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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:
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.
List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
Chapter 2: Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
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— Figure 4.4: The Composition and Tasks of
the Necessary Prelude to New Drugs . . . . . . . . . . . . . . . . . . . . . . . . . 17 a Drug Discovery Team. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
Figure 3.2: Risks and Benefits of Expanding Figure 4.5: Target Class Focus of 50 Focus Companies. . . . . . . . . 34
Use of Existing Drugs Versus the Creation
of New Chemical Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Figure 5.1: Target Validation and Drug
Discovery Tools Available for P. falciparum,
Figure 3.3: Attrition Rates and Current M. tuberculosis, and T. brucei. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Neglected Disease Pipelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Figure 5.2: Target Classes Are Transferable
Figure 3.4: The Innovation Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 Across Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Figure 3.5: Annual R&D Spending by Figure 5.3: Target Classes Shared by
Biotechnology Companies and PDPs. . . . . . . . . . . . . . . . . . . . . . . . . . 23 P. falciparum, M. tuberculosis, and T. brucei. . . . . . . . . . . . . . . . . . . 41
Figure 3.6: Building a Continuum of Players Figure 6.1: Hurdles to the Biotechnology
to Move from Basic Research to Product Registration . . . . . . . . 26 Industry’s Involvement in Neglected
Disease Drug Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
Figure 4.1: The Origins of Small Molecule
Drugs in Clinical Trials (January 2007). . . . . . . . . . . . . . . . . . . . . . . . . 28 Figure 6.2: The Costs of Producing a Single New Drug. . . . . . . . . 47
Figure 4.2: Biotechnology Companies Can Figure 6.3: Possible Roles for a Discovery-Focused PDP . . . . . . . 50
Be Segmented by Capabilities. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Table 3.4: Target Product Profiles for Uncomplicated Sidebar 5.3: Harnessing diverse biotechnology solutions . . . . . 44
P. falciparum Malaria, Active Pulmonary TB,
and Late-stage HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Sidebar 6.1: Solving the innovation gap for neglected
disease drug discovery: How much will it cost? . . . . . . . . . . . . . . . 51
Table 3.5: Treatment Goals for Malaria, TB, and HAT . . . . . . . . . . 21
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 Although biotechnology companies are best known
care benefits the richest fifth of the world’s population. for developing protein drugs such as human growth
Technological breakthroughs fueled by billions of dollars hormone and monoclonal antibodies, they are also now
of investment have transformed health care for the affluent, leading innovators in small molecule drugs—the type
yet patients in resource-poor countries cannot afford high- of therapeutic best suited to meet developing-world
quality care. They lack the purchasing power that would needs for oral delivery, thermostability, and affordability.
draw investment in new medicines to treat infectious The challenge is to bring the biotechnology industry’s
diseases that are unknown, or long since eradicated, in discovery assets, know-how, and project management
wealthy countries. capabilities—developed over 30 years and with nearly
$400 billion of equity capital—to the fight against
The devastation caused by these “neglected diseases” has diseases of the developing world.
attracted renewed attention in the past decade, as it’s been
recognized that focused investment and commitment could In this study, BIO Ventures for Global Health (BVGH)
yield powerful new vaccines, drugs, and diagnostics based examined the core capabilities of the biotechnology
on the same technologies that have revolutionized health industry, academia, and the nonprofit entities that focus on
care for the affluent. clinical development of new drugs for neglected diseases.
Based on a preliminary assessment that reviewed areas of
For the first time, several hundred million dollars from significant alignment between biotechnology industry capa-
donors such as the Bill & Melinda Gates Foundation are bilities, basic disease understanding, and unmet medical
being invested annually in important research and develop- need, we focused on three classes of diseases—malaria,
ment (R&D) for diseases such as malaria and tuberculosis. tuberculosis, and trypanosomal diseases (human African
But relatively little of this investment is devoted to the trypanosomiasis, Chagas disease, and leishmaniasis).
discovery of drugs with the potential for providing break-
through therapeutic benefits. As a result, an innovation gap Central to our findings is the transferability of the tech-
is increasingly apparent in the discovery of new medicines nologies used to address cardiovascular disease, neuro-
for neglected diseases. logical disease, and cancer to the infectious diseases of the
developing world caused by parasites and bacteria. Several
This innovation gap stems from insufficient investment families of proteins that have served as principal targets
devoted to early-stage drug discovery, limited public sector for drug discovery for chronic diseases of the industrial-
access to key technologies and drug discovery expertise, ized world are also present in infectious pathogens and can
and the scarcity of capable innovators devoted to creating serve as targets for drug discovery. In principle, this means
new medicines for neglected diseases. that biotechnology companies are in an advantageous posi-
tion to apply their discovery resources and expertise to
Today, product development for neglected diseases is neglected diseases.
mainly carried out in the public and nonprofit sectors,
with for-profit companies serving as partners and subcon- To narrow the scope of our study, we focused on a
tractors in a number of cases. In contrast, the vast majority select group of over 120 companies that have capability,
of new treatments for diseases with markets in the devel- scale, and track records of innovation in small molecule
oped world are created by biotechnology and pharmaceu- discovery that could be highly relevant to neglected disease
tical companies, which together have the expertise and the drug discovery. We further chose to analyze 50 companies
infrastructure to carry discovery and development of prod- in greater depth, including the originators of more than 20
ucts from bench to bedside. small molecule drugs now approved by the FDA.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases
Key findings
Drug discovery for neglected diseases is hindered nology companies have the speed, flexibility, and persis-
by an “innovation gap.” tence to take leadership roles in attacking new challenges
Despite a revolution in funding for neglected diseases to create new products.
and the evolution of new R&D partnerships, the current
neglected disease pipeline will not fully address key treat- Substantial investment in discovery will be
ment goals (e.g., substantially shortening the duration of required.
certain treatments). The investment in product discovery The pharmaceutical industry typically allocates up to 40
and “translational” research for neglected diseases remains percent of its R&D budget to discovery. Using similar
a fraction of the level necessary to move promising criteria, to build a discovery pipeline that will feed the
discoveries from academic laboratories into commercial existing development infrastructure for diseases such as
settings—far too little to ensure a steady stream of new tuberculosis and malaria will require substantial additional
medicines for neglected diseases. Long-term investments investment. We estimate that a sustained investment of at
in innovation are needed to build a sustainable pipeline least $40 million per year for each disease is required to
of drugs that meet the needs of patients and offer hope of ensure a pipeline that delivers a new, approved therapeutic
alleviating the suffering from these diseases. every three years.
Bringing drug discovery assets built for developed- Significant hurdles hinder biotechnology industry
world diseases to bear on neglected diseases is involvement.
scientifically feasible. Three major hurdles have discouraged many biotech-
For malaria, tuberculosis, and trypanosomal diseases, suffi- nology companies from becoming engaged in global health
cient scientific tools exist for drug discovery R&D efforts product discovery:
to be initiated. Importantly, for many human molecular n Information hurdles. Companies need to become
targets that have received extensive attention from drug much more familiar with neglected diseases,
discovery companies, there are analogous targets in potential markets, and partners.
neglected disease pathogens. This means, in particular, that n Managerial hurdles. They need to build expertise
researchers can employ proprietary compound libraries in managing collaborations with partners in the
used for drug discovery for major diseases for neglected not-for-profit and academic sectors.
disease drug discovery. n Financial hurdles. They need market incentives to
invest in R&D and overcome “opportunity cost”—
Biotechnology companies that focus on small the potential profit lost by not working on a core
molecule drugs and have taken novel small business project.
molecules into clinical development are well
positioned to address the innovation gap. New approaches will be required for effective
Hundreds of biotechnology companies have resources that investment in discovery.
could contribute to the fight against neglected diseases. There is a great need to encourage collaborations between
Many of these are well positioned to take the lead in biotechnology companies with discovery expertise and
developing new drugs, vaccines, or diagnostics to address academic experts with deep understanding of the target
these diseases. For example, many proprietary compound diseases and sophisticated biochemical and molecular tools
libraries used by biotechnology companies for small mole- useful in drug discovery. Such partnerships can lower the
cule drug discovery have been optimized around target barriers to industry involvement. Managerial and financial
classes that are also relevant to neglected diseases. These hurdles must be overcome to attract biotechnology compa-
resources and capabilities would be prohibitively expensive nies to participate in global health initiatives.
to duplicate in the nonprofit sector. Moreover, biotech-
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases
Chapter 2: Introduction
The challenge of neglected diseases access to the biotechnology industry’s most advanced
Major advances in biotechnology over the last 30 years have technologies and expertise for discovering and developing
transformed medicine in the industrialized world, but these new medicines.3
innovations have yet to reach the world’s poorest countries,
where 3 billion people live on less than two dollars a day. Today’s medicines are insufficient
A fundamental transformation in commitment to solving
Each year more than 10 million people in the devel- global health problems has occurred during the first
oping world die of infectious diseases such as HIV/AIDS, decade of the 21st century. In 2000, the United Nations
malaria, tuberculosis, diarrheal diseases, and acute lower adopted the Millennium Development Goals (MDGs),
respiratory infections. Millions more suffer from debili- setting forth ambitious health-related objectives: cutting
tating parasitic diseases, which often incapacitate people child mortality by two-thirds, reducing maternal mortality
in their most productive years. The burden of infec- by three-quarters, and reversing the tide of HIV/AIDS,
tious illness falls most heavily on children and pregnant malaria, and other major infectious diseases. In response,
women. In poor countries, the magnitude of suffering governments, foundations, and international nongovern-
caused by infectious diseases makes economic develop- mental organizations (NGOs) in the developed world have
ment nearly impossible [1]. provided billions of dollars to purchase existing vaccines
and drugs for patients in the developing world.
Many of these infectious diseases have earned the label
“neglected”1 because health-care markets in the afflicted The global health crisis demands a comprehensive and
countries are insufficient to attract biopharmaceutical integrated response that begins with faster delivery of
industry2 investment in research and development (R&D). existing drugs, vaccines, and diagnostics to those most in
Over the past decade, a revolution has occurred in public need. While programs to ensure access to current medi-
sector investment combating infectious diseases of the devel- cines can yield substantial benefits, they will not offer
oping world. Governments, multilateral organizations, and complete solutions. Many of the treatments available today
foundations spend billions of dollars purchasing treatments. are decades old and are often limited by problems of drug
Millions more are invested each year in neglected disease R&D. resistance, inadequate safety, and efficacy.
Most of the R&D investment devoted to neglected diseases For example, current treatments for river blindness
is deployed through public-private, not-for-profit, product (onchocerciasis) only kill immature parasitic worms in
development partnerships (PDPs). Since 1996, over a early stages of infection and are ineffective for advanced
dozen PDP organizations have arisen to tackle the develop- disease. The sole therapy for a major form of human
ment of new vaccines, drugs, and diagnostics for devel- African trypanosomiasis is marginally effective, requires
oping-world diseases (see Sidebar 2.1). In addition, several intravenous administration, and is so toxic that it can kill
research institutes, a few large pharmaceutical companies, up to 5 percent of patients. No effective vaccine exists for
and a handful of biotechnology companies initiated their any disease on the World Health Organization’s Special
own programs, in many cases working with PDPs. Programme for Research and Training in Tropical Diseases
(WHO/TDR) list of neglected diseases (see Footnote 1).
The challenge now is to augment these public and private Diagnostics, where they exist, are often impractical for field
sector efforts. What today’s partnerships lack most is use in the developing world.
1 The 10 critical “neglected diseases” as defined by the WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR) are
African trypanosomiasis, Chagas disease, dengue, leishmaniasis, leprosy, lymphatic filariasis, malaria, onchocerciasis (river blindness), schistosomiasis,
and tuberculosis. Other major killers include diarrheal diseases and lower respiratory tract infections. Although HIV disproportionately affects the
developing world, it is not considered a neglected disease because billions of dollars are going into product development for the developed world.
2 For the purpose of this report, the “biopharmaceutical industry” comprises the 20 large, innovative pharmaceutical companies and the biotechnology industry.
3 The term “medicine” is used here to encompass vaccines, drugs, and diagnostics.
Drugs for Neglected Diseases Initiative (DNDi) International Partnership in Microbicides (IPM)
Focus: Drug development for malaria and trypanosomal diseases Focus: Microbicide development for HIV prevention
Headquarters: Geneva, Switzerland Headquarters: Silver Spring, MD, USA
Founded: 2003 Founded: 2002
Foundation for Innovative New Diagnostics (FIND) Medicines for Malaria Venture (MMV)
Focus: Diagnostic development for TB, malaria, and human Focus: Malaria drug development
African trypanosomiasis Headquarters: Geneva, Switzerland
Headquarters: Geneva, Switzerland Founded: 1999
Founded: 2003
Malaria Vaccine Initiative (MVI)
Global Alliance for TB Drug Development (TB Alliance) Focus: Malaria vaccine development
Focus: TB drug development Headquarters: Bethesda, MD, USA
Headquarters: New York, NY, USA Founded: 1999 as an independent program within PATH
Founded: 2000
Pediatric Dengue Vaccine Initiative (PDVI)
Human Hookworm Vaccine Initiative (HHVI) Focus: Dengue vaccine development
Focus: Vaccine development for hookworm Headquarters: Seoul, Korea
Headquarters: Washington, DC, USA Founded: 2003
Founded: 2000
Program for Appropriate Technology in Health (PATH)
Institute for OneWorld Health (iOWH) Focus: Development of health technologies
Focus: Drug development for visceral leishmaniasis, malaria, Headquarters: Seattle, WA, USA
and diarrheal diseases Founded: 1977
Headquarters: San Francisco, CA, USA
Founded: 2000
Several PDPs, often through outsourcing and partnering, l Pyramax®: Combination therapy (pyronaridine-artesunate)
have assembled substantial clinical development infrastruc- for malaria, developed by Medicines for Malaria Venture
tures. PDPs also manage sophisticated clinical programs in (MMV), currently in phase III clinical trials.
multiple developing countries. Their efforts, and those of a
small number of biopharmaceutical companies, are begin- l RTS,S/ASO2A: Malaria vaccine, developed jointly through
the Malaria Vaccine Initiative (MVI) and GSK, has completed
ning to pay off. New products have succeeded in clinical
phase II trials.
trials, and a few have already been registered for sale in
developing countries (Sidebar 2.2).
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 11
These products offer important opportunities to improve Long-term investments in innovation are needed to build a
standards of care for key neglected diseases, but are just sustainable pipeline of drugs meeting the needs of patients
a start. Continued investment will be required to expand now and into the future. Experience has shown that
the pipeline of products that can keep improving care for returns on pharmaceutical R&D investments are measured
neglected diseases. For example, we need: in decades, not years. Moreover, the lesson from all expe-
n a shorter course of TB therapy that works against rience with treatments for infectious diseases—whether
drug-resistant microbes; it’s antibiotics for streptococcal bacteria or anti-retrovirals
n a safe and affordable treatment for human African (ARVs) for HIV/AIDS—is that the pathogens eventually
trypanosomiasis; develop resistance to drugs. Researchers must constantly
n a diagnostic that distinguishes between malaria fight back by inventing new drugs that kill pathogens
and bacteremia in a feverish child; through novel mechanisms of action.
n a drug that kills adult forms of the many species
of worm, causing such diseases as lymphatic Study approach and objectives
filariasis, that deform and incapacitate millions BIO Ventures for Global Health (BVGH) undertook this
of patients; and study to assess whether the biotechnology industry’s
n new vaccines to prevent millions of deaths diverse technology platforms and expertise can be applied
each year. to inventing products for neglected diseases and, if so,
how. We focused on opportunities and challenges facing
An innovation gap impedes progress development of therapeutics for key neglected diseases:
Achieving the most ambitious public health goals for tuberculosis (TB), malaria, and three diseases caused by
the treatment and prevention of neglected diseases will trypanosomatids4—human African trypanosomiasis (HAT,
require extensive discovery efforts supported by long-term also known as African sleeping sickness), leishmaniasis,
funding. Most of today’s global health product pipeline and Chagas disease. For simplicity’s sake, at several points
in therapeutics, however, focuses on products amenable in this report we use Trypanosoma brucei, the cause of
to rapid clinical development, mainly by repurposing HAT, to represent all trypanosomatids.
known drugs for new uses. Finding new uses for existing
drugs makes sense because it speeds development and We focused on therapeutics in this report because it
makes it possible to reach those in need in the shortest gave us the opportunity to include the largest number of
possible time. Currently, a relatively small portion of the biopharmaceutical companies. The vast majority of inno-
investment in R&D for neglected diseases is directed to vative biopharmaceutical companies develop therapeu-
discovering new chemical entities (NCEs)—that is, novel tics; a smaller number focus on vaccines and diagnostics.
compounds with the potential of providing breakthrough Drugs represent the largest segment of global pharma-
therapeutic benefits. ceutical markets. We selected TB, malaria, and the three
trypanosomal diseases for several reasons: Each is associ-
This report highlights the current innovation gap in the ated with a high disease burden; current treatments have
discovery of new medicines for neglected diseases. The serious limitations; and each has strong scientific founda-
investments in product discovery and “translational” tions upon which new therapeutic R&D might be based
research necessary to move promising discoveries from (see Table 2.1).
academic laboratories into commercial settings are at a very
early stage and are insufficient in scale to ensure a steady We should emphasize that our goal was to be inclusive,
stream of new medicines for neglected diseases. Without not exclusive. Biopharmaceutical companies can clearly
increased effort and investment in discovery research, contribute in many other areas. Future studies can and
bringing neglected diseases under control will be delayed should assess biotechnology innovation in other diseases
by years, perhaps even decades. and interventions, including diagnostics and vaccines.
4 Trypanosomatids are flagellated, parasitic protozoa (single-celled eukaryotic organisms) with complex life cycles during which they alternate
between vertebrate hosts and insect vectors.
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
HAT 1.5 M Safety, efficacy, resistance, long treatment Pathogen genome sequenced; genetic
time, treatment administration manipulation facile; animal models
of disease
Chagas Disease 0.7 M No treatments available for chronic Pathogen genome sequenced; genetic
form of disease manipulation possible; animal models
of disease
Leishmaniasis 2.1 M Safety, administration, and long pathogen genome(s) sequenced; genetic
treatment time manipulation possible; animal models
of disease
*One disability adjusted life year (DALY) is equivalent to one year of healthy life lost.
Source of DALY information: WHO/TDR.
We began our analysis by interviewing academic fill it for each of the diseases we evaluated. Chapter 4
researchers focused on TB, malaria, and trypanosomal describes the critical role that the biotechnology industry
diseases (see Appendix III). We aimed to determine the has played in developed-world drug discovery and the
availability of biological and molecular tools for drug wealth of biotechnology industry expertise and infra-
discovery and identify critical bottlenecks. We then evalu- structure that can be applied to neglected disease drug
ated current product pipelines against international public discovery. Chapter 5 evaluates the status of the molecular
health goals and drug target product profiles (TPPs) to tools for TB, malaria, and HAT, and it maps biotech-
determine where new discovery efforts are required for nology industry capabilities against drug targets for the
each disease. three diseases.
To evaluate whether industry has the capability and rele- Applying biotechnology to global health will call for new
vant tools to address the gaps we identified, we selected collaborative models and financial incentives to encourage
50 leading biotechnology companies from the hundreds industry to take on the risk and cost of product devel-
focused on small molecule drug discovery. These compa- opment. This will require vision, new partnerships,
nies were chosen for their discovery capabilities in small risk-taking, innovative business strategies, and financial
molecule therapeutics, the scale of their discovery efforts, commitment. Chapter 6 explores these issues and proposes
and their track records of bringing NCEs into the clinic. several approaches to investing in new global health R&D.
These are some of the most experienced companies in Chapter 7 outlines our conclusions and recommendations.
small molecule drug discovery today. They are listed in
Appendix IV, and their capabilities are described further The obstacles to developing new drugs for neglected
in Chapter 4. diseases are formidable. But they are not insurmountable.
If the worldwide health-care community can make the
This report makes the case that there is a compelling role same progress against malaria, tuberculosis, and trypano-
for the biopharmaceutical industry in building the global somal diseases that it has in the past 20 years against
health product pipeline and shortening the critical R&D cancer, diabetes, and cardiovascular disease, we can look
timelines on the way to achieving that goal. Chapter 3 forward to millions of lives saved and a better world for
defines the innovation gap and what may be needed to us all.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 13
Chapter 3: The Innovation Gap in Discovering
New Therapeutics for Neglected Diseases
Creating innovative pharmaceutical products is a urged. Artemisinin-based combination therapies (ACTs)
complex process that typically takes 10 to 15 years. have proven especially efficacious. Artemisinin, a structur-
Donor funding and the emergence of product develop- ally complex natural product, is comparatively expensive
ment partnerships has led to an unprecedented number to manufacture, which, until recently, precluded the use of
of late-stage candidate medicines in the pipeline for ACTs in many impoverished countries.
neglected diseases. R&D efforts at the drug discovery
stage, however, are insufficient to ensure a continuous Tuberculosis. One-third of the global population—more
flow of products entering clinical development. This than 2 billion people—harbors a latent or asymptomatic
innovation gap results from insufficient investment, infection by Mycobacterium tuberculosis, the bacterium
limited access to key technologies and drug discovery causing tuberculosis (TB). About 10 percent of those
expertise, and difficulties in assembling the collabora- infected will develop active TB at some point during their
tions necessary to transform a laboratory discovery lifetime, translating into nearly 9 million cases of active
into an investigational new drug. Failure to address disease and more than 2 million deaths annually. In immu-
the innovation gap will impede the creation of the next nocompromised populations, such as those with HIV, rates
generation of treatments for malaria, tuberculosis, and of active TB are extremely high. Worldwide, TB is now the
trypanosomal diseases. leading cause of death among AIDS patients [6].
New drugs for old diseases First-line treatment for active TB consists of two or four
Many of the available medicines for neglected diseases are antibiotic drugs taken in combination for a minimum
outdated, impractical, insufficiently efficacious, or subject of six to nine months. The duration of the regimen,
to pathogen resistance and unacceptable toxicities [3-5]. combined with the medications’ toxicities, causes many
New medicines are urgently needed for tuberculosis, all patients to fail to complete the full course of treatment
diseases caused by protozoan parasites, and many of the [7]. This, in turn, has hampered TB control programs and
helminth (worm) infections. fueled the proliferation of antibiotic-resistant M. tubercu-
losis strains. Recently, extensively drug-resistant TB (XDR-
This study focuses on the need for new drugs for malaria, TB) has entered communities with high HIV prevalence
tuberculosis, and trypanosomal diseases. Each disease is and is killing people at alarming rates [8, 9].
summarized below and in Table 3.1, along with the status
and limitations of today’s treatments. Trypanosomal diseases. Three major classes of
trypanosomal diseases affect humans: human African
Malaria. More than 40 percent of the world’s population trypanosomiasis (HAT), Chagas disease, and leishmaniasis.
is at risk for malaria, and up to 500 million people develop n HAT (also referred to as African sleeping sickness)
the disease each year. Malaria results from infections by is found only in sub-Saharan Africa, where 60
parasitic protozoa from the genus Plasmodium. Young million people are at risk for the disease. Each
children and pregnant women, especially those living in year, there are up to 300,000 cases, resulting in
sub-Saharan Africa where the more virulent Plasmodium nearly 50,000 deaths.
falciparum parasite is dominant, are most vulnerable to n Chagas disease is endemic in rural areas in South
malaria and account for the majority of the 1 million and Central America, placing an estimated 25
deaths estimated to occur annually. million at risk. In total, as many as 9 million
people may be infected with the Chagas parasite.
Commonly used antimalarials are increasingly ineffec- Annually, 14,000 deaths result from Chagas
tive due to widespread drug resistance. To combat the cardiomyopathy associated with the chronic form
emergence of resistance to the drugs remaining in the of the disease and often occurring 10 to 20 years
antimalarial arsenal, use of combination therapies has been after initial infection.
TB 2 million 9 million Pandemic; Immuno- Mycobacterium All first-line treatments have issues
A bacterial disease that most (active TB) 2 billion are compromised tuberculosis concerning resistance, toxicity, and
commonly affects the lungs. In infected with populations treatment length (6-9 months):
otherwise healthy individuals, are at
latent TB. Rifampicin (1963)
most infections are latent and
highest risk
asymptomatic. About 10% of those Ethambutol (1962)
infected develop active pulmonary
disease; symptoms include a cough Streptomycin (1955)
lasting more than two weeks, Pyrazinamide (1954)
coughing up blood, fatigue, fever,
chills, night sweats, and weight and Isoniazid (1952)
appetite loss.
HAT 50,000 Up to 60 million; Trypanosoma Pentamidine (1941): lacks oral formulation,
A parasitic disease transmitted 300,000 (sub-Saharan brucei side effects, early-stage specific, most
by tsetse flies. HAT progresses Africa) (subspecies effective against T. b. gambiense
from fever and fatigue (early-stage
gambiense Suramin (1921): lacks oral formulation,
disease) to severe neurological
and side effects, early-stage specific, first-line
conditions (late-stage or chronic
rhodesiense) treatment against T. b. rhodesiense
disease). Untreated HAT is fatal.
Melarsoprol (1949): toxicity, resistance
Eflornithine (1980): toxicity, administration,
spectrum of activity, supply, cost, only
effective against T. b. gambiense
Chagas disease 14,000 750,000 25 million; 8-9 million Trypanosoma Chronic disease - no treatments available
A parasitic disease that over time (Latin are currently cruzi
Acute disease -
causes damage to the nervous America and infected Nifurtimox (1960): resistance, safety,
system, digestive tract, and the
Caribbean) efficacy
heart. The disease is contracted via
the feces of an infected Reduviid bug. Benznidazole (1970s): resistance, safety,
efficacy
Leishmaniasis >50,000 1.5-2 million 350 million 12 million ~20 Leishmania Visceral leishmaniasis:
A collection of parasitic diseases are currently species
Miltefosine (2003): safety
transmitted by the Phlebotomine infected
sandfly that affects the skin, Paromomycin (2006): delivery
mucosa, or internal organs,
resulting in severe disfigurement, Pentosam (1944), Amphotericin B (1950s),
disability or death. Ketoconazole (1980s), Pentamidine (1941),
and antimony-containing compounds:
resistance, efficacy
Sources: WHO/TDR and Hotez, P.J., et al., Control of neglected tropical diseases. N Engl J Med, 2007. 357(10): p. 1018-27.
n Leishmaniasis is a collection of diseases; there HAT, Chagas disease, and all forms of leishmaniasis are
are cutaneous, mucosal, and visceral forms. caused by divergent species of single-celled protozoa called
Worldwide, about 350 million people are at risk trypanosomatids. These pathogens share many unusual
for leishmaniasis. Cutaneous and mucosal forms molecular and biochemical pathways, but their infectious
cause severe disfigurement and disability. The cycles and target tissues for infection are very different.
visceral form is fatal if untreated. An estimated 12 While there is precedent that a treatment designed for one
million people are infected with leishmania, and pathogen may have efficacy toward another [5, 10], it is
each year there are over 50,000 deaths. likely that drug discovery and development will mostly
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 15
proceed independently for different species. For simplicity’s Drug discovery refers to the earliest stages of generating
sake, at several points in this report we use Trypanosoma an actual product. It begins with the difficult process of
brucei, the cause of HAT, to represent the entire class. translating findings from basic research into candidate
molecules with the potential to treat disease. Researchers
Problems associated with existing drugs for trypanosomal organize their work around a target product profile
diseases include lack of efficacy, drug resistance, long (TPP), essentially a list of minimum characteristics a drug
treatment duration, availability, expense, and safety. For must possess to warrant development and use in people.
instance, melarsoprol, the only treatment for HAT caused “Small molecule” drug discovery is a chemistry-intensive
by one subspecies of T. brucei, is so toxic that it kills up process in which a library of thousands or even millions
to 5 percent of those who receive it [11]. There are no of compounds is screened for molecules with drug-
drugs to treat the chronic form of Chagas disease. Visceral like activity potentially meeting TPP requirements. The
leishmaniasis treated with paromomycin requires 21 days compounds identified by screening, often called “hits,” are
of injections. An orally available alternative, miltefosine, is then refined for other essential drug-like properties into
unsafe for pregnant women. “leads.” A lead is a compound that interacts with accept-
able potency and selectivity with a cellular “target” macro-
The drug development process molecule such as a protein.
To understand the serious challenges presented by
today’s global health drug pipeline, we must first under- For an infectious disease, the target is usually a macro-
stand the process of creating a new drug. More complex molecule belonging to the pathogen, and ideally the
and time-consuming than nearly any other commercial interaction between the drug and its target kills the
endeavor, pharmaceutical R&D requires technological pathogen and cures the disease. In an iterative process,
and scientific expertise, teamwork, leadership, risk-taking, lead compounds are optimized and retested for improved
time—and most of all, money. The steps of the process activity, specificity, potency, and safety. A more detailed
are commonly broken into three phases: basic research discussion of the intricacies of the small molecule drug
that establishes biological knowledge of disease causality discovery process is presented in Appendix I. There is no
and creates tools for R&D; discovery, the innovative steps hard-and-fast point where the iterative process of drug
by which new therapeutic compounds are identified and discovery ends.
evaluated; and development, or testing first in animals
of small numbers of compounds winnowed from the Drug development is most simply defined as the point at
discovery steps, leading to a single, promising candidate which an optimized lead compound with good efficacy
compound to evaluate for therapeutic efficacy and safety in animal models and acceptable toxicity and pharmaco-
in human clinical trials. kinetic5 properties is selected for preclinical evaluation
[12]. Once a “preclinical candidate” has been chosen, it
Basic research refers to the scientific exploration of disease must pass a rigorous series of tests designed to ensure
and, in the case of infectious diseases, the pathogens that safety in animals and provide persuasive indications
cause them. The goal of most basic research is to develop of efficacy. With a successful preclinical compound in
a molecular, genetic, and biochemical understanding of hand, researchers may then apply to the U.S. Food and
disease pathology in the hope that this knowledge will Drug Administration (FDA) for investigational new drug
lead to treatments and cures. Developing this knowledge (IND) status, which permits the compound to be tested
requires an extensive set of tools for research. The process in humans. The IND candidate’s safety, dosing, and effi-
of inventing research tools is in itself another component cacy in humans are then established by clinical trials.
of basic research. Products with demonstrated efficacy and safety in humans
5 “Pharmacokinetics” refers to the study of how an externally administered agent behaves in animals or humans—“what the body does to a drug.”
Routinely examined pharmacokinetic properties of a drug are its absorption, distribution, metabolism, excretion, and toxicological properties
(ADME/Tox).
Screening Lead Lead Optimization Preclinical Phase I Phase II Phase III Registration
for Hits Identification
Clinical Trials
3-6 years 1 year 6-7 years 1 year
are approved by regulatory authorities such as the FDA or investment since 1999 [2]. Although certain large pharma-
European Medicines Agency (EMEA) and registered in the ceutical companies, academic centers, and biotechnology
countries in which they will be sold. companies have begun to participate, the driving forces for
therapeutic R&D in global health have been PDPs [21].
Together, projects in discovery and development make
up the product “pipeline.” As illustrated in Figure 3.1, PDPs are not-for-profit organizations funded and championed
the process of discovering and developing drugs requires by the donor community6 to develop novel vaccines, drugs,
an average of 10–15 years [13, 14]. Although the failure and diagnostics for specific neglected diseases. Like many for-
rate is greatest at the earliest stages of discovery, prod- profit biopharmaceutical companies, PDPs drive preclinical
ucts can fail at any point. Indeed, high rates of attrition and clinical development of new product portfolios, picking
partially explain why the process of inventing a drug takes and choosing which products to advance through the pipe-
so long. According to the Pharmaceutical Research and line, including which to launch or terminate. In contrast to
Manufacturers of America (PhRMA), for every 5,000–10,000 for-profit companies, many PDPs are “virtual” organizations
compounds that enter the pipeline, only one becomes a with comparatively small staffs and no laboratories of their
registered product [14]. Thus, because of attrition, the vast own. Most, if not all, of the projects in their portfolios are
majority of compounds that enter drug discovery and devel- carried out by partners, including researchers in academic
opment will never progress to success in clinical trials [15]. institutions, contract research organizations (CROs), and
large pharmaceutical companies. The larger PDPs oversee
New players build the therapeutics and coordinate projects occurring all over the globe.
pipeline for neglected diseases
From 1975 to 2004, out of 1,556 new drugs approved by Four leading PDPs focus on therapeutics for malaria, TB,
the FDA, EMEA, and other government authorities, only 21 and trypanosomal diseases:
were registered for tuberculosis, malaria, and other neglected n The Medicines for Malaria Venture (MMV)
diseases [16, 17]. This oft-cited statistic reflects the lack promotes new antimalarials.
of incentives for biopharmaceutical companies to invest in n The Global Alliance for TB Drug Development (TB
products for which there are insufficient paying markets. Alliance) focuses exclusively on drug development
for tuberculosis.
In 2006 alone, U.S. pharmaceutical and biotechnology n The Drugs for Neglected Disease Initiative (DNDi)
companies invested over $55 billion of their own resources creates new drugs to treat trypanosomal diseases
to invent medicines for diseases of the developed world and malaria.
[18]. Yet, they directed only a fraction of that sum—we n The Institute for OneWorld Health (iOWH)
estimate based on two recent studies less than $100 concentrates on leishmaniasis, malaria, and
million—for R&D aimed at two of the world’s biggest diarrheal diseases.
killers, malaria and tuberculosis [19, 20].
All four are mostly virtual and work extensively with
To remedy this imbalance, over the past decade new public nonprofit and for-profit partners to conduct discovery and
sector R&D efforts have arisen to build a pipeline of new development. By supporting PDPs, donors have created
products for neglected diseases, with over $1.2 billion of centers of expertise for each disease area.
6 We use the term “donor community” to refer to governments, nonprofit organizations, and foundations.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 17
Table 3.2: PDP Drugs Registered or in Clinical Trials
Paromomycin Visceral leishmaniasis Registered in 2006 (India) Existing (new use) iOWH
Phase III (East Africa) DNDi
Artesunate-amodiaquine Malaria Registered in 2007 (Morocco) Existing (new combination therapy) DNDi
Coartem® dispersible tablet Malaria Phase III New formulation of existing combination therapy MMV
Dihydroartemisinin-piperaquine Malaria Phase III Existing (new combination therapy) MMV
*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.
Zithromax® chloroquine Malaria Phase III Existing (new combination therapy) Pfizer
Fosmidomycin-clindamycin Malaria Phase II Existing (new combination therapy) Jomaa Pharma Gmbh
DB289 (pafuramidine) HAT Phase III NCE UNC Consortium for Parasitic
Drug Development
Figure 3.2: Risks and Benefits of Expanding Use of Existing Drugs Versus the Creation of New Chemical Entities
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 19
Requirements for effective drugs The World Health Organization (WHO), via the Stop TB
for neglected diseases partnership and TDR, has drawn together the views of
Any new drug emerging from the pipeline for neglected leading scientists in global health into a set of ambitious
diseases must be safe, inexpensive to manufacture, prac- goals for discovering new treatments for tuberculosis,
tical to administer, stable in harsh climates, potent against malaria, HAT, and other neglected diseases [12, 24]. Table
resistant strains, and effective within time frames compa- 3.5 summarizes these goals. New medicines that fulfill
rable to or better than existing products. In addition, these objectives might halt and even reverse the spread of
as illustrated in Table 3.4, each disease has a specific, these diseases.
minimum TPP that a new product must meet [22, 23].
Table 3.4: Target Product Profiles for Uncomplicated P. falciparum Malaria, Active Pulmonary TB, and Late-stage HAT
Resistance
Dosing
Oral formulation
Fast acting
Pediatric formulation
Safety
Safe/low toxicity
Manufacturing
Broad Spectrum
Combination Use
Other
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 Efficacy against all stages of disease and all subspecies Goal unlikely to be met
The activity and safety of the drugs now in development lack of credible screening hits, failure to optimize efficacy
will be fully apparent only upon completion of clinical versus toxicity, lack of oral bioavailability, and failure in
trials. But it is clear already that these drugs will not meet animal proof-of-concept models. Project failure rates before
some of the ambitious goals in Table 3.5, such as short- identifying an IND candidate are routinely over 75 percent.
ening the duration of TB treatment to two months or less Subsequent attrition due to clinical failures, safety concerns,
[25], reducing malaria treatment to a single, curative dose, and market forces reduces the success rate to less than 5
and developing a treatment effective against all stages of percent, sometimes only 1 to 2 percent. Thus, a credible
HAT. For these advances, a new generation of therapeutics effort to develop a new drug in the biopharmaceutical industry
will be required. requires substantial numbers of discovery projects—enough to
ensure that a product with the desired TPP will emerge from
An innovation gap impedes creation the pipeline.
of the next generation of drugs
As the current generation of drug candidates advances The pipeline of clinical-stage programs for malaria, TB,
toward clinical success and registration, or toward clinical and HAT is expected to yield several new products in
failure and abandonment, a new generation of drug candi- the next few years [21]. However, as Figure 3.3 shows,
dates must follow that offers the promise of achieving more a major disparity exists between early-stage pipelines of
ambitious goals. Similar to drug development for cancer these diseases and the profile of a typical industry-driven
and diabetes, neglected disease drug development pipe- program for a disease with an established market. For
lines require “high-quality” discovery programs7 backed instance, our analysis found that there are five, six, and
by substantial, sustained investment as occurs when the one discovery projects in the lead optimization stage
biopharmaceutical industry tackles diseases such as cancer for malaria, TB, and HAT, respectively. Assuming that
or diabetes. the average industry project failure rates will also apply
to neglected disease projects, these numbers are far shy
For instance, a major biopharmaceutical company intent of the 20 projects typically required to yield a single
on developing a new oral treatment for a chronic disease new drug. Indeed, for all of the neglected diseases we
market such as heart disease would explore 10 to 20 examined, none has a drug discovery effort sufficient to
targets generated by genomics and biochemistry, and ensure that the next generation of candidate compounds
advance five to 10 targets in parallel into high-throughput will be ready to enter clinical development in the coming
screening. Each project would initially screen thousands years. This observation has also been noted by others
to millions of compounds. Most of these projects will [26]. This deficiency, or innovation gap, restricts the
fail because of myriad interrelated reasons: for example, flow of new, approved medicines for neglected diseases
inability to express the target protein and develop an assay, (Figure 3.4).
7 A high-quality program is defined as having the following characteristics: 1) a solid molecular target associated with disease pathology, validated
by genomics, molecular biology, cellular systems, and animal pharmacology; 2) a druggable target—one where a small molecule drug would exert
a positive therapeutic effect; 3) creating new compositions-of-matter that have the desired effect or improve upon known compounds, with low or
no side effects; 4) the ability to manufacture the drug at reasonable cost for desired benefit; 5) the ability to get a clear clinical answer in a defined
population quickly; and 6) a clearly defined path to regulatory approval.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 21
Figure 3.3: Attrition Rates and Current Neglected Disease Pipelines
100.0
100 Out of 100 programs entering the Expected program
screening phase of discovery, on survival rate
90 average 1.3 drugs will successfully
reach the market 12–14 years later
Number of Programs Entering Each Phase
80 Malaria
of Drug Discovery and Development
70 TB
Innovation Gap
HAT
60
50
40
30.0
30
19.5
20
10.7
10 5.8 1.9
4.0 1.3
1.3
0
Phase Screening Lead Lead Preclinical Phase I Phase II Phase III Registration Approved
for Hits Identification Optimization
Limited
5 Clinical Candidates Clinical
Candidates
30
By contrast, PDPs have focused smaller proportions of
Millions of Dollars
in-kind contributions of manpower and resources. Sources: Company SEC Filings and BVGH/L.E.K analysis
8 Discovery-only companies are defined as those capable of screening for hits and generating leads and optimized lead compounds. Few carry out
preclinical work except on a contract basis. Early-development companies possess comparable capabilities to discovery-only companies, but they can
also carry out preclinical work and phase I clinical trials.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 23
Access to technology and expertise and limited Publicly available compound libraries, on the other hand,
scale of operations are largely limited to diversity libraries obtained from
The technological platforms, assets, and expertise neces- commercial sources. Many academic research facilities have
sary to transform biological findings into NCEs are well assembled libraries from commercial sources, but few if any
established (see Chapter 4). Biotechnology and phar- compare with those available in industry. The most well-
maceutical companies engaged in drug discovery have constructed and diverse public library is a new collection of
purchased or synthesized large compound libraries. They over 100,000 small molecules accessible through the NIH
have assembled capabilities in advanced technologies such Molecular Libraries Screening Center Network (MLSCN).9
as high-throughput screening, X-ray crystallography, and
computational modeling. They have teams of scientists With a few exceptions, publicly available libraries do
with expertise in assay development, medicinal chemistry, not have the target-class focus common to proprietary,
and pharmacology. purpose-built libraries in biotechnology and pharmaceutical
companies. Commercial libraries are based almost solely
Academic centers and individual investigators carrying on structural novelty, much like the early combinatorial
out neglected disease research have identified compelling libraries used by industry, as opposed to relevance to the
new targets for therapeutic intervention [26, 31, 32]. targets of interest. Screening large numbers of such unbiased
For the most part, however, they lack the tools available compounds against a target may generate hits, but hit rates
to industry to extend their research into drug discovery. are extremely low (less than 1 in 1,000) and can be expected
Even with the advent of academic- and government-based to identify a distracting number of false positives [35].
high-throughput drug screening (HTS) initiatives such as
the NIH Roadmap for Medical Research [33], advances Although these concerns limit the utility of publicly
in neglected disease biology are not adequately matched available libraries, two trends may make it possible for
with the tools and expertise that lead to the discovery of public sector researchers to avoid some of these pitfalls.
NCEs [34]. First, there are now commercial sources of target-focused
libraries. These libraries offer much higher yields when
In interviews with academic leaders in malaria, tubercu- screened against members of a target family. Second, it
losis, and trypanosomal diseases (for list, see Appendix is possible and cost-effective to engage chemistry CROs,
III), we found they face three key obstacles in progressing many of which are offshore, to design certain types of
beyond generating hits through small molecule screening: custom compound libraries. Nonetheless, the public sector
first, limited access to the most advanced drug discovery still does not have access to the breadth of target-focused
technology and compound libraries; second, lack of drug libraries available to industry—a reality that limits the
discovery experience and expertise; and third, insufficient types of NCEs that can emerge from a neglected disease
scale of operations. drug discovery campaign.
Limited access to the best compound libraries Limited access to discovery infrastructure and
Compound libraries are collections of organic chemicals chemistry expertise
assembled by purchase or custom synthesis for repeated In recent years, high-throughput screening centers—facili-
screening in multiple biological assays. An industrial ties allowing chemical compounds to be tested for activity
compound library is organized around a biological target against putative or established drug targets in high-
class, drug-like properties, or chemical structural diversity. throughput mode—have been installed at universities and
A company’s organized, selected, and annotated compound public research institutes all over the world. These centers
library is a core, proprietary asset. are particularly abundant in North America and Europe
9 MLSCN is an NIH-funded consortium that provides the following: high-throughput screening (HTS) to identify compounds active in
target- and phenotype-based assays; medicinal chemistry to transform hits into tool compounds; and deposition of screening data into
a freely accessible public database. See Austin, C.P., et al., NIH Molecular Libraries Initiative. Science, 2004. 306(5699): p. 1138-9.
10 GSK’s Diseases of the Developing World program in Tres Cantos, Spain; the Novartis Institute for Tropical Diseases (NITD) in Singapore;
AstraZeneca’s TB Research Programme in Bangalore, India.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 25
Figure 3.6: Building a Continuum of Players to Move from Basic Research to Product Registration
Academia and
Research Biotechnology Companies Multinational Pharmaceutical Companies
Institutions
Basic Screening Lead Lead Preclinical Phase I Phase II Phase III Registration
Research for Hits Identification Optimization
CLINICAL TRIALS
NEGLECTED DISEASES
Multinational Pharmaceutical Companies
Academia and
Research Innovation
Institutions Gap Product Development Partnerships
Legend: Neglected disease R&D lacks the continuum of players and handoffs that has evolved for developed-world diseases.
Many academics pursuing neglected disease research If not addressed soon, the innovation gap could delay
have developed tools and technologies that might be put for years, and potentially decades, victory over neglected
to work in drug discovery. But the options for transfer- diseases. Moreover, these efforts need to be sustained;
ring their findings to industry are limited, in part because no new drug, no matter how powerful, can forever
an appropriate structure for licensing arrangements that evade the development of drug resistance. Researchers
may not generate revenue has yet to be established. As a must constantly fight back with drugs that have new
result, organizations lack sufficient incentives to overcome mechanisms of action.
barriers to forming partnerships and moving neglected
disease product development forward [34]. It is essential that neglected disease pipelines include
large numbers of high-quality discovery programs to
Closing the innovation gap ensure continuing improvements in care. The innovation
Achieving the ambitious goals for treatment of tubercu- gap cannot be closed with money alone. We must also
losis, malaria, and human African trypanosomiasis will do a better job aligning the efforts of basic researchers
entail extensive drug discovery efforts requiring long- with biotechnology drug discovery tools and expertise—
term commitment and funding that does not exist today. described in detail in the next chapter.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 27
Over the past decade and a half, industry’s landscape percent of the new medicines approved by the FDA origi-
changed dramatically. Biotechnology companies recog- nated from biotechnology company R&D [27, 42]. In
nized the increasing demand for treatments using small early 2007, nearly two-thirds of the small molecule drug
molecules, especially for orally administered drugs against candidates in clinical trials originated in biotechnology
chronic diseases. Taking advantage of a revolution in companies (Figure 4.1). By this measure, the biotech-
miniaturization, discovery technologies, and vast increases nology industry has overtaken large pharmaceutical
in throughput in screening small molecules for drug companies and assumed the leading role in innovation of
activity, biotechnology companies became leading origina- small molecule drugs.
tors of small molecule drugs.
Large pharmaceutical companies have traditionally devoted
This change is critical to whether biotechnology can significant resources to making drug analogs (modified
contribute to developing new drugs for neglected diseases. versions of known compounds) or creating new drugs
This is because most large molecule biologics (excluding that act on previously validated drug targets. A defining
vaccines) are produced in small quantities, are compara- characteristic of biotechnology companies has been their
tively expensive (in many cases extremely expensive), must willingness to take on risk and engage in innovation, and
be stored in the cold, and are delivered only by injection. thus the biotechnology industry has taken a different
The profile of most drugs envisioned for the developing approach. Capitalizing on breakthroughs in understanding
world demands the opposite: large quantities produced at of the biochemistry of disease and technical advances such
very low cost, heat stability, and oral delivery. Only small as genomics and proteomics, biotechnology companies
molecule drugs typically achieve this profile. developed technologies for screening compound libraries
for activity against novel molecular targets or new target
The biotechnology industry has achieved therapeutic classes, such as cell receptors or intracellular messengers
success with small molecule anti-infectives, anticancer that regulate biochemical processes involved in disease.
agents, and cardiovascular disease drugs. As of 2005, These technologies are competitive with the drug discovery
the top 10 small molecule drugs originating in biotech- capabilities of pharmaceutical companies, and they
nology had sales totaling $7.5 billion. More than half of routinely enable screening millions of compounds against a
the drugs that originated in biotechnology companies and new biological target in a matter of weeks [35, 43].
received regulatory approval in 2004–2006 were small
molecules [41]. Between 1998 and 2006, more than 25 Biotechnology companies focused on drug discovery can
be segmented by capabilities. As summarized in Figure
Figure 4.1: The Origins of Small Molecule Drugs in Clinical 4.2, companies can be classified as fully integrated, early
Trials (January 2007) development, or discovery only:
n Many larger, mature biotechnology companies
600 have fully integrated discovery and development
Small Molecule Drugs in Clinical Development
Basic Target Target Screening Lead Lead Preclinical Phase I Phase II Phase III
Research Identification Validation for Hits Identification Optimization
Less well-developed
n Discovery-only companies are typically young and develop platform technologies, vaccines, drugs and diag-
privately held. They have some of the most novel nostics, not to mention agricultural, environmental, and
drug technology platforms. Lacking in-house industrial products. To concentrate on the companies
preclinical capabilities, they contract with CROs potentially most relevant to closing the drug discovery
and partner with larger companies to advance innovation gap for select diseases, we winnowed a list
drug candidates through preclinical development of over 1,500 U.S. and European companies12 down to
and into IND status. approximately 120 that: (a) focus on small molecule drugs,
(b) have significant discovery programs, (c) have succeeded
Small molecule innovation in the in taking new compounds into human clinical trials, and
biotechnology industry (d) have sufficient scale to pursue multiple programs with
Given the risk and high attrition rate of drug discovery, at least some vertical integration (see Sidebar 4.2). To
biotechnology companies typically aim to develop truly refine our analysis, we analyzed in depth 50 representative
novel products for high-impact therapeutic markets. companies. These companies are listed in Appendix IV and
Hence, few apply their skills to neglected diseases. But are summarized as a group in Table 4.1.
if markets and incentives were available, would the
Table 4.1: Summary of 50 Focus Companies
infrastructure of the industry be applicable to neglected
diseases? Would companies be in a position to undertake Approved drugs originating from focus companies 23
discovery projects against unfamiliar pathogens?
Programs in active clinical development (Jan 2007) 121
12 We elected to focus on U.S. and European biotechnology companies because they represent the most innovative companies.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 29
The companies we examined closely have collectively on a scientific foundation in cellular biochemistry. At least
raised over $20 billion in public equity capital and as important—and even harder to import or build from
received billions more in partnering revenues from collabo- scratch—is their drug discovery expertise. Companies
rators. Their financial strength is also concentrated: just have assembled highly experienced teams of biologists,
over half the $20 billion was raised by the five largest structural biologists, pharmacologists, and chemists. Their
companies (Figure 4.3). skills are indispensable to “lead optimization,” the itera-
tive process of synthesizing and testing compounds for
The resources of the biotechnology industry potency, efficacy, and low toxicity.
Through interviews with executive and scientific manage-
ment of many companies in our representative set, we Biotechnology industry resources: Infrastructure
found that the industry possesses three key resources for Companies have used their equity and partnering revenues
discovering new drugs for neglected diseases: infrastruc- to build their infrastructure and develop their proprietary
ture, technological assets, and expertise. technologies (Table 4.2). To compete with the pharmaceu-
tical industry in small molecule discovery and development,
Biotechnology companies have invested heavily in early-stage biotechnology companies had to innovate. Most
high-throughput compound screening facilities, X-ray biotechnology companies were founded upon a single tech-
crystallography, computational modeling, and other infra- nological insight and then focused on a therapeutic applica-
structure to support drug discovery programs. Foremost tion of the technology. Subsequent partnering or outright
among many companies’ technological assets are the sale of the technology funded further drug discovery
combination of highly evolved compound libraries used programs. Most companies invest $100 million to $250
in drug screening and proprietary assay technologies built million to reach this point in early-stage development.
1,008
Small Molecule Therapeutic Focus 1,000 focus on small molecule therapeutics
Companies
123 Over 120 have a track record of taking new drugs into the clinic
Development Experience
Companies
tical assets. To reach this level of maturity, with multiple Compound storage and retrieval systems
compounds in clinical development, likely represents more Computational modeling (for structure-based design)
than half a billion dollars in total investment. High throughput screening robotics
Figure 4.3: The Financial Strength of the 50 Focus companies: Equity Capital Raised
Equity Capital Invested in the 50 Focus Companies Equity Capital Invested in Select Smaller
Companies within Sample
25 250
15 150
10 100
5 50
0 0
m nce
s or ls tex g 45 al ta st y any ys
niu rac tica Ver inin Tot Syn cry Arra Alb yps
Mil
len d Scie Sep a ceu m a Bio Kal
a rm Re
Gile Pha
OSI
Note: Equity capital invested based on additional paid in capital, capital surplus, and proceeds from venture rounds
Sources: Company SEC filings, VentureXpert, and BVGH/L.E.K. analysis
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 31
compounds. There are no definitive rules on what makes An important advantage of developing highly focused
a “good” compound library, but certain characteristics libraries is that screens once requiring a few million
dictated in part by a compound’s backbone, or “scaffold,” compounds, many of which were unassociated with any
have been proposed as predictive of orally available small biological activity, can now be performed with about
molecule drugs [40]. 100,000 compounds, winnowed down by computer algo-
rithms to represent a chosen attribute (function, shape, or
Biotechnology companies have taken many approaches target class). Highly focused libraries save time and money.
to building compound libraries. A diversity library, as They, and their associated computational modeling tools,
its name implies, aims to capture a broad array of drug- provide potentially unique starting points for medicinal
like molecules without selecting any particular target chemistry and lead optimization—and are critical to accel-
or scaffolds. This type of library can be employed in a erating drug discovery and development for any disease.
wide range of drug discovery programs. A focused library
strives for just the opposite: its compounds are biased The majority of our 50 focus companies have been
by structure or function in favor of interaction with a successful in discovering and developing novel small
specific target class. Because of the effort and inven- molecule drugs and clinical candidates. Each company
tiveness required to develop a refined and annotated generally possesses a mix of diversity and focused libraries.
collection of compounds, compound libraries are among Proprietary compound libraries that have yielded lead
drug discovery companies’ most important and closely compounds are likely to be of increasing value because
guarded assets. of the inherent drug-like qualities of the compounds
Description Biologists are needed for Biologists are needed for Biologists and Biologists and
target biology and assay screening and follow up pharmacologists are needed pharmacologists are needed
Candidate selection
Representative Staff
Biologists and
Pharmacologists
Chemists
Structural Biologists/
Computationalists
Outsourced
Unfortunately, the industry’s compound libraries have At successful biotechnology companies, the convergence of
rarely been mined for hits and leads against targets relevant focus and expertise almost always augments the next level
to global health. For neglected diseases, specific natural of development, where knowing how to develop drugs and
products (and small collections of such compounds) have knowing which drugs not to develop are equally impor-
historically been the main source of new lead compounds. tant. Constant pipeline triage is instrumental to working
But things have changed. Today, genomics technologies quickly and within budget constraints. For example, our
have identified molecular targets specific to neglected 50 focus companies have collectively discontinued more
disease pathogens. This is of tremendous importance. It than 700 internal discovery programs [27]. Moreover,
means that screening compound libraries using either pipeline triage can accelerate project timelines to IND
phenotypic or target-based screens should significantly and result in more focused clinical trials. Combining this
expedite neglected disease drug discovery programs. discipline with the inherent value of the company’s R&D
infrastructure and proprietary assets continuously creates
Biotechnology industry resources: Expertise opportunities for evaluation and action.
As biotechnology companies evolved into leaders in small
molecule discovery, they built teams with scientific exper- Biotechnology industry resources: Target focus
tise in many disciplines, including basic biology, structural Companies focused on small molecule drug discovery are
biology, pharmacology, and analytic, synthetic, and medic- typically thought of in terms of the diseases they tackle.
inal chemistry. The composition of a typical drug discovery In fact, many are organized not around a disease but
team at each stage of a project is summarized in Figure around specialized molecular targets that may underlie
4.4. Although the mixture of skills changes over the course mechanisms of several unrelated diseases. Their targets
of a project, advancing to lead optimization frequently are typically members of an extended target family,
requires a dozen or more medicinal chemists, making such as G protein–coupled receptors (GPCRs) (Arena
chemistry expertise integral to success. Our 50 focus Pharmaceuticals), kinases (OSI Pharmaceuticals, Exelixis,
companies report employing between 20 and 50 medicinal Ambit BioSciences), ion channels (Neuromed), and
chemists each, either on staff or outsourced to CROs often phosphodiesterases (PDEs) (Plexxikon) (Figure 4.5).
located in India or China. Breakthrough drugs have been found in all these classes
across a range of therapeutic indications, from the kinase
Of those companies we examined, most have been in inhibitor Gleevec® for treating chronic myelogenous
operation for more than 10 years. By assembling industry leukemia, to PDE-5 inhibitors like Viagra® for cardiovas-
veterans and motivated younger scientists into small, cular function and erectile dysfunction.
highly focused teams, biotechnology companies build
cohesive discovery-driven cultures and increase exper- Target expertise is critical for a company’s competitive posi-
tise in the specific areas of interest. Discovery teams in a tion. Concentrated expertise, technology, and intellectual
successful company are likely to become internationally property are why pharmaceutical companies seek commer-
recognized leaders in their particular area. This special cial partnerships with biotechnology companies to build
expertise is valuable to the company in ongoing efforts their pipelines. Target expertise can result in a continual
to build a pipeline of projects, and it also adds valuable source of compounds spanning many therapeutic areas,
corporate memory. For example, many companies have simply because specific members of the target family have
“legacy programs,” in which extensive medicinal chemistry been associated with different disease pathologies. A target-
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 33
Figure 4.5: Target Class Focus of 50 Focus Companies
SRI International
CV Therapeutics
Kinases Nucleic acid Ion channels
ChemoCentryx
Pharmacopeia
Cytokinetics
Theravance
Millennium
Neuromed
Metabasis
Replidyne
Neurogen
Plexxikon
Cephalon
Genelabs
Amphora
Immtech
Sepracor
Kalypsys
Achillion
Sequella
BioCryst
Optimer
Celgene
Renovis
Lexicon
Sunesis
Exelixis
Rexahn
Infinity
ACADIA
Anadys
ArQule
Icagen
Vertex
Gilead
Kémia
Ambit
Arena
Locus
Synta
Kinex
Astex
Array
Ariad
Vitae
Rigel
Eisai
Telik
OSI
Kinases
Proteases
Metabolic enzymes
Cytoskeleton
Host response
Proteasomes
Phosphodiesterases
Nuclear receptors
GPCRs
Ion channels
based approach allows companies to attack different diseases Can biotechnology industry drug
by attacking distinct proteins within a single target class. discovery technologies be adapted
Often the same compound libraries and similar biochemical to neglected diseases?
assays can be used to tackle entirely different diseases. Clearly, there are important questions to address. Can
drug discovery tools be shared? Is the overlap among drug
The classic example of how a library developed for one targets between noninfectious diseases like diabetes and
disease was applied to another involved compounds origi- many cancers and developing-world pathogens more than
nally made to inhibit the human enzyme renin, an aspartyl superficial? How relevant to drug discovery for neglected
protease implicated in hypertension. These libraries were diseases are shared molecular structures? How can we
enlisted in drug discovery for HIV in the urgent early years harness the tools of the biotechnology industry that are
of the pandemic. Screening of these very same compounds so effective in developing new therapies for the affluent to
against the HIV aspartyl protease provided the first lead develop new therapies for the poor?
compounds against the viral target and yielded such
breakthrough drugs as saquinavir (Fortovase®), indinavir In the remaining chapters, we will examine the scientific
(Crixivan®) and many more protease inhibitors in broad rationale for extending biotechnology companies’ capa-
clinical use today. This example, repeated often in the bilities to neglected diseases, the hurdles that stand in
last 20 years, provides a clear road map for target-based the way, and new models for collaboration between the
drug discovery, regardless of the disease. The very same biotechnology industry, academic organizations, and PDPs.
approach can generate drugs for neglected diseases.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 35
protozoan parasites. In order to examine specific opportu- much less effective than for bacteria with doubling times
nities within protozoan diseases, we limited our analysis to on the order of minutes. Furthermore, the thick, waxy
P. falciparum (malaria) and T. brucei (HAT). surface coat of M. tuberculosis is not at all like a mamma-
lian cell membrane and is an impossible barrier for many
Malaria is caused by four species of Plasmodium parasites, drug-like molecules to cross. In addition, due to a poorly
each with its own unique biology and pathology. Nearly all understood phenomenon known as “persistence,” a frac-
efforts to invent new malaria drugs, however, are directed tion of M. tuberculosis in an individual with active disease
at P. falciparum, the deadliest and best understood species can survive in the presence of currently available drugs for
and the most common throughout Africa. months [51].
Leishmaniasis, Chagas disease, and HAT are caused by T. brucei. T. brucei hides in privileged spaces, where it
divergent species of protozoa (called trypanosomatids) with can be difficult for drugs to reach. In late-stage disease,
unique life cycles and insect vectors. Leishmaniasis is not a the parasite leaves the bloodstream and enters the central
single disease. It exists in visceral, cutaneous, and mucosal nervous system and brain. For a drug to be effective in
forms and is caused by more than 20 separate Leishmania this stage, it must be able to cross the blood-brain barrier
species. Although Leishmania, T. cruzi (the pathogen that (BBB), a gradient mechanism that normally serves to
causes Chagas disease), and T. brucei evolved from a protect the brain from most chemicals circulating in the
common ancestor, and therefore share many molecular blood. Designing a drug capable of crossing the blood-
and biochemical pathways, their infection cycles and the brain barrier (BBB) without any associated toxicities pres-
tissues they target are very different. We focused our anal- ents an enormous challenge.
ysis on T. brucei because the set of research tools available
for its study are better developed than for any other type of Drug discovery tools for neglected diseases:
trypanosomatid. The state of the art
Several factors have primed M. tuberculosis, P. falciparum,
. . . and their challenges and T. brucei for major therapeutic advances:
P. falciparum. The life cycle of P. falciparum is extraor- n Their genomes have been sequenced and annotated;
dinarily complex. The parasite targets several tissue types n Genetic tools have been developed to validate
and shifts between living freely in the blood and entering potential drug targets; and
and inhabiting the host’s cells. The parasite undergoes n Animal models of infection exist, making it
radical changes in morphology and metabolism as it passes possible to test the ability of compounds to kill
through these stages. Drug discovery in P. falciparum, pathogens in vivo.
however, is effectively restricted to the red blood cell or
erythrocytic stage of its life cycle—the stage responsible Each of these topics is described in more detail below.
for the symptoms of uncomplicated malaria—because only
this stage of the parasite can be cultured in the labora- The importance of genomic information
tory. Laboratory culture is not routine for the forms of for target identification
the parasite that infect the liver or for those that survive The revolution in DNA sequencing and bioinformatics,
ingestion by mosquitoes and complete the transmission along with order-of-magnitude increases in speed and
cycle. These obstacles make developing a drug that relieves reductions in cost, has made it possible to sequence the
symptoms and also prevents infection and transmission genomes of dozens of infectious microbes. Beginning with
much more difficult. the M. tuberculosis genome in 1998 [52], scientists have
reported fully sequenced and annotated genomes for P.
M. tuberculosis. Even under optimal laboratory condi- falciparum [53], T. brucei, [54] and closely related organ-
tions, M. tuberculosis grows extremely slowly (a doubling isms [55-58]. Pathogen-specific genomic information is
time of about 24 hours). As a result, antibiotics that accessible through a variety of publicly available databases
disrupt processes required for rapid growth are rendered (see Figure 5.1) [59-61].
Target validation depends on genetic tools A genetically validated target proves useful only if it is
Target validation is the determination of whether a gene shown to be “druggable”: not only is the enzyme integral
encoding a pathogen protein is essential to the viability or to the disease process, but it can also be inhibited through
virulence of the pathogen. That is, can the pathogen survive specific binding with small molecules. For reasons such as
under laboratory culture or infect an animal when a gene’s functional obscurity or redundancy, physical inaccessibility,
function is lost? If a parasite with a mutation in a specific or even the shape and size of a unique binding site (or lack
gene dies, is severely weakened, or cannot maintain an thereof), many potential drug targets prove undruggable.
infection, scientists may decide to design a drug to inhibit
the function of the gene product to yield a similar outcome. The importance of mouse models in
target validation
For a neglected disease pathogen, most validated targets Researchers depend on animal models of infectious disease
will be proteins or protein complexes. Inhibition of the to identify and validate potential drug targets. Mouse
activity of these proteins with an effective small molecule models are most often used in early-stage drug discovery
drug will cause the pathogen either to stop growing or die. because large numbers of experiments can be conducted
Historically, most antibiotics have interfered with pathogen at comparatively low cost to predict effects in humans.
“housekeeping functions” such as DNA replication, RNA Researchers can test if a target that has been genetically
transcription, protein translation, or cell wall synthesis. validated in vitro is also required to initiate or maintain an
Thus, pathogen genes involved in these processes continue infection in animals. A mouse model allows compounds
to be viewed as potential drug targets. identified on the basis of in vitro activity (for example,
compounds identified for inhibiting a target pathogen
Several techniques can test if a gene is essential for protein in test tube experiments) to be tested for the ability
viability. The most straightforward is to “knock out,” or to prevent infection or cure an infected animal.
permanently disrupt the target gene, thereby eliminating
the production of the protein it ordinarily encodes. This M. tuberculosis and T. brucei can be grown in mice with
genetic engineering technique has become routine for relative ease. For T. brucei, mouse models exist that
P. falciparum, M. tuberculosis, and T. brucei [48, 62, 63]. mimic both acute and chronic stages of disease, making
There are, however, technical limitations associated with it possible to evaluate compounds for their ability to clear
gene knock-outs. To overcome them, M. tuberculosis and both types of infection. The latter is especially important
T. brucei researchers developed methods of “condition- because for a drug to cure chronic infections, it must
ally” knocking out gene function [64, 65]. That is, they are cross the BBB. The chronic-infection mouse model allows
able to turn off a gene’s expression temporarily and then researchers to test compounds for ability to kill T. brucei
observe if the organism remains viable. that have entered the central nervous system.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 37
In contrast to M. tuberculosis and T. brucei, P. falciparum routine, but does require later confirmation because at the
cannot normally survive in mice. Instead, the rodent amino acid level P. berghei and P. falciparum proteins share
malaria parasite P. berghei is commonly used as an imper- on average just over 60 percent sequence identity [55]. In
fect substitute for infected animal studies. Establishing that instances where the structure of the P. falciparum target
a compound effective at killing P. falciparum in culture differs substantially from that in P. berghei, the P. berghei
will kill P. berghei in a mouse via the homologous target is gene can be replaced with the relevant P. falciparum gene
Figure 5.1: Target Validation and Drug Discovery Tools Available for P. falciparum, M. tuberculosis, and T. brucei
Basic Research: Target Screening: Target Validation Lead Identification Lead Optimization
Identification
Genome: sequenced and Gene knock-outs: increasingly Whole-cell screening: Primate disease models
P. falciparum
annotated; comparative routine (erythrocytic stage only) routine for erythrocytic available
genomics possible with other stage; assay for DNA
Conditional gene knock-outs: P. falciparum does not
human and rodent species of replication
in development normally grow in rodents;
Plasmodium
new immunocompromised
Transposon mutagenesis:
Key databases: and ‘humanized’ mouse
possible
– www.plasmodb.org models emerging
– tdrtargets.org RNAi: no
The rodent malarial parasite
Erythrocytic-stage parasite Gene microarrays: available P. berghei is frequently used
can be grown in culture in place of P. falciparum;
Proteomics: extensive
allelic replacement can be
Safety: BSL2 laboratory
Crystal structures: not extensive used to generate improved
P. berghei
Genome: sequenced and Gene knock-outs: routine Whole-cell screening: Animal models: mouse for
M. tuberculosis
Genome: sequenced and Gene knock-outs: routine Whole-cell screening: Animal models: mouse
T. brucei
annotated; comparative routine; assay for for acute and chronic (late-
Conditional gene knock-outs:
genomics possible with ATP production stage) forms of disease
routine
Leishmania sp. and T. cruzi
RNAi: routine
Key databases:
– www.genedb.org/genedb/tryp/ Gene microarrays: available,
– tdrtargets.org but polycistronic transcription
limits usefulness
Bloodstream stage parasite
can be grown in culture or Proteomics: limited
in rodents
Crystal structures: limited
Safety: BSL1 for standard
lab strain
14 “Mechanism of action” refers to how a drug interacts with its target to produce its pharmacological effect.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 39
Biotechnology companies are expert in identifying and particular target classes and then launch programs on
validating new biochemical targets that mediate cell growth multiple diseases. For example, one company special-
and viability and that play key roles in diseases such as izing in kinases attacks multiple types of cancer. Another
cancer and neurological disorders. For small molecule drug specializing in ion channels has programs in pain, hyper-
targets, early evidence of chemical tractability and dose tension, and epilepsy.
responsiveness can come from compound screening. This
evidence is then confirmed by making potency improve- A company’s specialized technologies for a particular target
ments during lead optimization. Examples of proteins class could be applied in drug discovery programs against
widely employed as targets for drug discovery include a neglected disease pathogen, where the pathogen shares
proteases (proteins that degrade other proteins), protein a target with a chronic disease such as cancer. As summa-
kinases (intracellular messengers), ion channels (transmit- rized in Figure 5.2, significant target class overlap exists
ting molecules across the cell membrane), and farnesyl between chronic noninfectious diseases and neglected
transferases (cell signaling). Leading drug discovery infectious diseases. Moreover, many of the same major
companies have developed technologies and built tools target classes are shared between P. falciparum and T.
around specific target classes (see Table 5.1). brucei, or among P. falciparum and M. tuberculosis and T.
brucei (Figure 5.3). Shared targets include kinases, prote-
Certain classes of drug targets, such as kinases and ion ases, protein farnesyl transferases, and phosphodiesterases.
channels, have different roles in different cell types. Target-specialized drug discovery know-how and target-
Related targets in different cell types can function in specialized compound libraries have already been applied
entirely different diseases. This explains why many compa- successfully to selecting compounds active against targets
nies build drug discovery technologies specializing on in P. falciparum and T. brucei [72].
Table 5.1: Drug Targets Favored by Biotechnology Companies and the Tools Available to Tackle Them
Target class Compound libraries High-throughput screening assays & screens Crystal structures
Cytoskeleton
(flagella)
Phosphodiesterases Glycosome
T. brucei
Nucleic
acid Proteases
(transcription/
translation)
Kinases
Ion channels Proteasome
Cell wall
synthesis
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 41
pains has been validated and is being pursued as part of these enzymes, TbrPDEB1 and TbrPDEB2 [74]. Because
a collaboration between MMV and GSK. As of late 2006, the catalytic sites of TbrPDEB1 and TbrPDEB2 are nearly
these teams were selecting clinical candidates from the identical, it may be possible to design a single inhibitor of
falcipain inhibitor programs. The metalloprotease falcilysin both enzymes. PDEs are also considered validated targets
is another protease required for hemoglobin breakdown in P. falciparum [75].
and other functions. Its potential as a P. falciparum target
is currently under evaluation. Other proteases have been Protein kinases are enzymes that transfer a phosphate
validated in M. tuberculosis and T. brucei. group from an adenosine triphosphate (ATP) molecule to
a protein substrate in a process called phosphoryation.
Cyclic nucleotide phosphodiesterases (PDEs) break Kinases play fundamental roles in cell division and signal
the phosphodiester bond found in cyclic nucleotides transduction, processes that often malfunction in cancerous
involved in eukaryotic signal transduction. Inhibitors of the cells. Kinase inhibitors hold enormous therapeutic poten-
PDE-5 subclass are used as vasodilators to treat pulmonary tial for cancer. For example, Gleevec®, an inhibitor of
arterial hypertension and erectile dysfunction (e.g., Viagra®). the protein kinase BCR-ABL, has been approved for use
New inhibitors of different PDEs are being pursued for in chronic myeloid leukemia and gastrointestinal stromal
conditions ranging from depression to inflammation. tumors, and it is being pursued for treatment of a variety
of additional cancers. Because of their essential role in cell
The T. brucei genome encodes five PDEs. The bloodstream proliferation, kinases may also be key targets in preventing
form of T. brucei cannot survive in the absence of two of replication of infectious pathogens.
Table 5.2: Validated Targets in Neglected Disease Pathogens for Which the Tools and Expertise of Biotechnology Companies
Might Be Leveraged
Proteases
– Serine
– Cysteine Falcipains TbCatb, brucipain
– Other Falcilysin (metalloprotease) PDF (metalloprotease)
Metabolic enzymes
– Folate metabolism DHFR-TS; dihydropteroate synthase DHFR-TS
– Fatty acid synthesis Fab H; FabI (apicoplast) FabI Enoyl-ACP reductase (InhA)
– Glycolosis Lactate dehydrogenase Glycosome enzymes
– Other Malate synthase (glcB) Trypanothione reductase
Isocitrate lyase (ICL1/2) Trypanothione synthase
Ornithine decarboxylase
Nucleic acid
– DNA synthesis DNA gyrase (apicoplast) DNA gyrase
– Transcription RNA polymerase (apicoplast) rpoB
– Purine salvage PfNT1
– Pyrimidine salvage Dihydroorotate dehydrogenase ATP synthase (AtpE)
– Other CTP synthetase
Note: G protein–coupled receptors are not found in P. falciparum, M. tuberculosis, or T. brucei and thus have been omitted from this table. Similarly, nuclear recep-
tors are not relevant to a nonnucleated organism such as M. tuberculosis and have not yet been validated for P. falciparum or T. brucei. Heat-shock proteins also
have not been validated for any of these pathogens.
15 Chemogenomics is the systematic analysis of chemical-biological interactions, specifically the investigation of classes of compounds (libraries)
against families of functionally related proteins.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 43
The case for further exploration Unfortunately, most of these efforts were not pursued
Several of the companies we interviewed have investi- further because any or all of the following reasons: inability
gated applying their platform technologies and propri- to obtain funding, lack of preclinical pharmacology
etary compound libraries to neglected diseases. On their support, high opportunity costs, or absence of a clear route
own, or in collaboration with academic researchers, a to commercialization. These initial efforts nonetheless indi-
number have carried out early-discovery efforts. Of the cate that biotechnology company participation is a problem
companies we interviewed, nine either had a compound of incentives, not capabilities.
they considered worth testing on a neglected disease
or have been in active collaborations with neglected Chapter 6 details the hurdles to biotechnology company
disease researchers. In nearly every case, interest in involvement in neglected disease drug discovery. We also
a neglected disease was driven by target homologies present ways in which these problems might be overcome.
that suggested new utilities for existing compound
sets, many of which were synthesized as candidates for
chronic disease indications.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 45
n Information hurdles. They need to become much Managerial hurdles
more familiar with neglected diseases, potential Biotechnology companies are particularly concerned about
markets, and prospective partners; the costs of project management. For a biotechnology
n Managerial hurdles. They need to build expertise in company to manage a neglected disease drug discovery
managing collaborations with prospective partners project on its own, foreseeable tasks include securing
in the not-for-profit and academic sectors; and grant funding, managing staff, linking drug discovery
n Financial hurdles. They need market incentives to invest efforts with a specific target product profile, and coor-
in R&D and overcome “opportunity cost”—the profit dinating with academic and PDP collaborators for capa-
lost by not working on a core business project. bilities not available in-house. Biotechnology company
managers are unlikely to have neglected disease exper-
Information hurdles tise. Assembling expertise internally would distract from
A key challenge for bringing biotechnology resources to their core business. To the extent that neglected disease
bear is identifying opportunities and convening collabora- drug discovery projects can be managed externally, these
tors. Biotechnology companies lack expertise in neglected concerns can be relieved.
diseases, while academic institutions and PDPs lack deep
familiarity with the proprietary tools available in the Financial hurdles
biotechnology industry. Efforts must be made to educate Financial hurdles for biotechnology companies stem from
both sectors and bring these groups together. insufficient market “pull,” lack of excess capital to support
discovery R&D, and the opportunity cost of allocating
BVGH is devoted to bridging this information gap, forming resources to a neglected disease project. Unlike large phar-
coalitions around specific discovery opportunities to build maceutical companies, biotechnology companies are often
the global health product pipeline. Many attractive collabo- cash-constrained and must triage short-term choices in
ration opportunities exist, but they will not happen without favor of the greatest value to their investors. Resources are
diligent efforts to bring decision makers together and illus- often tightly budgeted to support programs that will move
trate how collaborations can serve their interests. rapidly toward approved products for high-value markets.
Figure 6.1: Hurdles to the Biotechnology Industry’s Involvement in Neglected Disease Drug Discovery
Hurdles
Hurdle Companies lack access Companies cannot devote Companies require market
to and experience with management time to incentive and funding to
neglected disease science non-core activities overcome opportunity costs
Year 1 2 3 4 5 6 7 8 9 10 11
Screening Lead
Lead Optimization Preclinical Phase I Phase II Phase III
for Hits Identification
Clinical Trials
50
45 43 43
35
Annual Cost in Millions ($)
30
25
20
15 15
12 12
10
5
3.3 3.3 3.3
0.8 0.8 1.5
0
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 47
Finally, other costs—particularly opportunity costs— Models for increasing industry engagement
cannot be underestimated. Biotechnology companies in neglected disease drug discovery
operate at capacity, especially with regard to medicinal We explored several different models for overcoming the
chemistry. So there are significant costs to reallocating staff hurdles to industry participation in neglected disease drug
for a neglected disease project. These costs consist of direct discovery: subcontracting to biotechnology companies
labor (e.g., chemist and biologist salaries), indirect over- directly, building partnerships, donor-directed portfolio
head (e.g., allocation of discovery assets), and opportunity management, and establishing a discovery-focused PDP.
cost. For biotechnology companies to engage in neglected
disease drug discovery, a substantial portion of these costs Subcontracting to biotechnology companies
must be addressed by external funding. In selected cases, PDPs have forged new alliances with
biotechnology companies, allowing them access to
Engaging the biotechnology industry advanced drug discovery technologies and compound
It is unlikely that biotechnology companies will over- libraries that exist nowhere else. An example of this
come these hurdles on their own. Their immediate approach is the collaboration launched in 2006 between
economic concerns keep them too focused on devel- the TB Alliance and BG Medicine, Inc., to identify novel
oping drugs for developed-world markets. Only a few tuberculosis biomarkers [91].
dozen of the 1,500 U.S. and European institutionally-
backed biotechnology companies are profitable; none of The advantage of this approach is that PDPs act as “portfolio
the rest has positive cash flow to support even modest managers.” They have a strong command of their diseases
philanthropy. Thus, accessing biotechnology assets for and can offer biotechnology much-needed guidance on TPPs.
global health product development is most likely to be Leadership and program management can remain centered
achieved by new “push” and “pull” financial incentives. on the PDP, minimizing the need for joint development
Push incentives are direct funding to reduce the risk committees or other overarching management structures.
and cost of R&D. Pull incentives enhance the market to
encourage new R&D. The limitation to this approach is that not all PDPs are
set up to take full advantage of discovery technologies in
Examples of push incentives include: industry. In some cases, the formation of drug discovery
n Grants to fund early-stage R&D, including alliances will require a shift in managerial focus. This is
through the U.S. National Institutes for Health or because drug development and drug discovery are very
the UK Medical Research Council. different processes. If PDPs were to seek to integrate
n Tax credits that allow companies to reduce their upstream into discovery, they would need to add manage-
tax liability by deducting R&D expenditures. rial talent with particular experience in managing indus-
trial-scale, small molecule discovery projects.
Examples of pull incentives include:
n Advance Market Commitments that guarantee Building partnerships
markets for new medicines in developing Another model is to form more expansive partnerships
countries [90]. among biotechnology companies, PDPs, and academic
n Transferable “priority” vouchers to speed up institutions. Partnerships can maximally leverage biotech-
regulatory review, provided to companies upon nology expertise, proprietary technology, and infrastruc-
approval of a developing-world vaccine or drug. ture. These partnerships need leadership and operational
n Willingness of donors, PDPs, or pharmaceutical management to leverage the strengths of each participant.
companies to pay a “risk premium” to license new Some discovery efforts can be initiated through biotech-
medicines that have shown proof-of-concept such PDP or biotech-academia collaborations; others will require
as phase II efficacy and safety. the participation of all three.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 49
A discovery-focused PDP could overcome the key informa- n Drive Science Transfer: An ability to guide the
tion and managerial hurdles preventing the formation of process of transferring academic science into
new discovery partnerships (Figure 6.3). It could provide biotechnology discovery assets will be needed.
dedicated project management essential to coordinating n Invest in Gaps: Research funding is required
efforts involving multiple participants. And it could to overcome gaps in research tools needed for
address the financial hurdles by helping to secure R&D neglected disease drug discovery.
funding and identify potential “hand-offs” to PDPs and
large pharmaceutical companies. Managerial Capabilities:
n Project Champion: The discovery-focused PDP will
Operationally, a discovery-focused PDP will need to need to function as an external project champion
assemble the informational, managerial, and financial to ensure that biotechnology companies give
capabilities and resources needed to establish productive neglected disease drug discovery collaborations
collaborations. appropriate attention.
n Provide Project Management: Duties include
Informational Capabilities: coordinating grant support, managing staff, and
n Convene Leading Academics: Academic experts guiding programs toward target product profiles
will be needed to select drug targets, assay that allow biotechnology companies minimal
technologies, and tools for pathogen manipulation. distraction from their core businesses.
n Identify Industry Collaborators: Deep knowledge of n Manage Timelines: Grant support must be aligned
biotechnology capabilities will be needed to match with realistic timelines for lead identification and
the right companies with the right academic optimization programs instead of the annual grant
science and projects. cycles. This will enable biotechnology companies to
staff neglected disease discovery programs efficiently.
Funding Organizations
$$$
Project Management/Coordination
Provide access to
neglected disease
expertise
Development
Targets Candidates
Product
Academic Science Biotechnology Companies Development
Partnerships
Sidebar 6.1: Solving the innovation gap for neglected disease drug discovery:
How much will it cost?
The discovery programs we are advocating for neglected diseases can take advantage of existing R&D infrastructure
in industry, but they will nonetheless incur the variable costs of actually performing the research. Costs for neglected
disease drug discovery are likely to be similar to those for developed-world diseases, and they may actually be
higher because the specifications for affordability, oral delivery, and thermostability may “raise the bar” for selecting
compounds that could enter the clinic.
We found that “top down” and “bottom up” analyses yielded similar answers: roughly $40 million per year in discovery
R&D funding for each disease to yield a minimum flow of clinical candidates and the potential for a new approved
drug every three to five years.
In a recent article, Hopkins et al. reckoned that a single discovery program costs on average $20 million to generate a
single clinical candidate [94]. For anti-infectives, they estimated attrition rates of 84 percent, meaning that six such
programs are needed to generate a single approved drug.
A small biotechnology company with a robust discovery platform typically spends $20 million per year on early-
stage R&D, and it may have between three and six programs running in parallel. For a developed-world disease such
as diabetes, dozens of biotechnology companies will be taking different approaches to the problem. Since R&D
success in any one group experiences periods of productivity and drought, success and failure, sustained effort of
“two biotechnology company units” of discovery R&D seems the minimum commitment required to smooth out
variability in rates of attrition. The advantage of harnessing industry resources is that a large number of screening and
hit-generation projects can be undertaken in parallel at low cost to identify the most promising approaches across
multiple platforms.
We estimate the investment in malaria and tuberculosis therapeutic R&D at roughly $100 million worldwide each.
The majority of this investment is in development, with a smaller portion devoted to discovery. If we apply the
pharmaceutical industry allocation of 35 to 40 percent of R&D to discovery, this would argue for an additional $50
million investment in discovery R&D for each disease at a minimum.
We analyzed in detail the discovery R&D costs of a “model” biotechnology company running three discovery
programs in parallel. Each costs a little more than $13 million over a three-year period, yielding a $40 million steady-
state run rate. Notably, costs in the earliest stages were under $2.5 million to get to a “lead” molecule, which allows
considerable winnowing and optimization before larger commitments are made. Our estimate of discovery spending
matches DiMasi et al.’s (2003) estimates [95] of variable costs for discovery to preclinical research. It also matches
estimates of discovery spending per IND filed over the past three to five years [27].
Taken together, the evidence supports the idea of highly-focused, tightly-managed programs building to a $40 million
per-year investment in drug discovery for each of the neglected diseases.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 51
Chapter 7: Conclusions and Recommendations
The biotechnology and pharmaceutical industries have The companies best able to meet the challenges of drug
invested billions of dollars in building small molecule discovery for the three neglected diseases selected for this
drug discovery capabilities. These companies possess report are those that focus on small molecule drugs and
target expertise and compound libraries highly appli- that have advanced novel small molecules into clinical
cable to neglected diseases. Therapeutic R&D for development. Approximately 120 biotechnology compa-
neglected diseases will proceed most effectively by nies—of the many that could contribute to global health—
enlisting the biopharmaceutical industry’s infrastruc- are particularly well matched for these criteria. They have
ture, drug discovery capabilities, and expertise. Engaging discovered and developed some of the most innovative
the biotechnology industry will accelerate the arrival of new small molecule therapies, including ones targeting
better medicines for neglected diseases. HIV and cancer.
Groups in the public sector have succeeded in pushing Key findings from our review of select drug
forward new therapies for neglected disease. Despite their discovery companies
many achievements, an innovation gap remains that limits n Extensive Experience: The companies we examined
the translation of academic discoveries in disease biology in depth have impressive accomplishments
into new medicines. Unless this gap is closed, neglected in launching small molecule drugs and have
disease pipelines will generate far fewer drugs in the long ongoing discovery and development programs
term. Based on experience with antibiotics and anti-virals, and alliances.
we may reasonably expect that drug-resistant pathogens n Existing Infrastructure: Billions of dollars in equity
are going to emerge and thus compromise existing medi- financing have allowed these companies to create
cines. Without more new drugs, many more years will pass infrastructure and expertise in small molecule
before neglected diseases are called neglected no longer drug discovery that would be prohibitively time
and are brought under control. consuming and costly to duplicate.
n Overlapping Targets and Technologies: Target-based
Leading biotechnology companies recognize the tremen- discovery assets are potentially applicable to
dous unmet needs in global health. Many are seeking ways analogous systems in neglected disease pathogens.
to participate that are consistent with their business strate- n Significant Interest: Biotechnology companies are
gies and limited cash resources. They are open to applying interested in participating in neglected disease
their capabilities through R&D collaborations with disease drug discovery to extend the reach of their
experts in PDPs and academia. Such collaborations will technologies, establish relationships with larger
leverage small molecule discovery infrastructure, accelerate companies, and contribute to global health.
innovation, and address the innovation gap in neglected n Obstacles to Participation: Though biotechnology
disease drug discovery most efficiently. companies are interested in participating in global
health campaigns, scientific, managerial, and
especially, financial issues prevent them from
doing so.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 53
References
1. Sachs, J.D., Helping the World’s Poorest, The Economist. 17. Chirac, P., and E. Torreele, Global framework on essential
August 14, 1999. health R&D. Lancet, 2006. 367(9522): p. 1560-1.
2. Cohen, J., Global health. The new world of global health. 18. PhRMA. R&D spending by U.S. Biopharmaceutical
Science, 2006. 311(5758): p. 162-7. Companies Reaches a Record $55.2 Billion in 2006. 2007;
[cited September 5, 2007]; available from: http://www.phrma.
3. Harries, A.D., and C. Dye, Tuberculosis. Ann Trop Med
org/news_room/press_releases/r%26d_spending_by_u.s._
Parasitol, 2006. 100(5-6): p. 415-31.
biopharmaceutical_companies_reaches_a_record_%2455.2_
4. Baird, J.K., Effectiveness of antimalarial drugs. N Engl J billion_in_2006/.
Med, 2005. 352(15): p. 1565-77.
19. Malaria Research & Development Alliance, Malaria Research
5. Fairlamb, A.H., Chemotherapy of human African & Development: An Assessment of Global Investment. 2005.
trypanosomiasis: current and future prospects. Trends Parasitol,
20. Feurer, C., Tuberculosis Research & Development: A Critical
2003. 19(11): p. 488-94.
Analysis, J. Syed, M. Harrington, and B. Huff, Editors. 2006.
6. Centers for Disease Control and Prevention. The Deadly
21. Moran, M., A breakthrough in R&D for neglected diseases:
Intersection between TB and HIV. 1999; [cited September 5,
new ways to get the drugs we need. PLoS Med, 2005. 2(9): p.
2007]; available from: http://www.cdc.gov/hiv/resources/
e302.
factsheets/hivtb.htm.
22. Medicines for Malaria Venture, Product Profiles for
7. Munro, S.A., et al., Patient adherence to tuberculosis
Antimalarial Drugs. 2006. p. 1-8.
treatment: a systematic review of qualitative research. PLoS
Med, 2007. 4(7): p. e238. 23. Nwaka, S., and A. Hudson, Innovative lead discovery
strategies for tropical diseases. Nat Rev Drug Discov, 2006.
8. Gandhi, N.R., et al., Extensively drug-resistant tuberculosis
5(11): p. 941-55.
as a cause of death in patients co-infected with tuberculosis and
HIV in a rural area of South Africa. Lancet, 2006. 368(9547): 24. The Working Group on new TB drugs, Strategic Plan: Stop TB
p. 1575-80. Partnership Working Group on New TB Drugs. 2006.
9. Dorman, S.E., and R.E. Chaisson, From magic bullets back 25. Harper, C., Tuberculosis, a neglected opportunity? Nat Med,
to the magic mountain: the rise of extensively drug-resistant 2007. 13(3): p. 309-12.
tuberculosis. Nat Med, 2007. 13(3): p. 295-8.
26. Casenghi, M., Development of new drugs for TB
10. Pecoul, B., New drugs for neglected diseases: from pipeline chemotherapy: analysis of the current pipeline. 2006, Campaign
to patients. PLoS Med, 2004. 1(1): p. e6. for Access to Essential Medicines: Medecins Sans Frontieres.
11. Pepin, J., and F. Milord, The treatment of human African 27. L.E.K Consulting, 2007.
trypanosomiasis. Adv Parasitol, 1994. 33: p. 1-47.
28. Medicines for Malaria Venture, Annual Reports. 2001-2006.
12. UNICEF/UNDP/World Bank/WHO Special Programme for
29. Drugs for Neglected Diseases Initiative, Report of
Research & Training in Tropical Diseases (TDR), Drug Discovery
Independent Auditors: Financial Statements. 2005.
and Drug Development. March 2004.
30. Global Alliance for TB Drug Development, Annual Report.
13. GAO, New Drug Development: Science, Business, Regulatory,
2005-2006.
and Intellectual Property Issues Cited as Hampering Drug
Development Efforts, U.S.G.A. Office, Editor. 2006. p. 1-52. 31. Ridley, R.G., Medical need, scientific opportunity and the drive
for antimalarial drugs. Nature, 2002. 415(6872): p. 686-93.
14. PhRMA, Drug Discovery and Development: Understanding the
R&D Process. 2007. [cited October 28, 2007]; available from 32. Renslo, A.R., and J.H. McKerrow, Drug discovery and
http://www.phrma.org/files/RD%20Brochure%20022307.pdf. development for neglected parasitic diseases. Nat Chem Biol,
2006. 2(12): p. 701-10.
15. Duyk, G., Attrition and translation. Science, 2003.
302(5645): p. 603-5. 33. Austin, C.P., et al., NIH Molecular Libraries Initiative.
Science, 2004. 306(5699): p. 1138-9.
16. Trouiller, P., et al., Drugs for neglected diseases: a failure
of the market and a public health failure? Trop Med Int Health, 34. Butler, D., Lost in translation. Nature, 2007. 449(7159):
2001. 6(11): p. 945-51. p. 158-9.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 55
69. Moreno, A., et al., Plasmodium falciparum-infected mice: 84. Scherr, N., et al., Structural basis for the specific inhibition
more than a tour de force. Trends Parasitol, 2007. 23(6): p. of protein kinase G, a virulence factor of Mycobacterium
254-9. tuberculosis. Proc Natl Acad Sci U S A, 2007. 104(29): p.
12151-6.
70. Gomez, J.E., and J.D. McKinney, M. tuberculosis
persistence, latency, and drug tolerance. Tuberculosis (Edinb), 85. Herrling, P., Experiments in social responsibility. Nature,
2004. 84(1-2): p. 29-44. 2006. 439(7074): p. 267-8.
71. Duncan, K., Progress in TB drug development and what is 86. Bill & Melinda Gates Foundation, Grand Challenges in Global
still needed. Tuberculosis (Edinb), 2003. 83(1-3): p. 201-7. Health Initiative Selects 43 Groundbreaking Research Projects
for More Than $436 Million in Funding. 2005 [cited September
72. Sabry, J., Personal communication. 2007.
13, 2007]; available from: http://www.gatesfoundation.
73. Rosenthal, P.J., Antimalarial drug discovery: old and new org/GlobalHealth/BreakthroughScience/GrandChallenges/
approaches. J Exp Biol, 2003. 206(Pt 21): p. 3735-44. Announcements/Announce-050627.htm.
74. Oberholzer, M., et al., The Trypanosoma brucei cAMP 87. SiliconFen Business Report, TheDirectory. 2006
phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar [cited September 13, 2007]; available from: http://www.
enzymes that are essential for parasite virulence. FASEB J, siliconfenbusiness.com/viewcomp.php?id=123.
2007. 21(3): p. 720-31.
88. McKerrow, J.H., Designing drugs for parasitic diseases of the
75. Yuasa, K., et al., PfPDE1, a novel cGMP-specific developing world. PLoS Med, 2005. 2(8): p. e210.
phosphodiesterase from the human malaria parasite Plasmodium
89. Eli Lilly and Company, Lilly Not-for-Profit Partnership for TB
falciparum. Biochem J, 2005. 392(Pt 1): p. 221-9.
Early Phase Drug Discovery. 2007 [cited October 19, 2007];
76. Ward, P., et al., Protein kinases of the human malaria available from: http://newsroom.lilly.com/ReleaseDetail.
parasite Plasmodium falciparum: the kinome of a divergent cfm?ReleaseID=248931.
eukaryote. BMC Genomics, 2004. 5(1): p. 79.
90. Tremonti, G., Advanced market committments for vaccines:
77. Naula, C., M. Parsons, and J.C. Mottram, Protein kinases as a new tool to fight against disease and poverty, in Report to the
drug targets in trypanosomes and Leishmania. Biochim Biophys G8 Finance Ministers. 2005.
Acta, 2005. 1754(1-2): p. 151-9.
91. BG Medicine, TB Alliance and BG Medicine initiate
78. Waters, N.C., and J.A. Geyer, Cyclin-dependent protein biomarker discovery program. 2006 [cited September 13,
kinases as therapeutic drug targets for antimalarial drug 2007]; available from: http://www.bg-medicine.com/content/
development. Expert Opin Ther Targets, 2003. 7(1): p. 7-17. news-center/news/q/id/23.
79. Woodard, C.L., et al., Evaluation of broad spectrum protein 92. Genzyme. Medicines for Malaria Venture: Genzyme
kinase inhibitors to probe the architecture of the malarial cyclin Corporation and the Broad Institute Expand Collaboration to
dependent protein kinase Pfmrk. Bioorg Med Chem Lett, 2007. Discover New Drugs for Malaria. 2006 [cited October 23,
17(17): p. 4961-6. 2007]; available from: http://www.genzyme.com/corp/media/
HAND_PR.pdf.
80. Tu, X., and C.C. Wang, The involvement of two cdc2-related
kinases (CRKs) in Trypanosoma brucei cell cycle regulation 93. Wellcome Trust. Strategic Translation Awards in Seeding
and the distinctive stage-specific phenotypes caused by CRK3 Drug Discovery. 2007 [cited October 23, 2007]; available from:
depletion. J Biol Chem, 2004. 279(19): p. 20519-28. http://www.wellcome.ac.uk/node2630.html.
81. Hammarton, T.C., J.C. Mottram, and C. Doerig, The cell 94. Hopkins, A.L., M.J. Witty, and S. Nwaka, Mission possible.
cycle of parasitic protozoa: potential for chemotherapeutic Nature, 2007. 449(7159): p. 166-9.
exploitation. Prog Cell Cycle Res, 2003. 5: p. 91-101.
95. DiMasi, J.A., R.W. Hansen, and H.G. Grabowski, The price
82. Ferguson, M.A., Personal communication. 2007. of innovation: new estimates of drug development costs. J Health
Econ, 2003. 22(2): p. 151-85.
83. Walburger, A., et al., Protein kinase G from pathogenic
mycobacteria promotes survival within macrophages. Science,
2004. 304(5678): p. 1800-4.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 57
Only when orally bioavailable candidates are identified can
in vivo proof-of-concept studies to validate the biological
linkage of the target and the disease be initiated in animals.
The few compounds that survive all of these hurdles
are thoroughly evaluated in animals for their efficacy
and possible toxicity. From the potential candidates that
advance through these in vivo studies, usually only a single
compound and a backup are nominated for further highly
regimented, FDA-mandated IND-enabling work—with no
guarantee that any compound will be qualified for subse-
quent clinical development.
A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases 61
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