Data Support Further Exploration of Duvelisib
in Combination with Anti-PD-1/PD-L1 or Co-Stimulatory Antibodies in
Patients with B Cell Malignancies
Verastem, Inc. (NASDAQ:VSTM), focused on discovering and
developing drugs to improve the survival and quality of life of
cancer patients, today announced that a poster highlighting the
synergistic effects of duvelisib in combination with immune
checkpoint or co-stimulatory antibodies in preclinical models of B
cell lymphoma was presented at ASCO-SITC Clinical Immuno-Oncology
Symposium being held January 25-27, 2018 in San Francisco.
Duvelisib is a first-in-class oral dual inhibitor of
phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma that is
currently being developed for the treatment of relapsed or
refractory chronic lymphocytic leukemia/small lymphocytic lymphoma
(CLL/SLL) and follicular lymphoma (FL). In addition, duvelisib is
being studied in other hematologic malignancies including
peripheral T cell lymphoma (PTCL).
“In patients with relapsed or refractory chronic lymphocytic
leukemia/small lymphocytic lymphoma and follicular lymphoma, oral
duvelisib monotherapy has demonstrated efficacy, along with a
consistent and manageable safety profile. However, emerging data
suggest that some aggressive lymphomas will likely require
combination therapy to improve clinical outcomes,” said Jonathan
Pachter, PhD, Chief Scientific Officer of Verastem. “Our research
presented this year at ASCO-SITC indicates that the dual
PI3K-delta/PI3K-gamma inhibitory activity of duvelisib enables
duvelisib to reduce both T-regulatory (Treg) and myeloid
immunosuppressive cells in a murine A20 B cell lymphoma model. As a
result of these beneficial changes within the tumor
microenvironment, we observed a striking enhancement by duvelisib
of the anti-tumor efficacy of immune checkpoint or co-stimulatory
antibodies in this preclinical B cell lymphoma model. These data
support further exploration of duvelisib in combination with
immunotherapeutic agents for the treatment of aggressive
lymphomas.”
Oral duvelisib is the first PI3K inhibitor to show efficacy as
an oral monotherapy in a randomized Phase 3 study in patients with
relapsed or refractory CLL/SLL (the DUO™ study). In the Phase 2
DYNAMO study, duvelisib achieved meaningful clinical activity in
patients diagnosed with follicular lymphoma (FL), small lymphocytic
lymphoma (SLL), or marginal zone lymphoma (MZL) whose disease is
refractory to rituximab and to a chemotherapy regimen or
radioimmunotherapy. Verastem plans to submit a New Drug Application
(NDA) to the U.S. Food and Drug Administration (FDA) during the
first quarter of 2018 requesting full approval of duvelisib for the
treatment of patients with relapsed or refractory CLL/SLL and
accelerated approval for the treatment of patients with relapsed or
refractory follicular lymphoma (FL).
Details for the poster presentation at ASCO-SITC 2018
are:
Title: Dual PI3K-δ,γ inhibitor duvelisib reduces
immunosuppressive Tregs and myeloid cells enhancing efficacy of
checkpoint and co-stimulatory antibodies in a B cell lymphoma
modelSession: Developmental Therapeutics – Poster Session
BAbstract #: 33Location: Golden Gate Hall – B2 Level
– Poster Board D1Date and time: Friday, January 26, 2018;
11:30am to 1:00pm PT and 5:30 to 6:30pm PTSummary: Prior
published research has shown that PI3K-delta inhibition reduces
immunosuppressive Tregs and PI3K-gamma inhibition reduces
immunosuppressive myeloid cells. As a result, it was hypothesized
that duvelisib may augment the efficacy of immune checkpoint or
co-stimulatory antibodies. For this study, Verastem researchers
administered duvelisib alone, anti-PD-1 alone, anti-OX40 alone,
duvelisib + anti-PD-1, duvelisib + anti-OX40, or vehicle control to
mice bearing syngeneic A20 B cell lymphoma tumors.
Duvelisib alone, anti-PD-1 alone and anti-OX40 alone each
induced tumor growth delay. When duvelisib and anti-PD-1 were
combined, strong anti-tumor synergy was observed. When duvelisib
and anti-OX40 were combined, tumor regression was observed which
correlated with strong reduction of tumor Tregs, M2 macrophages and
myeloid-derived suppressor cells. Immune memory was also assessed
by injecting mice that had become tumor free with A20 cells
following anti-OX40 alone or duvelisib + anti-OX40 with no further
treatment. The mice that had received anti-OX40 alone grew new
tumors upon A20 re-challenge, however, all mice that had received
duvelisib + anti-OX40 did not grow tumors upon re-challenge and
showed elevated memory T cells in blood and spleen. These findings
indicate that treatment with duvelisib + anti-OX40 established
immune memory. The dual inhibition of PI3K-δ and PI3K-γ appears to
make duvelisib effective in reducing both lymphoid and myeloid
immuno-suppressive populations, consistent with prior data
suggesting that PI3K-δ inhibition reduces immunosuppressive Tregs,
whereas PI3K-γ inhibition reduces immunosuppressive myeloid cells.
We believe these results showing that dual PI3K-δ and PI3K-γ
inhibition can enhance the anti-tumor efficacy of immune checkpoint
and co-stimulatory antibodies which potentially support the
clinical exploration of duvelisib in combination with these
agents.
A copy of the poster presentation will be available here
following the conclusion of the poster sessions.
About the Tumor Microenvironment
The tumor microenvironment encompasses various cellular
populations and extracellular matrices within the tumor or cancer
niche that support cancer cell survival. This includes
immunosuppressive cell populations such as regulatory T-cells,
myeloid-derived suppressor cells, M2 TAMS, as well as
tumor-associated fibroblasts and extracellular matrix proteins
which can hamper the entry and therapeutic benefit of cytotoxic
immune cells and anti-cancer drugs. In addition to targeting the
proliferative and survival signaling of cancer cells, Verastem’s
compounds duvelisib and defactinib target the tumor
microenvironment as a mechanism of action to potentially improve a
patient’s response to therapy.
About Duvelisib
Duvelisib is a first-in-class investigational, dual inhibitor of
phosphoinositide 3-kinase (PI3K)-delta and PI3K-gamma, two enzymes
known to help support the growth and survival of malignant B-cells
and T-cells. PI3K signaling may lead to the proliferation of
malignant B- and T-cells and is thought to play a role in the
formation and maintenance of the supportive tumor
microenvironment.1,2,3 Duvelisib is currently being evaluated
in late- and mid-stage extension trials, including DUO™, a
randomized, Phase 3 monotherapy study in patients with relapsed or
refractory chronic lymphocytic leukemia (CLL)/small lymphocytic
lymphoma (SLL),4 and DYNAMO™, a single-arm, Phase 2
monotherapy study in patients with refractory indolent non-Hodgkin
lymphoma (iNHL).5 Both DUO and DYNAMO achieved their primary
endpoints and Verastem intends to submit a New Drug
Application (NDA) requesting the full approval of duvelisib for the
treatment of patients with relapsed or refractory CLL/SLL, and
accelerated approval for the treatment of patients with relapsed or
refractory follicular lymphoma (FL). Duvelisib is also being
developed by Verastem for the treatment of peripheral
T-cell lymphoma (PTCL), and is being investigated in combination
with other agents through investigator-sponsored studies.6
Information about duvelisib clinical trials can be found
on www.clinicaltrials.gov.
About Verastem, Inc.
Verastem, Inc. (NASDAQ:VSTM) is a biopharmaceutical company
focused on discovering and developing drugs to improve outcomes for
patients with cancer. Verastem is currently developing duvelisib, a
dual inhibitor of PI3K-delta and PI3K-gamma, which has successfully
met its primary endpoint in a Phase 2 study in iNHL and a Phase 3
clinical trial in patients with CLL/SLL. In addition, Verastem is
developing the FAK inhibitor defactinib, which is currently being
evaluated in three separate clinical collaborations in combination
with immunotherapeutic agents for the treatment of several
different cancer types, including pancreatic cancer, ovarian
cancer, non-small cell lung cancer, and mesothelioma. Verastem’s
product candidates seek to treat cancer by modulating the local
tumor microenvironment, enhancing anti-tumor immunity, and reducing
cancer stem cells. For more information, please visit
www.verastem.com.
Verastem, Inc. forward-looking statements notice:
This press release includes forward-looking statements about
Verastem's strategy, future plans and prospects, including
statements regarding the development and activity of Verastem's
investigational product candidates, including duvelisib and
defactinib, and Verastem's PI3K and FAK programs generally, the
structure of our planned and pending clinical trials and the
timeline and indications for clinical development and regulatory
submissions. The words "anticipate," "believe," "estimate,"
"expect," "intend," "may," "plan," "predict," "project," "target,"
"potential," "will," "would," "could," "should," "continue," and
similar expressions are intended to identify forward-looking
statements, although not all forward-looking statements contain
these identifying words. Each forward-looking statement is subject
to risks and uncertainties that could cause actual results to
differ materially from those expressed or implied in such
statement. Applicable risks and uncertainties include the risks
that the preclinical testing of Verastem's product candidates and
preliminary or interim data from clinical trials may not be
predictive of the results or success of ongoing or later clinical
trials; that the full data from the DUO study will not be
consistent with the previously presented results of the study; that
data may not be available when expected, including for the Phase 3
DUO™ study; that even if data from clinical trials is positive,
regulatory authorities may require additional studies for approval
and the product may not prove to be safe and effective; that the
degree of market acceptance of product candidates, if approved, may
be lower than expected; that the timing, scope and rate of
reimbursement for our product candidates is uncertain; that there
may be competitive developments affecting our product candidates;
that data may not be available when expected; that enrollment of
clinical trials may take longer than expected; that our product
candidates will cause unexpected safety events or result in an
unmanageable safety profile as compared to their level of efficacy;
that duvelisib will be ineffective at treating patients with
lymphoid malignancies; that Verastem will be unable to successfully
initiate or complete the clinical development of its product
candidates; that the development of Verastem's product candidates
will take longer or cost more than planned; that Verastem may not
have sufficient cash to fund its contemplated operations; that
Verastem or Infinity Pharmaceuticals, Inc. (Infinity) will fail to
fully perform under the duvelisib license agreement; that Verastem
may be unable to make additional draws under its debt facility or
obtain adequate financing in the future through product licensing,
co-promotional arrangements, public or private equity, debt
financing or otherwise; that Verastem will not pursue or submit
regulatory filings for its product candidates, including for
duvelisib in patients with CLL or iNHL; and that Verastem's product
candidates will not receive regulatory approval, become
commercially successful products, or result in new treatment
options being offered to patients. Other risks and uncertainties
include those identified under the heading "Risk Factors" in
Verastem's Annual Report on Form 10-K for the year ended December
31, 2016 and in any subsequent filings with the U.S. Securities and
Exchange Commission. The forward-looking statements contained in
this press release reflect Verastem's views as of the date of this
release, and Verastem does not undertake and specifically disclaims
any obligation to update any forward-looking statements.
References
1 Winkler et al. PI3K-delta and PI3K-gamma inhibition by IPI-145
abrogates immune responses and suppresses activity in autoimmune
and inflammatory disease models. Chem Biol 2013; 20:1-11.
2 Reif et al. Cutting Edge: Differential roles for
phosphoinositide 3 kinases, p110-gamma and p110-delta, in
lymphocyte chemotaxis and homing. J Immunol 2004:173:2236-2240.
3 Schmid et al. Receptor tyrosine kinases and TLR/IL1Rs
unexpectedly activate myeloid cell PI3K, a single convergent point
promoting tumor inflammation and progression. Cancer Cell
2011;19:715-727.
4 www.clinicaltrials.gov, NCT02004522
5 www.clinicaltrials.gov, NCT01882803
6 www.clinicaltrials.gov, NCT02783625, NCT02158091
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version on businesswire.com: http://www.businesswire.com/news/home/20180126005567/en/
Verastem, Inc.Marianne Lambertson, 781-292-4273Vice
President, Corporate CommunicationsInvestor Relations/Public
Relationsmlambertson@verastem.com
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