Karyopharm Therapeutics Inc. (Nasdaq: KPTI) announced a modification to the co-primary endpoint of its pivotal Phase 3 SENTRY trial (NCT04562389) for myelofibrosis, following feedback from the U.S. Food and Drug Administration (FDA). The original co-primary endpoint, Total Symptom Score Improvement of ≥ 50% (TSS50), will be replaced with Absolute Total Symptom Score (Abs-TSS). The other co-primary endpoint remains Spleen Volume Response Rate ≥ 35% (SVR35).
Rationale for Endpoint Change
Abs-TSS measures the average improvement in patient symptom scores over 24 weeks relative to the patient's baseline symptom score. This change is supported by key investigators and patient advocacy organizations, who view Abs-TSS as a more accurate assessment of symptom improvement in clinical trials. According to Dr. Ruben Mesa, President of Atrium Health Levine Cancer, Abs-TSS may better represent the cumulative benefit patients experience on symptom burden.
Promising Phase 1 Data
Data from Karyopharm's Phase 1 trial, which evaluated selinexor 60mg plus ruxolitinib in JAKi-naïve myelofibrosis patients, showed that 79% of patients (n=14) achieved SVR35, and an average Abs-TSS improvement of 18.5 points was observed in the efficacy evaluable population (n=9) at week 24 relative to baseline. These results compare favorably to historical ruxolitinib monotherapy data, which indicates that less than half of patients achieve SVR35 and an Abs-TSS improvement of 11 to 14 points.
SENTRY Trial Details
The SENTRY trial is evaluating a once-weekly dose of 60mg of selinexor in combination with twice-daily ruxolitinib versus placebo plus ruxolitinib in JAKi-naïve patients with platelet counts >100 x 10^9/L. Karyopharm is proactively increasing the total sample size to approximately 350 patients to further increase the statistical powering. Top-line data read-out is expected in the second half of 2025.
Myelofibrosis Treatment Landscape
Myelofibrosis is a chronic bone marrow disorder characterized by ineffective blood cell production and scarring of the bone marrow. Current treatments, including JAK inhibitors like ruxolitinib, have limitations, with less than half of patients achieving SVR35. Many patients eventually stop responding to these treatments, highlighting the unmet need for more effective therapies.
About Selinexor
Selinexor, marketed as XPOVIO®, is a first-in-class, oral exportin 1 (XPO1) inhibitor. It is approved in the U.S. for multiple oncology indications, including multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Selinexor functions by selectively binding to and inhibiting the nuclear export protein XPO1.
