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This is
a challenging time for the pharmaceutical industry. The
question of the day — How can pharma produce more
successful medicines more economically? — has never
been more vital. I use the word “vital” very
deliberately. The lives of patients, employees,
shareholders, and countless others are affected by our
industry’s ability to answer that question. There will
be multiple answers, but it is clear that systematically
and economically finding new uses for safe but stalled
late-stage drug candidates — drug repositioning —
would significantly benefit all the industry’s
stakeholders.
Most
drug candidates start out as modulators of a particular
drug target in a particular therapeutic indication.
Nearly all fail. While most fall short at the earliest
stages when the cost of failure is relatively low, a
significant number fail as late as Phase II or Phase
III, after companies have spent considerable time,
effort, and money. There are serendipitous examples such
as Viagra or Evista, but most stalled drugs don’t get
a second chance; they finish their development path as a
sunk cost sitting on a shelf. However, drug
repositioning is now beginning to offer a compelling
alternative.
Repositioning
drugs systematically has been rare to date for a number
of reasons. Pharmaceutical R&D efforts are typically
organized around franchise therapeutic indications. Even
for a large company with multiple franchises, there have
been few mechanisms for researchers in the
cardiovascular area, for example, to test a company
compound that failed in oncology. Even organizations
that try to limit the “silo” approach to drug
development face a choice of testing a failed candidate
from another therapeutic area or putting their resources
into the most promising candidate within the franchise.
Without an economical way to find out where else a drug
candidate may have potential, the choice has almost
always been to shelve the clinical failure in favor of
the next drug candidate.
But the
economics are changing as industry developments open the
door to drug repositioning:
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In-licensed
candidates are of unknown quality and have become
extremely expensive.
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A
better understanding of biology is helping us see
the interrelationships of pathways in different
diseases.
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High-throughput
assay technologies are making testing faster and
more affordable.
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Our
understanding of genomics’ role has increased
hand-in-hand with improvements in bioinformatics.
And
consider the pedigree of Phase II failures. They are the
result of years of refinement, safety and
proof-of-concept tests, and human clinical trials.
Compared to in-licensed drug candidates, they are better
understood, the intellectual property position is
usually clearer, and manufacturing challenges have
likely been overcome. And, most pharmaceutical companies
have stalled candidates in storage.
In
response to these developments, repositioning companies
have emerged to search for new life for stalled drug
candidates. Their approaches vary, but all use
efficient, systematic, and cost-effective methods to
evaluate a compound for additional activity rather than
wait for serendipitous clues to appear in clinical
testing. Gene Logic has assembled a portfolio of
complementary technologies, and we are seeking to
reposition more than 30 small-molecule drug candidates
using our biology-based Phase R program. My experience
has been that diverse but complementary technologies,
rather than a single tool, allow examination of a
compound across a variety of disease indications,
independently confirming other’s findings and catching
other’s misses.
The
good news about safe but stalled Phase II drug
candidates—and there are thousands of them—is that a
significant number may now be ripe for new life. New
approaches and new and higher-throughput technologies
offer the compelling prospect of the molecule telling
the researcher what biology it will affect. So how can
we produce more successful medicines more economically?
One answer to the industry’s key question appears to
be on pharma’s own shelves.
Louis
A. Tartaglia, Ph.D. is the Senior Vice President and
General Manager, Drug Repositioning and Selection for
Gene Logic Inc.
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