NEWTON, Mass., Nov. 2, 2020 /PRNewswire/ -- Karyopharm
Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical
company pioneering novel cancer therapies, today announced positive
top-line results from the Phase 3 portion of the randomized, double
blind, placebo controlled, cross-over, SEAL study evaluating single
agent, oral XPOVIO® (selinexor) versus matching placebo in patients
with advanced unresectable dedifferentiated liposarcoma. The SEAL
study met its primary endpoint of a statistically significant
increase in progression-free survival (PFS); hazard ratio=0.70;
p=0.023. These data indicate that treatment with XPOVIO reduced the
risk of disease progression or death by approximately 30%, compared
to placebo. The trial allowed patients on placebo with objective
progression to cross over to the XPOVIO treatment arm. Among those
patients who received XPOVIO, there was a trend towards an
improvement in the median overall survival compared to those
patients who began on the placebo arm of the study and never
crossed over to the XPOVIO treatment arm. The safety profile for
XPOVIO was consistent with previous clinical studies with fewer
hematologic and infectious adverse events as compared to XPOVIO
studies in patients with multiple myeloma and diffuse large B-cell
lymphoma (DLBCL).
The detailed results from the SEAL study will be presented
virtually in an oral presentation at the Connective Tissue Oncology
Society (CTOS) Annual Meeting on Friday,
November 20, 2020 at 10:30 AM
ET.
"We are delighted to share these significant top-line results
from the Phase 3 portion of the SEAL study, the first, late-stage
clinical data for XPOVIO in a solid tumor indication," said
Sharon Shacham, PhD, MBA, President
and Chief Scientific Officer of Karyopharm. "The top-line results
from the SEAL study are particularly encouraging as advanced
dedifferentiated liposarcoma represents a very difficult to treat
cancer with no established standard of care and limited treatment
options available to patients. XPOVIO may be particularly promising
as it represents the first oral therapy to show activity in
patients with previously treated liposarcoma. We look forward to
presenting the detailed results at the upcoming CTOS Annual Meeting
and plan to submit a New Drug Application (NDA) to the U.S. Food
and Drug Administration (FDA) in the first quarter of 2021
requesting the approval of XPOVIO to treat the patient population
studied in SEAL. If approved, XPOVIO would represent the first
oral, non-chemotherapy agent available for patients with
dedifferentiated liposarcoma. The encouraging data from the SEAL
study also provide additional rationale for advancing the clinical
development of XPOVIO in other solid tumor indications, including
in endometrial, glioblastoma, lung and other cancers where
Karyopharm is currently conducting clinical studies."
XPOVIO is currently approved by the FDA as a treatment for
patients with relapsed or refractory multiple myeloma and relapsed
or refractory DLBCL. XPOVIO is currently the only XPO1 inhibitor
approved by the FDA and has been extensively tested in clinical
trials across numerous cancer indications worldwide since
2012. Karyopharm has also submitted a supplemental New Drug
Application (sNDA) for XPOVIO that is currently under review by the
FDA for the expansion of XPOVIO's label to include XPOVIO as a
treatment for patients with multiple myeloma after at least one
prior line of therapy. The sNDA has been assigned an action date by
the FDA of March 19, 2021 under the
Prescription Drug User Fee Act (PDUFA).The full Prescribing
Information for XPOVIO is available at www.XPOVIO.com.
About the SEAL Study
SEAL (Selinexor in Advanced
Liposarcoma) is a Phase 2/3, randomized, double blind,
placebo controlled, multicenter study (NCT02606461) designed to
evaluate the efficacy and safety of twice-weekly, 60mg fixed dose
of XPOVIO (selinexor) in patients with advanced unresectable
dedifferentiated liposarcoma following at least two prior
therapies. The Phase 2 portion of the study enrolled approximately
57 patients (1:1 randomization) and the Phase 3 portion enrolled
approximately 285 patients (2:1 randomization). Patients on the
placebo arm with confirmed progressive disease were permitted to
cross over to the XPOVIO treatment arm. The primary endpoint of the
study is PFS.
Conference Call Information
Karyopharm will host a conference call on November 20, 2020, at 12:00 p.m. Eastern Time, to discuss the results
from the SEAL study. To access the conference call, please dial
(877) 870-4263 (local) or (412) 317-0790 (international) at least
10 minutes prior to the start time and ask to be joined into the
Karyopharm Therapeutics call. A live audio webcast of the call will
be available under "Events & Presentations" in the Investor
section of the Company's website,
http://investors.karyopharm.com/events-presentations. An archived
webcast will be available on the Company's website approximately
two hours after the event.
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. Karyopharm has also
submitted a Marketing Authorization Application (MAA) to the
European Medicines Agency (EMA) with a request for conditional
approval of selinexor in this same RRMM indication. Karyopharm's
supplemental New Drug Application (sNDA) requesting an expansion of
its current indication to include the treatment for patients with
multiple myeloma after at least one prior line of therapy has been
accepted for filing by the FDA. 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 2 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), in liposarcoma (SEAL) 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
IMPORTANT SAFETY INFORMATION
Thrombocytopenia: XPOVIO can cause life-threatening
thrombocytopenia, potentially leading to hemorrhage.
Thrombocytopenia was reported in patients with multiple myeloma
(MM) and developed or worsened in patients with DLBCL.
Thrombocytopenia is the leading cause of dosage modifications.
Monitor platelet counts at baseline and throughout treatment.
Monitor more frequently during the first 3 months of treatment.
Institute platelet transfusion and/or other treatments as
clinically indicated. Monitor patients for signs and symptoms of
bleeding and evaluate promptly. Interrupt, reduce dose, or
permanently discontinue based on severity of adverse reaction.
Neutropenia: XPOVIO can cause life-threatening
neutropenia, potentially increasing the risk of infection.
Neutropenia and febrile neutropenia occurred in patients with MM
and in patients with DLBCL.
Obtain white blood cell counts with differential at baseline and
throughout treatment. Monitor more frequently during the first 3
months of treatment. Monitor patients for signs and symptoms of
concomitant infection and evaluate promptly. Consider supportive
measures, including antimicrobials and growth factors (e.g.,
G-CSF). Interrupt, reduce dose, or permanently discontinue based on
severity of adverse reaction (AR).
Gastrointestinal Toxicity: XPOVIO can cause severe
gastrointestinal toxicities in patients with MM and DLBCL.
Nausea/Vomiting: Provide prophylactic antiemetics.
Administer 5-HT3 receptor antagonists and other anti-nausea agents
prior to and during treatment with XPOVIO. Interrupt, reduce dose,
or permanently discontinue based on severity of ARs. Administer
intravenous fluids to prevent dehydration and replace electrolytes
as clinically indicated.
Diarrhea: Interrupt, reduce dose, or permanently
discontinue based on severity of ARs. Provide standard
anti-diarrheal agents, administer intravenous fluids to prevent
dehydration, and replace electrolytes as clinically indicated.
Anorexia/Weight Loss: Monitor weight, nutritional
status, and volume status at baseline and throughout treatment.
Monitor more frequently during the first 3 months of treatment.
Interrupt, reduce dose, or permanently discontinue based on
severity of ARs. Provide nutritional support, fluids, and
electrolyte repletion as clinically indicated.
Hyponatremia: XPOVIO can cause severe or
life-threatening hyponatremia. Hyponatremia developed in patients
with MM and in patients with DLBCL.
Monitor sodium level at baseline and throughout treatment.
Monitor more frequently during the first 2 months of treatment.
Correct sodium levels for concurrent hyperglycemia (serum glucose
>150 mg/dL) and high serum paraprotein levels. Assess hydration
status and manage hyponatremia per clinical guidelines, including
intravenous saline and/or salt tablets as appropriate and dietary
review. Interrupt, reduce dose, or permanently discontinue based on
severity of the AR.
Serious Infection: XPOVIO can cause
serious and fatal infections. Most infections were not associated
with Grade 3 or higher neutropenia. Atypical infections reported
after taking XPOVIO include, but are not limited to, fungal
pneumonia and herpesvirus infection.
Monitor for signs and symptoms of infection, and evaluate and
treat promptly.
Neurological Toxicity: XPOVIO can cause
life-threatening neurological toxicities.
Coadministration of XPOVIO with other products that cause
dizziness or mental status changes may increase the risk of
neurological toxicity.
Advise patients to refrain from driving and engaging in
hazardous occupations or activities, such as operating heavy or
potentially dangerous machinery, until the neurological toxicity
fully resolves. Optimize hydration status, hemoglobin level, and
concomitant medications to avoid exacerbating dizziness or mental
status changes. Institute fall precautions as appropriate.
Embryo-Fetal Toxicity: XPOVIO can cause fetal harm
when administered to a pregnant woman.
Advise pregnant women of the potential risk to a fetus. Advise
females of reproductive potential and males with a female partner
of reproductive potential to use effective contraception during
treatment with XPOVIO and for 1 week after the last dose.
ADVERSE REACTIONS
The most common adverse reactions
(ARs) in ≥20% of patients with MM are thrombocytopenia, fatigue,
nausea, anemia, decreased appetite, decreased weight, diarrhea,
vomiting, hyponatremia, neutropenia, leukopenia, constipation,
dyspnea, and upper respiratory tract infection.
The most common ARs, excluding laboratory abnormalities, in ≥20%
of patients with DLBCL are fatigue, nausea, diarrhea, appetite
decrease, weight decrease, constipation, vomiting, and pyrexia.
Grade 3-4 laboratory abnormalities in ≥15% of patients included
thrombocytopenia, lymphopenia, neutropenia, anemia, and
hyponatremia. Grade 4 laboratory abnormalities in ≥5% were
thrombocytopenia, lymphopenia, and neutropenia.
In patients with MM, fatal ARs occurred in 9% of patients.
Serious ARs occurred in 58% of patients. Treatment discontinuation
rate due to ARs was 27%. The most frequent ARs requiring permanent
discontinuation in ≥4% of patients included fatigue, nausea, and
thrombocytopenia.
In patients with DLBCL, fatal ARs occurred in 3.7% of patients
within 30 days, and 5% of patients within 60 days of last
treatment; the most frequent fatal AR was infection (4.5% of
patients). Serious ARs occurred in 46% of patients; the most
frequent serious AR was infection. Discontinuation due to ARs
occurred in 17% of patients.
USE IN SPECIFIC POPULATIONS
In MM, no overall
difference in effectiveness of XPOVIO was observed in patients
>65 years old when compared with younger patients. Patients ≥75
years old had a higher incidence of discontinuation due to an AR
than younger patients, a higher incidence of serious ARs, and a
higher incidence of fatal ARs.
Clinical studies in patients with relapsed or refractory DLBCL
did not include sufficient numbers of patients aged 65 and over to
determine whether they respond differently from younger
patients.
The effect of end-stage renal disease
(CLCR <15 mL/min) or hemodialysis on XPOVIO
pharmacokinetics is unknown.
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.
Please see XPOVIO Full Prescribing Information available
at www.XPOVIO.com.
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 novel first-in-class drugs directed against
nuclear export and related targets for the treatment of cancer and
other major 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), received accelerated approval from the U.S.
Food and Drug Administration (FDA) in July
2019 in combination with dexamethasone as a treatment for
patients with heavily pretreated multiple myeloma. In June 2020, XPOVIO was approved by the FDA as a
treatment for patients with relapsed or refractory diffuse large
B-cell lymphoma. A Marketing Authorization Application for
selinexor for patients with heavily pretreated multiple myeloma is
also currently under review by the European Medicines Agency. 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 patients with advanced unresectable dedifferentiated
liposarcoma; commercialization of XPOVIO or any of its drug
candidates and the commercial performance of XPOVIO; submissions
to, and the review and potential approval of selinexor by,
regulatory authorities, including the Company's regulatory
strategy, the anticipated availability of data to support such
submissions, timing of such submissions and actions by regulatory
authorities and the potential availability of accelerated approval
pathways; 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 Karyopharm will successfully commercialize XPOVIO;
that regulators will agree that selinexor qualifies for conditional
approval in the E.U. as a result of data from the STORM study or
confirmatory approval in the U.S. or EU based on the BOSTON study in patients with relapsed or
refractory multiple myeloma; or 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 of drug candidates
by Karyopharm's competitors for diseases in which Karyopharm is
currently developing its drug candidates; and Karyopharm's ability
to obtain, maintain and enforce patent and other intellectual
property protection for any drug candidates it is developing. These
and other risks are described under the caption "Risk Factors" in
Karyopharm's Quarterly Report on Form 10-Q for the quarter ended
June 30, 2020, which was filed with
the Securities and Exchange Commission (SEC) on August 4, 2020, 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.
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