Pharmaceuticals and Merck & Co. recently
$1-billion collaboration to develop and commercialize
AP23573, ARIAD’s novel mTOR inhibitor, for use in
cancer. We talked to Timothy P. Clackson, Ph.D., Senior
Vice President and Chief Scientific Officer at ARIAD, who
explained why mTOR is such an important target. Clackson
also described what the alliance with Merck signifies for
the future of AP23573 and for ARIAD in general.
PharmaWeek: Why makes mTOR such a valuable target?
Clackson: mTOR (mammalian target of rapamycin) provides us
with a broad range of opportunities to demonstrate
clinical benefit. It is a “master switch” inside tumor
cells, affecting pathways involved in growth, division,
metabolism and angiogenesis. As such, it represents an
opportunity to attack a number of pathways important to
tumors with a single drug.
One of mTOR’s most intriguing features is that it
has been aberrantly activated in essentially all tumor
types that we have looked at. This implies that AP23573,
as an mTOR inhibitor, has very broad potential in
oncology. That’s in contrast to a target such as HER2,
which is important in certain types of breast cancer but
is not believed to be involved in most other cancers. The
mTOR inhibitor AP23573 appears to hit the sweet spot of
exhibiting potentially broad anti-tumor activity while
showing an encouraging safety profile.
One key advantage about mTOR is the potential for
identifying a predictive biomarker profile that would
serve as a molecular signature of patients likely to
respond best to AP23573. Development of a diagnostic could
be the end consequence of successfully identifying a
predictive biomarker or biomarker profile. Such a product
could then be used to screen patients ahead of time to
determine who would benefit most from AP23573. I am
personally very excited about working with Merck on
biomarkers, given their long-standing expertise in this
PharmaWeek: Is there potential for AP23573 to work in
combination with other drugs?
Clackson: Yes, absolutely. Combinations will likely be a
significant part of AP23573’s future development.
Because mTOR is so central to tumor cell signaling, there
is great potential to add—into the mix with an mTOR
inhibitor—a second agent that blocks elsewhere in that
signaling pathway. We have non-clinical data showing that
AP23573 can be combined with a wide variety of both
classical chemotherapeutic agents as well as targeted
At this year’s ASCO meeting, we presented early
clinical data on AP23573 combined with paclitaxel, a
widely used agent. We have other trials testing AP23573
with capecitabine and with doxorubicin. We’re also
intrigued about the potential to combine AP23573 with
targeted therapies. We will be working with our partners
at Merck to determine which of these many opportunities we
PharmaWeek: What does the collaboration with Merck portend for
ARIAD’s future development plans?
Clackson: We believe our collaboration with Merck will be
transformational for ARIAD in many ways. With respect to
AP23573, it will allow us to pursue its full potential to
benefit patients. We will be able to study it in several
different indications simultaneously, both as a single
agent and in combination with others. We’re excited
about being able to spread our wings and embark on that
journey with Merck, who shares our enthusiasm.
Until now, there’s been a lot of attention on our
sarcoma program, and rightly so. We’re very excited
about the signals seen in Phase II studies of AP23573 for
sarcoma. As a result, we believe there’s a lot of
excitement in the sarcoma community about AP23573’s
potential. At the same time, AP23573 holds promise for
treating other types of cancers too, and I believe the
Merck collaboration will allow us to finally unleash that
More generally, in terms of what it means for ARIAD,
this collaboration agreement will enable us to grow our
organization in ways consistent with our long-stated
strategic plan. This includes the eventual establishment
of commercial operations in the US and building out our
clinical development operations, not only for AP23573 but
for other pipeline candidates as well.
For example, ARIAD’s drug candidate AP24534 is a
kinase inhibitor being studied for chronic myeloid
leukemia and solid tumors. We plan to file an
investigational new drug (IND) application for AP24534 by
the end of this year. With the additional resources
resulting from this partnership, we are in a good position
to move forward expeditiously with that compound, and then
with other pipeline candidates in due course.
PharmaWeek: Finally, what were challenges specific to
developing an mTOR inhibitor?
Clackson: One consequence of having a broad range of
potential activity is struggling to decide where to best
focus initial clinical efforts. That was an intriguing
early challenge we faced. Based on a combination of
non-clinical and scientific considerations, and early
signals detected in initial clinical safety studies, we
chose sarcomas as our first clinical priority. Sarcomas
are a very important challenge in the cancer arena and an
area of great unmet medical need. In addition, the patient
population was of an appropriate size for us to tackle,
and we believe it is a population that has been neglected.
We saw quite striking anti-tumor effects in our
early clinical studies. The most dramatic example is the
very first patient to receive AP23573 in our first Phase I
trial. The patient was considered terminally ill, with a
rare form of uterine sarcoma, and had been given less than
nine months to live. Four years later, she is still
receiving AP23573 and has experienced dramatic
shrinkage—nearly disappearance—of her tumor. This was
extremely gratifying for us to see, and obviously
profoundly important for the patient. We saw a number of
other encouraging responses and, based on those results,
we elected to initially focus on sarcomas, an indication
for which we’ll soon be initiating a Phase III
registration trial of AP23573.
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