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At $50 million dollars
annually, the market for cutaneous T-cell lymphoma (CTCL)
is an unlikely gold mine. But for companies like
Merck, Gloucester Pharmaceuticals, and Novartis that
are developing histone deacetylase (HDAC) inhibitors,
CTCL may be the path to one.
All three companies are
testing their HDAC inhibitors in CTCL, and two expect
to file for FDA approval for that indication within
the next year. “While CTCL is the tip of the
iceberg, and an odd duck disease, we believe that we
will have activity, not only in hematological tumors,
like lymphoma, myeloma, and leukemias, but also in
solid tumors,” says Stan Frankel, senior director of
clinical research at Merck. That’s stiff competition
just within oncology. Meanwhile, companies like
Sirtris Pharmaceuticals are already starting to look
at HDACs in other arenas, such as age-related
disorders.
Oncology, though, is
clearly the first battlefront. Already, Phase IIb
results with Merck’s HDAC inhibitor Zolinza (also
known as vorinostat or SAHA) show the drug is
effective in CTCL. Approximately one-third of patients with advanced disease responded
to the drug in a Phase II trial, despite having failed
two or more prior therapies. Those data, Frankel says,
will form the core of the FDA filing the company will
submit before the end of 2006.
Zolinza is expected to
be the first HDAC inhibitor approved by the FDA, but
several other drugs in the class won’t be far
behind. Gloucester Pharmaceuticals expects to apply
for approval of its HDAC inhibitor, depsipeptide (FK228), in 2007 based on
data from an ongoing Phase II pivotal trial in CTCL.
Additionally, the Novartis drug, LBH589, is currently
in a Phase I trial in CTCL patients.
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The HDAC inhibitors
have been developed with the idea that they can
reactivate genes that have been turned off by
epigenetic silencing. Specifically, when histone
proteins are acetylated, the modification masks the
positive charge on their lysine tails and reduces
their affinity for the negatively charged DNA
backbone. Without those acetyl groups — when HDACs
are active — the DNA is more tightly wound into
nucleasomes and cannot be transcribed. HDAC inhibitors
should relieve that gene silencing.
Clinical trial results
suggest that the agents have activity in hematologic
cancers, including leukemia and myelodysplastic
syndrome (MDS). For example, in a Phase I study
testing MethylGene’s compound MGCD0103 in 20 patients with
treatment-refractory leukemia or MDS, three had a
complete resolution of the disease in their bone
marrow for at least one month.
Combined, those two
diseases create a market worth approximately $400
million annually. Analysts caution, however, that
there are other agents available for the treatment of
these malignancies, so just how much of the market the
new agents can capture will depend on their efficacy.
“We are not limiting
our approach to only the hematology setting at this
time,” says Donald F. Corcoran, president and CEO of
MethylGene, noting that there is considerable evidence
that solid tumors also harbor HDAC abnormalities.
“If you look at our competitors, some are working in
multiple myeloma, colon cancer, prostate, CTCL, other
lymphomas. I don’t think one can project with any
accuracy what the market will be for these HDAC
inhibitors.”
In fact, Zolinza has
already shown activity in mesothelioma , a type of
lung cancer associated with asbestos exposure. And
early data with MS-275, an HDAC inhibitor being
developed by Schering AG (Berlin, Germany), suggest
the drug might have activity in metastatic cancer.
“Moving forward,
having established some degree of clinical activity
with these drugs, I think we have to ask the hard
questions that targeted therapy scientists are
starting to ask about other drugs: How does it work,
and why does it work? says Jean-Pierre Issa, professor
of medicine at the University of Texas M.D. Anderson
Cancer Center and a pioneer in the field of epigenetic
control of cancer.
A variety of
pharmacokinetic studies on blood cells isolated from
patients before and after treatment with HDAC
inhibitors provides some evidence that the drugs are
working as expected. In a study presented at the
annual meeting of the American Society of Clinical
Oncology, H. Miles Prince, of the Peter MacCallum
Cancer Centre in Melbourne,Australia, reported that
histone acetylation increased in CTCL patients treated
with LBH589.Yet there was no correlation between the
degree of increase and response. Moreover, analyzing
gene activity using an Affymetrix array before and
after treatment, the researchers found that
approximately 5 percent of the transcripts had a
twofold or greater increase or decrease. Only 5
percent of those genes (0.25 percent of the total)
were shared between the two patients who had a
complete response.
Control over gene
expression is not likely to be the whole story in how
HDAC inhibitors work, says Steve Grant, professor of
hematology-oncology at the Virginia Commonwealth
University School of Medicine in Richmond. Researchers
now know, for example, that HDAC activity directly
influences cell signaling pathways, protein stability,
and production of cell-damaging reactive-oxygen
species. Nor, he says, are all of the HDAC inhibitors
likely to be working in the same way as one another.
There are three major
classes of HDAC enzymes. The class I and II enzymes,
which are targeted by the oncology-targeted
inhibitors, have different functions, and at least one
company, MethylGene, is trying to exploit that fact.
Class I enzymes are restricted to the nucleus where it
modifies histones as well as several substrates that
are involved in proliferation and differentiation,
including p53, NF-κB, and Bcl-6. By contrast,
class II enzymes shuttle between the nucleus and the
cytoplasm and modify proteins that are involved in
posttranslational modification and protein trafficking
in addition to histones. Some of the class III
enzymes, also known as sirtuins, affect mitochondrial
activity and stress responses.
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Exactly which class of
HDACs is important depends on whom one asks. After
characterizing HDAC activity in cancers, the
MethylGene group opted to develop a class-I-specific
inhibitor, MGCD0103. By contrast, researchers
developing pan inhibitors, such as Zolinza and LBH589,
are convinced that hitting class II is important as
well, particularly because these inhibitors
destabilize hsp90 and lead to destruction of numerous
oncogenes that are hsp90 clients.
“Our chemists were
able to come up with molecules that were selective for
some of the isoforms that we believe are involved in
cancer, and spare some of the ones that we believe are
not involved in cancer and could potentially contribute to side
effects,” says Corcoran. Whether that promise will
hold true will only be apparent after the drugs have
moved through more clinical trials.
In the meantime, the
team has found interesting ways of exploiting their
large library of potential inhibitors. After realizing
that epigenetic silencing contributes to azole
resistance in funguses, MethylGene researchers
screened the compounds for one that inhibited fungal
HDACs but not mammalian ones. The compound, not yet
tested in the clinic, reduced drug resistance and
acted synergistically with ketoconazole in animal
models.
Understanding the
downstream impact of HDAC inhibition may become more
important as companies move out of oncology and into
other disease settings. Preclinical work indicates
that the inhibitors may have value in fighting diabetes and
inflammation, slowing neurodegenerative diseases
including Huntington’s disease. Sirtris, which is
led by Christoph Westphal, has amassed $82
million in venture capital to develop sirtuins for the
treatment of age-related diseases, including
Alzheimer’s disease and diabetes. The company’s
lead compound, SRT501, entered a Phase I safety and
pharmacokinetic trial in June.
So while the CTCL
market is small, the future market for HDAC inhibitors
could be huge.
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