Karyopharm Therapeutics Inc.
KPTI, a clinical-stage pharmaceutical company, today announced the
presentation of positive clinical and preclinical combination data in multiple
myeloma for its lead product candidate, Selinexor (KPT-330), a first-in-class,
oral Selective Inhibitor of Nuclear Export / SINE™ compound, at the 56th
American Society of Hematology (ASH) Annual Meeting, held December 6-9, 2014
in San Francisco.
"We are encouraged to see the clinical response rates afforded by adding
Selinexor to currently approved multiple myeloma therapies, including
dexamethasone and carfilzomib," said Sharon Shacham, PhD, MBA, President and
Chief Scientific Officer of Karyopharm. "Given the promising durability and
preclinical support for synergistic activity with approved agents, we look
forward to further evaluating the clinical benefits of Selinexor combination
therapy in multiple myeloma."
In an ongoing Phase 1 clinical trial being conducted by Karyopharm, Selinexor
in combination with low-dose dexamethasone demonstrated high rates of durable
responses, including a 67% overall response rate (partial response or better)
and an 89% clinical benefit rate (minimal response or better) in nine
evaluable patients with heavily pre-treated and refractory multiple myeloma
(one patient was not evaluable for response). Six of these patients remained
on study for at least 16 weeks, including two for 28 and 43 weeks,
respectively, who remained on study as of December 1, 2014. The overall median
duration of response (DOR), which measures time from response to
progression, is approximately 7 months.
A Phase 1/2 investigator sponsored study (IST) to evaluate tolerability and
efficacy of the combination of Selinexor with the proteasome inhibitor
carfilzomib (Kyprolis®) and low-dose dexamethasone (Car-Dex) is being
conducted by the University of Chicago. In the first three treated patients,
all of whom have myeloma refractory to carfilzomib and dexamethasone,
Selinexor-Car-Dex induced one very good partial response (VGPR) and two
partial responses (PR) with good tolerability. Dose escalation in this Phase 1
clinical study is ongoing.
In a related preclinical study conducted at the University of Chicago,
Selinexor combined with carfilzomib induced both autophagy and apoptosis in
multiple myeloma cell lines and patient samples, suggesting synergy through a
combination-based priming effect. The combination had minimal effects on
normal lymphocytes.
"Although early, the activity demonstrated with Selinexor in combination with
carfilzomib and dexamethasone in these heavily pretreated patients with
carfilzomib- and dexamethasone-refractory multiple myeloma in this ongoing
clinical study is very encouraging," said Andrzej Jakubowiak, MD, PhD,
Professor of Medicine, Director, Myeloma Program, University of Chicago.
"Despite the advent of several new treatments for multiple myeloma, patients
continue to have relapsed and refractory disease, and new agents with distinct
mechanisms of action are needed."
Selinexor in combination with low-dose dexamethasone
In a poster presentation on Monday, December 8, 2014, entitled, "Selinexor
Demonstrates Marked Synergy with Dexamethasone (Sel-Dex) in Preclinical Models
and in Patients with Heavily Pretreated Refractory Multiple Myeloma (MM),"
Karyopharm collaborators described the activity of Selinexor in combination
with low-dose dexamethasone in heavily pre-treated and refractory multiple
myeloma patients, including:
* Overall response rate of 67%, with one stringent complete response (sCR,
11%) and five partial responses (PR, 56%), and a clinical benefit rate of
89% in nine patients with heavily pretreated and refractory multiple
myeloma treated with Selinexor in combination with low-dose dexamethasone
(Sel-Dex), each dosed twice weekly at 45mg/m^2 and 20mg, respectively.
* The Sel-Dex combination demonstrated reduction in nausea grades and very
little weight loss compared with Selinexor alone. The most common Grade
1/2 adverse events were: nausea, fatigue, anorexia and vomiting.
* The Sel-Dex combination was also associated with an increase in time on
study relative to Selinexor alone, with 66% of these nine evaluable
patients remaining on study for at least 16 weeks, including two for 28
and 43 weeks, respectively, who remained on study as of December 1, 2014.
* During the dose evaluation part of the study, the 60 mg/m^2 Selinexor dose
was deemed intolerable in this heavily pretreated patient population.
Selinexor 45 mg/m^2 is the recommended future study dose.
Best Responses in Evaluable (N=9) Multiple Myeloma Patients
Oral Selinexor (45 mg/m^2) and Dexamethasone (20 mg) (as of 1-Dec-2014)
Treatment N CBR ORR sCR PR MR PD
Selinexor (45 mg/m^2) +
Low-Dose Dexamethasone (20 9 8 (89%) 6 (67%) 1 (11%) 5 (55%) 2 (22%) 1 (11%)
mg) (each 2x/week)
Selinexor in combination with carfilzomib
In a poster presentation on Saturday, December 6, 2014, entitled, "Gene
Expression and Transcription Factor (TF) Activation Profiling Identifies
Suppression of Multiple Myeloma (MM) Cell Survival and Chemoresistance
Pathways by Inhibition of XPO1/CRM1-dependent Nuclear Export with Selinexor,"
Dr. Jakubowiak and colleagues at the University of Chicago described the
activity of Selinexor in combination with carfilzomib and low-dose
dexamethasone (Car-Dex) in patients with carfilzomib-refractory multiple
myeloma in this ongoing Phase 1/2 clinical study. The group observed one very
good partial response (VGPR) and two partial responses (PRs) in the first
three patients with carfilzomib-refractory multiple myeloma evaluated to date.
Dose escalation in this Phase 1/2 clinical study is ongoing. This study
follows a previously completed preclinical study conducted by the University
of Chicago in which Selinexor in combination with carfilzomib in this patient
population demonstrated a novel intracellular membrane-embedded mechanism of
caspase activation suggesting a model of synergy wherein the
Selinexor-carfilzomib combination promotes caspase activation, likely by
induced proximity, cleavage of other caspases, and subsequent apoptosis as
well as autophagy.
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