Karyopharm Therapeutics Announces Positive Phase 3 SENTRY Trial Results in Myelofibrosis

Key Points from the Report

• Phase 3 SENTRY Trial: Karyopharm reported topline results from its pivotal Phase 3 SENTRY trial evaluating selinexor (XPOVIO®) in combination with ruxolitinib in frontline myelofibrosis.
• Co-Primary Endpoints:
  • The trial met its first co-primary endpoint, demonstrating a statistically significant improvement in spleen volume reduction (SVR35) for patients treated with the selinexor-ruxolitinib combination.
  • The second co-primary endpoint, improvement in absolute total symptom score (Abs-TSS), was not met; symptom improvements were similar in both arms and not statistically significant.
• Overall Survival:
  • A promising signal in overall survival (OS) was observed, with a hazard ratio of 0.43 (95% CI [0.19, 1.00], nominal one-sided p=0.0222), suggesting a >50% reduction in the risk of death versus ruxolitinib alone.
  • Continued follow-up will further evaluate this signal.
• Rapid and Sustained Spleen Response:
  • At week 24, 50% of patients on the combination achieved SVR35 versus 28% on ruxolitinib alone (p<0.0001).
  • Rapid response: 49% achieved SVR35 at week 12 on the combination vs. 20% on ruxolitinib alone.
  • Sustained effect: 47% at week 36 on combination vs. 23% on ruxolitinib alone.
• Potential Disease Modification:
  • Evidence of disease modification was seen, with 32% of patients on the combination achieving ≥20% reduction in variant allele frequency (VAF) for JAK2, MPL, and CALR mutations at week 24, compared to 24% on ruxolitinib alone.
• Safety Profile:
  • No new safety signals identified for the combination.
  • Most common all-grade adverse events: thrombocytopenia (59% vs. 43%), anemia (57% vs. 58%), nausea (57% vs. 17%), constipation (32% vs. 36%), and neutropenia (27% vs. 9%).
  • Grade 3+ TEAEs occurred in 70% of combination arm vs. 50% in ruxolitinib arm.
  • Discontinuation due to TEAEs: 15% in combination arm, 9% in ruxolitinib arm.
  • Confirmed leukemic transformation: 1.7% in both arms.
• Other Endpoints:
  • No meaningful difference between arms for progression-free survival, hemoglobin stabilization, and bone marrow fibrosis improvement at the data cut-off.
• Regulatory Path:
  • Karyopharm will meet with the FDA to discuss the totality of the SENTRY data and potential supplemental new drug application (sNDA) filing.
  • Additional SENTRY data will be presented at an upcoming medical meeting, and a manuscript will be submitted to a peer-reviewed journal.
  • Potential inclusion in relevant compendia could occur in the second half of 2026.
• Market Opportunity:
  • Myelofibrosis affects ~20,000 patients in the US and ~17,000 in the EU.
  • Current approved therapies are limited to JAK inhibitors, with a clear need for new options.
• XPOVIO (Selinexor):
  • First-in-class oral XPO1 inhibitor approved in multiple oncology indications in the US and internationally.
  • Currently marketed for multiple myeloma and diffuse large B-cell lymphoma.
  • Selinexor is being investigated in further mid- and late-stage trials for myelofibrosis and other cancers.

Shareholder and Price Sensitive Considerations

• Statistically Significant Spleen Volume Reduction: The clear superiority in SVR35 rates for selinexor plus ruxolitinib versus ruxolitinib monotherapy may position the combination as a new standard of care in frontline myelofibrosis, which could be a major value driver if approved.
• Promising Overall Survival Signal: The >50% reduction in risk of death, while not yet mature, is likely to be seen as highly favorable by investors and clinicians. If confirmed in further follow-up, this could substantially increase market uptake and revenue potential.
• Potential Disease Modification: The observed reduction in VAF suggests selinexor may impact underlying disease biology beyond symptom control—this is an important differentiator.
• Regulatory Engagement: The imminent meeting with FDA about a potential sNDA is a key catalyst. Positive regulatory feedback or sNDA acceptance would be highly price sensitive.
• Safety Profile: No new safety signals is reassuring, though higher rates of grade 3+ TEAEs and discontinuations in the combination arm should be monitored by investors.
• Upcoming Data Presentations: Additional data and peer-reviewed publication, as well as potential compendia inclusion, are near-term catalysts.
• Market Opportunity: Large addressable population and unmet medical need increases upside if the combination is approved and adopted.
• Forward-Looking Statements: Management cautions that there is no guarantee of commercial success, regulatory approval, or continued positive developments. Risks include regulatory outcomes, competition, market adoption, and patent protection.

Detailed Trial and Drug Information

The SENTRY (XPORT-MF-034; NCT04562389) Phase 3 trial randomized JAK inhibitor-naïve myelofibrosis patients with platelet counts >100 x 10⁹/L 2:1 to receive once-weekly 60 mg selinexor plus ruxolitinib or placebo plus ruxolitinib. The co-primary endpoints were SVR35 at week 24 and mean change in Abs-TSS over 24 weeks. All data were as of February 20, 2026.

XPOVIO (selinexor) is a selective XPO1 inhibitor, approved in combination with bortezomib and dexamethasone (XVd) for multiple myeloma after at least one prior therapy, in combination with dexamethasone for heavily pre-treated multiple myeloma, and under accelerated approval for diffuse large B-cell lymphoma after at least two lines of systemic therapy. The drug is marketed in the US and 50 ex-US territories and countries.

Management and Expert Commentary

“The results from SENTRY are an important development… the combination of selinexor plus ruxolitinib meaningfully improved spleen response and we observed a promising signal in overall survival.” — Dr. John Mascarenhas, Icahn School of Medicine at Mount Sinai

“Selinexor’s differentiated mechanism provides a complementary approach to JAK inhibition… I am encouraged by the speed and magnitude of spleen response, and the promising overall survival signal and evidence of potential disease modification.” — Dr. Claire Harrison, Guy’s and St. Thomas’ NHS Foundation Trust

“Improving overall survival is the ultimate goal for people living with myelofibrosis and I am incredibly encouraged by these results.” — Kapila Viges, CEO, MPN Research Foundation

Next Steps and Investor Catalysts

• Karyopharm will meet with the FDA to discuss SENTRY trial data and sNDA filing plans.
• Further data will be shared at an upcoming medical conference and in a peer-reviewed manuscript.
• Potential compendia inclusion and regulatory milestones expected in second half of 2026.

Disclaimer

This article is for informational purposes only and does not constitute investment advice. All forward-looking statements are subject to risks and uncertainties. Investors are encouraged to review Karyopharm Therapeutics Inc.’s filings and consult their financial advisors before making investment decisions. No guarantee is made regarding regulatory outcomes, commercial success, or future share price movements.

View Karyopharm Therapeutics Inc. Historical chart here