Karyopharm Submits XPOVIO Combination Application to FDA for Myelofibrosis, Seeks Priority Review

Karyopharm Therapeutics submitted a supplemental New Drug Application to the U.S. Food and Drug Administration seeking accelerated approval of XPOVIO, or selinexor, in combination with ruxolitinib for patients with myelofibrosis. The company also requested Priority Review, which could shorten the agency’s review goal if the designation is granted.

The August 31 filing moves the program from clinical development into formal regulatory review, but two important decisions still lie ahead. FDA must first accept the application for filing, and Priority Review has not yet been granted. Karyopharm said it expects notice on filing acceptance and anticipated review timelines in the fourth quarter after the agency’s 60-day filing review period.

In its announcement of the submission, Karyopharm said the application relies in part on the Phase 3 SENTRY trial and asks FDA to use a spleen-volume endpoint as the basis for accelerated approval. The company plans to continue collecting long-term overall survival data from SENTRY to verify clinical benefit if FDA agrees with the proposed regulatory approach.

SENTRY showed a stronger spleen response but missed the symptom endpoint

SENTRY enrolled 353 patients with JAK inhibitor-naive myelofibrosis and randomized them 2-to-1 to once-weekly selinexor plus ruxolitinib or placebo plus ruxolitinib. The Phase 3 portion was double-blind and placebo-controlled, and the two coprimary endpoints were a spleen volume reduction of at least 35% at week 24, known as SVR35, and the absolute mean change in total symptom score over the same period.

The spleen endpoint favored the selinexor combination. At week 24, 49.8% of patients receiving selinexor plus ruxolitinib achieved SVR35, compared with 28.0% in the control arm. The difference was 21.8 percentage points, with an odds ratio of 2.58 and a p-value below 0.0001. The benefit appeared earlier as well, with SVR35 rates of 49.4% versus 20.3% at week 12 and 46.9% versus 23.0% at week 36.

The symptom coprimary endpoint did not meet statistical significance. Mean absolute total symptom score improved by 9.9 points in the combination group and 10.9 points in the ruxolitinib-alone group at week 24. The adjusted difference was 0.97 points, with a p-value of 0.825. That result matters because the trial did not succeed on both coprimary measures, even though the spleen response was clearly stronger with selinexor.

Safety also adds context to the filing. Treatment-emergent adverse events occurred in 99.1% of patients in the combination arm and 97.4% in the control arm in the company’s detailed SENTRY presentation. Grade 3 or higher treatment-emergent adverse events were reported in 70% of patients receiving selinexor plus ruxolitinib and 50% receiving placebo plus ruxolitinib. The most common all-grade events in the combination arm included thrombocytopenia, anemia and nausea. Karyopharm said no new safety signals were observed, but the higher rate of severe events is part of the benefit-risk evidence FDA will evaluate.

Accelerated approval depends on FDA accepting the proposed surrogate

Karyopharm is not asking FDA to treat the SENTRY spleen result as traditional proof of a survival benefit. Instead, the company said accelerated approval would require the agency to agree that SVR35 is reasonably likely to predict overall survival. That distinction is central to the application because the accelerated approval pathway permits earlier approval for serious conditions based on a surrogate or intermediate endpoint that is considered reasonably likely to predict clinical benefit.

Under the FDA’s Priority Review framework, a sponsor may request the designation, but the agency makes the decision. FDA says a Priority Review designation carries a goal of acting on an application within six months rather than the 10-month goal for standard review, and the designation does not reduce the scientific or medical standard required for approval. FDA says it informs applicants of the review designation within 60 days of receiving an original NDA, biologics application or efficacy supplement.

Accelerated approval is a separate regulatory concept. FDA explains that drugs approved through that pathway are still subject to studies intended to confirm the anticipated clinical benefit. If those studies do not verify benefit, the agency has procedures that can lead to withdrawal of the indication. Karyopharm said it intends to use long-term overall survival data from the ongoing SENTRY study as confirmatory evidence and expects to work with FDA during review to finalize that plan.

The survival data therefore remain important even though they are not the endpoint on which the company is asking FDA to base the initial decision. Karyopharm has described the available survival findings as a promising signal, not as definitive proof that the combination extends life. The SENTRY study record lists overall survival as a secondary endpoint and shows the study continuing beyond the February 2026 primary completion date, with overall study completion estimated for 2028.

FDA filing acceptance is the next concrete milestone

XPOVIO is already an approved cancer drug in the United States, but myelofibrosis is not part of its current U.S. label. FDA’s April 2026 prescribing information lists two multiple myeloma uses: XPOVIO with bortezomib and dexamethasone after at least one prior therapy, and XPOVIO with dexamethasone for heavily pretreated relapsed or refractory multiple myeloma. Approval of the new application would expand selinexor into a different hematologic cancer and pair it with the JAK inhibitor ruxolitinib.

Myelofibrosis is a blood cancer in which bone marrow fibrosis can impair normal blood-cell production and contribute to an enlarged spleen, anemia and disease-related symptoms. Ruxolitinib and other JAK inhibitors are established treatments in the disease. Karyopharm has said the selinexor combination could become the first approved combination therapy for myelofibrosis if the application succeeds, but that outcome remains contingent on FDA review.

The next regulatory milestone is not an approval decision. It is FDA’s determination on whether the sNDA is sufficiently complete to be filed for review, followed by confirmation of the review classification and any target action date. Karyopharm expects those details in the fourth quarter of 2026. Until then, the company has a submitted application and a Priority Review request, not an accepted filing, a Priority Review designation or an approved myelofibrosis indication.