Karyopharm Therapeutics (KPTI) Study Update summary

Study Design and Updates

• The SENTRY Phase 3 trial in myelofibrosis randomizes approximately 350 JAK inhibitor-naïve patients 2:1 to selinexor plus ruxolitinib versus ruxolitinib plus placebo, stratified by DIPSS risk, spleen volume, and platelet count.

• Co-primary endpoints are SVR35 (spleen volume reduction ≥35%) and Absolute TSS (Abs-TSS) at week 24, replacing TSS50, in alignment with FDA guidance and to better capture patient symptom improvement.

• Sample size was increased to 350 patients to enhance statistical power, with top-line results expected in the second half of 2025.

• The trial maintains its two-to-one randomization, selinexor dosing (60mg once weekly), and antiemetic protocol, with no significant changes to cost or schedule.

• Abs-TSS is recognized as a meaningful endpoint by investigators and patient advocacy groups.

Rationale and Background

• Absolute TSS is a more granular and sensitive measure of symptom improvement than TSS50, especially in combination therapy settings.

• The shift to Abs-TSS reflects evolving regulatory and clinical perspectives, with FDA and key opinion leader support.

• Myelofibrosis is a progressive disease with significant symptom burden, risk of leukemic transformation, and reduced survival, especially after ruxolitinib discontinuation.

• Current JAK inhibitors improve symptoms and spleen size but have limitations, including hematologic toxicities and suboptimal responses in some patients.

• XPO1 inhibition by selinexor targets key pathways in myelofibrosis pathogenesis, including nuclear export of tumor suppressors and inflammatory signaling.

Phase 1 Data and Combination Therapy Insights

• Phase 1 data for selinexor plus ruxolitinib showed SVR35 rates of 78.6–79% and an average Absolute TSS improvement of 18.5 points at week 24.

• Median duration of response was not reached, with durable responses observed up to 51 weeks.

• The combination demonstrated durable responses and manageable toxicity, especially with proactive GI prophylaxis.

• Efficacy was observed even in patients receiving suboptimal ruxolitinib doses, supporting XPO1 as a key mechanism.

• No new safety signals identified; safety profile remains consistent with known adverse events.