NEWTON, Mass., Nov. 20, 2020 /PRNewswire/ -- Karyopharm
Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical
company pioneering novel cancer therapies, today reported it will
present positive 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 liposarcoma at the Connective Tissue
Oncology Society 2020 Annual Meeting (CTOS 2020). As previously
reported, the SEAL study met its primary endpoint of a
statistically significant increase in median progression-free
survival (PFS) in patients with advanced unresectable
dedifferentiated liposarcoma following at least two prior
therapies.
"Dedifferentiated liposarcoma is a particularly aggressive
cancer that arises in the body's fat tissue and is typically
associated with high rates of metastatic recurrence and mortality.
Unfortunately, there are few effective treatment options available
for patients with advanced disease," said Mrinal M. Gounder, MD, Attending Physician,
Sarcoma Service and Developmental Therapeutics Service, Memorial
Sloan Kettering Cancer Center, and lead investigator of the SEAL
study. "The data presented at CTOS 2020 demonstrated that patients
treated with XPOVIO experienced a statistically significant
improvement in median PFS compared to placebo in patients with at
least two prior therapies. Extending PFS is an important clinical
goal for these patients because the rapid progression of this
disease often translates into early mortality."
"We are delighted to share these significant 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. "We believe these data strongly
support our goal of developing twice-weekly XPOVIO as an effective,
convenient, novel oral therapy that can extend PFS for patients
with advanced unresectable dedifferentiated liposarcoma. We are
especially excited by these data because XPOVIO is the first oral
therapy to show activity in patients with previously treated
liposarcoma. We look forward to submitting a New Drug
Application to the U.S. Food and Drug Administration (FDA) during
the first quarter of 2021, requesting 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."
Results from the Phase 3 Portion of the Phase2/3 SEAL
Study
The median PFS in the XPOVIO arm of the Phase 3 portion of the
SEAL study was 2.83 months compared to 2.07 months in the placebo
arm (hazard ratio (HR)=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 estimated
6-month PFS survival probability was 23.9% on the selinexor arm
compared to 13.9% on placebo. Additionally, the 12-month PFS
survival probability was 8.4% on the selinexor arm compared to 2%
on the placebo arm. Finally, 7.5% of patients on the
selinexor arm had a 15% or greater reduction in their disease
burden as measured by target lesion size while none of the patients
on the placebo arm achieved this level of reduction. The trial
allowed patients on placebo with objective progression to cross
over to the XPOVIO treatment arm. The median overall survival for
patients who received XPOVIO was 9.99 months compared to 9.07
months for patients who never crossed over to the XPOVIO treatment
arm (HR=0.69; p=0.122).
The most common treatment-related adverse events (AEs) were
cytopenias, along with gastrointestinal and constitutional symptoms
and were consistent with those previously reported from other
selinexor studies. Most AEs were manageable with dose modifications
and/or standard supportive care. The most common non-hematologic
treatment-related AEs were nausea (81%), decreased appetite (60%),
fatigue (51%), and vomiting (49%) and were mostly Grade 1 and 2
events. The most common Grade 3 and 4 treatment-related AEs were
anemia (19%), hyponatremia (11%), thrombocytopenia (10%) and
asthenia (10%).
XPOVIO is currently approved by the FDA as a treatment for
patients with relapsed or refractory multiple myeloma and relapsed
or refractory diffuse large B-cell lymphoma (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. The full Prescribing Information for XPOVIO is available
at www.XPOVIO.com.
Details for the oral presentation at CTOS 2020 are as
follows:
Title: A Phase 2/3, Randomized, Double-Blind,
Cross-Over Study of Selinexor Versus Placebo in Advanced
Unresectable Dedifferentiated Liposarcoma (DDLS)
Presenter: Mrinal Gounder, MD, Memorial Sloan Kettering
Cancer Center
Paper #: 20
Session: 7. Liposarcoma
Date and Time: Friday, November 20, 2020, 10:30 a.m. to 11:30 a.m. ET
Conference Call Information
Karyopharm will host a conference call today, Friday, November 20, 2020, at 12:00 p.m. Eastern Time, to discuss the results
from the SEAL study. The call will feature Dr. Gounder and another
recognized sarcoma expert Sant P.
Chawla, MD, FRACP, Director of the Sarcoma Oncology Center,
Santa Monica, CA, along with
members of the Karyopharm executive leadership team. 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, along with slides, 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 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.
About Liposarcoma
Liposarcoma is a rare type of cancer that occurs in the fat
cells in the body, most often in the muscles of the limbs or
abdomen. Dedifferentiated liposarcoma (DDLS) is a high grade type
of liposarcoma that grows more aggressively than a low grade, well
differentiated liposarcoma and is associated with poorer
prognosis.1 Liposarcoma accounts for approximately 20%
of all soft tissue sarcomas2. In liposarcoma, the risk
of recurrence and metastasis increases with higher grade
disease.3
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 or 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
September 30, 2020, which was filed with the Securities and
Exchange Commission (SEC) on November 2, 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.
References
1Livingston, J.A.,
et al. Role of chemotherapy in dedifferentiated liposarcoma of the
retroperitoneum: defining the benefit and challenges of the
standard. Sci Rep 7, 11836 (2017).
https://doi.org/10.1038/s41598-017-12132-w
2 https://pubmed.ncbi.nlm.nih.gov/25115417/
3 http://sarcomahelp.org/liposarcoma.html
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