Karyopharm Presents Positive Clinical Data For Selinexor In NHL Patients

Karyopharm Therapeutics Inc.

, a clinical-stage pharmaceutical company, today announced the presentation of positive clinical data 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. In an ongoing Phase 1 clinical trial evaluating the activity of Selinexor in patients with heavily pre-treated, progressive non-Hodgkin's lymphoma (NHL), including aggressive B-cell NHL such as diffuse large B-cell lymphoma (DLBCL), Richter's transformation, Burkitt lymphoma, mantle cell lymphoma, T-cell lymphoma and follicular/indolent lymphoma, Selinexor demonstrated a 37% overall response rate (partial response or better) and a 73% disease control rate (stable disease or better) in 52 patients who were evaluable as of December 1, 2014. Responses included five complete responses, four in patients with DLBCL and one in a patient with T-cell lymphoma, and Selinexor demonstrated a median duration of response (DOR) of approximately 7 months. "We are extremely encouraged by the response rates, durability and tolerability observed with Selinexor in patients with advanced and progressing non-Hodgkin's lymphomas whose disease has relapsed after, or is refractory to, multiple previous regimens," said Sharon Shacham, PhD, MBA, President and Chief Scientific Officer of Karyopharm. "In particular, these data further support our near-term focus on diffuse large B-cell lymphoma and Richter's transformation as part of our expedited registration strategy for hematologic malignancies." "Patients with aggressive NHL that has relapsed after standard therapy have limited options and ultimately a minority are eligible for aggressive, curative treatment strategies such as stem cell transplantation. Patients who are ineligible for that type of treatment and those who have disease that recurs after transplant represent an area of high unmet medical need," said John Kuruvilla, MD, Division of Medical Oncology and Hematology at the Princess Margaret Cancer Center in Toronto, Canada. "Additionally, there are no therapies indicated to treat patients with Richter's transformation and these patients face an especially poor prognosis. We look forward to continuing to evaluate Selinexor in advanced NHL, particularly DLBCL and Richter's Transformation, with the goal of further improving clinical benefit and patient outcomes." In an oral presentation on Monday, December 8, 2014, entitled, "The Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) Demonstrates Broad and Durable Clinical Activity in Relapsed / Refractory Non-Hodgkin's Lymphoma (NHL)," Dr. Kuruvilla described the activity of single-agent Selinexor in 52 heavily pre-treated NHL patients including: Overall response rate (partial response or better) of 37% (19/52) and disease control rate (stable disease or better) of 73% (38/52) in evaluable patients treated with single-agent Selinexor at doses of 3 to 80 mg/m2 taken orally once, twice, or three times each week in 28-day cycles (see Table below). Across all NHL types studied, responses could improve over time, with best responses including five complete responses (CR) (four in DLBCL and one in T-NHL). Eleven patients out of 52 have remained on therapy for more than 7 months (and up to 23 months) without clinically significant cumulative toxicities or major organ dysfunction. Clear activity was observed across all DLBCL subtypes evaluated, including a 36% overall response rate and an 82% disease control rate in 11 patients with Germinal Center B-Cell (GCB) like DLBCL and a 40% overall response rate (2 of 5) and an 80% disease control rate in patients with non-Germinal Center B-Cell (non-GCB, also called ABC)-like DLBCL. The disease control rate among four patients with "Double Hit" DLBCL was 75%; one patient achieved a CR with time on study in excess of 14 months, and a second patient with a PR on study for ~8 months. Selinexor treatment was generally well tolerated with supportive care and can be administered over a prolonged period. Grade 3/4 adverse events (≥5%) include thrombocytopenia (37%), neutropenia (22%), anemia (16%), fatigue (12%), leukopenia (10%) and hyponatremia (10%). The most common Grade 1/2 adverse events were: nausea (63%), anorexia (52%), fatigue (46%), and vomiting (36%) that tend to lessen in severity with supportive care and were seen less frequently following cycle 1. Increases in XPO1 mRNA levels, the pharmacodynamic marker for selinexor, were observed at all doses and sustained for up to 48 hours, supporting twice weekly dosing. The recommended maximal Phase 2/3 dose is 60 mg/m2 (~100mg flat dose) based on results across all Phase 1 studies. Cancer Type Selinexor Dose (mg/m2) N* ORR (%) CR (%) PR (%) SD (%) PD (%) Aggressive B-NHL ≤ 20 4 1 (25%) -- 1 (25%) 1 (25%) 2 (50%) (DLBCL, Transformed, 20 – 50 19 7 (37%) 4 (21%) 3 (16%) 5 (26%) 7 (37%) FL-3b) ≥ 60 10 4 (40%) -- 4 (40%) 4 (40%) 2 (20%) Follicular and ≤ 30 4 -- -- -- 4 (100%) -- Other Indolent NHL ≥ 35 4 2 (50%) -- 2 (50%) 1 (25%) 1 (25%) Burkitt's Lymphoma ≥ 60 1 -- -- -- -- 1 (100%) Mantle Cell Lymphoma ≤ 30 2 1 (50%) -- 1 (50%) 1 (50%) -- ≥ 35 1 -- -- -- -- 1 (100%) T-Cell Lymphoma ≤ 30 2 1 (50%) -- 1 (50%) 1 (50%) -- ≥ 35 1 1 (100%) 1 (100%) -- -- -- Richter's ≤ 30 3 1 (33%) -- 1 (33%) 2 (67%) -- Transformation ≥ 35 1 1 (100%) -- 1 (100%) -- -- TOTAL 52 19 (37%) 5 (10%) 14 (27%) 19 (37%) 14 (27%) *Patients evaluable for disease response Based on these data, Karyopharm has designed two registration-directed Phase 2 clinical trials: Selinexor in Relapsed/Refractory Richter's Transformation (SIRRT, NCT No. 02138786), a 50-patient single arm clinical trial that was initiated in November 2014. Selinexor and Dexamethasone in Aggressive Lymphoma (SADAL, NCT No. 02227251), a two arm trial in 200 patients with DLBCL following at least two prior chemoimmunotherapy regimens that is expected to begin prior to the end of 2014. In addition, a randomized study of Selinexor in Older Patients with Relapsed AML (SOPRA, NCT No. 02088541) was initiated in mid-2014. Karyopharm expects to initiate at least one additional registration-directed study in the first half of 2015.