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Heat Shock and Awe
As Hsp-90 inhibitors multiply, investors hope for mega payoff.
By Rabiya S. Tuma, Ph.D.
November/December
2006
The first heat shock protein 90 (Hsp90)
inhibitor has reached Phase II clinical trials, but already experts are
saying they expect the drugs to have broad activity in oncology. In
addition, it is predicted that Hsp90 inhibitors are heading towards large
and financially rewarding markets.
Kosan Bioscience's tanespimycin (formerly
known as KOS-953 and 17-AAG), is furthest along in clinical development. In
collaboration with the National Cancer Institute, Kosan has achieved
positive Phase Ib clinical trial data and expects to launch a Phase II
registration trial later this year for tanespimycin in combination with
Velcade for the treatment of refractory or relapsed multiple myeloma. The
company also has an on-going Phase II trial testing tanespimycin in
combination with Herceptin in Her2/neu-positive breast cancer.
"Velcade will be a billion dollar market
in a couple of years, and we have the ability to have Velcade work better in
combination with tanespimycin. We are very excited about that
possibility," says Robert Johnson, CEO of Kosan. "In Her2-positive
breast cancer, we have the opportunity to extend life cycle of Herceptin,
and to have activity in first and second line therapy. That is a very large
indication for a company the size of a Kosan."
If all goes well, Johnson expects approval
for tanespimycin in 2009 and he intends to be the first to get there. That
might not be so easy, however. Tanespimycin is currently furthest along in
clinical development, but the competition for that designation will be
fierce with at least four other Hsp90 inhibitors already in clinical trials,
and over a dozen companies working in the field.
Adelene Perkins, executive vice president and
chief business officer of Infinity Pharmaceuticals, is convinced that their
Hsp90 inhibitor, IPI-504, will be the first drug to gain approval, though it
is only now in Phase I trials for multiple myeloma and gastrointestinal
stromal tumors (GIST). "We really believe that we have the opportunity
to have our agent come out as the first-in-class Hsp90 inhibitor. We very
carefully selected our clinical trial strategy and believe we have an
extraordinarily rapid path to registration," she says.
Hsp90 Inhibition Has Broad Effect
Excitement about the agents appears to be well founded based on their
mechanism of action. Hsp90 is a molecular chaperone that helps other
proteins, called client proteins, fold into their functional conformation.
Client proteins that fail to fold properly are rapidly degraded by the cell.
Many of the signaling proteins that drive cancer cell proliferation and
survival are Hsp90 clients, including Raf, AKT, Erb-B2, Bcr-Abl, HIF-1, p53.
Thus, many types of cancer cells are exquisitely sensitive to Hsp90
inhibition. By relieving the blocks that prevent apoptosis, the inhibitors
likely make tumor cells more sensitive to existing therapies.
"I think it is pretty safe to say that
these agents will be widely used in combinations," says Francis
Barrows, who was previously with Conforma and became senior director of
molecular discovery at Biogen Idec when the two companies merged earlier
this year. "The number of drug resistance and survival pathways that
can be slowed down or shut down is larger than any other target I know
of."
Not all Hsp90 inhibitors are alike, however.
The agents that are currently in late-stage development or in clinical
trials are derivatives of the natural product geldanamycin which was first
identified as an Hsp90 inhibitor in the late 1990s. Geldanamycin itself
elicits significant liver toxicity and never got past Phase I clinical
trials. Its derivatives, such as tanespimycin, IPI-504, and Biogen-Idec's
compound CNF-1010, demonstrate better tolerability.
Nonetheless, researchers are moving toward
small molecule inhibitors that have a better therapeutic index. "What
has held up the field are the limitations of the natural product," says
David Parkinson, head of oncology research and development at Biogen Idec.
"We were missing small molecules with better drug behavior." The
company's second Hsp90 inhibitor, CNF-2024, was the first such small
molecule Hsp90 inhibitor to enter clinical trials and is currently being
tested in solid tumors in a Phase I trial.
Similarly, Serenex has used their chemical
proteomics approach to identify small molecules that are structurally
distinct from geldanamycin. "All of the other companies built their
Hsp90 programs off the existing chemical scaffold," says Steven Hall,
senior vice president of research and development at Serenex. "Ours was
discovered de novo using our core technology. It bears no resemblance to
other Hsp90 inhibitors in development. That gives us a very strong
intellectual property position."
Serenex's chemical proteomics approach is
also used to identify client-specific inhibitors of Hsp90. In the short
term, such client-specific inhibitors would help them explore the biology
more completely, says Hall. For example, the agents could be used to learn
which client proteins are more important in different malignancies, as well
as to what degree the targets need to be knocked down in order to kill the
cells. In the long-term, however, specific Hsp90 inhibitors could produce
better responses with less toxicity.
"Theoretically it should be possible to
interfere with this mechanism at multiple levels," says Kosan's
Johnson. "I don't know anyone who has had luck with a 'target specific'
inhibitory mechanism, but it is theoretically possible." In Kosan's own
third generation inhibitor program, the company is attempting to block the
ATP binding site of Hsp90, which is the classic target, as well as other
sites on the molecule. Recent evidence suggests that client proteins bind to
Hsp90 via accessory proteins. Thus, blocking one or another of the accessory
proteins might provide some client protein specificity, as well as a good
therapeutic index.
So if the future is so bright and rich for
Hsp90 inhibitors, then where is big pharma? Thus far, Novartis and Biogen
Idec are the only large companies to appear in the field. Yet all of the
experts interviewed agreed that the big companies are following the field
closely and many have research programs of their own-as evidenced by
publications from the likes of GlaxoSmithKline and Johnson & Johnson
scientists. Moreover, though no one is willing to share details, deals
appear to be in the works for several companies. Kosan says they will
partner as they get ready to move forward with large indications. Though
Serenex's Hall declined to give any specifics, he said that they were
"in discussion with a number of pharmaceutical companies, large and
small."
Novartis made an early entry into the field
by establishing a collaboration to develop Hsp90 inhibitors with Vernalis in
2003. In December 2005, the companies announced that they had identified a
lead compound and were moving forward with it. A further announcement is
expected within the next month or two, but in the meantime Novartis, too, is
keeping quiet. Though when asked why they moved into the field so early,
Novartis' Jeremy Levin, global head of strategic alliances for the Novartis
Institutes for BioMedical Research didn't hesitate to talk. "If you
inhibit ATP binding, you disrupt the chaperone-client interaction, which
leads to degradation of multiple oncoproteins. Hsp90 inhibitors will
probably have broad spectrum anti-tumor effects-they can potentially act as
broadly as chemotherapy but with lower toxicity."
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