Karyopharm Reports Positive Combo Data for Selinexor in MM Patients

Karyopharm Therapeutics Inc.

, 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.