NEWTON, Mass., Nov. 12, 2020 /PRNewswire/
-- Karyopharm Therapeutics Inc. (Nasdaq: KPTI), a
commercial-stage pharmaceutical company pioneering novel cancer
therapies, today announced that the results of the Phase 3 BOSTON
(Bortezomib, Selinexor and
Dexamethasone) study evaluating XPOVIO in patients
with relapsed or refractory multiple myeloma were published online
in The Lancet. The BOSTON
study evaluated once weekly XPOVIO, the Company's first-in-class,
oral Selective Inhibitor of Nuclear Export (SINE) compound, in
combination with once weekly Velcade® (bortezomib) and
low-dose dexamethasone against standard twice weekly Velcade
in adult patients with multiple myeloma who had received one to
three prior lines of therapy.
"The results from the BOSTON
study published in The Lancet demonstrate that the
once-weekly regimen of XPOVIO and Velcade®, with low-dose
dexamethasone (SVd) reduced the risk of disease progression or
death by 30% and induced a higher rate of overall and deep
responses compared to patients receiving a standard twice-weekly
Velcade® and low-dose dexamethasone regimen (Vd). This was observed
despite approximately 40% less Velcade®, 25% less
dexamethasone and approximately 35% fewer clinic visits on the SVd
arm as compared with the standard Vd therapy arm.
Encouragingly, the efficacy of the SVd regimen was consistent and
noteworthy across several key subgroups, including patients who
were frail or 65 years and older, patients with high-risk
cytogenetics, patients with moderate renal impairment and patients
who had either prior bortezomib or lenalidomide treatment," said
Dr. Paul Richardson, MD, Clinical
Program Leader and Director of Clinical Research, Jerome Lipper
Multiple Myeloma Center at the Dana-Farber Cancer Institute and
co-senior author of the manuscript.
"Despite the enrollment of 50% of patients with high risk
cytogenetics, a particularly difficult to treat population, the SVd
regimen demonstrated a 47% improvement in progression-free survival
as compared to the Vd regimen and an overall response rate of
76.4%. Additionally, the rate and severity of peripheral
neuropathy, a key treatment-limiting side effect commonly seen with
Velcade® therapy, was significantly lower on the SVd arm compared
to the Vd arm and may lead to improved patient quality of life,"
said Sundar Jagannath, MD, Director of the Center of Excellence for
Multiple Myeloma and Professor of Medicine, Hematology and Medical
Oncology, at the Tisch Cancer Institute at the Icahn School of
Medicine at Mount Sinai, and an investigator in the BOSTON study.
"We are honored to have the Phase 3 BOSTON data selected for
publication in such a highly esteemed medical journal and to be
shared with the global oncology community," said Sharon Shacham, PhD, MBA, President and Chief
Scientific Officer of Karyopharm. "We believe the successful
outcome of this study represents an important advancement for
myeloma patients and we are sincerely grateful to all of the
patients and investigators who participated in the BOSTON study. While XPOVIO received
accelerated FDA approval last year for patients with
penta-refractory multiple myeloma, a supplemental New Drug
Application requesting approval for XPOVIO as a treatment for
patients with multiple myeloma who have received one prior line of
therapy has been accepted by the FDA and assigned a PDUFA action
date of March 19, 2021. We are
working closely with the regulatory authorities in both the U.S.
and Europe to make this potential
new treatment option, with a completely novel mechanism of action,
available to patients as quickly as possible, if approved."
Once-weekly SVd is a novel, effective and convenient triplet
therapy that utilizes approximately 40% less Velcade® and 25% less
dexamethasone and requires approximately 35% fewer clinic visits
during the first 24 weeks of treatment compared to the standard Vd
regimen. Because Velcade® is given as a subcutaneous injection
rather than as an infusion, clinic visits may be shorter with the
SVd regimen than with other non-Velcade® regimens that may be
employed to treat relapsed multiple myeloma and require intravenous
infusions.
The Phase 3 BOSTON Study Results as Published in the
Lancet
The published BOSTON study
results are based on the multi-center, Phase 3, randomized study
(NCT03110562), which evaluated 402 adult patients with relapsed or
refractory multiple myeloma who had received one to three prior
lines of therapy. The study was designed to compare the efficacy,
safety and certain health-related quality of life parameters of
once-weekly selinexor in combination with once-weekly Velcade®
(bortezomib) plus low-dose dexamethasone (SVd) versus twice-weekly
Velcade® plus low-dose dexamethasone (Vd). The primary endpoint of
the study was progression-free survival (PFS) and key secondary
endpoints included overall response rate (ORR), rate of peripheral
neuropathy, and others. Additionally, the BOSTON study allowed for patients on the Vd
control arm to crossover to the SVd arm following objective
(quantitative) progression of disease verified by an Independent
Review Committee (IRC). The BOSTON
study was conducted at over 150 clinical sites internationally.
Although the study had one of the highest proportions of
patients with high-risk cytogenetics (~50%) as compared with other
Velcade-based studies in previously treated myeloma, the median PFS
in the SVd arm was 13.93 months compared to 9.46 months in the Vd
arm, representing a 4.47 month (47%) increase in median PFS (hazard
ratio[HR]=0.70; p=0.0075). The SVd group also demonstrated a
significantly greater ORR compared to the Vd group (76.4% vs.
62.3%, p=0.0012). Patients who had received only one prior line of
therapy also demonstrated a higher ORR on the SVd arm as compared
to the Vd arm (80.8% vs. 65.7%, p=0.0082). Importantly, SVd therapy
compared to Vd therapy showed consistent PFS benefit and higher ORR
across several important subgroups.
In addition, the following results favored SVd therapy as
compared to Vd therapy:
SVd therapy demonstrated a significantly higher rate of deep
responses, defined as ≥ Very Good Partial Response compared to Vd
therapy (44.6% vs. 32.4%) as well as a longer median duration of
response (20.3 months vs. 12.9 months). Additionally, 16.9% of
patients on the SVd arm achieved a Complete Response or a Stringent
Complete Response as compared to 10.6% of patients receiving Vd
therapy. All responses were confirmed by an IRC.
Data at the time of analysis showed a trend toward an overall
survival (OS) benefit associated with SVd therapy with fewer
deaths, numerically, reported on the SVd arm (47 vs. 62). Median OS
for the SVd arm had not yet been reached as of the data cut-off
date of February 18, 2020, while the
median OS for the Vd arm was 25.0 months. The median OS for the SVd
arm will be reported once it is reached and becomes available.
Peripheral neuropathy (PN) rates were significantly lower on SVd
compared to Vd (32.3% vs. 47.1%; p=0.0010). In addition, PN rates
of grade ≥2 were also significantly lower in the SVd arm compared
to Vd (21.0% vs. 34.3%, P=0.0013).
The most common treatment-emergent 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 (50%), fatigue (42%), decreased
appetite (35%), and diarrhea (32%) and were mostly Grade 1 and 2
events. The most common Grade 3 and 4 treatment-related AEs were
thrombocytopenia (39%), anemia (16%), and fatigue (13%).
About Multiple Myeloma
According to the National Cancer Institute (NCI), multiple
myeloma is one of the most common types of blood cancer in the U.S.
with more than 32,000 new cases each year and over 140,000 patients
living with the disease. It is most frequently diagnosed among
people aged 65-74 years old. Despite recent therapeutic advances,
there is currently no cure and most patients' disease will
typically progress following treatment with currently available
therapies. According to the NCI, nearly 13,000 deaths due to
multiple myeloma are expected in the U.S. in 2020.
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 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.
Please see full Prescribing Information.
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 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
relapsed or refractory multiple myeloma or relapsed or refractory
diffuse large B-cell lymphoma; 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; 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 E.U. based on the BOSTON study in patients with 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 indications 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.
Velcade® is a registered trademark of Takeda Pharmaceutical
Company Limited.
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