NEWTON, Mass., July 28, 2021 /PRNewswire/ -- Karyopharm
Therapeutics Inc. (NASDAQ: KPTI), a commercial-stage pharmaceutical
company pioneering novel cancer therapies, today announced dosing
of the first patients in two new company-sponsored Phase 2 and 1/2
clinical studies evaluating XPOVIO® (selinexor), the Company's
first-in-class, oral Selective Inhibitor of Nuclear Export (SINE)
compound in combination with approved therapies in patients with
advanced melanoma and in patients with treatment naïve
myelofibrosis. These company-sponsored studies follow encouraging
results from preclinical research and earlier stage,
investigator-sponsored clinical studies conducted by Karyopharm's
scientific collaborators.
"Despite recent advances in treatment options for both
metastatic melanoma and myelofibrosis, far too many patients either
do not respond or have short-lived responses to currently available
treatment options, making the development of novel drug treatment
approaches incredibly important for these diseases," said
Sharon Shacham, PhD, MBA, Chief
Scientific Officer of Karyopharm. "Substantial need remains for
continued research into new druggable targets and identifying
multiple targets and pathways that have the potential to be
inhibited synergistically using combination approaches. We believe
XPOVIO's oral administration, along with its novel mechanism of
action, make it a promising treatment candidate for new, single and
synergistic combination regimens across both hematologic and solid
tumors."
Summary of Newly Initiated Clinical Studies:
A Phase 2 Study Evaluating XPOVIO in Combination with
Keytruda® (pembrolizumab) in Recurrent Advanced Melanoma
This Phase 2, multicenter, open-label study (XPORT-MEL-033;
NCT04768881) will evaluate the safety and efficacy of XPOVIO in
combination with Keytruda® and is expected to enroll
approximately 40 patients with locally advanced or metastatic
melanoma that is resistant to initial checkpoint inhibitor therapy.
Patients will receive once-weekly oral XPOVIO (80mg) and
Keytruda® (400mg intravenously once every six weeks) until
disease progression, toxicity or withdrawal from the study,
whichever occurs first. The primary endpoint of the study is
overall response rate (ORR). Secondary endpoints include safety,
progression-free survival, overall survival (OS), and complete
response rate, among several others.
Preclinical studies have shown that XPOVIO selectively kills
malignant melanoma cells and synergistically increases the
antitumor activity of check point inhibitors1,2,3. Two
early clinical studies, one
investigating XPOVIO as a single agent4 and one investigating XPOVIO plus
Keytruda5, in heavily
pretreated advanced melanoma, have
shown that this activity is borne out in clinical studies.
A Phase 1/2 Study Evaluating XPOVIO in Combination with
Jakafi® (ruxolitinib) in Treatment Naïve Myelofibrosis
This global Phase 1/2, multicenter, open-label study
(XPORT-MF-034; NCT04562389) will evaluate the safety and efficacy
of XPOVIO in combination with Jakafi® and is expected to
enroll approximately 237 patients with treatment naïve
myelofibrosis. The study will be conducted in two phases: Phase
1a/1b and Phase 2. The Phase 1a dose
escalation portion of the study will determine the maximum
tolerated dose and the recommended Phase 2 dose (RP2D) and will
evaluate safety and preliminary efficacy. The Phase 1b dose expansion portion of the study will be
conducted at the determined RP2D and will further assess the safety
and preliminary efficacy at this dose level. In the Phase 2 portion
of the study, patients will be randomized 1:1 to receive either
once weekly XPOVIO plus Jakafi® (15mg or 20mg twice daily)
or Jakafi® (15mg or 20mg twice daily) monotherapy. The
primary endpoint for the Phase 2 portion of the study is the
percentage of patients who achieve spleen volume reduction of at
least 35% from baseline. Secondary endpoints for the Phase 2
portion of the study include safety, percentage of patients who
achieve total symptom score reduction of ≥50%, OS, anemia response
and ORR, among several others.
This new Phase 1/2 study is supported by multiple preclinical
data sets which showed that (i) nuclear cytoplasmic transport is
essential for survival of JAK2V617F-mutant HEL cells
in vitro, a major vulnerability and a potential therapeutic
target in MF6, (ii) that XPOVIO significantly reduced
white blood cells (WBCs), granulocytes and spleen GFP+ cells in
in vivo models of JAK2V617F-driven
myeloproliferative neoplasms, and (iii) the combination of XPOVIO
and ruxolitinib in vivo showed significant reduction in
WBCs, granulocytes, spleen GFP+ cells, as well as in spleen weight
when compared to either agent alone7.
Collectively, these data support the clinical investigation of
XPOVIO combined with ruxolitinib in patients with
myelofibrosis.
About XPOVIO® (selinexor)
XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear
Export (SINE) compound. XPOVIO functions by selectively binding to
and inhibiting the nuclear export protein exportin 1 (XPO1, also
called CRM1). XPOVIO blocks the nuclear export of tumor suppressor,
growth regulatory and anti-inflammatory proteins, leading to
accumulation of these proteins in the nucleus and enhancing their
anti-cancer activity in the cell. The forced nuclear retention of
these proteins can counteract a multitude of the oncogenic pathways
that, unchecked, allow cancer cells with severe DNA damage to
continue to grow and divide in an unrestrained fashion. Karyopharm
received accelerated U.S. Food and Drug Administration (FDA)
approval of XPOVIO in July 2019 in
combination with dexamethasone for the treatment of adult patients
with relapsed refractory multiple myeloma (RRMM) who have received
at least four prior therapies and whose disease is refractory to at
least two proteasome inhibitors, at least two immunomodulatory
agents, and an anti-CD38 monoclonal antibody. NEXPOVIO® (selinexor)
has also been granted conditional marketing authorization for adult
patients with heavily pretreated multiple myeloma by the European
Commission. Karyopharm's supplemental New Drug Application (sNDA)
requesting an expansion of its indication to include the treatment
for patients with multiple myeloma after at least one prior therapy
was approved by the FDA on December 18,
2020. In June 2020, Karyopharm
received accelerated FDA approval of XPOVIO for its second
indication in adult patients with relapsed or refractory diffuse
large B-cell lymphoma (DLBCL), not otherwise specified, including
DLBCL arising from follicular lymphoma, after at least two lines of
systemic therapy. Selinexor is also being evaluated in several
other mid-and later-phase clinical trials across multiple cancer
indications, including as a potential backbone therapy in
combination with approved myeloma therapies (STOMP) and in
endometrial cancer (SIENDO), among others. Additional Phase 1,
Phase 2 and Phase 3 studies are ongoing or currently planned,
including multiple studies in combination with approved therapies
in a variety of tumor types to further inform Karyopharm's clinical
development priorities for selinexor. Additional clinical trial
information for selinexor is available at
www.clinicaltrials.gov.
For more information about Karyopharm's products or clinical
trials, please contact the Medical Information department at:
Tel: +1 (888) 209-9326
Email: medicalinformation@karyopharm.com
XPOVIO® (selinexor) is a prescription medicine
approved:
- In combination with bortezomib and dexamethasone for the
treatment of adult patients with multiple myeloma who have
received at least one prior therapy (XVd).
- In combination with dexamethasone for the treatment of adult
patients with relapsed or refractory multiple myeloma who have
received at least four prior therapies and whose disease is
refractory to at least two proteasome inhibitors, at least two
immunomodulatory agents, and an anti‐CD38 monoclonal antibody
(Xd).
- For the treatment of adult patients with relapsed or refractory
diffuse large B‐cell lymphoma (DLBCL), not otherwise specified,
including DLBCL arising from follicular lymphoma, after at least 2
lines of systemic therapy. This indication is approved under
accelerated approval based on response rate. Continued approval for
this indication may be contingent upon verification and description
of clinical benefit in confirmatory trial(s).
SELECT IMPORTANT SAFETY INFORMATION
Warnings and
Precautions
- Thrombocytopenia: Monitor platelet counts throughout treatment.
Manage with dose interruption and/or reduction and supportive
care.
- Neutropenia: Monitor neutrophil counts throughout treatment.
Manage with dose interruption and/or reduction and granulocyte
colony‐stimulating factors.
- Gastrointestinal Toxicity: Nausea, vomiting, diarrhea,
anorexia, and weight loss may occur. Provide antiemetic
prophylaxis. Manage with dose
interruption and/or reduction, antiemetics, and supportive care.
- Hyponatremia: Monitor serum sodium levels throughout treatment.
Correct
for concurrent hyperglycemia and high serum
paraprotein levels. Manage with dose interruption, reduction,
or discontinuation, and supportive care.
- Serious Infection: Monitor for infection and treat
promptly.
- Neurological Toxicity: Advise patients to refrain from driving
and engaging in hazardous occupations or activities until
neurological toxicity resolves. Optimize hydration status and
concomitant medications to avoid dizziness or mental status
changes.
- Embryo‐Fetal Toxicity: Can cause fetal harm. Advise females of
reproductive potential and males with a female partner of
reproductive potential, of the potential risk to a fetus and use of
effective contraception.
- Cataract: Cataracts may develop or progress. Treatment of
cataracts usually requires surgical removal of the cataract.
Adverse Reactions
- The most common adverse reactions (≥20%) in patients with
multiple myeloma who receive XVd are fatigue, nausea, decreased
appetite, diarrhea, peripheral neuropathy, upper respiratory tract
infection, decreased weight, cataract and vomiting. Grade 3‐4
laboratory abnormalities (≥10%) are thrombocytopenia, lymphopenia,
hypophosphatemia, anemia, hyponatremia and neutropenia. In the
BOSTON trial, fatal adverse
reactions occurred in 6% of patients within 30 days of last
treatment. Serious adverse reactions occurred in 52% of patients.
Treatment discontinuation rate due to adverse reactions was
19%.
- The most common adverse reactions (≥20%) in patients with
multiple myeloma who receive Xd are thrombocytopenia, fatigue,
nausea, anemia, decreased appetite, decreased weight, diarrhea,
vomiting, hyponatremia, neutropenia, leukopenia, constipation,
dyspnea and upper respiratory tract infection. In the STORM trial,
fatal adverse reactions occurred in 9% of patients. Serious adverse
reactions occurred in 58% of patients. Treatment discontinuation
rate due to adverse reactions was 27%.
- The most common adverse reactions (incidence ≥20%) in patients
with DLBCL, excluding
laboratory abnormalities, are fatigue, nausea,
diarrhea, appetite decrease, weight decrease, constipation,
vomiting, and pyrexia. Grade 3‐4 laboratory abnormalities (≥15%)
are thrombocytopenia, lymphopenia, neutropenia, anemia, and
hyponatremia. In the SADAL trial, fatal adverse reactions occurred
in 3.7% of patients within 30 days, and 5% of patients within 60
days of last treatment; the most frequent fatal adverse reactions
was infection (4.5% of patients). Serious adverse reactions
occurred in 46% of patients; the most frequent serious adverse
reaction was infection(21% of patients). Discontinuation due to
adverse reactions occurred in 17% of patients.
Use In Specific Populations
Lactation: Advise not to
breastfeed.
For additional product information, including full prescribing
information,
please visit www.XPOVIO.com.
To report SUSPECTED ADVERSE REACTIONS, contact Karyopharm
Therapeutics Inc. at 1‐888‐209‐9326 or FDA at 1‐800‐FDA‐1088 or
www.fda.gov/medwatch.
About Karyopharm Therapeutics
Karyopharm Therapeutics Inc. (NASDAQ: KPTI) is a
commercial-stage pharmaceutical company pioneering novel cancer
therapies and dedicated to the discovery, development, and
commercialization of first-in-class drugs directed against nuclear
export for the treatment of cancer and other diseases. Karyopharm's
Selective Inhibitor of Nuclear Export (SINE) compounds function by
binding with and inhibiting the nuclear export protein XPO1 (or
CRM1). Karyopharm's lead compound, XPOVIO® (selinexor), is approved
in the U.S. in multiple hematologic malignancy indications,
including in combination with Velcade® (bortezomib) and
dexamethasone for the treatment of adult patients with multiple
myeloma after at least one prior therapy, in combination with
dexamethasone for the treatment of adult patients with heavily
pretreated multiple myeloma and as a monotherapy for the treatment
of adult patients with relapsed or refractory diffuse large B-cell
lymphoma. NEXPOVIO® (selinexor) has also been granted conditional
marketing authorization in combination with dexamethasone for adult
patients with heavily pretreated multiple myeloma by the European
Commission. In addition to single-agent and combination activity
against a variety of human cancers, SINE compounds have also shown
biological activity in models of neurodegeneration, inflammation,
autoimmune disease, certain viruses and wound-healing. Karyopharm
has several investigational programs in clinical or preclinical
development. For more information, please visit
www.karyopharm.com.
Forward-Looking Statements
This press release contains forward-looking statements within
the meaning of The Private Securities Litigation Reform Act of
1995. Such forward-looking statements include those regarding
Karyopharm's expectations and plans relating to XPOVIO for the
treatment of hematologic malignancies or certain solid tumors; the
expected design of the Company's clinical trials; and the
therapeutic potential of and potential clinical development plans
for Karyopharm's drug candidates, especially selinexor. Such
statements are subject to numerous important factors, risks and
uncertainties, many of which are beyond Karyopharm's control, that
may cause actual events or results to differ materially from
Karyopharm's current expectations. For example, there can be no
guarantee that any of Karyopharm's drug candidates, including
selinexor, will successfully complete necessary clinical
development phases or that development of any of Karyopharm's drug
candidates will continue. Further, there can be no guarantee that
any positive developments in the development or commercialization
of Karyopharm's drug candidate portfolio will result in stock price
appreciation. Management's expectations and, therefore, any
forward-looking statements in this press release could also be
affected by risks and uncertainties relating to a number of other
factors, including the following: the risk that the COVID-19
pandemic could disrupt Karyopharm's business more severely than it
currently anticipates, including by negatively impacting sales of
XPOVIO, interrupting or delaying research and development efforts,
impacting the ability to procure sufficient supply for the
development and commercialization of selinexor or other product
candidates, delaying ongoing or planned clinical trials, impeding
the execution of business plans, planned regulatory milestones and
timelines, or inconveniencing patients; the adoption of XPOVIO in
the commercial marketplace, the timing and costs involved in
commercializing XPOVIO or any of Karyopharm's drug candidates that
receive regulatory approval; the ability to retain regulatory
approval of XPOVIO or any of Karyopharm's drug candidates that
receive regulatory approval; Karyopharm's results of clinical
trials and preclinical studies, including subsequent analysis of
existing data and new data received from ongoing and future
studies; the content and timing of decisions made by the U.S. Food
and Drug Administration and other regulatory authorities,
investigational review boards at clinical trial sites and
publication review bodies, including with respect to the need for
additional clinical studies; the ability of Karyopharm or its third
party collaborators or successors in interest to fully perform
their respective obligations under the applicable agreement and the
potential future financial implications of such agreement;
Karyopharm's ability to obtain and maintain requisite regulatory
approvals and to enroll patients in its clinical trials; unplanned
cash requirements and expenditures; development or regulatory
approval of drug candidates by Karyopharm's competitors for
products or product candidates in which Karyopharm is currently
commercializing or developing; and Karyopharm's ability to obtain,
maintain and enforce patent and other intellectual property
protection for any of its products or product candidates. These and
other risks are described under the caption "Risk Factors" in
Karyopharm's Quarterly Report on Form 10-Q for the quarter ended
March 31, 2021, which was filed with
the Securities and Exchange Commission (SEC) on May 4, 2021, and in other filings that Karyopharm
may make with the SEC in the future. Any forward-looking statements
contained in this press release speak only as of the date hereof,
and, except as required by law, Karyopharm expressly disclaims any
obligation to update any forward-looking statements, whether as a
result of new information, future events or otherwise.
XPOVIO®(selinexor) is a registered trademark of Karyopharm
Therapeutics Inc. Any other trademarks referred to in this press
release are the property of their respective owners.
References
1 Fragomeni RA,
et al. Cancer Ther. 2013 Jul 1;12(7):1171-9.
2 Breit MN, et al. Mol Cancer Ther. 2017
Mar 1;16(3):417-27.
4 Abdul Razak AR, et al. J Clin Oncol. 2016
Dec 1;34(34):4142.
5 Data on file at Karyopharm.
6 Deininger, MW, et al. Clin Cancer Res April 1 2019 (25) (7)
2323-2335.
7 Tan, D, et al. Clin
Cancer Res . 2019 Apr
1;25(7):2323-2335.
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SOURCE Karyopharm Therapeutics Inc.