NEWTON, Mass., Oct. 6, 2020 /PRNewswire/ -- Karyopharm
Therapeutics Inc. (Nasdaq: KPTI), a commercial-stage pharmaceutical
company pioneering novel cancer therapies, today announced an oral
presentation at the International Society for Influenza and Other
Respiratory Virus Diseases Antiviral Group (ISIRV-AVG) Virtual
Conference on Therapeutics for COVID-19 taking place from
October 6 - 8, 2020. The presentation
will feature data from a Phase 2 clinical study evaluating low dose
oral selinexor in hospitalized patients with severe COVID-19
(NCT04349098).
While an interim analysis indicated that the trial was unlikely
to meet its pre-specified primary endpoint across the entire
patient population studied, and has since been discontinued, the
results demonstrated encouraging anti-viral and anti-inflammatory
activity in an important subset of treated patients. The
randomized, multi-center, placebo-controlled Phase 2 study was
designed to assess the activity and safety of 20mg of selinexor
given orally three times a week for two weeks, a dosing level
significantly lower than the U.S. Food and Drug Administration
(FDA) approved dose of selinexor, marketed as XPOVIO®, to treat
patients with relapsed or refractory multiple myeloma or relapsed
or refractory diffuse large B-cell lymphoma.
A post-hoc analysis of 66 patients with either baseline serum
lactate dehydrogenase (LDH) ≤370 U/L or D-dimer ≤600 mcg/L FEU (Low
LDH/DD) showed that treatment with selinexor (n=38) compared to
placebo (n=28) was associated with a significantly higher
percentage of patients discharged by Day 14 (78.9% vs 57.1%;
p=0.029) with a trend towards superior ≥2-point improvement in the
Ordinal Scale (OSI-2) on Day 14 (78.9% vs 64.3%; p=0.095).
Additionally, a positive trend was observed in patients treated
with selinexor to convert to a negative COVID-19 PCR test as
compared to placebo (42.1% vs 28.6%; p=0.13) and a significant
reduction in IL1-RA, IL-6, IL-7, IP-10, and TNF-a levels,
measurements of inflammation, was also seen within eight days of
selinexor treatment (p<0.05). Adverse events occurred in 63.2%
of patients treated with selinexor and 51.9% of patients with
placebo in the subset, with similar occurrences of deaths across
the treatment arms (2 vs. 1). Blood levels of LDH and D-dimer are
important prognostic markers for in-hospital mortality in patients
admitted for COVID-19.
"We are encouraged by the promising results observed following
low dose oral administration of selinexor in hospitalized patients
with severe COVID-19 and Low LDH/DD and believe they warrant the
need for additional clinical studies. Additionally, we believe
non-hospitalized patients with moderate COVID-19 may also benefit
from this treatment regimen and should be considered for future
evaluation," said Sharon Shacham,
PhD, MBA, Founder, President and Chief Scientific Officer of
Karyopharm. "We plan to continue ongoing discussions with potential
clinical development partners, including U.S. and international
government and academic organizations advancing COVID-19 clinical
studies, to further evaluate selinexor in patients with
COVID-19."
In addition to data from the Phase 2 selinexor study being
presented at the ISIRV-AVG Conference, a case report from one of
the clinical investigators in this trial has been published in the
Annals of Case Reports and can be found online, here. In
this case report, Marcelo Gareca,
MD, an Infectious Disease specialist at Lehigh Valley Hospital,
Allentown, PA, provides details of a patient with severe
COVID-19 and progressive hypoxia who demonstrated marked clinical
improvements following selinexor treatment without any reported
adverse effects.
XPO1 inhibitors, including selinexor, have demonstrated activity
against over 20 different viruses, including the RNA viruses,
influenza, respiratory syncytial virus (RSV) and other common
causes of respiratory infection. XPO1 inhibition has been
identified in several assays as having potential activity
specifically against SARS-CoV-2. One of the most important aspects
of COVID-19 is the marked pulmonary inflammation with high levels
of cytokines such as IL6, IL1, IFNg and others. Selinexor and
other Selective Inhibitor of Nuclear Export (SINE) compounds have
demonstrated potent anti-inflammatory activity through the
inhibition of Nuclear Factor kB (NF-kB), leading to reductions in
all of these cytokines in a variety of models, which may be
particularly beneficial to hospitalized patients with COVID-19.
Details for the ISIRV-AVG oral presentation are as
follows:
Title: Treatment of Severe COVID-19 with Low-Dose
Selinexor: Demonstration of Anti-Viral and Anti-Inflammatory
Activities in a Randomized, International, Multicenter,
Placebo-Controlled Phase 2 Clinical Trial
Presenter: George F. Geils,
M.D., Roper St. Francis Healthcare
Date: October 7, 2020; 10:50 EST
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.
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 selinexor as a potential treatment for
hospitalized patients with severe COVID-19; the design and
execution of a global randomized clinical trial to study this
potential application of selinexor, including the dosing regimen;
and the potential anti-viral and anti-inflammatory properties of
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 complete necessary clinical development phases of
selinexor in this indication; that data from a clinical trial of
selinexor would support its use in treatment of hospitalized
patients with severe COVID-19; that regulators will approve the use
of selinexor in hospitalized patients with severe COVID-19; or that
such approval will be made on an accelerated timeline. 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 reducing
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 selinexor for treatment of COVID-19 in the
commercial marketplace, the timing and costs involved in
commercializing selinexor for such indication or any of
Karyopharm's drug candidates that receive regulatory approval; the
ability to retain regulatory approval of selinexor for such
indication 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
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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