-- Oral Selinexor Achieves 26.2% Overall Response
Rate in STORM Study, 4.4 Month Median Duration of Response, 8.6
Month Median Overall Survival and 15.6 Month Median Survival in
Patients with MR or Better --
Karyopharm Therapeutics Inc. (Nasdaq:KPTI), a clinical-stage
pharmaceutical company, today announced presentations highlighting
updated data from the Phase 2b STORM study evaluating selinexor,
the Company’s first-in-class, oral Selective Inhibitor of Nuclear
Export (SINE) compound, in patients with penta-refractory multiple
myeloma, and from two arms of the Phase 1b/2 STOMP study evaluating
selinexor and dexamethasone in combination with standard approved
therapies, Pomalyst (pomalidomide) or Darzalex (daratumumab), in
patients with previously treated multiple myeloma. The data
were featured in oral and poster presentations at American Society
of Hematology (ASH) 2018 Annual Meeting taking place December 1-4,
2018 in San Diego. A New Drug Application (NDA) seeking
accelerated approval for oral selinexor with low dose dexamethasone
as a treatment for patients with penta-refractory multiple myeloma
is under Priority Review by the U.S. Food and Drug Administration
(FDA) with an action date of April 6, 2019, under the Prescription
Drug User-Fee Act (PDUFA).
“As an increasing number of myeloma patients
experience progressive disease despite treatment with combination
regimens, there is a growing need for new therapies, particularly
those with novel mechanisms, to help treat patients with relapsed
and/or refractory myeloma. The 26.2% ORR determined by the
Independent Review Committee (IRC) in the STORM study is highly
compelling and reinforces the potential of selinexor in this
difficult to treat patient population,” said Sharon Shacham, PhD,
MBA, Founder, President and Chief Scientific Officer of Karyopharm.
“Additionally, the Phase 1b/2 STOMP study continues to generate
encouraging efficacy and safety data from multiple ongoing arms
evaluating once weekly oral selinexor and dexamethasone (dex) in
combination with the standard approved therapies in patients with
newly diagnosed and relapsed/refractory multiple myeloma. The
data presented at this year’s ASH annual meeting show impressive
response rates across several high unmet need patient subgroups,
including Darzalex-naïve or Pomalyst-naïve and Revlimid®
(lenalidomide)-relapsed or -refractory myeloma. Given the
synergistic activity observed to date with once weekly oral
selinexor plus these approved myeloma therapies, we continue to
believe that selinexor holds tremendous potential as a future
combination backbone therapy in myeloma.”
Updated Phase 2b STORM
Results
These clinical results are from Part 2 of the
international, multi-center, single-arm Phase 2b STORM
(Selinexor Treatment
of Refractory
Myeloma) study, which enrolled 122 heavily
pretreated patients (median of seven prior treatment regiments)
with penta-refractory myeloma. Patients with penta-refractory
myeloma have previously received the two proteasome inhibitors
(PIs), Velcade® (bortezomib) and Kyprolis® (carfilzomib), the two
immunomodulatory drugs (IMiDs), Revlimid® and Pomalyst, and the
anti-CD38 monoclonal antibody Darzalex, as well as alkylating
agents, and their disease is refractory to glucocorticoids, at
least one PI, at least one IMiD, Darzalex and their most recent
therapy. Each patient started 80mg oral selinexor twice
weekly in combination with low-dose dexamethasone (dex; 20mg twice
weekly).
For the STORM study’s primary objective, oral
selinexor achieved a 26.2% ORR, which included two stringent
complete responses (sCRs), six very good partial responses (VGPRs)
and 24 partial responses (PRs). The two sCRs were negative
for minimal residual disease, one at the level of 1x10-6 and one at
1x10-4; this is particularly significant in this penta-refractory
population. Both patients who had relapsed after CAR-T
therapy achieved PRs. The ORR in patients who had previously
received Darzalex combination therapy (n=86) was 29.1%. The
disease control rate for patients who had achieved stable disease
or better was 78.7%. All responses were confirmed by an
IRC. Median progression-free survival (PFS) was 3.7 months
and the median duration of response (DOR) was 4.4 months.
Median overall survival (OS) across the study was 8.6 months.
Median OS in the approximately 40% of patients with at least a
minimum response (MR) on selinexor + dex was 15.6 months compared
to a median OS of 1.7 months in patients whose disease progressed
or where response was not evaluable (p<0.0001). The short
median OS of patients with no response to selinexor is consistent
with the lack of available effective therapies for the very heavily
pretreated population who entered the study. Real world OS
data were also obtained from the Flatiron Health Analytic Database
(FHAD). These results further highlight the limited
life-expectancy in patients with highly refractory multiple
myeloma. OS data from the FHAD indicate that patients with
triple-class refractory myeloma (n=69) had a median OS of 3.5
months, also consistent with previously reported data from the
literature.
The most common treatment-related adverse events
(AEs) were cytopenias, along with gastrointestinal and
constitutional symptoms and were consistent with those previously
reported from Part 1 of this study (Vogl et al., J Clin Oncol,
2018) and from other selinexor studies. Most were manageable
with dose modifications and/or standard supportive care. The
most common non-hematologic treatment-related AEs were nausea
(69%), fatigue (56%), anorexia (52%), and weight loss (47%) and
mostly Grade 1 and 2 events. As expected, the most common
Grade 3 and 4 treatment-related AEs were thrombocytopenia (54%),
anemia (29%), neutropenia (19%) and fatigue (19%). No
significant major organ toxicities were observed, and bleeding and
infection rates were low.
Selinexor has been granted Orphan Drug
Designation in multiple myeloma and Fast Track designation for the
patient population evaluated in the STORM study. A NDA
seeking accelerated approval for oral selinexor with low dose
dexamethasone as a new treatment for patients with penta-refractory
multiple myeloma was accepted and filed with Priority Review by the
U.S. FDA. The FDA assigned an action date of April 6, 2019
under the Prescription Drug User-Fee Act (PDUFA). Provided
marketing approval is granted by the FDA, Karyopharm plans to
commercialize selinexor in the U.S. in the first half of
2019. The Company also plans to submit a Marketing
Authorization Application to the European Medicines Agency (EMA) in
early 2019 with a request for conditional approval.
Updated Phase 1b/2 STOMP Study
(Selinexor plus Darzalex and Low-dose Dexamethasone
(SDd))
In this arm of the Phase 1b/2 STOMP
(Selinexor and Backbone
Treatments of Multiple
Myeloma Patients) study, oral
selinexor (dose escalated using either 100mg once weekly or 60mg
twice weekly) is being evaluated in combination with Darzalex
(16mg/kg intravenously once weekly) and low dose dexamethasone
(dex; orally, 40mg once weekly or 20mg twice weekly) in patients
with relapsed or refractory multiple myeloma who received at least
three prior lines of therapy, including a PI and an IMiD, or
patients with myeloma refractory to both a PI and an IMiD.
The following table is a summary of the efficacy results:
Best Responses1 in Evaluable SDd Patients as of
15-Nov-20182 |
Category |
N3 |
ORR |
VGPR |
PR4 |
Darzalex naïve |
24 |
19 (79%) |
7 (29%) |
12 (50%) |
All |
26 |
19 (73%) |
7 (27%) |
12 (46%) |
Key: ORR=Overall Response Rate (VGPR+PR)1
Responses were adjudicated according to the International Myeloma
Working Group criteria2 Based on interim unaudited data3 Two
patients were not evaluable for response withdrew consent prior to
disease follow up4 Two unconfirmed PR
Despite the heavily pretreated nature of the
patients in the study, with 100% of the patients having dual- (PI
and IMID) refractory disease, only 19% of patients did not respond
(≤stable disease). Median PFS and DOR have not been
reached. Based on published data the expected ORR for
Darzalex therapy without selinexor in the Darzalex-naïve population
is ~30%. Thus, the ORR of 79% provides a basis for further
evaluation of the SDd combination.
Among the patients evaluated for safety as of
the data cutoff date, the most common treatment-related AEs were
cytopenias, along with gastrointestinal and constitutional
symptoms; most manageable with dose modifications and/or standard
supportive care. The most common non-hematologic
treatment-related AEs were nausea (60%), fatigue (48%), diarrhea
(32%), vomiting (24%) and anorexia (28%) and mostly Grade 1 and 2
events. As expected, the most common Grade 3 and 4
treatment-related AEs were thrombocytopenia (44%), anemia (28%),
leukopenia (28%) and neutropenia (24%). No Grade 5 AEs were
reported. The maximum tolerated dose was not reached.
Two dose-limiting toxicities (DLTs) (Grade 3 thrombocytopenia and
Grade 2 fatigue) were observed in patients receiving selinexor 60mg
twice weekly. No DLTs were reported in the 100mg once weekly
cohort. The longest duration of therapy is over 60
weeks. Based on these preliminary tolerability and efficacy
data, the RP2D of SDd is selinexor (100mg orally, once weekly),
Darzalex (16mg/kg, once weekly) and dex (40mg orally, weekly).
Updated Phase 1b/2 STOMP Study
(Selinexor plus Pomalyst and Low-dose Dexamethasone
(SPd))
In this arm of the Phase 1b/2 STOMP study, oral
selinexor is being evaluated in combination with Pomalyst (3
or 4mg orally, once daily) and low dose dex (orally, 40mg once
weekly or 20mg twice weekly) in patients with relapsed or
refractory multiple myeloma who received at least three prior lines
of therapy, including a PI and an IMiD, or patients with myeloma
refractory to both a PI and an IMiD. The following table is a
summary of the efficacy results:
Best Responses1 in Evaluable SPd Patients as of
15-Nov-20182 |
Prior Therapy Status |
N3 |
ORR |
VGPR |
PR4 |
Median PFS |
Pomalyst-naïve and Revlimid refractory or relapsed |
26 |
14 (54%) |
5 (19%) |
9 (35%) |
12.2 months |
Pomalyst and Revlimid refractory |
8 |
3 (38%) |
- |
3 (38%) |
5.5 months |
All |
34 |
17 (50%) |
5 (15%) |
12 (35%) |
12.2 months |
Key: ORR=Overall Response Rate (VGPR+PR)1
Responses were adjudicated according to the International Myeloma
Working Group criteria2 Based on interim unaudited data3 Four
patients not evaluable for response: one death unrelated to
myeloma, one non-compliance with study procedures, two withdrawal
of consent before disease follow up4 One unconfirmed PR
Responses tended to occur rapidly with a median
of one month to onset. Median PFS among all evaluable
patients was 12.2 months, with a follow up of 9.4 months.
Median PFS in Pomalyst and Revlimid-refractory myeloma was
5.5 months. Among patients with a PR or better (n=17), the
median time on treatment was 9.4 months.
Among the patients evaluated for safety as of
the data cutoff date, the most common treatment-related AEs were
cytopenias, along with gastrointestinal and constitutional
symptoms; most manageable with dose modifications and/or standard
supportive care. The most common non-hematologic
treatment-related AEs were nausea (53%), fatigue (50%) and weight
decreased (34%). As expected, the most common
treatment-related Grade 3 and 4 AEs were neutropenia (55%),
thrombocytopenia (34%), anemia (29%) and leukopenia (18%).
There were three Grade 5 treatment-related events (febrile
neutropenia, intracranial hemorrhage and pneumonia). Based on
these tolerability and efficacy data, doses of oral selinexor
60-80mg once weekly are being evaluated in combination with
Pomalyst (3mg orally, once daily) and low dose dex to determine the
RP2D for this combination regimen.
In parallel with the ongoing Phase 1b/2 STOMP
study, Karyopharm is conducting the pivotal, randomized Phase 3
BOSTON study evaluating once weekly selinexor in combination with
the proteasome inhibitor Velcade and dex (SVd) for the treatment of
patients with multiple myeloma who have had one to three prior
lines of therapy. The Company expects to complete enrollment
in the BOSTON study by the end of 2018, with top-line data
anticipated at the end of 2019. Assuming a positive outcome,
Karyopharm plans to use the results from the BOSTON study to
support an application for full approval of selinexor in
relapsed/refractory multiple myeloma.
Details for the ASH 2018 presentations
highlighting the STORM and STOMP studies are as
follows:
Title: Results of the Pivotal
STORM Study (Part 2) in Penta-Refractory Multiple Myeloma (MM):
Deep and Durable Responses with Oral Selinexor Plus Low Dose
Dexamethasone in Patients with Penta-Refractory
MMPresenter: Ajai Chari, Icahn School of Medicine
at Mount Sinai, New York, New YorkAbstract
Number/Publication ID: 598Session: 653.
Myeloma: Therapy, excluding Transplantation: Antibodies
and Targeted TherapiesDate and Time: Monday,
December 3, 2018; 7:45 AM PTLocation: San Diego
Convention Center, Room 6F
Title: Deep and Durable
Responses with Selinexor, Daratumumab, and Dexamethasone (SDd) in
Patients with Multiple Myeloma (MM) Previously Exposed to
Proteasome Inhibitors and Immunomodulatory Drugs: Results of Phase
1b Study of SDdPresenter: Cristina Gasparetto,
Duke University Cancer Center, Durham, North
CarolinaAbstract Number/Publication ID:
599Session: 653. Myeloma: Therapy, excluding
Transplantation: Antibodies and Targeted TherapiesDate and
Time: Monday, December 3, 2018; 8:00 AM
PTLocation: San Diego Convention Center, Room
6F
Title: Selinexor Plus
Pomalidomide and Low Dose Dexamethasone (SPd) in Patients with
Relapsed or Refractory Multiple MyelomaPresenter:
Christine Chen, Princess Margaret Cancer Center, Toronto,
OntarioAbstract Number/Publication ID:
1993Session: 653. Myeloma: Therapy, excluding
Transplantation: Poster IDate and Time: Saturday,
December 1, 2018; 6:15-8:15 PM PTLocation: San
Diego Convention Center, Hall GH
About Selinexor
Selinexor is a first-in-class, oral Selective
Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by
binding with and inhibiting the nuclear export protein XPO1 (also
called CRM1), leading to the accumulation of tumor suppressor
proteins in the cell nucleus. This reinitiates and amplifies their
tumor suppressor function and is believed to lead to the selective
induction of apoptosis in cancer cells, while largely sparing
normal cells. To date, over 2,800 patients have been treated with
selinexor. In April and September 2018, Karyopharm reported
positive data from the Phase 2b STORM study evaluating selinexor in
combination with low-dose dexamethasone in patients with
penta-refractory multiple myeloma. Selinexor has been granted
Orphan Drug Designation in multiple myeloma and Fast Track
designation for the patient population evaluated in the STORM
study. Karyopharm’s New Drug Application (NDA) has been accepted
for filing and granted Priority Review by the FDA, and oral
selinexor is currently under review by the FDA as a possible new
treatment for patients with penta-refractory multiple myeloma. The
Company also plans to submit a Marketing Authorization Application
(MAA) to the European Medicines Agency (EMA) in early 2019 with a
request for conditional approval. Selinexor is also being evaluated
in several other mid-and later-phase clinical trials across
multiple cancer indications, including in multiple myeloma in a
pivotal, randomized Phase 3 study in combination with Velcade®
(bortezomib) and low-dose dexamethasone (BOSTON), as a potential
backbone therapy in combination with approved therapies (STOMP), in
diffuse large B-cell lymphoma (SADAL), liposarcoma (SEAL), and an
investigator-sponsored study 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.
About Karyopharm
Therapeutics
Karyopharm Therapeutics Inc. (Nasdaq:KPTI) is a
clinical-stage pharmaceutical company focused on the discovery and
development of novel first-in-class drugs directed against nuclear
transport and related targets for the treatment of cancer and other
major diseases. Karyopharm's SINE compounds function by binding
with and inhibiting the nuclear export protein XPO1 (or CRM1). 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, which was
founded by Dr. Sharon Shacham, currently 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 our expectations relating to submissions and to the
review and potential approval of selinexor by regulatory
authorities, including the anticipated timing of such submissions
and actions, and the potential availability of accelerated approval
pathways, the therapeutic potential of and potential clinical
development plans for Karyopharm's drug candidates, especially
selinexor, and the plans for commercialization. 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
regulators will agree that selinexor qualifies for accelerated
approval in the U.S. or conditional approval in the E.U. as a
result of the data from the STORM study in patients with
penta-refractory myeloma or the SADAL study in patients with
relapsed or refractory DLBCL 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 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: 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; 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, 2018, which was filed with
the Securities and Exchange Commission (SEC) on November 8, 2018,
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 LimitedRevlimid® and Pomalyst® are
registered trademarks of Celgene CorporationKyprolis® is a
registered trademark of Onyx Pharmaceuticals, Inc.Darzalex® is a
registered trademark of Janssen Biotech, Inc.
Contacts:
Investors:Karyopharm
Therapeutics Inc.Ian KarpVice President, Investor and Public
Relations857-297-2241 | ikarp@karyopharm.com
Media:Argot PartnersDavid
Rosen212-600-1902 | david.rosen@argotpartners.com
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