Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 15
2
Approaches to Accelerating
Translational Science
Key Messagesa
Promise for Translational Science
· New technologies would help change the translation process in positive ways
rather than simply enhancing processes that are already in place.
· Open innovation could decentralize and speed the development of new drugs
and diagnostics.
Approaches for CAN
· Partnerships among institutions help accelerate the rate at which new dis
coveries are translated into products that can improve health. CAN could
incentivize, de-risk, and facilitate research at the academiaindustry interface.
· CAN could curate features of promising and successful alliances among aca-
demic, philanthropic, and industry groups and make available a compilation of
the most promising features as guidelines or best practices templates.
· Planning on a programmatic, not episodic, basis will help facilitate overall effec-
tiveness of drug development and the impact of CAN to improve and accelerate
development of cures.
· Effectiveness of and communication among the project management team is
a key element of success.
· A consensus-based traditional funding review process could undermine sup-
port for needed breakthrough projects.
a Identified by individual speakers.
15
OCR for page 16
16 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK
CAN is part of a much broader effort in NCATS and NIH to help
accelerate the translation of biomedical discoveries into products and pro-
cesses that improve human health. The second session of the workshop
focused on ways to achieve this goal, with an emphasis on exemplary
projects that have met with success. Past experience has provided lessons
about how to replicate successes and what to avoid. CAN will have the
capability to support translational science both through projects aimed
at specific diseases and through the development of more generic tools,
and the proper balance between these two was discussed throughout the
workshop.
CYSTIC FIBROSIS AND THE NEED FOR PARTNERSHIPS1
Cystic fibrosis is caused by mutations in the CFTR gene, which
encodes a protein that pumps chloride across epithelial cell walls. As a
result, mucus gradually plugs the lungs, degrading their function. Cystic
fibrosis causes a loss in lung function of about 2 percent a year. Once lung
function gets below about 50 percent, severe disability results. When
lung function drops below 40 percent, death is likely from one of a variety
of causes.
About 15 years ago, Vertex Pharmaceuticals and the Cystic Fibrosis
Foundation began working together to lower lung decline to 1 percent
per year, said Joshua Boger, who founded Vertex Pharmaceuticals in 1989
and still serves on its board. If that could be achieved, people with cystic
fibrosis could live nearly a normal life expectancy. Yet, at the time, that
goal seemed out of the realm of a pharmaceutical intervention.
Vertex took two approaches to enhance mutant CFTR function. One
was to find small molecules, known as CFTR potentiators, that could
increase the channel activity of CFTR protein at the cell surface, resulting
in enhanced ion transport. The other was to identify molecules known
as CFTR correctors that could increase the quantity of functional CFTR
protein at the cell surface, also resulting in enhanced ion transport. In the
late 1990s, these goals were generally considered to be science fiction, said
Boger, especially given that many patients would need both treatments.
The most important step in making these goals a reality, said Boger,
was to create a good assay for the performance of test molecules. "Once
we had the right assays, compounds that did exactly what we wanted
them to do were relatively easy to find." More than 300,000 compounds
were screened, resulting in the identification of several effective com-
pounds, including a drug now known as ivacaftor. Clinical trials dem-
1 This section, including subsections, is based on the presentation by Joshua Boger, F
ounder,
Vertex Pharmaceuticals.
OCR for page 17
APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 17
onstrated that treatment with ivacaftor in patients who have a particular
mutation can produce a 10 percent increase in lung function within a
matter of weeks. Young patients who struggled to keep their weight up
gained weight almost immediately with the drug. And adverse effects
were greater in the placebo group than in the treated group because the
placebo group was sicker.
Beginning with patient observations in 2008, three Phase 2 trials were
held and a New Drug Application was filed in October 2011. Regulators
acted with great speed and approved the drug in just over 90 days. The
drug development process cannot be done much faster than it was done
for ivacaftor, Boger said. "This is a success story in large part due to
unique cooperation between Vertex and the Cystic Fibrosis Foundation,
which has become a model in the field," said Boger.
Partnerships and Approaches
Until the late 1990s, the Cystic Fibrosis Foundation supported "won-
derful science," according to Boger, but the foundation's leadership real-
ized it was not directly helping patients. As a result, leadership shifted
the organization's research focus from late in the laboratory to early in
the clinic. They also founded the partnership with Vertex, which Boger
termed a "very bold idea" that would not have gotten through most
review processes in government or disease foundations. Total support for
the collaboration from the foundation was about $75 million. This is about
the maximum size of the project that CAN could support if appropria-
tions were available, Boger noted.
The development of ivacaftor was a "high-wire act from beginning
to end," Boger commented. Success was never obvious or guaranteed. "If
you are looking for dramatic changes in medicine, you are not looking to
be comfortable in research and development." Such a project would not
be possible in most of NIH because, as Boger said, "every breakthrough
project that I know about has passionate detractors." A review process
that depends on consensus will not support breakthrough projects. He
noted that breakthroughs require human passion. "In any sort of multi-
stakeholder project that is being talked about through CAN, think about
how you are going to put human passion into it."
He also noted the importance of developing assays that report rel-
evant information. Boger emphasized that assays are different from vali-
dated models (which tend not to be aimed at breakthroughs) and from
disease models (which may or may not be part of determining how to
treat that disease).
OCR for page 18
18 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK
Critical Needs for Translational Science
These observations from the example of cystic fibrosis point to sev-
eral critical needs for translational science, according to Boger. One is for
technologies that positively change the translation process, not just add
to processes already in place. For example, how can a technology make
translation faster, cheaper, or more effective? How can risk be lowered
while safety is enhanced? How can technology enable greater leaps?
Technologies that are simply more accurate are not sufficient answers to
these questions. Technologies need to contribute to systems that replace
other systems.
Today, a drug development effort can be shut down with one negative
result. Some drugs can be rescued, but even more important is to create
a process that eliminates false negatives in the first place. "I am positive
that we have fantastic drugs that have been killed in development," said
Boger. "False negatives, I believe, are the biggest problem in the drug
development process right now."
Cures for the kinds of diseases that are a focus of the CAN legislation
also require that a significantly more effective and efficient regulatory
system be envisioned "from scratch," said Boger. The current process is
built on historical precedent, but, he said, even though regulators do their
best, the process is too expensive and too long. Safety, risk, and efficacy
assessments need to be conducted on the continuum of both premarket
and postmarket, not as an ad hoc, focal point process that evaluates only
one drug, one development process, at a time. Boger emphasized that
public health and overall societal benefits need to be incorporated into
the evaluation process on a routine and continuing basis. Expenditures
of time and money need to be optimized, and patients need to receive
benefits sooner.
ALZHEIMER'S DISEASE AND THE DRUG
DEVELOPMENT ECOSYSTEM2
The biomedical enterprise is capable of stunning successes, but it is
also falling short of meeting the needs of patients in many ways, said
R. Sanders (Sandy) Williams, President, the Gladstone Institutes. The suc-
cessful treatment of some cases of cystic fibrosis, as described above, or
the soon-to-be-accomplished victory over hepatitis C virus, demonstrates
what can be done. But failures in such areas as Alzheimer's disease, heart
disease, or the development of an HIV vaccine illustrate both the scientific
and business challenges of drug discovery.
2This section, including subsections, is based on the presentation by R. Sanders (Sandy)
Williams, President, the Gladstone Institutes.
OCR for page 19
APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 19
In a 2010 interview, NIH Director Francis Collins described the
pressing need for "new paradigms of publicprivate partnership[s] . . .
effectively `de-risking' projects for downstream commercial investment"
(Collins, 2010). New forms of partnerships among academic experts,
industry professionals, and public and private sources of investment
can improve what Williams and other workshop participants called the
"drug development ecosystem." This ecosystem is diverse, encompass-
ing universities, independent research institutions, biotechnology and
pharmaceutical companies, voluntary health organizations, foundations,
philanthropists, investors, and government. CAN, within the NCATS
umbrella and through relationships with other federal agencies and other
players in the ecosystem, has an unprecedented opportunity to replace
failing processes with effective complementary teamwork, providing
measurable results to Congress, to disease advocacy groups, and to the
taxpayers who support the effort, said Williams. Academia and industry
have differing skills, mindsets, and incentive structures. CAN can help
find new and creative ways to form flexible alliances that combine their
complementary attributes with funding sufficient to achieve measurable
goals. "If we can do that, we can preserve and advance America's leader
ship position in medical sciences and industry and, most importantly,
bring new solutions to the most vexing and resistant medical needs."
To illustrate his points, Williams focused on Alzheimer's disease. More
than 5 million Americans are currently living with Alzheimer's disease,
and by 2050 that number will climb as high as 16 million. Alzheimer's
disease will cost the United States $200 billion in 2012 and $1 trillion in
2050 if nothing changes. Alzheimer's disease plays out within the daunt-
ing biological milieu of 100 billion neurons and over 100 trillion synapses
in the human brain. A great variety of pathological events occur in the
brains of Alzheimer's patients at the cellular and molecular levels, includ-
ing proteinopathies, vascular insufficiency, and inflammatory responses.
"It is little wonder that, time and time again, preclinical research geared
largely to test reductionist unidimensional models is not predictive of
success with patients," said Williams.
Suggestions for CAN
Williams offered three suggestions for how CAN could address the
scientific dimension of what is needed to accelerate cures. First, CAN
could support and catalyze research to develop and validate a new gen-
eration of animal models created to exhibit clinically relevant phenotypes.
This likely will require multiple genetic manipulations that are carefully
selected to bring the models into more faithful representation of human
disease. For example, CAN could issue a request for proposals to fund
OCR for page 20
20 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK
development of better mouse models. Williams suggested that some of
the mouse models could then be deployed in an iterative manner to
inform innovation in adaptive clinical trials.3 This concept is being cre-
atively tested at present within the cancer research community, Williams
said, but the possibilities may be much broader. In particular, the creativ-
ity of academic labs could be released more productively for this purpose,
particularly if combined with industrial know-how within an intellectual
property landscape that allows industry and academia to collaborate.
Second, CAN could support the revolution in stem cell biology,
in which techniques have been discovered that can generate induced
pluripotent stem cells that subsequently can be induced to form virtually
any differentiated cell type. A next generation of cellular reprogramming
techniques is now emerging by which mouse or human fibroblast or white
blood cells can be converted directly into a variety of cell types to model
human diseases in culture. In particular, reprogrammed human neurons
can form multi cellular networks and recapitulate important features of
neurodegenerative diseases. The extent to which reprogrammed human
cells from diseased patients and relevant controls can be useful for target
validation, primary and secondary drug screening, toxicology, or other
purposes remains to be seen, but CAN could stimulate progress toward
this end.
Third, CAN could support newly emerging scientific approaches that
can reveal more fully how the targets of medications function within
systems, pathways, and networks within cells. An example is the new
ability to define the set of proteins within human cells that form physical
complexes with the proteins elaborated during HIV infection. CAN could
stimulate the creation and validation of this and other enabling platform
technologies with the potential to reveal molecular signatures of disease
progression and drug responses.
Business Challenges
Challenges exist in the business arena as well as in the science of
drug discovery, noted Williams. The vast reservoir of talent, imagina-
tion, and expertise in academia could be connected more effectively with
the complementary pools of talent, professionalism, discipline, techni-
cal prowess, and financial power in companies. As Williams and Susan
Desmond-Hellmann wrote in Science last year, "needed now are creative
programs that transcend the traditional technology transfer functions of
non-profit research enterprises to promote fruitful academic/industry
partnerships for drug development" (Williams and Desmond-Hellmann,
3 See later in this chapter for further discussion of the need for and utility of animal models.
OCR for page 21
APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 21
2011). Accelerating cures requires deeply embedded partnerships, focused
on defined projects and carried out by teams that work together over time.
A number of new and creative relationships of this nature have sprung
up around the country, with research responsibilities divided according
to each party's individual strengths and capabilities. For example, even
in a period of limited funding, CAN could curate, to the extent possible,
features of promising and successful alliances among academic, philan-
thropic, and industry groups and make the compilation of these attributes
available as guidelines or templates for best practices that can inform
subsequent contractual negotiations.
As CAN's funding increases, the program is ideally placed to develop
a diversified portfolio of projects over time. Other worthwhile actions for
CAN include
· facilitation of early engagement of industry experts into academic
projects,
· rescuing and repurposing of drugs,
· strengthening computational pharmacology, and
· supporting regulatory science.
Williams said that he favors an emphasis on smaller and midsize projects
built on investigator ideas as opposed to a few really big infrastructure
projects or a few large clinical trials, "but all would be worthwhile."
NUT MIDLINE CARCINOMA AND OPEN INNOVATION4
Understanding of the cancer genome has undergone a revolution,
said James Bradner, Instructor in Medicine, Dana-Farber Cancer Institute,
and Assistant Professor, Harvard Medical School. Hundreds of thousands
of somatic mutations in different cancers are known, and hundreds have
been identified as the drivers of cancer pathogenesis. But the ability to act
on this understanding is in its infancy, Bradner added. A small-molecule
therapeutic is available for only about 14 cancer genomic rearrangements
or mutations.
Bradner described a very rare and very lethal cancer called NUT
midline carcinoma, which affects approximately 100 people per year
in the United States. A molecular pathologist at Brigham and Women's
Hospital named Christopher French cultivated cells from patients who
have the disease, and Bradner and his colleagues used these cells to test
4 This section, including subsection, is based on the presentation by James Bradner,
Instructor in Medicine, Dana-Farber Cancer Institute, and Assistant Professor, Harvard
Medical School.
OCR for page 22
22 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK
small molecules that would inhibit the cancer. In particular, they focused
on a molecule named JQ1, which interferes with a protein called BRD4.
Although there was no mouse model to study the cancer, Bradner at the
time was caring for a 29-year-old firefighter succumbing to the disease,
who provided a cell sample that was successfully grown in laboratory
mice. When mice with tumors received the drug, they survived, whereas
those that did not receive the drug died.
JQ1 was a prototype drug not yet optimized for drug-like properties
such as solubility or oral bioavailability. In order to access the infrastruc-
ture required to bring a molecule into the clinic, Bradner and his colleagues
decided to be creative. Using Google, they created a registry for people
with midline carcinoma, which revealed a lot of information about the
disease profile, such as where it is diagnosed and by whom. Many people
have the disease but do not know it, Bradner said. "They should, not just
because targeted therapy may soon be available, but because this is the
poorest prognostic group of all squamous carcinomas, with a 6.7-month
median survival."
At a cost of $45,000 to his laboratory, Bradner and his colleagues made
the drug freely available to anyone who wanted to learn about its effects
in other diseases. A TED lecture on the drug had more than a half million
viewers, and at least 200 people wrote to ask Bradner and his team to share
the molecule. "They're under no special obligation to call us back, but they
almost always do, to share the exciting findings of their research."
In multiple myeloma, JQ1 downregulates what Bradner called "the
central horseman of the cancer apocalypse," a gene called MYC that trig-
gers growth. Mice with multiple myeloma driven by MYC had a complete
response. In mixed-lineage leukemia, leukemia cells exposed to JQ1 "for-
get they're leukemia and become more mature-appearing, normal mono-
cytes," Bradner said. And in Burkitt's lymphoma, the downregulation
of MYC again demonstrated the efficacy of JQ1. Why particular cancers
respond is a major area of ongoing research.
Open Innovation Leading to Bringing the Compound to Humans
Bradner and his colleagues have found through sharing the com-
pound with scientists at other institutions that in 10 to 15 percent of cases
of every major form of cancer, the cancer "just melts away to this drug."
These data establish a compelling rationale to bring this compound for-
ward into humans, said Bradner. With internal funding from the accelera-
tor program at Dana-Farber, Bradner and chemist Jun Qi led a medicinal
chemistry effort that resulted in the creation of 400 to 500 chemical deri-
vates. Ultimately, they were able to produce a stable of drugs of high
potency and high stability in pharmacological studies.
OCR for page 23
APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 23
Bradner and his colleagues also have taken a creative approach to
translation. For example, they determined that Xanax, a bromodomain
inhibitor, is very similar to the JQ1 molecule; however, the amount of
Xanax that would be needed to be administered to have an effect on can-
cer would be excessive. A literature search revealed that GlaxoSmithKline
had a bromodomain inhibitor for the management of acute septic shock.
They negotiated with the company for investigational use in cancer.
Although the molecule is 10 times less potent than JQ1 and performs less
adequately in the animal models of the disease, it is available for testing
in humans immediately.
Bradner cited the development of JQ1 as an example of open innova-
tion, which has been extremely successful in the information technology
field. "We are so much smarter than each of us," he said. The drug they
were examining was a prototype and immature, but the index technology
sparked rapid innovation when it was publicly and broadly disseminated.
Bradner termed patent documents and Investigational New Drug (IND)
applications some of the best kept secrets in the pharmaceutical world
and argued that such documents should be publicly available to all. If
findings about other small molecules were publicly available for scientific
research, more drugs like JQ1 could be brought to patients much more
quickly.
SICKLE CELL ANEMIA AND THE NEED FOR HEDGEHOGS5
Sickle cell disease was the first disease discovered to be caused by a
genetic mutation--by Linus Pauling in 1949. Yet only one drug had been
labeled for use in sickle cell--the anticancer agent hydroxyurea, which
does not work for all patients and can have adverse side effects.
Stephen Seiler, Founder, AesRx, described the biotechnology com-
pany's efforts to develop a therapeutic specifically for sickle cell disease.
The company has put together a multistage, multi-institute, public private
translational research program centered on the compound Aes-103. The
members of the collaboration include AesRx, the National Heart, Lung,
and Blood Institute, the Therapeutics for Rare and Neglected Diseases
program--which used to be part of the National Human Genome Research
Institute and is now part of NCATS--the NIH Clinical Center, and the
NIH Clinical Pharmacy. Two weeks before the workshop, the collaboration
announced that it is starting a clinical trial with sickle cell patients.
The collaboration has made rapid progress. The IND application was
filed less than a year after the collaboration was announced, the healthy vol-
5 This section, including subsection, is based on the presentation by Stephen Seiler,
Founder, AesRx.
OCR for page 24
24 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK
unteer safety trial was completed in less than 15 months, and the first dose
was administered to sickle cell patients in less than 18 months. A successful
type C meeting with FDA clarified the clinical endpoints and regulatory
pathway, which, Seiler noted, is very helpful in de-risking a drug.
Small biotechnology companies like AesRx have been an important
part of the drug development supply chain since the 1970s. They have
taken early-stage ideas, typically from academia, and converted them
to more mature products. They have then handed these products off to
big pharmaceutical companies, have been bought by those companies,
or have become fully integrated pharmaceutical companies themselves.
Over the past 5 or so years, this system has undergone a dramatic
change, according to Seiler. "The ecosystem has changed so dramatically
that it's become doubtful whether companies like us can continue to pro-
vide the role that we have traditionally had in the drug development sup-
ply chain." Venture capital funds are dramatically reducing their commit-
ment to early-stage biotechnology companies for several reasons, Seiler
said. First, the suppliers of venture capital increasingly have required
more mature programs, which has put early-stage biotechnology projects
beyond venture capital's investment horizons. Also, whether or not the
perceptions are correct, suppliers of venture capital perceive there to be
more regulatory risk. Finally, venture capital focuses on chasing the "next
big thing" and yielding a quick return.
Lessons Learned
Seiler drew several lessons from his experiences developing Aes-103.
The first is that a key element for success is to have programmatic and
not episodic planning. AesRx started with early preclinical development
and had a goal of taking the drug all the way across the biotechnology
valley of death, with planning and budgeting done up front for the entire
program. This programmatic planning allowed for early investments in
resources that will be needed after project initiation but prior to the data
emerging from the first experiments.
Another key to success was an effective management team with a
genuinely collaborative focus. Good science is a necessary, but not suf-
ficient, condition for success, Seiler said. "Many venture capitalists spend
as much time doing due diligence on the management team they're going
to invest in as they spend doing due diligence on the science. So if you're
trying to set up a partnership, do the due diligence on your partners well."
Flexibility provided the capability to pursue new programmatic
insights and unfolding data. The project was run as a virtual model with
very low overhead. At the same time, the personnel involved with the
OCR for page 25
APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 25
project brought experience with clinical trials from the perspective of
many different kinds of companies.
The ingredients that drove the program so quickly and so far were
focus and quick and transparent decision making, according to Seiler. He
observed that small biotech companies bring incredible focus to a project.
He noted that key decisions could be made in less than 2 weeks, adding
that management is very impatient to move them forward. In contrast,
collaborators at government agencies or in academia have many other
responsibilities. Seiler recalled the statement attributed to the ancient
Greek poet Archilachus, which is that the fox knows many things and
the hedgehog knows one big thing. Programs like the development of
Aes-103 "need a lead hedgehog," he said.
One of the corresponding challenges to success was the government
procurement process. Because it was a virtual program, some of the pieces
had to be procured from contractors, and the procurement process is com-
plicated, expensive, and slow. Another challenge is that diffuse responsi-
bility can make tight budget control difficult.
LEUKEMIA AND LYMPHOMA AND THE
NEED FOR PARTNERSHIPS6
The goal of the Leukemia & Lymphoma Society (LLS) is supporting
advancement of therapies for patients. The resources of LLS to find cures
for the hematological malignancies are limited, said Louis DeGennaro,
Executive Vice President and Chief Mission Officer, LLS. The society
therefore needs to select and prioritize its projects carefully and foster
publicprivate partnerships to drive the translation of science into treat-
ments. One way that the organization selects and prioritizes projects
is through a careful examination of the survival rate, age of onset, and
incidence of the diseases that fall within its purview. By comparing these
factors to the dollars dedicated to those diseases in the current research
portfolio, funding can be compared to unmet medical needs. DeGennaro
noted that although the analysis is not perfect, it is an example of multiple
tools that could be brought to bear to think about how to prioritize where
dollars should go in terms of research.
LLS also has a new Therapy Acceleration Program (TAP), which seeks
to fill the gap between academic research and new therapies. The pro-
gram has a dedicated staff that searches for small biotechnology compa-
nies with promising assets that have potential. Staff members also mine
the society's research grant portfolio for projects that have moved out of
6 This section, including subsection, is based on the presentation by Louis DeGennaro, Exec
utive Vice President and Chief Mission Officer, the Leukemia & Lymphoma Society (LLS).
OCR for page 26
26 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK
basic research and into the development stage. The TAP staff prioritizes
the projects and does due diligence of the medicine, the science, and the
business in the case of biotechnology companies. In part through accessing
outside resources such as medical experts, business experts, and intellectual
property experts, the program's funding is distributed not through grants
but through contracts with timelines, milestones, deliverables, and cost-
sharing components. These contractual standards serve as built-in metrics
for every project, to determine how well the project is going. "We bring
industry-quality project management to every program," said DeGennaro.
Partnerships
DeGennaro emphasized that cost and risk sharing can work. LLS does
not have sufficient resources to fund the full development program, so
its goal is to partner with biotechnology and pharmaceutical companies
to get the projects through key hurdles. At that point, the companies can
approach the capital market to raise additional dollars or partner with
another company to continue the project. DeGennaro added that the LLS
portfolio of about 14 projects has an annual investment of $16 million, not
far from what is currently allocated for CAN.
At this point LLS has more than a dozen drugs in the pipeline. Roughly
half are being developed through partnerships with small biotechnology
companies. By supporting late preclinical Phase 1 and Phase 2 trials, and
even one Phase 3 registration trial, the society has been able to accelerate
the rate at which these programs have moved through development. As
just one example of success, DeGennaro cited a partnership with Celator
Therapeutics to conduct a controlled Phase 2 trial on acute myeloid leuke-
mia. The agent for secondary acute myeloid leukemia resulting from this
trial has doubled the number of patients achieving complete remission,
cut treatment-related mortality by a factor of five, and tripled the number
of patients still alive at a year.
DeGennaro concluded by briefly mentioning a novel partnership
among the society, NCATS, and the University of Kansas to repurpose
existing drugs to treat hematological malignancies. A memorandum of
understanding set objectives and responsibilities, with commercialization
a prominent objective. To enable that, the partnership includes a coopera-
tive R&D agreement with NIH to make certain that the intellectual prop-
erty generated could be used in commercialization. Within 12 months,
two Phase 1 clinical trials of existing FDA-approved agents that are being
repurposed to treat hematological malignancies have begun.
OCR for page 27
APPROACHES TO ACCELERATING TRANSLATIONAL SCIENCE 27
CROSS-CUTTING ISSUES
During the discussion period, several topics arose that cut across the
five talks on approaches to accelerating translational science.
The Alignment of Partnerships and Culture
One sticking point in partnerships is that academic and commercial
organizations have very different operating procedures, goals, and metrics
of success. University researchers have incentives for the advancement of
their students and their own research. Similarly, as Seiler observed, the
style of programmatic organization in the private sector is very different
from the typical NIH grant cycle.
Williams added that industry has a legitimate but sometimes over-
stated need for confidentiality. This issue often arises when trying to settle
on contract language, where new types of agreements may be needed to
get more expertise involved in collaborations. He also noted that science
in academia tends to develop through deeply embedded relationships,
not through the "short touches" that characterize academic researchers'
involvement with industry, such as consulting arrangements or scientific
advisory boards.
Bill Chin, Harvard Medical School, noted that many of the obsta-
cles to collaboration reside in academia and not in industry, saying that
behaviors reinforced over time in academia can be obstructive to get-
ting groups together. For example, most university researchers have little
understanding of what biotechnology companies actually do and of the
levels of expertise, creativity, and imagination that are required. "There's
a tendency to think of the latter stages of the development pathways as
turning the crank on routine, uninteresting work, and that's a mispercep-
tion." He also said that academic researchers have a tendency to over-
value what they have, "and therefore they don't come to the table with
realistic views."
DeGennaro emphasized the importance of better training for clinical
investigators about the regulatory process. "The more of those clini-
cal investigators we can train, and the better they understand the regula-
tory process and their obligations, the faster the trials can get conducted."
A particularly promising approach is to make use of the CTSAs to align
the training and the education of a large number of clinical investigators
toward regulatory science.
The Use of Animals
Boger remarked that Vertex has put three drugs into the market and
none has had an animal model. He termed animal models "overrated,"
OCR for page 28
28 MAXIMIZING THE IMPACT OF THE CURES ACCELERATION NETWORK
because they do not take into account the complexities of the system that
dictates drug responses in humans.
Bradner pointed out that the successful development of cancer drugs
has for years relied on the early assessment and demonstration of a thera-
peutic window in animal models. Animals obviously are used as spar-
ingly as possible, but for drugs relying on new mechanisms, establishing
the therapeutic value in animals has been valuable. On the other hand,
he noted, there is no obvious animal model for sickle cell disease, but that
has not been a barrier to moving the science forward.
Williams sought to distinguish the demands of the science from the
demands of regulation. He said that although animal models are not
required for drug development, each situation has different requirements.
Some diseases will have more authentic animal models that produce
evidence capable of overcoming the obstacles to a cure. He argued for an
integration of all of the tools that could be applied.
Cool Tools
The presenters also discussed the "cool tools" that Kathy Hudson,
NIH, called for in her opening remarks. Bradner said that tools could
be "absolutely revolutionary" if they could perform the exhaustive and
expensive predictive toxicology studies mandated in regulatory pathways
at an early enough stage to prompt candidate selection. "Any of these
technologies that can be released early on regarding drug metabolism
would be hugely beneficial to our work."
As an example of a cool tool, Tom Insel, NCATS, mentioned the
NCATS pharmaceutical collection, which is a collection of all approved
compounds in Europe, the United States, and Asia. Currently almost
4,000 compounds are in a repository and can be used to go directly from
an approved compound to a new indication. He also mentioned the hun-
dreds of thousands of compounds in a molecular libraries program that
are publicly available as part of the National Chemical Genomics Center
at NCATS, which NCATS will continue to streamline.
Among the other tools, methodologies, and approaches mentioned
by presenters were
· systems pharmacology,
· models representing various biological processes,
· informatics,
· crowdsourcing,
· prizes,
· small-molecule databases,
· chemical probes, and
· collaborative tools.
