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8/9/2019 BVGH Therapeutics Innovation Map
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Closing the Global HealthInnovation Gap
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases
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Closing the Global HealthInnovation Gap
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases
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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 documentMaria Freire, Carl Nathan, Tito Serafini, Natalie
Barndt, and the BVGH Board of Directors; Anastasia Semienko, who assisted in the final push
to complete the project; and the many individuals from the global health community and
biopharmaceutical industry who participated in our interviews and shared their enthusiasm
and ideas. Special thanks to Dr. Corey Goodman for the initial inspiration for this project.
To request additional print copies of this report or other information from BVGH, please
contact:
BIO Ventures for Global Health
1225 Eye Street, NW, Suite 1010
Washington, DC 20005
Tel: +1 202.312.9260
Fa: +1 443.320.4430
E-mail: [email protected]
Web: www.bvgh.org
The full tet 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 NIHs 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.
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Contents
List of Select Abbreviations . . . . . . . . . . . . . . . . . . . . . . . 3
List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
List of Tables and Sidebars . . . . . . . . . . . . . . . . . . . . . . . . 5
Chapter 1: Eecutive 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
Appendi I: Why Small Molecule
Drug Discovery Is a Risky Business . . . . . . . . . . . . . . . . 57
Appendi II: Snapshots of the Drug Development
Pipelines for Malaria, TB, and HAT . . . . . . . . . . . . . . . . 59
Appendi III: Academic and Company Interviewees . . . 60
Appendi IV: List of 50 Focus Companies . . . . . . . . . . 61
About BVGH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses
Select Abbreviations
ACT . . . . . . . . . . artemisinin-based combination therapy
ADME . . . . . . . . absorption, distribution, metabolism, and ecretion
ARV . . . . . . . . . . anti-retroviral
ATP . . . . . . . . . . adenosine triphosphateBBB . . . . . . . . . . blood-brain barrier
B V G H . . . . . . . . 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 proteincoupled 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
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Figures
Figure 3.1: Drug Discovery and Development
the Necessary Prelude to New Drugs. . . . . . . . . . . . . . . . . . . . . . . . . 17
Figure 3.2: Risks and Benefits of ExpandingUse of Existing Drugs Versus the Creation
of New Chemical Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Figure 3.3: Attrition Rates and Current
Neglected Disease Pipelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 3.4: The Innovation Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 3.5: Annual R&D Spending by
Biotechnology Companies and PDPs . . . . . . . . . . . . . . . . . . . . . . . . . 23
Figure 3.6: Building a Continuum of Players
to Move from Basic Research to Product Registration . . . . . . . 26
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 4.4: The Composition and Tasks of
a Drug Discovery Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2
Figure 4.5: Target Class Focus of 50 Focus Companies . . . . . . . . 34
Figure 5.1: Target Validation and Drug
Discovery Tools Available for P. falciparum,
M. tuberculosis, and T. brucei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Figure 5.2: Target Classes Are Transferable
Across Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Figure 5.3: Target Classes Shared by
P. falciparum, M. tuberculosis, and T. brucei . . . . . . . . . . . . . . . . . . 41
Figure 6.1: Hurdles to the Biotechnology
Industrys Involvement in NeglectedDisease Drug Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Figure 6.2: The Costs of Producing a Single New Drug . . . . . . . . 47
Figure 6.3: Possible Roles for a Discovery-Focused PDP . . . . . . 50
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Tables
Table 2.1: initial Assessment of the Need
for New Therapeutics and the Scientific Feasibility
of Creating Them for Key Neglected Diseases. . . . . . . . . . . . . . . . 13
Table 3.1: Malaria, Tuberculosis, and Human African
Trypanosomiasis. Summary of Disease Characteristics,
Pathogen, and Current Standard of Care . . . . . . . . . . . . . . . . . . . . . 15
Table 3.2: PDP Drugs Registered or in Clinical Trials . . . . . . . . . . .18
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
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
Sidebars
Sidebar 2.1: List of select global health
product development partnerships (PDPs) . . . . . . . . . . . . . . . . . . . 11
Sidebar 2.2: Examples of new global health products . . . . . . . . 11
Sidebar 4.1: Characteristics of small molecule drugs . . . . . . . . . 27
Sidebar 4.2: Company selection process . . . . . . . . . . . . . . . . . . . . . . 30
Sidebar 5.1: The tool kit for modern drug discovery . . . . . . . . . . 35
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
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses
Ninety percent of the worlds ependiture on medical
care benefits the richest fifth of the worlds 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 high-
quality 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 its been
recognized that focused investment and commitment could
yield powerful new vaccines, drugs, and diagnostics basedon 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 develop-
ment (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 break-
through therapeutic benefits. As a result, an innovation gap
is increasingly apparent in the discovery of new medicinesfor 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 epertise,
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 subcon-tractors in a number of cases. In contrast, the vast majority
of new treatments for diseases with markets in the devel-
oped world are created by biotechnology and pharmaceu-
tical companies, which together have the epertise and the
infrastructure to carry discovery and development of prod-
ucts 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 drugsthe type
of therapeutic best suited to meet developing-world
needs for oral delivery, thermostability, and affordability.
The challenge is to bring the biotechnology industrys
discovery assets, know-how, and project management
capabilitiesdeveloped over 30 years and with nearly
$400 billion of equity capitalto the fight against
diseases of the developing world.
In this study, BIO Ventures for Global Health (BVGH)
eamined the core capabilities of the biotechnologyindustry, 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 capa-
bilities, basic disease understanding, and unmet medical
need, we focused on three classes of diseasesmalaria,
tuberculosis, and trypanosomal diseases (human African
trypanosomiasis, Chagas disease, and leishmaniasis).
Central to our findings is the transferability of the tech-
nologies used to address cardiovascular disease, neuro-logical 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 industrial-
ized 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 posi-
tion to apply their discovery resources and epertise to
neglected diseases.
To narrow the scope of our study, we focused on aselect 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.
Chapter 1: Executive Summary
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closing the gloBAl heAlth innovAtion gAp
nology companies have the speed, fleibility, and persis-
tence 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
eisting 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 biotech-
nology 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 epertise
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 epertise and
academic eperts 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 compa-
nies to participate in global health initiatives.
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 currentneglected disease pipeline will not fully address key treat-
ment 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
settingsfar 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 developed-
world diseases to bear on neglected diseases is
scientifically feasible.
For malaria, tuberculosis, and trypanosomal diseases, suffi-
cient scientific tools eist for drug discovery R&D efforts
to be initiated. Importantly, for many human molecular
targets that have received etensive 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 eample, many proprietary compound
libraries used by biotechnology companies for small mole-
cule drug discovery have been optimized around target
classes that are also relevant to neglected diseases. These
resources and capabilities would be prohibitively epensive
to duplicate in the nonprofit sector. Moreover, biotech-
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Recommendations
1. THE BIOTECHNOLOGY INDUSTRYS MOST CAPABLE
INNOVATORS HAVE AN INTEGRAL ROLE IN CLOSING
THE INNOVATION GAP. Biotechnology companies have
track records of employing advanced technologies to createnew therapeutics that have met with success in human
clinical trials. This epertise 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 advan-
tage of their technology platforms, they need to access
disease epertise and biochemical assays that are resident
in academia, research institutions, and product develop-
ment 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 companiesincreasing 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 preclin-
ical development.
4. EFFECTIVE INVESTMENT WILL DEPEND ON DEDI-
CATED PORTFOLIO MANAGERS. Many of the current
participants in global health product development lack
deep epertise in managing early-stage drug discovery. The
scope of the partnerships and investments we recommend
call for project management capabilities that would stretch
the current capabilities of any single public sector organi-
zation. Dedicated project management to maimize R&D
productivity can be infused into PDPs or donor organiza-
tions, or it can be built as an independent discovery PDP.
Among the options:
n Independent consortiums of companies, academic
labs, and PDPs that work together to transform
neglected disease drug targets into optimized leadcompounds 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 eisting PDPs. Such
an organization could efficiently enlist the most
eperienced 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
eisting advanced drug discovery technologies, donor
community funds will be used to maimum effect, novel
drugs will be developed faster, and more lives will be saved.
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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 worlds poorest countries,
where 3 billion people live on less than two dollars a day.
Each year more than 10 million people in the devel-
oping world die of infectious diseases such as HIV/AIDS,
malaria, tuberculosis, diarrheal diseases, and acute lower
respiratory infections. Millions more suffer from debili-
tating parasitic diseases, which often incapacitate people
in their most productive years. The burden of infec-
tious illness falls most heavily on children and pregnant
women. In poor countries, the magnitude of sufferingcaused by infectious diseases makes economic develop-
ment nearly impossible [1].
Many of these infectious diseases have earned the label
neglected1 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 devel-
oping 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 develop-
ment of new vaccines, drugs, and diagnostics for devel-
oping-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 todays partnerships lack most is
access to the biotechnology industrys most advanced
technologies and epertise for discovering and developing
new medicines.3
Todays 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 nongovern-mental organizations (NGOs) in the developed world have
provided billions of dollars to purchase eisting 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
eisting drugs, vaccines, and diagnostics to those most in
need. While programs to ensure access to current medi-
cines 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 drugresistance, inadequate safety, and efficacy.
For eample, 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 toic that it can kill
up to 5 percent of patients. No effective vaccine eists for
any disease on the World Health Organizations Special
Programme for Research and Training in Tropical Diseases(WHO/TDR) list of neglected diseases (see Footnote 1).
Diagnostics, where they eist, are often impractical for field
use in the developing world.
10 closing the gloBAl heAlth innovAtion gAp
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.
Chapter 2: Introduction
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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 2006flowed
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 infrastruc-
tures. PDPs also manage sophisticated clinical programs in
multiple developing countries. Their efforts, and those of a
small number of biopharmaceutical companies, are begin-
ning 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).
Aeras Global TB Vaccine Fondation (Aeras)
Focus: TB vaccine development
Headquarters: Rockville, MD, USA
Founded: 1997
Drgs for Neglected Diseases Initiative (DNDi)
Focus: Drug development for malaria and trypanosomal diseases
Headquarters: Geneva, Switzerland
Founded: 2003
Fondation for Innovative New Diagnostics (FIND)
Focus: Diagnostic development for TB, malaria, and human
African trypanosomiasis
Headquarters: Geneva, Switzerland
Founded: 2003
Global Alliance for TB Drg Development (TB Alliance)
Focus: TB drug developmentHeadquarters: New York, NY, USA
Founded: 2000
Hman Hookworm Vaccine Initiative (HHVI)
Focus: Vaccine development for hookworm
Headquarters: Washington, DC, USA
Founded: 2000
Institte for OneWorld Health (iOWH)
Focus: Drug development for visceral leishmaniasis, malaria,
and diarrheal diseases
Headquarters: San Francisco, CA, USA
Founded: 2000
International AIDS Vaccine Initiative (IAVI)
Focus: HIV vaccine development
Headquarters: New York, NY, USA
Founded: 1996
International Partnership in Microbicides (IPM)
Focus: Microbicide development for HIV prevention
Headquarters: Silver Spring, MD, USA
Founded: 2002
Medicines for Malaria Ventre (MMV)
Focus: Malaria drug development
Headquarters: Geneva, Switzerland
Founded: 1999
Malaria Vaccine Initiative (MVI)
Focus: Malaria vaccine development
Headquarters: Bethesda, MD, USAFounded: 1999 as an independent program within PATH
Pediatric Denge Vaccine Initiative (PDVI)
Focus: Dengue vaccine development
Headquarters: Seoul, Korea
Founded: 2003
Program for Appropriate Technology in Health (PATH)
Focus: Development of health technologies
Headquarters: Seattle, WA, USA
Founded: 1977
Sidebar 2.1: List of select global health prodct development partnerships (PDPs)
Sidebar 2.2: Examples of newglobal health prodcts
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.
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12 closing the gloBAl heAlth innovAtion gAp
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 epand
the pipeline of products that can keep improving care for
neglected diseases. For eample, we need:
n a shorter course of TB therapy that works againstdrug-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 etensive discovery efforts supported by long-term
funding. Most of todays 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 eisting
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. Eperience has shown that
returns on pharmaceutical R&D investments are measured
in decades, not years. Moreover, the lesson from all epe-
rience with treatments for infectious diseaseswhetherits antibiotics for streptococcal bacteria or anti-retrovirals
(ARVs) for HIV/AIDSis 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 industrys
diverse technology platforms and epertise 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
trypanosomatids4human African trypanosomiasis (HAT,
also known as African sleeping sickness), leishmaniasis,
and Chagas disease. For simplicitys 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 inno-
vative biopharmaceutical companies develop therapeu-
tics; a smaller number focus on vaccines and diagnostics.
Drugs represent the largest segment of global pharma-
ceutical markets. We selected TB, malaria, and the three
trypanosomal diseases for several reasons: Each is associ-
ated with a high disease burden; current treatments have
serious limitations; and each has strong scientific founda-
tions upon which new therapeutic R&D might be based
(see Table 2.1).
We should emphasize that our goal was to be inclusive,
not eclusive. 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.
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses 1
We began our analysis by interviewing academic
researchers focused on TB, malaria, and trypanosomal
diseases (see Appendi III). We aimed to determine the
availability of biological and molecular tools for drug
discovery and identify critical bottlenecks. We then evalu-
ated current product pipelines against international public
health goals and drug target product profiles (TPPs) to
determine where new discovery efforts are required foreach disease.
To evaluate whether industry has the capability and rele-
vant tools to address the gaps we identified, we selected
50 leading biotechnology companies from the hundreds
focused on small molecule drug discovery. These compa-
nies 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 eperienced companies in
small molecule drug discovery today. They are listed inAppendi IV, and their capabilities are described further
in Chapter 4.
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
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 epertise and infra-
structure 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 biotech-
nology industry capabilities against drug targets for thethree diseases.
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 devel-
opment. This will require vision, new partnerships,
risk-taking, innovative business strategies, and financial
commitment. Chapter 6 eplores these issues and proposes
several approaches to investing in new global health R&D.
Chapter 7 outlines our conclusions and recommendations.
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 trypano-
somal 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.
Table 2.1: Initial Assessment of the Need for New Therapetics and the Scientific Feasibility of Creating Themfor Key Neglected Diseases
*One disability adjusted life year (DALY) is equivalent to one year of healthy life lost.
Source of DALY information: WHO/TDR.
Disease
TB
Malaria
HAT
Chagas Disease
Leishmaniasis
Global brden (DALYs)*
34.7 M
46.4 M
1.5 M
0.7 M
2.1 M
Problems with existing treatments
Resistance and long treatment times
Resistance
Safety, efficacy, resistance, long treatment
time, treatment administration
No treatments available for chronic
form of disease
Safety, administration, and long
treatment time
Scientific fondation for new R&D
Pathogen genome sequenced; genetic
manipulation possible; animal models
of disease
Pathogen genome sequenced; genetic
manipulation possible; primate models
of disease
Pathogen genome sequenced; genetic
manipulation facile; animal models
of disease
Pathogen genome sequenced; genetic
manipulation possible; animal models
of disease
pathogen genome(s) sequenced; genetic
manipulation possible; animal models
of disease
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Creating innovative pharmaceutical products is a
complex process that typically takes 10 to 15 years.
Donor funding and the emergence of product develop-
ment 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 collabora-
tions necessary to transform a laboratory discovery
into an investigational new drug. Failure to addressthe innovation gap will impede the creation of the next
generation of treatments for malaria, tuberculosis, and
trypanosomal diseases.
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 toicities [3-5].
New medicines are urgently needed for tuberculosis, all
diseases caused by protozoan parasites, and many of the
helminth (worm) infections.
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 todays treatments.
Malaria. More than 40 percent of the worlds 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 insub-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 ineffec-
tive 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
urged. Artemisinin-based combination therapies (ACTs)
have proven especially efficacious. Artemisinin, a structur-
ally comple natural product, is comparatively epensive
to manufacture, which, until recently, precluded the use of
ACTs in many impoverished countries.
Tuberculosis. One-third of the global populationmore
than 2 billion peopleharbors 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 immu-nocompromised populations, such as those with HIV, rates
of active TB are etremely high. Worldwide, TB is now the
leading cause of death among AIDS patients [6].
First-line treatment for active TB consists of two or four
antibiotic drugs taken in combination for a minimum
of si to nine months. The duration of the regimen,
combined with the medications toicities, 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. tubercu-losis strains. Recently, etensively drug-resistant TB (xDR-
TB) has entered communities with high HIV prevalence
and is killing people at alarming rates [8, 9].
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 innearly 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.
Chapter 3: The Innovation Gap in DiscoveringNew Therapeutics for Neglected Diseases
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses 1
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
Table 3.1: Malaria, Tberclosis, and Hman African Trypanosomiasis: Smmary Of Disease Characteristics,Pathogen, and Crrent Standard of Care
MalariaA parasitic disease transmittedby Anopheles mosquitoes.Malaria is categorized as eitheruncomplicated (fever, chills,body aches, nausea, headache,vomiting, and diarrhea) or severe(anemia, acute respiratory distresssyndrome, coma, and death).
TBA bacterial disease that mostcommonly affects the lungs. Inotherwise healthy individuals,most infections are latent andasymptomatic. About 10% of thoseinfected develop active pulmonarydisease; symptoms include a coughlasting more than two weeks,
coughing up blood, fatigue, fever,chills, night sweats, and weight andappetite loss.
HATA parasitic disease transmittedby tsetse flies. HAT progressesfrom fever and fatigue (early-stagedisease) to severe neurologicalconditions (late-stage or chronicdisease). Untreated HAT is fatal.
Chagas disease
A parasitic disease that over timecauses damage to the nervoussystem, digestive tract, and theheart. The disease is contracted viathe feces of an infected Reduviid bug.
LeishmaniasisA collection of parasitic diseasestransmitted by the Phlebotominesandfly that affects the skin,mucosa, or internal organs,resulting in severe disfigurement,disability or death.
Disease Epidemiology Pathogen Crrent Standard of CareDeaths Cases Poplation Other (lanch year): Limitations
per Year per Year at Risk
> 1 million
2 million
50,000
14,000
>50,000
300-500
million
9 million
(active TB)
Up to
300,000
750,000
1.5-2 million
40% of global
population
Pandemic;
2 billion are
infected with
latent TB.
60 million;
(sub-Saharan
Africa)
25 million;
(Latin
America and
Caribbean)
350 million
Children and
pregnant
womenare most
susceptible
Immuno-
compromised
populations
are at
highest risk
8-9 million
are currently
infected
12 million
are currently
infected
Plasmodium
species;
P. falciparum
is the most
deadly
Mycobacterium
tuberculosis
Trypanosoma
brucei
(subspecies
gambiense
and
rhodesiense)
Trypanosoma
cruzi
~20 Leishmania
species
Chloroquine (1945): resistance
Primaquine (1948): safety
Fansidar (1961): resistance
Mefloquine (1984): resistance, safety
Artemisinin (1994): cost, compliance,Good Manufacturing Practice
Atovaquone/proguanil (1999): cost
All first-line treatments have issuesconcerning resistance, toxicity, andtreatment length (6-9 months):
Rifampicin (1963)
Ethambutol (1962)
Streptomycin (1955)
Pyrazinamide (1954)Isoniazid (1952)
Pentamidine (1941): lacks oral formulation,side effects, early-stage specific, mosteffective against T. b. gambiense
Suramin (1921): lacks oral formulation,side effects, early-stage specific, first-linetreatment against T. b. rhodesiense
Melarsoprol (1949): toxicity, resistance
Eflornithine (1980): toxicity, administration,spectrum of activity, supply, cost, onlyeffective against T. b. gambiense
Chronic disease - no treatments available
Acute disease -Nifurtimox (1960): resistance, safety,efficacy
Benznidazole (1970s): resistance, safety,efficacy
Visceral leishmaniasis:
Miltefosine (2003): safety
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.
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proceed independently for different species. For simplicitys
sake, at several points in this report we use Trypanosoma
brucei, the cause of HAT, to represent the entire class.
Problems associated with eisting drugs for trypanosomal
diseases include lack of efficacy, drug resistance, longtreatment duration, availability, epense, and safety. For
instance, melarsoprol, the only treatment for HAT caused
by one subspecies ofT. brucei, is so toic 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
todays global health drug pipeline, we must first under-
stand the process of creating a new drug. More comple
and time-consuming than nearly any other commercial
endeavor, pharmaceutical R&D requires technological
and scientific epertise, teamwork, leadership, risk-taking,
timeand 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 eploration 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 etensive 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 drugmust 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 drug-
like 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 accept-
able potency and selectivity with a cellular target macro-
molecule such as a protein.
For an infectious disease, the target is usually a macro-
molecule 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 Appendi 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 toicity and pharmaco-
kinetic5 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 candidates safety, dosing, and effi-
cacy 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 humanswhat the body does to a drug.
Routinely examined pharmacokinetic properties of a drug are its absorption, distribution, metabolism, excretion, and toxicological properties
(ADME/Tox).
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses 1
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 1015 years [13, 14]. Although the failure
rate is greatest at the earliest stages of discovery, prod-ucts can fail at any point. Indeed, high rates of attrition
partially eplain why the process of inventing a drug takes
so long. According to the Pharmaceutical Research and
Manufacturers of America (PhRMA), for every 5,00010,000
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 devel-
opment will never progress to success in clinical trials [15].
New players build the therapeutics
pipeline for neglected diseasesFrom 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 sumweestimate based on two recent studies less than $100
millionfor R&D aimed at two of the worlds 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
investment since 1999 [2]. Although certain large pharma-
ceutical 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 for-
profit biopharmaceutical companies, PDPs drive preclinicaland clinical development of new product portfolios, picking
and choosing which products to advance through the pipe-
line, 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 eclusively 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 etensively with
nonprofit and for-profit partners to conduct discovery and
development. By supporting PDPs, donors have created
centers of epertise for each disease area.
6 We use the term donor community to refer to governments, nonprofit organizations, and foundations.
Screeningfor Hits
Lead Optimization
3-6 years 1 year 6-7 years
LeadIdentification
Phase I
1 year
Preclinical Phase IIIPhase II
DRuG DISCOVERY
CLINICAL TRIALS
Registration
Figre 3.1: Drg Discovery and Developmentthe Necessary Prelde to New Drgs
DRuG DEVELOPMENT
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Table 3.2: PDP Drgs Registered or in Clinical Trials
Prodct
Paromomycin
Artesunate-amodiaquine
Artesunate-mefloquine
Cholorproguanil-dapsone
(Lapdap)-artesunate
Coartem dispersible tablet
Dihydroartemisinin-piperaquine
Pyronaridine-artesunate
(Pyramax)
Moxifloxicin (Avalox)
PA-824
Nifurtimox-eflornithine
Disease*
Visceral leishmaniasis
Malaria
Malaria
Malaria
Malaria
Malaria
Malaria
TB
TB
HAT
Development Stage
Registered in 2006 (India)
Phase III (East Africa)
Registered in 2007 (Morocco)
Phase III
Phase III
Phase III
Phase III
Phase III
Phase II/III
Phase II
various
Drg Type
Existing (new use)
Existing (new combination therapy)
Existing (new combination therapy)
Existing (new combination therapy)
New formulation of existing combination therapy
Existing (new combination therapy)
Existing (new combination therapy)
Existing (new use)
New Chemical Entity (NCE)
Existing (new combination therapy)
PDP Sponsor
iOWH
DNDi
DNDi
MMV
MMV
MMV
MMV
MMV
TB Alliance
TB Alliance
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: Biopharmacetical and Consortim-Based Drgs in Clinical Trials
Prodct
Zithromaxchloroquine
Ferroquine
Fosmidomycin-clindamycin
Gatifloxacin
TMC 207
OPC-67683
SQ-109
LL-3858
DB289 (pafuramidine)
Disease
Malaria
Malaria
Malaria
TB
TB
TB
TB
TB
HAT
Development Stage
Phase III
Phase II
Phase II
Phase III
Phase II
Phase II
Phase I
Phase I
Phase III
Drg Type
Existing (new combination therapy)
NCE*
Existing (new combination therapy)
Existing (new use)
NCE
NCE
NCE
NCE
NCE
Sponsor
Pfizer
Sanofi-Aventis
Jomaa Pharma Gmbh
OFLOTUB consortium**
Tibotec (Johnson & Johnson)
Otsuka
Sequella
Lupin Pharmaceuticals
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.
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses 1
Evaluation of neglected disease
drug pipelines
Eager to show early results in bringing new treatments
to afflicted populations, PDPs initially focused on testing
eisting drugs registered for other diseases against the
target pathogens. These efforts have borne fruit, with twoproducts launched (paromomycin and artesunate-amodia-
quine) 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 Appendi II.
Products in neglected disease drug pipelines can
be divided into
n eisting drugs being evaluated for new
indications,
n drugs in new formulations,
n novel fied-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 epanding uses
for eisting drugs versus creating NCEs. A key advantage
of using eisting drugs is that often they have etensiverecords 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 epanding the use of eisting
drugs. But with risks come benefits. NCEs targeted for
potency, specificity, and lack of toicity have greater
potential to provide breakthrough therapeutic benefits
within a wide safety margin. Thus, in the long run,
substantial improvement over eisting treatments will
require discovering NCEs.
Figre 3.2: Risks and Benefits of Expanding use of Existing Drgs Verss the Creation of New Chemical Entities
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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 fulfillthese objectives might halt and even reverse the spread of
these diseases.
Requirements for effective drugs
for neglected diseases
Any new drug emerging from the pipeline for neglected
diseases must be safe, inepensive to manufacture, prac-
tical to administer, stable in harsh climates, potent against
resistant strains, and effective within time frames compa-rable to or better than eisting products. In addition,
as illustrated in Table 3.4, each disease has a specific,
minimum TPP that a new product must meet [22, 23].
Table 3.4: Target Prodct Profiles for uncomplicated P. falciparum Malaria, Active Plmonary TB, and Late-stage HAT
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 womenno adverse effects on fetus
Manfactring
Inexpensive manufacturing to ensure low cost
Stability in tropical climateno special storage considerations
Broad Spectrm
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
P. falciparum
malaria
Necessary Desirable TB HAT
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.
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses 21
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 short-
ening 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 candi-
dates must follow that offers the promise of achieving more
ambitious goals. Similar to drug development for cancer
and diabetes, neglected disease drug development pipe-
lines 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 eplore 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 eample,
inability to epress the target protein and develop an assay,
lack of credible screening hits, failure to optimize efficacy
versus toicity, 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 projectsenough 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 epected to yield several new products in
the net few years [21]. However, as Figure 3.3 shows,
a major disparity eists 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, si, 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
eamined, none has a drug discovery effort sufficient to
ensure that the net 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).
Table 3.5: Treatment Goals for Malaria, TB, and HAT
Disease
Malaria
TB
HAT
Goal
Single-dose curative treatment
Reduce treatment time to 2 months or less
Shorten therapy of latent disease
Efficacy against all stages of disease and all subspecies
Ability of drgs in development to meet goal
Goal unlikely to be met
Goal unlikely to be met
Unknown
Goal unlikely to be met
Sources: WHO/TDR, DNDi, MMV, TB Alliance, and Stop TB Partnership
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 targetone 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.
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22 closing the gloBAl heAlth innovAtion gAp
NumberofProgramsEnteringEachPhase
ofDrugDiscoveryandDevelopment
100
90
80
70
60
50
40
30
20
10
0
Figre 3.3: Attrition Rates and Crrent Neglected Disease Pipelines
Sources : MMV, DNDi, TB Alliance, PharmaProjects, and BVGH/L.E.K. analysis
Out of 100 programs entering thescreening phase of discovery, onaverage 1.3 drugs will successfullyreach the market 1214 years later
Screeningfor Hits
LeadIdentification
LeadOptimization
Preclinical Phase I Phase II Phase III Registration Approved
INNOVATION GAP
Expected programsurvival rate
Malaria
TB
HAT
Phase
100.0
30.0
19.5
10.7
5.8 4.01.9
1.31.3
Figre 3.4: The Innovation Gap
NEGLECTED DISEASE DRuG DEVELOPMENT
Thosands of Potential Gene Targets
Dozens of Validated Targets
Few Chemical Leads
Few PreclinicalCandidates
LimitedClinical
Candidates
Novel Drgs
Rarely Approved
DEVELOPED WORLD DISEASE DRuG DEVELOPMENT
Thosands of Potential Gene Targets
Hndreds of Validated Targets
Tens of Chemical Leads
8 - 10 Preclinical Candidates
5 Clinical Candidates
1 Approved
Drg
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses 2
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 epertise, and difficulties
in assembling the collaborations necessary to transform a
laboratory discovery into an IND. We eplore these prob-lems in detail below.
Insufficient investment in discovery
The cost of clinical development is highestimated 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 diffi-
culties of finding a compound that meets all the pharma-
cologic 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 eaggeration 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 compa-
nies typically spend between $2 million and $4 million peryear 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 si early-stage projects to advance
lead compounds to IND candidate stage. Current PDP
investments are far less than this.
Among the biotechnology companies we eamined 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.
MillionsofDollars
35
30
25
20
15
5
0
Figre 3.5: Annal R&D Spending by BiotechnologyCompanies and PDPs
Sources: Company SEC Filings and BVGH/L.E.K analysis
Median Annual R&D Spending
Early-Development Discovery-Only Hypothetical PDPCompany Company
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.
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2 closing the gloBAl heAlth innovAtion gAp
Access to technology and expertise and limited
scale of operations
The technological platforms, assets, and epertise neces-
sary to transform biological findings into NCEs are well
established (see Chapter 4). Biotechnology and phar-
maceutical companies engaged in drug discovery havepurchased 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 epertise 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 etend 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 epertise that lead to the discovery of
NCEs [34].
In interviews with academic leaders in malaria, tubercu-
losis, and trypanosomal diseases (for list, see Appendi
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 eperience and epertise; 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 companys 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 well-
constructed and diverse public library is a new collection ofover 100,000 small molecules accessible through the NIH
Molecular Libraries Screening Center Network (MLSCN).9
With a few eceptions, 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 etremely low (less than 1 in 1,000) and can be epected
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 industrya 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 centersfacili-
ties allowing chemical compounds to be tested for activity
against putative or established drug targets in high-
throughput modehave 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.
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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses 2
[23, 36]. To capitalize on the potential value of their own
technology, many academic institutions now vie to estab-
lish 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 academiclaboratory into a true drug discovery facility. Without
industry epertise, 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 initia-
tives for neglected diseases.
Converting hits to lead compounds is an iterative,
chemistry-intensive process requiring epertise in
analytic, synthetic, and medicinal chemistry. For
academic biologists and biochemists pursuing drug
discovery, accessing chemistsparticularly those with
medicinal chemistry epertiserequires collabora-
tion with academic chemists sharing an interest in the
biological target or disease. Because of the epense and
long timelines associated with lead-optimization medic-
inal chemistry, and the high epected 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 eample, 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
chemistsper project [27]. Additionally, few universities
possess the instrumentation and epertise required for
high-throughput assay development, x-ray crystallog-
raphy, computational modeling, and in vitro pharmacoki-
netics and toicology studiesall 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 inthree 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 epertise. It is
also a problem of recruiting organizations eperienced 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 patients 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 institu-
tions. Biotechnology and pharmaceutical companies then
license these innovations, where industrial scientists,
eperienced in translating basic science into nascent prod-
ucts, undertake drug discovery. R&D typically concludes
with completion of clinical and regulatory activities by
the biotechnology industry innovator or a large pharma-
ceutical company that may license the product once it
shows persuasive evidence of preclinical or clinical efficacy.
Bi