Duvelisib’s Dual Inhibition of PI3K-Delta and
PI3K-Gamma Inhibits Migration and Proliferation of Mantle Cell
Lymphoma Cells More Effectively Than PI3K-Delta Alone in
Preclinical Models
Verastem, Inc. (Nasdaq:VSTM) (Verastem Oncology or the Company),
a biopharmaceutical company focused on developing and
commercializing medicines seeking to improve the survival and
quality of life of cancer patients, today announced a poster
highlighting new preclinical duvelisib (COPIKTRA™) data that will
be presented at the 5th International Conference on New Concepts in
Lymphoid Malignancies, which is hosted by the European School of
Haematology (ESH), and is taking place October 3-5, 2019, in
Estoril, Portugal. The poster features preclinical research that
compared duvelisib with idelalisib in preclinical models of mantle
cell lymphoma (MCL). COPIKTRA is not approved for use in MCL,
diffuse large B-cell lymphoma (DLBCL), or marginal zone lymphoma
(MZL).
“These data highlight MCL as a B-cell malignancy which expresses
both PI3K-delta and PI3K-gamma in the malignant B cells, in
addition to the role of PI3K-gamma which has already been
established in cells of the supportive tumor microenvironment,”
said Jonathan Pachter, PhD, Chief Scientific Officer of Verastem
Oncology. “Accordingly, the data show superior anti-cancer activity
of the dual PI3K-delta/gamma inhibitor duvelisib compared to the
PI3K-delta inhibitor idelalisib in these preclinical MCL models. At
Verastem Oncology, we are working to expand into additional
lymphoid malignancy indications and these data provide additional
support for the future study of duvelisib through clinical trials
in patients with MCL.”
Duvelisib in Preclinical Models of MCL
MCL is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) that
is incurable. The purpose of this research was to gain a functional
understanding of the distinctive features associated with the
malignant cells in MCL, with the goal of identifying potential new
treatment strategies. PI3K-delta is known to be equally expressed
in all B-cell malignancies and this research revealed that primary
MCL cells show elevated expression of PI3K-gamma relative to
primary cells from other B-cell malignancies, including chronic
lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse
large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and
marginal zone lymphoma (MZL). These preliminary data suggest that
high levels of PI3K-gamma in MCL cells correlate with poorer
disease outcomes.
The researchers then examined the effects of inhibition of
specific PI3K isoforms, including PI3K-alpha, PI3K-delta
(idelalisib), PI3K-gamma, and dual PI3K-delta/gamma (duvelisib), on
the migration and proliferation of malignant lymphocytes from
patients with MCL. These preclinical models showed that inhibition
of both PI3K-delta and gamma reduced the proliferation of MCL cells
whereas inhibition of PI3K-delta alone had no effect. The
functional role of PI3K-delta and gamma in MCL cells was further
differentiated from that of PI3K-delta alone. PI3K-delta and gamma
more effectively inhibited CCL21-induced migration of MCL cell
lines and primary MCL cells than did PI3K-gamma inhibition alone.
Inhibition of PI3K-delta or PI3K-alpha did not affect CCL21-induced
migration of MCL cells. These data suggest that when PI3K-gamma is
aberrantly expressed by MCL cells, these cells become reliant on
this PI3K isoform for chemokine-induced migration and tissue
residency. Thus, duvelisib may have potential in MCL therapy by
restricting entry, retention, and proliferation of the malignant
cells within the mantle zone.
Details for the ESH 2019 poster presentation are as
follows:
Title: Aberrantly Expressed PI3Kγ Contributes to Cell
Proliferation and Co-Operates with PI3δ to Mediate CCL21-Induced
Migration in Mantle-Cell Lymphoma: Therapeutic Implications for
Duvelisib Lead author: Kathy Till, University of Liverpool
Date and time: Thursday, October 3, 2019, beginning at 7am
through the end of the conference Location: Poster Area
A PDF copy of this poster presentation will be available here
after the meeting.
SELECT IMPORTANT SAFETY INFORMATION
This does not include all information needed to use COPIKTRA™
(duvelisib) safely and effectively. See full Prescribing
Information.
WARNING: FATAL AND SERIOUS TOXICITIES: INFECTIONS, DIARRHEA
OR COLITIS, CUTANEOUS REACTIONS, and PNEUMONITIS
See full Prescribing Information for
complete boxed warning
- Fatal and/or serious infections occurred in 31% of
COPIKTRA-treated patients. Monitor for signs and symptoms of
infection. Withhold COPIKTRA if infection is suspected.
- Fatal and/or serious diarrhea or colitis occurred in 18% of
COPIKTRA-treated patients. Monitor for the development of severe
diarrhea or colitis. Withhold COPIKTRA.
- Fatal and/or serious cutaneous reactions occurred in 5% of
COPIKTRA-treated patients. Withhold COPIKTRA.
- Fatal and/or serious pneumonitis occurred in 5% of
COPIKTRA-treated patients. Monitor for pulmonary symptoms and
interstitial infiltrates. Withhold COPIKTRA.
WARNINGS AND PRECAUTIONS
- Hepatotoxicity: Monitor hepatic function.
- Neutropenia: Monitor blood counts.
- Embryo-Fetal toxicity: COPIKTRA can cause fetal harm. Advise
patients of potential risk to a fetus and to use effective
contraception.
ADVERSE REACTIONS
The most common adverse reactions (≥20%) are diarrhea or
colitis, neutropenia, rash, fatigue, pyrexia, cough, nausea, upper
respiratory infection, pneumonia, musculoskeletal pain, and
anemia.
To report Adverse Reactions, contact FDA at 1-800-FDA-1088
(1-800-332-1088) or www.fda.gov/medwatch and Verastem Oncology at
1-877-7RXVSTM (1-877-779-8786).
DRUG INTERACTIONS
- CYP3A inducers: Avoid co-administration with strong CYP3A
inducers.
- CYP3A inhibitors: Monitor for COPIKTRA toxicities when
co-administered with strong or moderate CYP3A inhibitors. Reduce
COPIKTRA dose to 15 mg twice daily when co-administered with strong
CYP3A4 inhibitors.
- CYP3A substrates: Monitor for signs of toxicities when
co-administering COPIKTRA with sensitive CYP3A substrates.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed.
Please see accompanying full Prescribing Information,
including Boxed Warning.
About COPIKTRA™ (duvelisib)
COPIKTRA is an oral inhibitor of phosphoinositide 3-kinase
(PI3K), and the first approved dual inhibitor of PI3K-delta and
PI3K-gamma, two enzymes known to help support the growth and
survival of malignant B-cells. PI3K signaling may lead to the
proliferation of malignant B-cells and is thought to play a role in
the formation and maintenance of the supportive tumor
microenvironment.1,2,3 COPIKTRA is indicated for the treatment of
adult patients with relapsed or refractory chronic lymphocytic
leukemia/small lymphocytic lymphoma (CLL/SLL) after at least two
prior therapies and relapsed or refractory follicular lymphoma (FL)
after at least two prior systemic therapies. COPIKTRA is also being
developed by Verastem Oncology for the treatment of peripheral
T-cell lymphoma (PTCL), for which it has received Fast Track
status, and is being investigated in combination with other agents
through investigator-sponsored studies.4 For more information on
COPIKTRA, please visit www.COPIKTRA.com. Information about
duvelisib clinical trials can be found on
www.clinicaltrials.gov.
About Verastem Oncology
Verastem Oncology (Nasdaq: VSTM) is a commercial
biopharmaceutical company committed to the development and
commercialization of medicines to improve the lives of patients
diagnosed with cancer. We are driven by the strength, tenacity and
courage of those battling cancer – single-minded in our resolve to
deliver new therapies that not only keep cancer at bay, but improve
the lives of patients diagnosed with cancer. Because for us, it’s
personal.
Our first FDA approved product is now available for the
treatment of patients with certain types of indolent non-Hodgkin’s
lymphoma (iNHL). Our pipeline comprises product candidates that
seek to treat cancer by modulating the local tumor
microenvironment. For more information, please visit
www.verastem.com.
Forward looking statements notice
This press release includes forward-looking statements within
the meaning of the Private Securities Litigation Reform Act of 1995
that are subject to risks, uncertainties and other factors,
including whether preclinical testing of our product candidates and
preliminary or interim data from clinical trials will be predictive
of the results or success of ongoing or later clinical trials and
the uncertainties inherent in research and development of COPIKTRA.
These risks, uncertainties and other factors could cause actual
results to differ materially from those referred to in the
forward-looking statements. The reader is cautioned not to rely on
these forward-looking statements.
Other risks and uncertainties include those identified under the
heading "Risk Factors" in the Company’s Quarterly Report on Form
10-Q for the quarterly period ended June 30, 2019, as filed with
the Securities and Exchange Commission (SEC) on August 1, 2019, its
Annual Report on Form 10-K for the year ended December 31, 2018 as
filed with the SEC on March 12, 2019 and in any subsequent filings
with the SEC. The forward-looking statements contained in this
press release reflect Verastem Oncology’s views as of the date
hereof, and the Company does not assume and specifically disclaims
any obligation to update any forward-looking statements whether as
a result of new information, future events or otherwise, except as
required by law.
References
1 Winkler D.G., Faia K.L., DiNitto J.P. 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 K 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 M 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, NCT03372057.
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version on businesswire.com: https://www.businesswire.com/news/home/20191003005117/en/
Investors: John Doyle Vice President, Investor Relations &
Finance +1 781-469-1546 jdoyle@verastem.com
Media: Lisa Buffington Corporate Communications +1 781-292-4205
lbuffington@verastem.com
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