BVGH Therapeutics Innovation Map

8/9/2019 BVGH Therapeutics Innovation Map

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Closing the Global HealthInnovation Gap

A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases


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Closing the Global HealthInnovation Gap

A Role for the Biotechnology Industry in Drug Discovery for Neglected Diseases


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Closing the Global Health Innovation Gap: A Role for the Biotechnology Industry in Drug

Discovery for Neglected Diseases

Copyright 2007 BIO Ventures for Global Health.

All rights reserved.

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

Christopher D. Earl, Michael C. Venuti, Wendy Taylor, and Julie S. Klim.

Acknowledgments

BVGH wishes to thank L.E.K. Consulting for its role in the research underlying this report;

the individuals who reviewed this documentMaria Freire, Carl Nathan, Tito Serafini, Natalie

Barndt, and the BVGH Board of Directors; Anastasia Semienko, who assisted in the final push

to complete the project; and the many individuals from the global health community and

biopharmaceutical industry who participated in our interviews and shared their enthusiasm

and ideas. Special thanks to Dr. Corey Goodman for the initial inspiration for this project.

To request additional print copies of this report or other information from BVGH, please

contact:

BIO Ventures for Global Health

1225 Eye Street, NW, Suite 1010

Washington, DC 20005

Tel: +1 202.312.9260

Fa: +1 443.320.4430

E-mail: [email protected]

Web: www.bvgh.org

The full tet of this report is also available online at the BVGH website:

http://www.bvgh.org/documents/InnovationMap.pdf

Cover Image by J. Mainquist, courtesy of NIHs National Human Genome Research Institute.

The Kalypsys suite of ultra-high throughput robotic technologies can screen the biological

activity of more than one million chemical compounds per day.

Design and layout by Bussolati Associates.

Illustrations for Figures 3.4 and 3.6 by Jennifer Fairman.


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Contents

List of Select Abbreviations . . . . . . . . . . . . . . . . . . . . . . . 3

List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

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

Chapter 1: Eecutive Summary . . . . . . . . . . . . . . . . . . . . 7

Chapter 2: Introduction . . . . . . . . . . . . . . . . . . . . . . . . . 10

Chapter 3: The Innovation Gap in Discovering

New Therapeutics for Neglected Diseases . . . . . . . . . . . 14

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

Chapter 5: Mapping Biotechnology

Capabilities to Neglected Diseases . . . . . . . . . . . . . . . . . 35

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

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

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54

Appendi I: Why Small Molecule

Drug Discovery Is a Risky Business . . . . . . . . . . . . . . . . 57

Appendi II: Snapshots of the Drug Development

Pipelines for Malaria, TB, and HAT . . . . . . . . . . . . . . . . 59

Appendi III: Academic and Company Interviewees . . . 60

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

About BVGH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62


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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses

Select Abbreviations

ACT . . . . . . . . . . artemisinin-based combination therapy

ADME . . . . . . . . absorption, distribution, metabolism, and ecretion

ARV . . . . . . . . . . anti-retroviral

ATP . . . . . . . . . . adenosine triphosphateBBB . . . . . . . . . . blood-brain barrier

B V G H . . . . . . . . BIO Ventures for Global Health

CRO . . . . . . . . . . contract research organization

DALY . . . . . . . . . disability-adjusted life year

DNDi . . . . . . . . . Drugs for Neglected Diseases Initiative

EMEA . . . . . . . . . European Medicines Agency

FDA . . . . . . . . . . United States Food and Drug Administration

GPCR . . . . . . . . . G proteincoupled receptor

HAT . . . . . . . . . . human African trypanosomiasis

hGH . . . . . . . . . . human growth hormone

HTS . . . . . . . . . . high-throughput screening

IDRI . . . . . . . . . . Infectious Disease Research Institute

iOWH . . . . . . . . Institute for OneWorld Health

IND . . . . . . . . . . investigational new drug

MDGs . . . . . . . . . Millennium Development Goals

MLSCN . . . . . . . Molecular Libraries Screening Center Network

MMV . . . . . . . . . Medicines for Malaria Venture

NCE . . . . . . . . . . new chemical entity

NGO . . . . . . . . . nongovernmental organization

NIH . . . . . . . . . . United States National Institutes of Health

PDE . . . . . . . . . . phosphodiesterase

PDP . . . . . . . . . . product development partnership

R&D. . . . . . . . . . research and development

SAR . . . . . . . . . . structure-activity relationship

SBRI . . . . . . . . . . Seattle Biomedical Research Institute

TB . . . . . . . . . . . tuberculosis

TB Alliance . . . . . Global Alliance for TB Drug Development

TDR . . . . . . . . . . Special Programme for Research and Training in Tropical Diseases

TPP . . . . . . . . . . target product profile

WHO . . . . . . . . . World Health Organization


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closing the gloBAl heAlth innovAtion gAp

Figures

Figure 3.1: Drug Discovery and Development

the Necessary Prelude to New Drugs. . . . . . . . . . . . . . . . . . . . . . . . . 17

Figure 3.2: Risks and Benefits of ExpandingUse of Existing Drugs Versus the Creation

of New Chemical Entities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Figure 3.3: Attrition Rates and Current

Neglected Disease Pipelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Figure 3.4: The Innovation Gap . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Figure 3.5: Annual R&D Spending by

Biotechnology Companies and PDPs . . . . . . . . . . . . . . . . . . . . . . . . . 23

Figure 3.6: Building a Continuum of Players

to Move from Basic Research to Product Registration . . . . . . . 26

Figure 4.1: The Origins of Small Molecule

Drugs in Clinical Trials (January 2007). . . . . . . . . . . . . . . . . . . . . . . . . 28

Figure 4.2: Biotechnology Companies Can

Be Segmented by Capabilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Figure 4.3: The Financial Strength of the

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

Figure 4.4: The Composition and Tasks of

a Drug Discovery Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2

Figure 4.5: Target Class Focus of 50 Focus Companies . . . . . . . . 34

Figure 5.1: Target Validation and Drug

Discovery Tools Available for P. falciparum,

M. tuberculosis, and T. brucei . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38

Figure 5.2: Target Classes Are Transferable

Across Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

Figure 5.3: Target Classes Shared by

P. falciparum, M. tuberculosis, and T. brucei . . . . . . . . . . . . . . . . . . 41

Figure 6.1: Hurdles to the Biotechnology

Industrys Involvement in NeglectedDisease Drug Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Figure 6.2: The Costs of Producing a Single New Drug . . . . . . . . 47

Figure 6.3: Possible Roles for a Discovery-Focused PDP . . . . . . 50


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Tables

Table 2.1: initial Assessment of the Need

for New Therapeutics and the Scientific Feasibility

of Creating Them for Key Neglected Diseases. . . . . . . . . . . . . . . . 13

Table 3.1: Malaria, Tuberculosis, and Human African

Trypanosomiasis. Summary of Disease Characteristics,

Pathogen, and Current Standard of Care . . . . . . . . . . . . . . . . . . . . . 15

Table 3.2: PDP Drugs Registered or in Clinical Trials . . . . . . . . . . .18

Table 3.3: Biopharmaceutical and

Consortium-Based Drugs in Clinical Trials . . . . . . . . . . . . . . . . . . . . 18

Table 3.4: Target Product Profiles for Uncomplicated

P. falciparum Malaria, Active Pulmonary TB,

and Late-stage HAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Table 3.5: Treatment Goals for Malaria, TB, and HAT . . . . . . . . . . 21

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

Table 4.2: The Assets and Infrastructure

Used in Drug Discovery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Table 5.1: Drug Targets Favored by Biotechnology

Companies and the Tools Available to Tackle Them . . . . . . . . . . 40

Table 5.2: Validated Targets in Neglected Disease

Pathogens for Which the Tools and Expertise

of Biotechnology Companies Might Be Leveraged . . . . . . . . . . . 42

Sidebars

Sidebar 2.1: List of select global health

product development partnerships (PDPs) . . . . . . . . . . . . . . . . . . . 11

Sidebar 2.2: Examples of new global health products . . . . . . . . 11

Sidebar 4.1: Characteristics of small molecule drugs . . . . . . . . . 27

Sidebar 4.2: Company selection process . . . . . . . . . . . . . . . . . . . . . . 30

Sidebar 5.1: The tool kit for modern drug discovery . . . . . . . . . . 35

Sidebar 5.2: Critical tools for future development . . . . . . . . . . . . 39

Sidebar 5.3: Harnessing diverse biotechnology solutions . . . . 44

Sidebar 6.1: Solving the innovation gap for neglected

disease drug discovery: How much will it cost? . . . . . . . . . . . . . . 51


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Ninety percent of the worlds ependiture on medical

care benefits the richest fifth of the worlds population.

Technological breakthroughs fueled by billions of dollars

of investment have transformed health care for the affluent,

yet patients in resource-poor countries cannot afford high-

quality care. They lack the purchasing power that would

draw investment in new medicines to treat infectious

diseases that are unknown, or long since eradicated, in

wealthy countries.

The devastation caused by these neglected diseases has

attracted renewed attention in the past decade, as its been

recognized that focused investment and commitment could

yield powerful new vaccines, drugs, and diagnostics basedon the same technologies that have revolutionized health

care for the affluent.

For the first time, several hundred million dollars from

donors such as the Bill & Melinda Gates Foundation are

being invested annually in important research and develop-

ment (R&D) for diseases such as malaria and tuberculosis.

But relatively little of this investment is devoted to the

discovery of drugs with the potential for providing break-

through therapeutic benefits. As a result, an innovation gap

is increasingly apparent in the discovery of new medicinesfor neglected diseases.

This innovation gap stems from insufficient investment

devoted to early-stage drug discovery, limited public sector

access to key technologies and drug discovery epertise,

and the scarcity of capable innovators devoted to creating

new medicines for neglected diseases.

Today, product development for neglected diseases is

mainly carried out in the public and nonprofit sectors,

with for-profit companies serving as partners and subcon-tractors in a number of cases. In contrast, the vast majority

of new treatments for diseases with markets in the devel-

oped world are created by biotechnology and pharmaceu-

tical companies, which together have the epertise and the

infrastructure to carry discovery and development of prod-

ucts from bench to bedside.

Although biotechnology companies are best known

for developing protein drugs such as human growth

hormone and monoclonal antibodies, they are also now

leading innovators in small molecule drugsthe type

of therapeutic best suited to meet developing-world

needs for oral delivery, thermostability, and affordability.

The challenge is to bring the biotechnology industrys

discovery assets, know-how, and project management

capabilitiesdeveloped over 30 years and with nearly

$400 billion of equity capitalto the fight against

diseases of the developing world.

In this study, BIO Ventures for Global Health (BVGH)

eamined the core capabilities of the biotechnologyindustry, academia, and the nonprofit entities that focus on

clinical development of new drugs for neglected diseases.

Based on a preliminary assessment that reviewed areas of

significant alignment between biotechnology industry capa-

bilities, basic disease understanding, and unmet medical

need, we focused on three classes of diseasesmalaria,

tuberculosis, and trypanosomal diseases (human African

trypanosomiasis, Chagas disease, and leishmaniasis).

Central to our findings is the transferability of the tech-

nologies used to address cardiovascular disease, neuro-logical disease, and cancer to the infectious diseases of the

developing world caused by parasites and bacteria. Several

families of proteins that have served as principal targets

for drug discovery for chronic diseases of the industrial-

ized world are also present in infectious pathogens and can

serve as targets for drug discovery. In principle, this means

that biotechnology companies are in an advantageous posi-

tion to apply their discovery resources and epertise to

neglected diseases.

To narrow the scope of our study, we focused on aselect group of over 120 companies that have capability,

scale, and track records of innovation in small molecule

discovery that could be highly relevant to neglected disease

drug discovery. We further chose to analyze 50 companies

in greater depth, including the originators of more than 20

small molecule drugs now approved by the FDA.

Chapter 1: Executive Summary


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closing the gloBAl heAlth innovAtion gAp

nology companies have the speed, fleibility, and persis-

tence to take leadership roles in attacking new challenges

to create new products.

Substantial investment in discovery will be

required.

The pharmaceutical industry typically allocates up to 40

percent of its R&D budget to discovery. Using similar

criteria, to build a discovery pipeline that will feed the

eisting development infrastructure for diseases such as

tuberculosis and malaria will require substantial additional

investment. We estimate that a sustained investment of at

least $40 million per year for each disease is required to

ensure a pipeline that delivers a new, approved therapeutic

every three years.

Significant hurdles hinder biotechnology industry

involvement.

Three major hurdles have discouraged many biotech-

nology companies from becoming engaged in global health

product discovery:

n Information hurdles. Companies need to become

much more familiar with neglected diseases,

potential markets, and partners.

n Managerial hurdles. They need to build epertise

in managing collaborations with partners in the

not-for-profit and academic sectors.

n Financial hurdles. They need market incentives to

invest in R&D and overcome opportunity cost

the potential profit lost by not working on a core

business project.

New approaches will be required for effective

investment in discovery.

There is a great need to encourage collaborations between

biotechnology companies with discovery epertise and

academic eperts with deep understanding of the target

diseases and sophisticated biochemical and molecular tools

useful in drug discovery. Such partnerships can lower the

barriers to industry involvement. Managerial and financial

hurdles must be overcome to attract biotechnology compa-

nies to participate in global health initiatives.

Key findings

Drug discovery for neglected diseases is hindered

by an innovation gap.

Despite a revolution in funding for neglected diseases

and the evolution of new R&D partnerships, the currentneglected disease pipeline will not fully address key treat-

ment goals (e.g., substantially shortening the duration of

certain treatments). The investment in product discovery

and translational research for neglected diseases remains

a fraction of the level necessary to move promising

discoveries from academic laboratories into commercial

settingsfar too little to ensure a steady stream of new

medicines for neglected diseases. Long-term investments

in innovation are needed to build a sustainable pipeline

of drugs that meet the needs of patients and offer hope of

alleviating the suffering from these diseases.

Bringing drug discovery assets built for developed-

world diseases to bear on neglected diseases is

scientifically feasible.

For malaria, tuberculosis, and trypanosomal diseases, suffi-

cient scientific tools eist for drug discovery R&D efforts

to be initiated. Importantly, for many human molecular

targets that have received etensive attention from drug

discovery companies, there are analogous targets in

neglected disease pathogens. This means, in particular, that

researchers can employ proprietary compound libraries

used for drug discovery for major diseases for neglected

disease drug discovery.

Biotechnology companies that focus on small

molecule drugs and have taken novel small

molecules into clinical development are well

positioned to address the innovation gap.

Hundreds of biotechnology companies have resources that

could contribute to the fight against neglected diseases.

Many of these are well positioned to take the lead in

developing new drugs, vaccines, or diagnostics to address

these diseases. For eample, many proprietary compound

libraries used by biotechnology companies for small mole-

cule drug discovery have been optimized around target

classes that are also relevant to neglected diseases. These

resources and capabilities would be prohibitively epensive

to duplicate in the nonprofit sector. Moreover, biotech-


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Recommendations

1. THE BIOTECHNOLOGY INDUSTRYS MOST CAPABLE

INNOVATORS HAVE AN INTEGRAL ROLE IN CLOSING

THE INNOVATION GAP. Biotechnology companies have

track records of employing advanced technologies to createnew therapeutics that have met with success in human

clinical trials. This epertise can and should be applied to

neglected diseases.

2. NEW PARTNERSHIPS ARE NEEDED TO LOWER

BARRIERS FOR BIOTECHNOLOGY COMPANIES TO

INVEST THEIR RESOURCES. Most biotechnology compa-

nies are unfamiliar with neglected diseases. To take advan-

tage of their technology platforms, they need to access

disease epertise and biochemical assays that are resident

in academia, research institutions, and product develop-

ment partnerships (PDPs). R&D collaborations are the best

way to combine strengths and increase productivity.

3. ExPANDED RESEARCH FUNDING IS NEEDED TO

BUILD AN EARLY-STAGE PIPELINE. To produce a new,

approved therapeutic every three to five years for a single

disease, the minimum investment required for new

discovery R&D is comparable to the annual funding for

two small biotechnology companiesincreasing over

several years to roughly $40 million per year per disease.

This investment will fund several parallel drug discovery

programs and accommodate attrition at typical industry

rates, while allowing surviving programs to enter preclin-

ical development.

4. EFFECTIVE INVESTMENT WILL DEPEND ON DEDI-

CATED PORTFOLIO MANAGERS. Many of the current

participants in global health product development lack

deep epertise in managing early-stage drug discovery. The

scope of the partnerships and investments we recommend

call for project management capabilities that would stretch

the current capabilities of any single public sector organi-

zation. Dedicated project management to maimize R&D

productivity can be infused into PDPs or donor organiza-

tions, or it can be built as an independent discovery PDP.

Among the options:

n Independent consortiums of companies, academic

labs, and PDPs that work together to transform

neglected disease drug targets into optimized leadcompounds and preclinical drug candidates.

n Direct donor investment in company-led

programs with accompanying R&D management

and monitoring.

n Creation of a discovery PDP that can serve

as a portfolio manager for new neglected

disease discovery programs with a mission of

augmenting the pipelines of eisting PDPs. Such

an organization could efficiently enlist the most

eperienced innovators; forge partnerships among

companies, development-focused PDPs, and

academics; and manage and monitor numerous

discovery projects.

Biotechnology companies could contribute substantially

to the discovery and development of new therapeutics for

neglected diseases. This document provides a road map

for enlisting their capabilities in this fight. By employing

eisting advanced drug discovery technologies, donor

community funds will be used to maimum effect, novel

drugs will be developed faster, and more lives will be saved.


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The challenge of neglected diseases

Major advances in biotechnology over the last 30 years have

transformed medicine in the industrialized world, but these

innovations have yet to reach the worlds poorest countries,

where 3 billion people live on less than two dollars a day.

Each year more than 10 million people in the devel-

oping world die of infectious diseases such as HIV/AIDS,

malaria, tuberculosis, diarrheal diseases, and acute lower

respiratory infections. Millions more suffer from debili-

tating parasitic diseases, which often incapacitate people

in their most productive years. The burden of infec-

tious illness falls most heavily on children and pregnant

women. In poor countries, the magnitude of sufferingcaused by infectious diseases makes economic develop-

ment nearly impossible [1].

Many of these infectious diseases have earned the label

neglected1 because health-care markets in the afflicted

countries are insufficient to attract biopharmaceutical

industry2 investment in research and development (R&D).

Over the past decade, a revolution has occurred in public

sector investment combating infectious diseases of the devel-

oping world. Governments, multilateral organizations, and

foundations spend billions of dollars purchasing treatments.Millions more are invested each year in neglected disease R&D.

Most of the R&D investment devoted to neglected diseases

is deployed through public-private, not-for-profit, product

development partnerships (PDPs). Since 1996, over a

dozen PDP organizations have arisen to tackle the develop-

ment of new vaccines, drugs, and diagnostics for devel-

oping-world diseases (see Sidebar 2.1). In addition, several

research institutes, a few large pharmaceutical companies,

and a handful of biotechnology companies initiated their

own programs, in many cases working with PDPs.

The challenge now is to augment these public and private

sector efforts. What todays partnerships lack most is

access to the biotechnology industrys most advanced

technologies and epertise for discovering and developing

new medicines.3

Todays medicines are insufficient

A fundamental transformation in commitment to solving

global health problems has occurred during the first

decade of the 21st century. In 2000, the United Nations

adopted the Millennium Development Goals (MDGs),

setting forth ambitious health-related objectives: cutting

child mortality by two-thirds, reducing maternal mortality

by three-quarters, and reversing the tide of HIV/AIDS,

malaria, and other major infectious diseases. In response,

governments, foundations, and international nongovern-mental organizations (NGOs) in the developed world have

provided billions of dollars to purchase eisting vaccines

and drugs for patients in the developing world.

The global health crisis demands a comprehensive and

integrated response that begins with faster delivery of

eisting drugs, vaccines, and diagnostics to those most in

need. While programs to ensure access to current medi-

cines can yield substantial benefits, they will not offer

complete solutions. Many of the treatments available today

are decades old and are often limited by problems of drugresistance, inadequate safety, and efficacy.

For eample, current treatments for river blindness

(onchocerciasis) only kill immature parasitic worms in

early stages of infection and are ineffective for advanced

disease. The sole therapy for a major form of human

African trypanosomiasis is marginally effective, requires

intravenous administration, and is so toic that it can kill

up to 5 percent of patients. No effective vaccine eists for

any disease on the World Health Organizations Special

Programme for Research and Training in Tropical Diseases(WHO/TDR) list of neglected diseases (see Footnote 1).

Diagnostics, where they eist, are often impractical for field

use in the developing world.

10 closing the gloBAl heAlth innovAtion gAp

1 The 10 critical neglected diseases as defined by the WHO Special Programme for Research and Training in Tropical Diseases (WHO/TDR) are

African trypanosomiasis, Chagas disease, dengue, leishmaniasis, leprosy, lymphatic filariasis, malaria, onchocerciasis (river blindness), schistosomiasis,

and tuberculosis. Other major killers include diarrheal diseases and lower respiratory tract infections. Although HIV disproportionately affects the

developing world, it is not considered a neglected disease because billions of dollars are going into product development for the developed world.

2 For the purpose of this report, the biopharmaceutical industry comprises the 20 large, innovative pharmaceutical companies and the biotechnology industry.

3 The term medicine is used here to encompass vaccines, drugs, and diagnostics.

Chapter 2: Introduction


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A Role foR the Biotechnology industRy in dRug discoveRy foR neglected diseAses 11

Fortunately, PDPs, research institutes, and a small but

growing cadre of biopharmaceutical companies are

building a growing development pipeline of promising

products to address neglected diseases. The bulk of R&D

investment to date$1.2 billion as of early 2006flowed

to treatment and prevention of HIV/AIDS, tuberculosis,

and malaria [2]. The remainder is being devoted to other

viral, bacterial, protozoan, and helminth (worm) infections

where new medicines are desperately needed.

Several PDPs, often through outsourcing and partnering,

have assembled substantial clinical development infrastruc-

tures. PDPs also manage sophisticated clinical programs in

multiple developing countries. Their efforts, and those of a

small number of biopharmaceutical companies, are begin-

ning to pay off. New products have succeeded in clinical

trials, and a few have already been registered for sale in

developing countries (Sidebar 2.2).

Aeras Global TB Vaccine Fondation (Aeras)

Focus: TB vaccine development

Headquarters: Rockville, MD, USA

Founded: 1997

Drgs for Neglected Diseases Initiative (DNDi)

Focus: Drug development for malaria and trypanosomal diseases

Headquarters: Geneva, Switzerland

Founded: 2003

Fondation for Innovative New Diagnostics (FIND)

Focus: Diagnostic development for TB, malaria, and human

African trypanosomiasis


Founded: 2003

Global Alliance for TB Drg Development (TB Alliance)

Focus: TB drug developmentHeadquarters: New York, NY, USA

Founded: 2000

Hman Hookworm Vaccine Initiative (HHVI)

Focus: Vaccine development for hookworm

Headquarters: Washington, DC, USA

Founded: 2000

Institte for OneWorld Health (iOWH)

Focus: Drug development for visceral leishmaniasis, malaria,

and diarrheal diseases

Headquarters: San Francisco, CA, USA

Founded: 2000

International AIDS Vaccine Initiative (IAVI)

Focus: HIV vaccine development

Headquarters: New York, NY, USA

Founded: 1996

International Partnership in Microbicides (IPM)

Focus: Microbicide development for HIV prevention

Headquarters: Silver Spring, MD, USA

Founded: 2002

Medicines for Malaria Ventre (MMV)

Focus: Malaria drug development


Founded: 1999

Malaria Vaccine Initiative (MVI)

Focus: Malaria vaccine development

Headquarters: Bethesda, MD, USAFounded: 1999 as an independent program within PATH

Pediatric Denge Vaccine Initiative (PDVI)

Focus: Dengue vaccine development

Headquarters: Seoul, Korea

Founded: 2003

Program for Appropriate Technology in Health (PATH)

Focus: Development of health technologies

Headquarters: Seattle, WA, USA

Founded: 1977

Sidebar 2.1: List of select global health prodct development partnerships (PDPs)

Sidebar 2.2: Examples of newglobal health prodcts

l Paromomycin: A drug to treat visceral leishmaniasis

(Kala-Azar), developed by the Institute for OneWorld

Health (iOWH), registered in India in 2006.

l Rotarix: Novel rotavirus vaccine, developed by Avant

Immunotherapeutics and licensed to GlaxoSmithKline

(GSK), approved for use in 90 countries since 2004.

l Pyramax: Combination therapy (pyronaridine-artesunate)

for malaria, developed by Medicines for Malaria Venture

(MMV), currently in phase III clinical trials.

l RTS,S/ASO2A: Malaria vaccine, developed jointly through

the Malaria Vaccine Initiative (MVI) and GSK, has completed

phase II trials.


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These products offer important opportunities to improve

standards of care for key neglected diseases, but are just

a start. Continued investment will be required to epand

the pipeline of products that can keep improving care for

neglected diseases. For eample, we need:

n a shorter course of TB therapy that works againstdrug-resistant microbes;

n a safe and affordable treatment for human African

trypanosomiasis;

n a diagnostic that distinguishes between malaria

and bacteremia in a feverish child;

n a drug that kills adult forms of the many species

of worm, causing such diseases as lymphatic

filariasis, that deform and incapacitate millions

of patients; and

n new vaccines to prevent millions of deaths

each year.

An innovation gap impedes progress

Achieving the most ambitious public health goals for

the treatment and prevention of neglected diseases will

require etensive discovery efforts supported by long-term

funding. Most of todays global health product pipeline

in therapeutics, however, focuses on products amenable

to rapid clinical development, mainly by repurposing

known drugs for new uses. Finding new uses for eisting

drugs makes sense because it speeds development and

makes it possible to reach those in need in the shortest

possible time. Currently, a relatively small portion of the

investment in R&D for neglected diseases is directed to

discovering new chemical entities (NCEs)that is, novel

compounds with the potential of providing breakthrough

therapeutic benefits.

This report highlights the current innovation gap in the

discovery of new medicines for neglected diseases. The

investments in product discovery and translational

research necessary to move promising discoveries from

academic laboratories into commercial settings are at a very

early stage and are insufficient in scale to ensure a steady

stream of new medicines for neglected diseases. Without

increased effort and investment in discovery research,

bringing neglected diseases under control will be delayed

by years, perhaps even decades.

Long-term investments in innovation are needed to build a

sustainable pipeline of drugs meeting the needs of patients

now and into the future. Eperience has shown that

returns on pharmaceutical R&D investments are measured

in decades, not years. Moreover, the lesson from all epe-

rience with treatments for infectious diseaseswhetherits antibiotics for streptococcal bacteria or anti-retrovirals

(ARVs) for HIV/AIDSis that the pathogens eventually

develop resistance to drugs. Researchers must constantly

fight back by inventing new drugs that kill pathogens

through novel mechanisms of action.

Study approach and objectives

BIO Ventures for Global Health (BVGH) undertook this

study to assess whether the biotechnology industrys

diverse technology platforms and epertise can be applied

to inventing products for neglected diseases and, if so,

how. We focused on opportunities and challenges facing

development of therapeutics for key neglected diseases:

tuberculosis (TB), malaria, and three diseases caused by

trypanosomatids4human African trypanosomiasis (HAT,

also known as African sleeping sickness), leishmaniasis,

and Chagas disease. For simplicitys sake, at several points

in this report we use Trypanosoma brucei, the cause of

HAT, to represent all trypanosomatids.

We focused on therapeutics in this report because it

gave us the opportunity to include the largest number of

biopharmaceutical companies. The vast majority of inno-

vative biopharmaceutical companies develop therapeu-

tics; a smaller number focus on vaccines and diagnostics.

Drugs represent the largest segment of global pharma-

ceutical markets. We selected TB, malaria, and the three

trypanosomal diseases for several reasons: Each is associ-

ated with a high disease burden; current treatments have

serious limitations; and each has strong scientific founda-

tions upon which new therapeutic R&D might be based

(see Table 2.1).

We should emphasize that our goal was to be inclusive,

not eclusive. Biopharmaceutical companies can clearly

contribute in many other areas. Future studies can and

should assess biotechnology innovation in other diseases

and interventions, including diagnostics and vaccines.

4 Trypanosomatids are flagellated, parasitic protozoa (single-celled eukaryotic organisms) with complex life cycles during which they alternate

between vertebrate hosts and insect vectors.


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We began our analysis by interviewing academic

researchers focused on TB, malaria, and trypanosomal

diseases (see Appendi III). We aimed to determine the

availability of biological and molecular tools for drug

discovery and identify critical bottlenecks. We then evalu-

ated current product pipelines against international public

health goals and drug target product profiles (TPPs) to

determine where new discovery efforts are required foreach disease.

To evaluate whether industry has the capability and rele-

vant tools to address the gaps we identified, we selected

50 leading biotechnology companies from the hundreds

focused on small molecule drug discovery. These compa-

nies were chosen for their discovery capabilities in small

molecule therapeutics, the scale of their discovery efforts,

and their track records of bringing NCEs into the clinic.

These are some of the most eperienced companies in

small molecule drug discovery today. They are listed inAppendi IV, and their capabilities are described further

in Chapter 4.

This report makes the case that there is a compelling role

for the biopharmaceutical industry in building the global

health product pipeline and shortening the critical R&D

timelines on the way to achieving that goal. Chapter 3

defines the innovation gap and what may be needed to

fill it for each of the diseases we evaluated. Chapter 4

describes the critical role that the biotechnology industry

has played in developed-world drug discovery and the

wealth of biotechnology industry epertise and infra-

structure that can be applied to neglected disease drug

discovery. Chapter 5 evaluates the status of the molecular

tools for TB, malaria, and HAT, and it maps biotech-

nology industry capabilities against drug targets for thethree diseases.

Applying biotechnology to global health will call for new

collaborative models and financial incentives to encourage

industry to take on the risk and cost of product devel-

opment. This will require vision, new partnerships,

risk-taking, innovative business strategies, and financial

commitment. Chapter 6 eplores these issues and proposes

several approaches to investing in new global health R&D.

Chapter 7 outlines our conclusions and recommendations.

The obstacles to developing new drugs for neglected

diseases are formidable. But they are not insurmountable.

If the worldwide health-care community can make the

same progress against malaria, tuberculosis, and trypano-

somal diseases that it has in the past 20 years against

cancer, diabetes, and cardiovascular disease, we can look

forward to millions of lives saved and a better world for

us all.

Table 2.1: Initial Assessment of the Need for New Therapetics and the Scientific Feasibility of Creating Themfor Key Neglected Diseases

*One disability adjusted life year (DALY) is equivalent to one year of healthy life lost.

Source of DALY information: WHO/TDR.

Disease

TB

Malaria

HAT

Chagas Disease

Leishmaniasis

Global brden (DALYs)*

34.7 M

46.4 M

1.5 M

0.7 M

2.1 M

Problems with existing treatments

Resistance and long treatment times

Resistance

Safety, efficacy, resistance, long treatment

time, treatment administration

No treatments available for chronic

form of disease

Safety, administration, and long

treatment time

Scientific fondation for new R&D

Pathogen genome sequenced; genetic

manipulation possible; animal models

of disease


manipulation possible; primate models

of disease


manipulation facile; animal models

of disease



of disease

pathogen genome(s) sequenced; genetic


of disease


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Creating innovative pharmaceutical products is a

complex process that typically takes 10 to 15 years.

Donor funding and the emergence of product develop-

ment partnerships has led to an unprecedented number

of late-stage candidate medicines in the pipeline for

neglected diseases. R&D efforts at the drug discovery

stage, however, are insufficient to ensure a continuous

flow of products entering clinical development. This

innovation gap results from insufficient investment,

limited access to key technologies and drug discovery

expertise, and difficulties in assembling the collabora-

tions necessary to transform a laboratory discovery

into an investigational new drug. Failure to addressthe innovation gap will impede the creation of the next

generation of treatments for malaria, tuberculosis, and

trypanosomal diseases.

New drugs for old diseases

Many of the available medicines for neglected diseases are

outdated, impractical, insufficiently efficacious, or subject

to pathogen resistance and unacceptable toicities [3-5].

New medicines are urgently needed for tuberculosis, all

diseases caused by protozoan parasites, and many of the

helminth (worm) infections.

This study focuses on the need for new drugs for malaria,

tuberculosis, and trypanosomal diseases. Each disease is

summarized below and in Table 3.1, along with the status

and limitations of todays treatments.

Malaria. More than 40 percent of the worlds population

is at risk for malaria, and up to 500 million people develop

the disease each year. Malaria results from infections by

parasitic protozoa from the genus Plasmodium. Young

children and pregnant women, especially those living insub-Saharan Africa where the more virulent Plasmodium

falciparum parasite is dominant, are most vulnerable to

malaria and account for the majority of the 1 million

deaths estimated to occur annually.

Commonly used antimalarials are increasingly ineffec-

tive due to widespread drug resistance. To combat the

emergence of resistance to the drugs remaining in the

antimalarial arsenal, use of combination therapies has been

urged. Artemisinin-based combination therapies (ACTs)

have proven especially efficacious. Artemisinin, a structur-

ally comple natural product, is comparatively epensive

to manufacture, which, until recently, precluded the use of

ACTs in many impoverished countries.

Tuberculosis. One-third of the global populationmore

than 2 billion peopleharbors a latent or asymptomatic

infection by Mycobacterium tuberculosis, the bacterium

causing tuberculosis (TB). About 10 percent of those

infected will develop active TB at some point during their

lifetime, translating into nearly 9 million cases of active

disease and more than 2 million deaths annually. In immu-nocompromised populations, such as those with HIV, rates

of active TB are etremely high. Worldwide, TB is now the

leading cause of death among AIDS patients [6].

First-line treatment for active TB consists of two or four

antibiotic drugs taken in combination for a minimum

of si to nine months. The duration of the regimen,

combined with the medications toicities, causes many

patients to fail to complete the full course of treatment

[7]. This, in turn, has hampered TB control programs and

fueled the proliferation of antibiotic-resistant M. tubercu-losis strains. Recently, etensively drug-resistant TB (xDR-

TB) has entered communities with high HIV prevalence

and is killing people at alarming rates [8, 9].

Trypanosomal diseases. Three major classes of

trypanosomal diseases affect humans: human African

trypanosomiasis (HAT), Chagas disease, and leishmaniasis.

n HAT (also referred to as African sleeping sickness)

is found only in sub-Saharan Africa, where 60

million people are at risk for the disease. Each

year, there are up to 300,000 cases, resulting innearly 50,000 deaths.

n Chagas disease is endemic in rural areas in South

and Central America, placing an estimated 25

million at risk. In total, as many as 9 million

people may be infected with the Chagas parasite.

Annually, 14,000 deaths result from Chagas

cardiomyopathy associated with the chronic form

of the disease and often occurring 10 to 20 years

after initial infection.

Chapter 3: The Innovation Gap in DiscoveringNew Therapeutics for Neglected Diseases


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n Leishmaniasis is a collection of diseases; there

are cutaneous, mucosal, and visceral forms.

Worldwide, about 350 million people are at risk

for leishmaniasis. Cutaneous and mucosal forms

cause severe disfigurement and disability. The

visceral form is fatal if untreated. An estimated 12

million people are infected with leishmania, and

each year there are over 50,000 deaths.

HAT, Chagas disease, and all forms of leishmaniasis are

caused by divergent species of single-celled protozoa called

trypanosomatids. These pathogens share many unusual

molecular and biochemical pathways, but their infectious

cycles and target tissues for infection are very different.

While there is precedent that a treatment designed for one

pathogen may have efficacy toward another [5, 10], it is

likely that drug discovery and development will mostly

Table 3.1: Malaria, Tberclosis, and Hman African Trypanosomiasis: Smmary Of Disease Characteristics,Pathogen, and Crrent Standard of Care

MalariaA parasitic disease transmittedby Anopheles mosquitoes.Malaria is categorized as eitheruncomplicated (fever, chills,body aches, nausea, headache,vomiting, and diarrhea) or severe(anemia, acute respiratory distresssyndrome, coma, and death).

TBA bacterial disease that mostcommonly affects the lungs. Inotherwise healthy individuals,most infections are latent andasymptomatic. About 10% of thoseinfected develop active pulmonarydisease; symptoms include a coughlasting more than two weeks,

coughing up blood, fatigue, fever,chills, night sweats, and weight andappetite loss.

HATA parasitic disease transmittedby tsetse flies. HAT progressesfrom fever and fatigue (early-stagedisease) to severe neurologicalconditions (late-stage or chronicdisease). Untreated HAT is fatal.

Chagas disease

A parasitic disease that over timecauses damage to the nervoussystem, digestive tract, and theheart. The disease is contracted viathe feces of an infected Reduviid bug.

LeishmaniasisA collection of parasitic diseasestransmitted by the Phlebotominesandfly that affects the skin,mucosa, or internal organs,resulting in severe disfigurement,disability or death.

Disease Epidemiology Pathogen Crrent Standard of CareDeaths Cases Poplation Other (lanch year): Limitations

per Year per Year at Risk

> 1 million

2 million

50,000

14,000

>50,000

300-500

million

9 million

(active TB)

Up to

300,000

750,000

1.5-2 million

40% of global

population

Pandemic;

2 billion are

infected with

latent TB.

60 million;

(sub-Saharan

Africa)

25 million;

(Latin

America and

Caribbean)

350 million

Children and

pregnant

womenare most

susceptible

Immuno-

compromised

populations

are at

highest risk

8-9 million

are currently

infected

12 million

are currently

infected

Plasmodium

species;

P. falciparum

is the most

deadly

Mycobacterium

tuberculosis

Trypanosoma

brucei

(subspecies

gambiense

and

rhodesiense)

Trypanosoma

cruzi

~20 Leishmania

species

Chloroquine (1945): resistance

Primaquine (1948): safety

Fansidar (1961): resistance

Mefloquine (1984): resistance, safety

Artemisinin (1994): cost, compliance,Good Manufacturing Practice

Atovaquone/proguanil (1999): cost

All first-line treatments have issuesconcerning resistance, toxicity, andtreatment length (6-9 months):

Rifampicin (1963)

Ethambutol (1962)

Streptomycin (1955)

Pyrazinamide (1954)Isoniazid (1952)

Pentamidine (1941): lacks oral formulation,side effects, early-stage specific, mosteffective against T. b. gambiense

Suramin (1921): lacks oral formulation,side effects, early-stage specific, first-linetreatment against T. b. rhodesiense

Melarsoprol (1949): toxicity, resistance

Eflornithine (1980): toxicity, administration,spectrum of activity, supply, cost, onlyeffective against T. b. gambiense

Chronic disease - no treatments available

Acute disease -Nifurtimox (1960): resistance, safety,efficacy

Benznidazole (1970s): resistance, safety,efficacy

Visceral leishmaniasis:

Miltefosine (2003): safety

Paromomycin (2006): delivery

Pentosam (1944), Amphotericin B (1950s),Ketoconazole (1980s), Pentamidine (1941),and antimony-containing compounds:resistance, efficacy

Sources: WHO/TDR and Hotez, P.J., et al., Control of neglected tropical diseases. N Engl J Med, 2007. 357(10): p. 1018-27.


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proceed independently for different species. For simplicitys

sake, at several points in this report we use Trypanosoma

brucei, the cause of HAT, to represent the entire class.

Problems associated with eisting drugs for trypanosomal

diseases include lack of efficacy, drug resistance, longtreatment duration, availability, epense, and safety. For

instance, melarsoprol, the only treatment for HAT caused

by one subspecies ofT. brucei, is so toic that it kills up

to 5 percent of those who receive it [11]. There are no

drugs to treat the chronic form of Chagas disease. Visceral

leishmaniasis treated with paromomycin requires 21 days

of injections. An orally available alternative, miltefosine, is

unsafe for pregnant women.

The drug development process

To understand the serious challenges presented by

todays global health drug pipeline, we must first under-

stand the process of creating a new drug. More comple

and time-consuming than nearly any other commercial

endeavor, pharmaceutical R&D requires technological

and scientific epertise, teamwork, leadership, risk-taking,

timeand most of all, money. The steps of the process

are commonly broken into three phases: basic research

that establishes biological knowledge of disease causality

and creates tools for R&D; discovery, the innovative steps

by which new therapeutic compounds are identified and

evaluated; and development, or testing first in animals

of small numbers of compounds winnowed from the

discovery steps, leading to a single, promising candidate

compound to evaluate for therapeutic efficacy and safety

in human clinical trials.

Basic research refers to the scientific eploration of disease

and, in the case of infectious diseases, the pathogens that

cause them. The goal of most basic research is to develop

a molecular, genetic, and biochemical understanding of

disease pathology in the hope that this knowledge will

lead to treatments and cures. Developing this knowledge

requires an etensive set of tools for research. The process

of inventing research tools is in itself another component

of basic research.

Drug discovery refers to the earliest stages of generating

an actual product. It begins with the difficult process of

translating findings from basic research into candidate

molecules with the potential to treat disease. Researchers

organize their work around a target product profile

(TPP), essentially a list of minimum characteristics a drugmust possess to warrant development and use in people.

Small molecule drug discovery is a chemistry-intensive

process in which a library of thousands or even millions

of compounds is screened for molecules with drug-

like activity potentially meeting TPP requirements. The

compounds identified by screening, often called hits, are

then refined for other essential drug-like properties into

leads. A lead is a compound that interacts with accept-

able potency and selectivity with a cellular target macro-

molecule such as a protein.

For an infectious disease, the target is usually a macro-

molecule belonging to the pathogen, and ideally the

interaction between the drug and its target kills the

pathogen and cures the disease. In an iterative process,

lead compounds are optimized and retested for improved

activity, specificity, potency, and safety. A more detailed

discussion of the intricacies of the small molecule drug

discovery process is presented in Appendi I. There is no

hard-and-fast point where the iterative process of drug

discovery ends.

Drug development is most simply defined as the point at

which an optimized lead compound with good efficacy

in animal models and acceptable toicity and pharmaco-

kinetic5 properties is selected for preclinical evaluation

[12]. Once a preclinical candidate has been chosen, it

must pass a rigorous series of tests designed to ensure

safety in animals and provide persuasive indications

of efficacy. With a successful preclinical compound in

hand, researchers may then apply to the U.S. Food and

Drug Administration (FDA) for investigational new drug

(IND) status, which permits the compound to be tested

in humans. The IND candidates safety, dosing, and effi-

cacy in humans are then established by clinical trials.

Products with demonstrated efficacy and safety in humans

5 Pharmacokinetics refers to the study of how an externally administered agent behaves in animals or humanswhat the body does to a drug.

Routinely examined pharmacokinetic properties of a drug are its absorption, distribution, metabolism, excretion, and toxicological properties

(ADME/Tox).


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are approved by regulatory authorities such as the FDA or

European Medicines Agency (EMEA) and registered in the

countries in which they will be sold.

Together, projects in discovery and development make

up the product pipeline. As illustrated in Figure 3.1,

the process of discovering and developing drugs requires

an average of 1015 years [13, 14]. Although the failure

rate is greatest at the earliest stages of discovery, prod-ucts can fail at any point. Indeed, high rates of attrition

partially eplain why the process of inventing a drug takes

so long. According to the Pharmaceutical Research and

Manufacturers of America (PhRMA), for every 5,00010,000

compounds that enter the pipeline, only one becomes a

registered product [14]. Thus, because of attrition, the vast

majority of compounds that enter drug discovery and devel-

opment will never progress to success in clinical trials [15].

New players build the therapeutics

pipeline for neglected diseasesFrom 1975 to 2004, out of 1,556 new drugs approved by

the FDA, EMEA, and other government authorities, only 21

were registered for tuberculosis, malaria, and other neglected

diseases [16, 17]. This oft-cited statistic reflects the lack

of incentives for biopharmaceutical companies to invest in

products for which there are insufficient paying markets.

In 2006 alone, U.S. pharmaceutical and biotechnology

companies invested over $55 billion of their own resources

to invent medicines for diseases of the developed world

[18]. Yet, they directed only a fraction of that sumweestimate based on two recent studies less than $100

millionfor R&D aimed at two of the worlds biggest

killers, malaria and tuberculosis [19, 20].

To remedy this imbalance, over the past decade new public

sector R&D efforts have arisen to build a pipeline of new

products for neglected diseases, with over $1.2 billion of

investment since 1999 [2]. Although certain large pharma-

ceutical companies, academic centers, and biotechnology

companies have begun to participate, the driving forces for

therapeutic R&D in global health have been PDPs [21].

PDPs are not-for-profit organizations funded and championed

by the donor community6 to develop novel vaccines, drugs,

and diagnostics for specific neglected diseases. Like many for-

profit biopharmaceutical companies, PDPs drive preclinicaland clinical development of new product portfolios, picking

and choosing which products to advance through the pipe-

line, including which to launch or terminate. In contrast to

for-profit companies, many PDPs are virtual organizations

with comparatively small staffs and no laboratories of their

own. Most, if not all, of the projects in their portfolios are

carried out by partners, including researchers in academic

institutions, contract research organizations (CROs), and

large pharmaceutical companies. The larger PDPs oversee

and coordinate projects occurring all over the globe.

Four leading PDPs focus on therapeutics for malaria, TB,

and trypanosomal diseases:

n The Medicines for Malaria Venture (MMV)

promotes new antimalarials.

n The Global Alliance for TB Drug Development (TB

Alliance) focuses eclusively on drug development

for tuberculosis.

n The Drugs for Neglected Disease Initiative (DNDi)

creates new drugs to treat trypanosomal diseases

and malaria.

n The Institute for OneWorld Health (iOWH)concentrates on leishmaniasis, malaria, and

diarrheal diseases.

All four are mostly virtual and work etensively with

nonprofit and for-profit partners to conduct discovery and

development. By supporting PDPs, donors have created

centers of epertise for each disease area.

6 We use the term donor community to refer to governments, nonprofit organizations, and foundations.

Screeningfor Hits

Lead Optimization

3-6 years 1 year 6-7 years

LeadIdentification

Phase I

1 year

Preclinical Phase IIIPhase II

DRuG DISCOVERY

CLINICAL TRIALS

Registration

Figre 3.1: Drg Discovery and Developmentthe Necessary Prelde to New Drgs

DRuG DEVELOPMENT


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Table 3.2: PDP Drgs Registered or in Clinical Trials

Prodct

Paromomycin

Artesunate-amodiaquine

Artesunate-mefloquine

Cholorproguanil-dapsone

(Lapdap)-artesunate

Coartem dispersible tablet

Dihydroartemisinin-piperaquine

Pyronaridine-artesunate

(Pyramax)

Moxifloxicin (Avalox)

PA-824

Nifurtimox-eflornithine

Disease*

Visceral leishmaniasis

Malaria

Malaria

Malaria

Malaria

Malaria

Malaria

TB

TB

HAT

Development Stage

Registered in 2006 (India)

Phase III (East Africa)

Registered in 2007 (Morocco)

Phase III

Phase III

Phase III

Phase III

Phase III

Phase II/III

Phase II

various

Drg Type

Existing (new use)

Existing (new combination therapy)



New formulation of existing combination therapy



Existing (new use)

New Chemical Entity (NCE)


PDP Sponsor

iOWH

DNDi

DNDi

MMV

MMV

MMV

MMV

MMV

TB Alliance

TB Alliance

DNDi

*In this analysis, we are considering only drugs in development for P. falciparum malaria or P. falciparum and P. vivax malaria, but not P. vivax malaria alone.

Sources: DNDi, iOWH, MMV, and TB Alliance.

Table 3.3: Biopharmacetical and Consortim-Based Drgs in Clinical Trials

Prodct

Zithromaxchloroquine

Ferroquine

Fosmidomycin-clindamycin

Gatifloxacin

TMC 207

OPC-67683

SQ-109

LL-3858

DB289 (pafuramidine)

Disease

Malaria

Malaria

Malaria

TB

TB

TB

TB

TB

HAT

Development Stage

Phase III

Phase II

Phase II

Phase III

Phase II

Phase II

Phase I

Phase I

Phase III

Drg Type


NCE*


Existing (new use)

NCE

NCE

NCE

NCE

NCE

Sponsor

Pfizer

Sanofi-Aventis

Jomaa Pharma Gmbh

OFLOTUB consortium**

Tibotec (Johnson & Johnson)

Otsuka

Sequella

Lupin Pharmaceuticals

UNC Consortium for Parasitic

Drug Development

*New chemical entity

**OFLOTUB is a consortium of European and African partners focused on carrying out phase II and III clinical trials to test the safety and efficacy of a

gatifloxacin-containing regimen against TB.


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Evaluation of neglected disease

drug pipelines

Eager to show early results in bringing new treatments

to afflicted populations, PDPs initially focused on testing

eisting drugs registered for other diseases against the

target pathogens. These efforts have borne fruit, with twoproducts launched (paromomycin and artesunate-amodia-

quine) and eight additional products in clinical trials

(Table 3.2). Through the efforts of industry and various

consortiums, several other promising compounds or

combination therapies are also in clinical trials (Table 3.3).

A snapshot of the current therapeutic pipelines for malaria,

TB, and HAT is presented in Appendi II.

Products in neglected disease drug pipelines can

be divided into

n eisting drugs being evaluated for new

indications,

n drugs in new formulations,

n novel fied-dose combinations, or

n new chemical entities (NCEs).

Tables 3.2 and 3.3 show these classifications for products

currently in clinical trials.

Figure 3.2 compares risks and benefits of epanding uses

for eisting drugs versus creating NCEs. A key advantage

of using eisting drugs is that often they have etensiverecords of safety in humans and do not require years

and millions of dollars to establish safety in treating

neglected diseases. NCEs, on the other hand, are much

riskier to invent than epanding the use of eisting

drugs. But with risks come benefits. NCEs targeted for

potency, specificity, and lack of toicity have greater

potential to provide breakthrough therapeutic benefits

within a wide safety margin. Thus, in the long run,

substantial improvement over eisting treatments will

require discovering NCEs.

Figre 3.2: Risks and Benefits of Expanding use of Existing Drgs Verss the Creation of New Chemical Entities


23/66


The World Health Organization (WHO), via the Stop TB

partnership and TDR, has drawn together the views of

leading scientists in global health into a set of ambitious

goals for discovering new treatments for tuberculosis,

malaria, HAT, and other neglected diseases [12, 24]. Table

3.5 summarizes these goals. New medicines that fulfillthese objectives might halt and even reverse the spread of

these diseases.

Requirements for effective drugs

for neglected diseases

Any new drug emerging from the pipeline for neglected

diseases must be safe, inepensive to manufacture, prac-

tical to administer, stable in harsh climates, potent against

resistant strains, and effective within time frames compa-rable to or better than eisting products. In addition,

as illustrated in Table 3.4, each disease has a specific,

minimum TPP that a new product must meet [22, 23].

Table 3.4: Target Prodct Profiles for uncomplicated P. falciparum Malaria, Active Plmonary TB, and Late-stage HAT

Resistance

Low capacity to generate resistant organisms

Effective against drug-resistant strains

No cross resistance with other drugs

Dosing

Oral formulation

Short dosing duration

Fast acting

Pediatric formulation

Safety

Safe/low toxicity

Safe in pregnant womenno adverse effects on fetus

Manfactring

Inexpensive manufacturing to ensure low cost

Stability in tropical climateno special storage considerations

Broad Spectrm

Efficacy against multiple disease stages

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

Combination use

Evaluate for use in combination with other drugs

Pharmacokinetics and dynamics compatible with dosing regimen

No adverse interactions with anti-retrovirals (ARVs)

Other

Ability to cross blood-brain barrier

P. falciparum

malaria

Necessary Desirable TB HAT

Sources: DNDi, MMV, TB Alliance, and Nwaka, S., and A. Hudson, Innovative lead discovery strategies for tropical diseases.

Nat Rev Drug Discov, 2006. 5(11): p. 941-55.


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The activity and safety of the drugs now in development

will be fully apparent only upon completion of clinical

trials. But it is clear already that these drugs will not meet

some of the ambitious goals in Table 3.5, such as short-

ening the duration of TB treatment to two months or less

[25], reducing malaria treatment to a single, curative dose,

and developing a treatment effective against all stages of

HAT. For these advances, a new generation of therapeutics

will be required.

An innovation gap impedes creation

of the next generation of drugs

As the current generation of drug candidates advances

toward clinical success and registration, or toward clinical

failure and abandonment, a new generation of drug candi-

dates must follow that offers the promise of achieving more

ambitious goals. Similar to drug development for cancer

and diabetes, neglected disease drug development pipe-

lines require high-quality discovery programs7 backed

by substantial, sustained investment as occurs when the

biopharmaceutical industry tackles diseases such as cancer

or diabetes.

For instance, a major biopharmaceutical company intent

on developing a new oral treatment for a chronic disease

market such as heart disease would eplore 10 to 20

targets generated by genomics and biochemistry, and

advance five to 10 targets in parallel into high-throughput

screening. Each project would initially screen thousands

to millions of compounds. Most of these projects will

fail because of myriad interrelated reasons: for eample,

inability to epress the target protein and develop an assay,

lack of credible screening hits, failure to optimize efficacy

versus toicity, lack of oral bioavailability, and failure in

animal proof-of-concept models. Project failure rates before

identifying an IND candidate are routinely over 75 percent.

Subsequent attrition due to clinical failures, safety concerns,

and market forces reduces the success rate to less than 5

percent, sometimes only 1 to 2 percent. Thus, a credible

effort to develop a new drug in the biopharmaceutical industry

requires substantial numbers of discovery projectsenough to

ensure that a product with the desired TPP will emerge from

the pipeline.

The pipeline of clinical-stage programs for malaria, TB,

and HAT is epected to yield several new products in

the net few years [21]. However, as Figure 3.3 shows,

a major disparity eists between early-stage pipelines of

these diseases and the profile of a typical industry-driven

program for a disease with an established market. For

instance, our analysis found that there are five, si, and

one discovery projects in the lead optimization stage

for malaria, TB, and HAT, respectively. Assuming that

the average industry project failure rates will also apply

to neglected disease projects, these numbers are far shy

of the 20 projects typically required to yield a single

new drug. Indeed, for all of the neglected diseases we

eamined, none has a drug discovery effort sufficient to

ensure that the net generation of candidate compounds

will be ready to enter clinical development in the coming

years. This observation has also been noted by others

[26]. This deficiency, or innovation gap, restricts the

flow of new, approved medicines for neglected diseases

(Figure 3.4).

Table 3.5: Treatment Goals for Malaria, TB, and HAT

Disease

Malaria

TB

HAT

Goal

Single-dose curative treatment

Reduce treatment time to 2 months or less

Shorten therapy of latent disease

Efficacy against all stages of disease and all subspecies

Ability of drgs in development to meet goal

Goal unlikely to be met


Unknown


Sources: WHO/TDR, DNDi, MMV, TB Alliance, and Stop TB Partnership

7 A high-quality program is defined as having the following characteristics: 1) a solid molecular target associated with disease pathology, validated

by genomics, molecular biology, cellular systems, and animal pharmacology; 2) a druggable targetone where a small molecule drug would exert

a positive therapeutic effect; 3) creating new compositions-of-matter that have the desired effect or improve upon known compounds, with low or

no side effects; 4) the ability to manufacture the drug at reasonable cost for desired benefit; 5) the ability to get a clear clinical answer in a defined

population quickly; and 6) a clearly defined path to regulatory approval.


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NumberofProgramsEnteringEachPhase

ofDrugDiscoveryandDevelopment

100

90

80

70

60

50

40

30

20

10

0

Figre 3.3: Attrition Rates and Crrent Neglected Disease Pipelines

Sources : MMV, DNDi, TB Alliance, PharmaProjects, and BVGH/L.E.K. analysis

Out of 100 programs entering thescreening phase of discovery, onaverage 1.3 drugs will successfullyreach the market 1214 years later

Screeningfor Hits

LeadIdentification

LeadOptimization

Preclinical Phase I Phase II Phase III Registration Approved

INNOVATION GAP

Expected programsurvival rate

Malaria

TB

HAT

Phase

100.0

30.0

19.5

10.7

5.8 4.01.9

1.31.3

Figre 3.4: The Innovation Gap

NEGLECTED DISEASE DRuG DEVELOPMENT

Thosands of Potential Gene Targets

Dozens of Validated Targets

Few Chemical Leads

Few PreclinicalCandidates

LimitedClinical

Candidates

Novel Drgs

Rarely Approved

DEVELOPED WORLD DISEASE DRuG DEVELOPMENT

Thosands of Potential Gene Targets

Hndreds of Validated Targets

Tens of Chemical Leads

8 - 10 Preclinical Candidates

5 Clinical Candidates

1 Approved

Drg


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Causes of the innovation gap

The innovation gap results from insufficient investment

devoted to early-stage drug discovery, limited access to key

technologies and drug discovery epertise, and difficulties

in assembling the collaborations necessary to transform a

laboratory discovery into an IND. We eplore these prob-lems in detail below.

Insufficient investment in discovery

The cost of clinical development is highestimated in the

hundreds of millions of dollars for the cumulative successes

and failures required to bring a single new drug to market

in the developed world. The discovery stage of this process

also requires substantial investments of time and money to

n create an initial population of biologically active

molecules;

n optimize them through multiple iterations of

medicinal chemistry and pharmacologic assays; and

n select a small number for further development.

Industry studies show that innovative pharmaceutical and

large biotechnology companies typically spend between 35

and 40 percent of their R&D budget on discovery [27].

The need for this level of investment stems from the diffi-

culties of finding a compound that meets all the pharma-

cologic criteria required for proceeding into development.

Typically, thousands of compounds are intensely evaluated

for two to four years before a clinical candidate is selected.

Indeed, most discovery programs fail before an IND

application can be filed to initiate clinical trials. It is not

an eaggeration to say that the likelihood that any single

compound will reach the clinic is vanishingly small.

By contrast, PDPs have focused smaller proportions of

their R&D investments on drug discovery, although they

recognize the need to build sustainable pipelines and have

continually supported work on new compounds. Based on

publicly available information [28-30], these partnerships

have only been able to devote between 15 and 30 percent

of their funds to discovery, with MMV and the TB Alliance

putting the greatest investments into discovery. PDPs have

increased their discovery program productivity by partnering

with large pharmaceutical companies that make matching

in-kind contributions of manpower and resources.

While the upper limits of the proportion of their R&D

investments devoted to drug discovery is similar, the

absolute level of PDP investment in drug discovery is low

compared with commercial discovery efforts. Depending

on the size of the discovery team, drug discovery compa-

nies typically spend between $2 million and $4 million peryear per preclinical lead optimization project [27]. Even if

a hypothetical PDP had a $50 million budget, 30 percent

still represents only $15 million, which will support a

pipeline of only three to si early-stage projects to advance

lead compounds to IND candidate stage. Current PDP

investments are far less than this.

Among the biotechnology companies we eamined for

this report, discovery-only and early-development

companies8 spend a median of $20.9 million and $30.8

million per year, respectively, on research that does not

include clinical trial activities. This is substantially more

than the hypothetical PDP defined previously (Figure 3.5).

Companies typically view their levels of investment as the

minimum to maintain a discovery team and generate an

IND drug candidate at least every other year.

MillionsofDollars

35

30

25

20

15

5

0

Figre 3.5: Annal R&D Spending by BiotechnologyCompanies and PDPs

Sources: Company SEC Filings and BVGH/L.E.K analysis

Median Annual R&D Spending

Early-Development Discovery-Only Hypothetical PDPCompany Company

8 Discovery-only companies are defined as those capable of screening for hits and generating leads and optimized lead compounds. Few carry out

preclinical work except on a contract basis. Early-development companies possess comparable capabilities to discovery-only companies, but they can

also carry out preclinical work and phase I clinical trials.


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Access to technology and expertise and limited

scale of operations

The technological platforms, assets, and epertise neces-

sary to transform biological findings into NCEs are well

established (see Chapter 4). Biotechnology and phar-

maceutical companies engaged in drug discovery havepurchased or synthesized large compound libraries. They

have assembled capabilities in advanced technologies such

as high-throughput screening, x-ray crystallography, and

computational modeling. They have teams of scientists

with epertise in assay development, medicinal chemistry,

and pharmacology.

Academic centers and individual investigators carrying

out neglected disease research have identified compelling

new targets for therapeutic intervention [26, 31, 32].

For the most part, however, they lack the tools available

to industry to etend their research into drug discovery.

Even with the advent of academic- and government-based

high-throughput drug screening (HTS) initiatives such as

the NIH Roadmap for Medical Research [33], advances

in neglected disease biology are not adequately matched

with the tools and epertise that lead to the discovery of

NCEs [34].

In interviews with academic leaders in malaria, tubercu-

losis, and trypanosomal diseases (for list, see Appendi

III), we found they face three key obstacles in progressing

beyond generating hits through small molecule screening:

first, limited access to the most advanced drug discovery

technology and compound libraries; second, lack of drug

discovery eperience and epertise; and third, insufficient

scale of operations.

Limited access to the best compound libraries

Compound libraries are collections of organic chemicals

assembled by purchase or custom synthesis for repeated

screening in multiple biological assays. An industrial

compound library is organized around a biological target

class, drug-like properties, or chemical structural diversity.

A companys organized, selected, and annotated compound

library is a core, proprietary asset.

Publicly available compound libraries, on the other hand,

are largely limited to diversity libraries obtained from

commercial sources. Many academic research facilities have

assembled libraries from commercial sources, but few if any

compare with those available in industry. The most well-

constructed and diverse public library is a new collection ofover 100,000 small molecules accessible through the NIH

Molecular Libraries Screening Center Network (MLSCN).9

With a few eceptions, publicly available libraries do

not have the target-class focus common to proprietary,

purpose-built libraries in biotechnology and pharmaceutical

companies. Commercial libraries are based almost solely

on structural novelty, much like the early combinatorial

libraries used by industry, as opposed to relevance to the

targets of interest. Screening large numbers of such unbiased

compounds against a target may generate hits, but hit rates

are etremely low (less than 1 in 1,000) and can be epected

to identify a distracting number of false positives [35].

Although these concerns limit the utility of publicly

available libraries, two trends may make it possible for

public sector researchers to avoid some of these pitfalls.

First, there are now commercial sources of target-focused

libraries. These libraries offer much higher yields when

screened against members of a target family. Second, it

is possible and cost-effective to engage chemistry CROs,

many of which are offshore, to design certain types of

custom compound libraries. Nonetheless, the public sector

still does not have access to the breadth of target-focused

libraries available to industrya reality that limits the

types of NCEs that can emerge from a neglected disease

drug discovery campaign.

Limited access to discovery infrastructure and

chemistry expertise

In recent years, high-throughput screening centersfacili-

ties allowing chemical compounds to be tested for activity

against putative or established drug targets in high-

throughput modehave been installed at universities and

public research institutes all over the world. These centers

are particularly abundant in North America and Europe

9 MLSCN is an NIH-funded consortium that provides the following: high-throughput screening (HTS) to identify compounds active in

target- and phenotype-based assays; medicinal chemistry to transform hits into tool compounds; and deposition of screening data into

a freely accessible public database. See Austin, C.P., et al., NIH Molecular Libraries Initiative. Science, 2004. 306(5699): p. 1138-9.


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[23, 36]. To capitalize on the potential value of their own

technology, many academic institutions now vie to estab-

lish themselves in drug discovery by creating translational

research centers. These initiatives have facilitated target

validation and hit generation, but they represent only part

of the infrastructure required to transform an academiclaboratory into a true drug discovery facility. Without

industry epertise, resources, and scale, such efforts are

unlikely to be efficient generators of NCEs that can be

entered into commercial development. This limitation

holds true as well for academic translational research initia-

tives for neglected diseases.

Converting hits to lead compounds is an iterative,

chemistry-intensive process requiring epertise in

analytic, synthetic, and medicinal chemistry. For

academic biologists and biochemists pursuing drug

discovery, accessing chemistsparticularly those with

medicinal chemistry epertiserequires collabora-

tion with academic chemists sharing an interest in the

biological target or disease. Because of the epense and

long timelines associated with lead-optimization medic-

inal chemistry, and the high epected failure rate, it can

be challenging to identify and engage academic groups

with organic chemistry resources essential to optimize

leads into true drug candidates.

Insufficient Scale

Many of the organizations working on neglected disease

drug discovery are limited by the scale of their efforts.

For eample, TDR reports that its medicinal chemistry

network devoted to tropical diseases consists of 11

postdoctoral fellows scattered in eight organizations all

over the world to address all of their programs [23]. In

contrast, even the smallest drug discovery companies have

coordinated teams of at least eight in-house or contract

chemistsper project [27]. Additionally, few universities

possess the instrumentation and epertise required for

high-throughput assay development, x-ray crystallog-

raphy, computational modeling, and in vitro pharmacoki-

netics and toicology studiesall of which are essential

tools in drug discovery.

Current joint industry-PDP efforts provide a good model

for future collaborations, but the number of projects being

pursued in these programs is far from sufficient to ensure

a robust pipeline for any of the neglected diseases. In the

biopharmaceutical industry, the limited discovery research

under way for neglected diseases mostly takes place inthree companies: GSK, Novartis, and AstraZeneca.10

Two of these programs are partnered with MMV and TB

Alliance.

Building a continuum of players

The innovation gap is not only a problem of investment,

access to infrastructure, technology, and epertise. It is

also a problem of recruiting organizations eperienced in

different aspects of product development that together

can ensure that the fruits of R&D flow efficiently from the

laboratory into the clinic, and then to the patients bedside.

For diseases with a developed-world market, such a

system of collaborating organizations has been in place

for many years. It begins with commercially viable ideas

and inventions created in academia and research institu-

tions. Biotechnology and pharmaceutical companies then

license these innovations, where industrial scientists,

eperienced in translating basic science into nascent prod-

ucts, undertake drug discovery. R&D typically concludes

with completion of clinical and regulatory activities by

the biotechnology industry innovator or a large pharma-

ceutical company that may license the product once it

shows persuasive evidence of preclinical or clinical efficacy.

Bi

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