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TransTech and Pfizer Ink Mega
Deal for RAGE Inhibitor Development
Candidates have potential to modify course
of Alzheimer's disease.
November/December
2006
By Laurie Sullivan
To the tune of $155 million, Pfizer has obtained the exclusive worldwide
rights to develop and commercialize TransTech Pharma's portfolio of RAGE
inhibitors. These compounds have potential use for treatment of Alzheimer's
disease (AD) as well as diabetic nephropathy. The market for AD drug therapy
in the US, Europe, and Japan is substantial, exceeding $3 billion in 2005,
according to Millennium Research Group. By 2009, approximately 10 million
people in this global market will suffer from AD.
TransTech's portfolio comprises small- and
large-molecule compounds targeting Receptor for Advanced Glycation End
products (RAGE). RAGE is a member of the immunoglobulin super family of cell
surface molecules, and has a variety of disease-associated ligands. Ligands
of RAGE include amyloid fibrils (associated with AD), advanced glycation end
products (associated with diabetes and renal insufficiency), amphoterin
(associated with tumors), and S100/calgranulins (associated with
inflammation).
Stephen L. Holcombe, Senior VP and Chief
Financial Officer of TransTech, says, "RAGE is such an interesting drug
target because its ligands are associated with so many different diseases.
In these disease states, you see both an elevation of RAGE and an elevation
of the particular ligand associated with that disease. So a compound
preventing those ligands from binding RAGE is a potential therapeutic."
One of TransTech's most advanced RAGE
molecules is TTP488, which is an orally available, small-molecule compound
that reduces A-beta deposition in the brain. TTP488 has completed a Phase
IIa study for AD and is currently in a Phase II study in patients with
diabetic nephropathy. TransTech says the compound could have benefits beyond
alleviating purely symptomatic effects of AD to be useful as a
disease-modifying agent.
Pfizer agrees. Martin Jefson, vice president
of CNS discovery at Pfizer, says, "Disrupting the biology of RAGE has
the potential to be disease modifying for AD. Pfizer is not unique in the
field in that a major focus for us is discovering and developing agents that
modify the progression of this devastating disease. Current medicines are
not labeled and have not been proven to do that." Jefson added that
existing treatments are more applicable for treating the signs and symptoms
of AD, and improving cognition in diagnosed patients.
"Alzheimer's is an indication with so
much unmet need. We're very excited to be part of trying to deliver what
could potentially be a disease-modifying drug," Holcombe adds.
RAGE's Role in Alzheimer's
RAGE binds the amyloid peptide A-beta, which is presumed to be elevated in
Alzheimer's patients, and does one of two things: It can play a role in
transporting A-beta from plasma into the brain, potentially fueling the
deposition of amyloid plaques-one of the distinctive hallmarks of AD. Or,
the RAGE/A-beta interaction could trigger a cascade of events leading to
neuroinflammation, which is also implicated in the progression of AD.
Inhibiting RAGE thus prevents these events.
When asked why TransTech chose Pfizer as a
development partner, Holcombe said the decision rested on multiple factors.
While lots of companies were interested in TransTech's RAGE program,
"It came down to who we felt had a combination of the best economics of
the deal, the requisite expertise to successfully develop and commercialize
the drugs, and an existing franchise. With its Alzheimer's drug Aricept,
Pfizer already has a sales force working this market. All of these factors
led to our agreement with Pfizer."
Naturally, Pfizer was attracted to
TransTech's portfolio of RAGE inhibitors. "We believe that TransTech
has an interesting platform-in terms of both candidates and technology-to
explore the worth of RAGE biology in modifying the course of AD," says
Jefson.
Under the agreement, TransTech will receive
upfront and near-term milestone payments of $155 million. TransTech could
also receive significant milestone payments for the successful development
and commercialization of multiple RAGE antagonists in several indications,
and will receive royalties on worldwide sales of products. Pfizer will
provide TransTech additional funding during the research term to support
continued expansion of the RAGE portfolio.
Jefson adds that while the focus of this deal
is AD, "RAGE is a pretty complicated area of biology, and there are
other potential utilities for this as well."
In fact, another of TransTech's most advanced
RAGE molecules is TTP4000, which is a large-molecule compound expected to
enter Phase I clinical trials by the end of the year. In addition to AD, it
is being studied for diabetic nephropathy.
According to the American Diabetes
Association, the total annual economic cost of diabetes in 2002 was
estimated at $132 billion, or one out of every 10 health care dollars spent
in the United States. Nephropathy is a frequent complication of diabetes and
often ends in kidney failure. Ten to 21% of all people with diabetes have
nephropathy. The latest WHO (World Health Organization) estimate for the
number of people with diabetes, worldwide, in 2000, was 177 million. By 2025
WHO predicts that number will increase to at least 300 million people.
Holcombe points out, "There's a lot more
behind our two lead compounds. That's why this agreement is in place... to
move those forward as well as to develop others in the queue."
So what's the long-term benefit of this
mega-deal to Pfizer? "I don't think anyone knows where the successes
will come from," say Jefson. "But this is complementary to
Pfizer's overall portfolio of both externally acquired products and
candidates, as well as what we're doing internally."
For example, Pfizer recently acquired Rinat
Neuroscience, giving it access to a monoclonal antibody for the treatment of
AD. "The collaboration with TransTech strengthens our hand dramatically
in this area," concludes Jefson. "Taken together with the Rinat
acquisition, I think it's a strong show of Pfizer's commitment to finding a
treatment for this devastating disease, which is currently not served in the
way that we hope it will be in the future."
"By the nature of the Alzheimer's
indication alone, the collaboration has the potential to deliver significant
long-term value," says Holcombe. "TransTech is eager to move the
program forward in conjunction with Pfizer."
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