed a compound that will achieve IND
status and enter clinical trials.
The process of small molecule
drug discovery
To appreciate why most small molecule discovery efforts
fail, it is helpful to understand the small molecule
discovery process. Researchers begin with a target product
profile (TPP), a set of minimum characteristics a new drug
must possess to warrant development and use in people.
Researchers must possess a deep biological understanding
of the disease. They must also have a protein or macromolecule “target” through which the new drug is expected
to exert its function. Suitable compound libraries are then
“screened” through a battery of in vitro assays to identify
a small number of compounds with some hint of activity
against the target. Whether the candidate drugs are first
identified in vitro by HTS or by structure-based drug
design, any compound advancing as a “lead” candidate
must then be co-optimized by subsequent chemical structure modifications for as many as 20 or 30 properties that
contribute to the TPP. Lead optimization is an extremely
complex process in which failure is far more frequent than
success.
The screening and design processes yield families of
compounds related by their structure-activity relationships
(SAR). At this point a team of skilled medicinal chemists
takes over and synthesizes multiple versions of new but
related compounds. Biologists evaluate these compounds
for target binding in vitro, providing data that help the
chemists sharpen the SAR. Through further rounds of
refinement, chemists generate compounds with improved
performance against the TPP.
Even with powerful computational algorithms that
attempt to predict problems with particular compound
structures and compound families, iterative cycles of
synthesis and screening remain today the only viable
method to refine favorable properties and eliminate the
undesired ones in search of small molecule drug candidates for in vivo characterization. It is not uncommon for
drug discovery teams to sift through hundreds or thousands of compounds in careful in vitro assays—or screen
millions in high-throughput mode—to find a very limited
number of lead compounds in two or three classes related
by SAR.
If oral delivery is crucial to the TPP, as it is for most
infectious diseases, the degree of difficulty in identifying
lead compounds rises dramatically. The human body has
multiple layers of defense to resist intrusion by foreign
molecules. The body foils drug developers by a host of
protective mechanisms. For example, the body may simply
not absorb the drug from the stomach or gastrointestinal tract. Or the body may metabolize the drug rapidly.
Achieving sufficient and consistent oral bioavailability
is a high hurdle for passage to the next stage. The few
compound classes nominated for the in vitro medicinal
chemistry optimization cycle are now iteratively reoptimized (or more likely, eliminated) by this requirement for
an orally bioavailable molecule.
Only when orally bioavailable candidates are identified can
in vivo proof-of-concept studies to validate the biological
linkage of the target and the disease be initiated in animals.
The few compounds that survive all of these hurdles
are thoroughly evaluated in animals for their efficacy
and possible toxicity. From the potential candidates that
advance through these in vivo studies, usually only a single
compound and a backup are nominated for further highly
regimented, FDA-mandated IND-enabling work—with no
guarantee that any compound will be qualified for subsequent clinical development.
The time and manpower required to advance a compound
to candidate status is substantial. HTS and lead identification each require two to four full-time scientists working
for six to 12 months. Lead optimization is significantly
more demanding. A typical program has about 15 to 20
scientists and can last for two to three years, with a 10
to 20 percent chance to find an IND candidate out of the
thousands or millions of chemicals evaluated throughout
the process.
To find a potent, safe, and effective drug candidate for
clinical development, drug discovery as practiced today
results in a steep “de-selection funnel.” That is, during
serial assessment the undesirable properties of proposed
hit and lead compounds rapidly reduce the number of
candidates under evaluation. Thus, compound attrition
rates are very high.
Nevertheless, these steps, combined with scientific rigor
and luck, transform simple organic chemicals into valuable
drugs for the safe and effective treatment of human disease.
Appendix II. Snapshots of the Drug Development Pipelines
for Malaria, TB, and HAT
The drug development pipelines for malaria, TB, and HAT were compiled by examining publicly available data including
PDP and company websites and published and unpublished reports. In the early stages of drug discovery, programs are
added and dropped rapidly, and thus the “snapshots” below are likely to have changed by the time our report is published.
P. falciparum malaria pipeline
Drug Discovery
Screening
for Hits
Drug Development
Lead
Identification
PSAC Antagonists
(MMV, Broad Institute,
NIH / NIAID)
PfSub-1
Inhibitor
(TDR, Serono)
Lead Optimization
Clinical
OZ Next Generation
Isoquine
(MMV, Nebraska Univ, Monash
Univ, STI)
4(1H)-pyridones Back-ups
4(1H)-pyridone
Novartis Institute for
Tropical Diseases miniportfolio
Falcipains
SAR 97276
Dihydrofolate Reductase
Inhibitors
SAR 116242
Broad Institute/
Genzyme mini-portfolio
(MMV, BIOTEC, LSHTM, Monash Univ)
(MMV, GSK)
(MMV, NITD)
(MMV, UT Southwestern, Univ.
Washington)
PfCDK-1 Inhibitor
(TDR, Serono)
Artesunate-Mefloquine
(DNDi)
Chloroproguanil-dapsone
(Lapdap™) – Artesunate
Ferroquine
(Sanofi-Aventis)
(MMV, GSK, WHO/TDR, Liverpool Univ)
Pediatric Coartem
(Sanofi-Aventis)
Dihydro-orotate inhibitors
(MMV, Broad, Genzyme)
Phase III
(Jomaa)
(MMV, GSK)
(MMV, GSK, UCSF)
Phase II
Trials
Fosmidomycin +
Clindamycin
(MMV, GSK,
Liverpool Uni)
FAB I
(MMV, GSK)
Phase I
Preclinical
(MMV, Novartis)
Dihydro-artemisinin-piperaquine
(Sanofi-Aventis)
(MMV, Sigma Tau, Chongqing Holley,
Holleykin Pharma, Oxford Univ,
Mahidol Univ)
HDAC Inhibitor
(TopoTarget,
WHO / TDR)
Pyronaridine – Artesunate
(Pyramax®)
Artemisinin
(MMV, Univ Iowa, Shin Poong,
WHO/TDR)
(Amyris/iOWH))
PfGSK3 inhibitor
Zithromax + Chloroquine
(TDR, Serono)
(Pfizer)
Tuberculosis pipeline
Drug Discovery
Screening
for Hits
Target Identification
and screening
(AstraZeneca)
Target Identification
and screening
(Novartis Institute for
Tropical Disease)
Malate Synthase
Inhibitors
(GSK, Rockefeller Univ,
Texas A&M)
Drug Development
Lead
Identification
Multifunctional
Molecules
(TB Alliance, Univ of Auckland,
NITD, NIAID)
InhA Inhibitors
Pleuromutilins
(TB Alliance, GSK)
(TB Alliance, GSK)
Riminophenazines
Quinolones
(TB Alliance, Institute
of Materia Medica,
BTTTRI)
N-acetyltransferase
inhibitors
(Summit)
Protease Inhibitors
Thiolactomycin
analogs
(Medivir, Queen Mary,
Univ of London)
Nitroimidazole Analogs
(TB Alliance, Cumbre)
Proteasome Inhibitors
(Cornell Univ)
Lead Optimization
(NIAID, NIH)
Nitrofuranylamides
Dihydrolipoamide Acyl (NIAID, Univ
Tennessee)
transferase Inhibitors
(Cornell Univ/NIAID)
Phase I
Preclinical
Trials
SQ609
Pyrrole LL-3858
Diarylquinoline
FAS 20013
Diamine SQ109
(Sequella)
(Lupin)
(FASgene)
(TB Alliance, KRICT, Yonsei Univ)
Dications
(Univ of Illinois-Chicaco,
Immtech)
Bacterial Topoisomerase
Inhibitors
(TB Alliance, GSK)
(Sequella)
Phase III
TMC207
(Tibotec/Johnson &
Johnson)
Translocase
Inhibitors
Gatifloxacin
(OFLTUB Consortium)
Moxifloxacin
(Sankyo, Sequella)
PA-824
Nitroimidazole
Non-fluorinated
quinolones
(TB Alliance, Bayer)
(TaiGen)
(TB Alliance, Chiron,
Novartis)
Nitroimidazole
backup
Nitroimidazole
OPC-67683
(Otsuka)
(Otsuka)
Focused Screening
(electron transport inhibitors
and peptide deformylase
inhibitors)
Phase II
Clinical
Oxazolidinones
(Pfizer)
(TB Alliance, GSK)
Promazine analogs
(Salisbury Univ)
Cell-wall synthesis
inhibitors
(Colorado State Univ, NIAID)
Human African trypansomiasis pipeline
Drug Discovery
Screening
for Hits
Drug Development
Lead
Identification
Cysteine Protease
Inhibitors
Microtubule
Inhibitors
Trypanothione
Reductase Inhibitors
Novel Nitroheterocycles
Dihydrofolate
Reductase Inhibitors
Ascofuranone
(DNDi/Sandler center)
(DNDi/Dundee)
Lead Optimization
Phase I
Preclinical
Clinical
Nitroimidazoles
(DNDi)
Phase II
Nifurtimox-Eflornithine
(DNDi)
Phase III
Trials
DB 289 Pafuramidine maleate
(Immtech, UNC consortium)
(DNDi)
(DNDi)
(DNDi)
(DNDi/Dundee)
Kitasato Screening
(DNDi)
Screening Program
(Genzyme/DNDi)
Screening Program
(Scynexis)
Screening Program
(CDRI)
Screening Program
(TDR, Harvard, Dundee)
Appendix III. Academic and Company Interviews
Academics
Matt Berriman
William Bishai
George Cross
Kirk Deitsch
Joe DeRisi
Alan Fairlamb
Mike Ferguson
David Fidock
Dan Goldberg
Keith Gull
Luise Krauth-Siegel
Sanjeev Krishna
Michelle Larsen
Pascal Maeser
Jim McKerrow
John McKinney
Carl Nathan
Margaret Phillips
Pradipsinh Rathod
David Roos
Philip Rosenthal
Eric Rubin
David Russell
James Sacchettini
Thomas Seebeck
Clive Shiff
Christine Sizemore
David Sullivan
Juliano Timm
Catherine Vilcheze
Andy Waters
Paul Wyatt
Companies
Wellcome Trust Sanger Institute
Johns Hopkins University
Rockefeller University
Weill Medical College of Cornell University
University of California San Francisco
University of Dundee
Columbia University
Washington University
Oxford University
University of Heidelberg
St. Georges University
Albert Einstein College of Medicine
University of Bern
Ecole Polytechnique Fédérale de Lausanne
Weill Medical College of Cornell University
University of Texas Southwestern
University of Washington
University of Pennsylvania
Harvard School of Public Health
Cornell University
Texas A&M University
University of Bern
Johns Hopkins School of Public Health
National Institutes of Health
Johns Hopkins School of Public Health
Rockefeller University
Albert Einstein College of Medicine
Leiden University
Achillion Pharmaceuticals
Ambit BioSciences
Anadys Pharmaceuticals
Archemix
AstraZeneca
ChemoCentryx
Cytokinetics
Eisai Research Institute
Exelixis
GlaxoSmithKline (Tres Cantos)
Infinity Pharmaceuticals
Kémia
Locus Pharmaceuticals
Metabasis Therapeutics
Novartis Institute for Tropical Disease
Novocell
OSI Pharmaceuticals
Pharmacopeia Drug Discovery
Plexxikon
Replidyne
SRI International
Sunesis Pharmaceuticals
Vertex Pharmaceuticals
Vitae Pharmaceuticals
Appendix IV. List of 50 Focus Companies
Company
Location
Public/Private
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
ACADIA Pharmaceuticals
Achillion Pharmaceuticals
Albany Molecular Research
Ambit Biosciences
Amphora Discovery Corporation
Anadys Pharmaceuticals
Arena Pharmaceuticals
ARIAD Pharmaceuticals
ArQule
Array BioPharma
Astex Therapeutics
BioCryst Pharmaceuticals
Celgene Corporation
Cephalon ChemoCentryx CV Therapeutics
Cytokinetics
Eisai Research Institute
Exelixis
Genelabs Technologies
Gilead Sciences
Icagen
Immtech Pharmaceuticals
Infinity Pharmaceuticals
Kalypsys
Kémia
Kinex Pharmaceuticals
Lexicon Genetics
Locus Pharmaceuticals
Metabasis Therapeutics
Millennium Pharmaceuticals
Neurogen Corporation
Neuromed Pharmaceuticals
Optimer Pharmaceuticals
OSI Pharmaceuticals
Pharmacopeia Drug Discovery
Plexxikon
Renovis
Replidyne
Rexahn Pharmaceuticals
Rigel Pharmaceuticals
Sequella
Sepracor
SRI International
Sunesis Pharmaceuticals
Synta Pharmaceuticals
Telik
Theravance
Vertex Pharmaceuticals
Vitae Pharmaceuticals
San Diego, CA
New Haven, CT
Albany, NY
San Diego, CA
Research Triangle Park, NC
San Diego, CA
San Diego, CA
Cambridge, MA
Woburn, MA
Boulder, CO
Cambridge, UK
Birmingham, AL
Summit, NJ
Philadelphia, PA
San Francisco, CA
Palo Alto, CA
South San Francisco, CA
Andover, MA
Redwood City, CA
Foster City, CA
Durham, NC
Vernon Hills, IL
Cambridge, MA
San Diego, CA
San Diego, CA
Buffalo, NY
San Diego, CA
Blue Bell, PA
La Jolla, CA
Cambridge, MA
Branford, CT
Vancouver, BC, Canada
San Diego, CA
Melville, NY
Cranbury, NJ
Berkeley, CA
Louisville, CO
Rockville, MD
Rockville, MD
Marlborough, MA
Menlo Park, CA
San Francisco, CA
Lexington, MA
Palo Alto, CA
Cambridge, MA
Fort Washington, PA
ACAD
ACHN
AMRI
Private
Private
ANDS
ARNA
ARIA
ARQL
ARRY
Private
BCRX
CELG
CEPH
Private
CVTX
CYTK
ESALY
EXEL
GNLB
GILD
ICGN
IMM
INFI
Private
Private
Private
LEXG
Private
MBRX
MLNM
NRGN
Private
Private
OSIP
PCOP
Private
RNVS
RDYN
RXHN
RIGL
Private
SEPR
Private
SNSS
Private
TELK
THRX
VRTX
Private
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.
Washington, DC 20005 USA
Phone: +1 202-312-9260
Fax: +1 443-320-4430
www.bvgh.org
Building Biotech Solutions for Diseases of the Developing World
Innovation Gap

Closing the Global Health Innovation Gap

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