Selinexor

Karyopharm Therapeutics has announced plans to submit a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) in August 2026, seeking accelerated approval for selinexor in combination with ruxolitinib for the treatment of patients with myelofibrosis, a rare and debilitating blood cancer. The planned submission follows discussions with the FDA, during which the agency indicated that achieving 35 percent or greater spleen volume reduction (SVR35) appears to be a reasonably likely surrogate endpoint capable of predicting overall survival, making it suitable to support an application under the accelerated approval pathway. To confirm long-term clinical benefit, Karyopharm intends to rely on overall survival data from the ongoing Phase 3 SENTRY trial, where overall survival is a pre-specified secondary endpoint. The study remains blinded, with no patient crossover permitted, allowing continued unbiased assessment of treatment outcomes. If approved, the combination of selinexor and ruxolitinib would become the first approved combination therapy for myelofibrosis, introducing a novel treatment class for patients who currently rely primarily on JAK inhibitor therapy. The sNDA will be supported by results from the randomised, double-blind Phase 3 SENTRY trial, which compared selinexor plus ruxolitinib with placebo plus ruxolitinib in previously untreated, JAK inhibitor-naïve patients with myelofibrosis. The study demonstrated a statistically significant improvement in spleen volume reduction at Week 24, along with rapid, deep and sustained spleen responses. Investigators also reported encouraging signals for overall survival, reductions in variant allele frequency—suggesting potential disease modification—and a favourable overall safety profile. Karyopharm also plans to request Priority Review for the application. If granted, the FDA is expected to issue a decision approximately six months after accepting the filing under the Prescription Drug User Fee Act (PDUFA) timeline. The SENTRY trial enrolled 353 JAK inhibitor-naïve patients with platelet counts above 100 × 10?/L, who were randomized in a 2:1 ratio to receive either once-weekly 60 mg selinexor plus ruxolitinib or placebo plus ruxolitinib. The study's co-primary endpoints include achieving SVR35 at Week 24 and improvement in total symptom score over 24 weeks. Results from the trial were presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, simultaneously published in the Journal of Clinical Oncology, and later featured at the 2026 European Hematology Association (EHA) Congress, where the presentation was recognised among the conference's six best abstracts. Myelofibrosis affects an estimated 20,000 patients in the United States and 17,000 patients across the European Union. The disease causes progressive scarring of the bone marrow, enlarged spleen, anaemia and debilitating symptoms including fatigue, abdominal discomfort, early satiety, night sweats and bone pain. Current approved treatments are primarily limited to JAK inhibitors, highlighting the need for innovative therapeutic options.

Reporting a new miss in one indication, Karyopharm Therapeutics is plowing ahead with plans to advance its XPO1 inhibitor Xpovio in another, despite investors blanching at that dataset back in March. First up, Karyopharm has reported new results from its phase 3 trial of Xpovio (selinexor) as a maintenance treatment in adults with TP53 wild-type advanced or recurrent endometrial cancer. The study missed its primary endpoint of progression-free survival (PFS), although Karyopharm on Thursday pointed to a trend in favor of the study drug in a modified population, with a median PFS of 12.75 months was clocked on Xpovio versus 7.43 months on placebo. For the modified population of 236 patients, the XPORT-EC-042 study assessed Xpovio as maintenance therapy after chemotherapy, or after chemotherapy plus a checkpoint inhibitor, in patients with TP53 wild-type tumors and proficient mismatch repair (pMMR) status, or deficient status (dMMR) who are ineligible to receive checkpoint inhibitors. The original trial population looked at all patients with TP53 wild-type tumors, regardless of MMR status. Xpovio overcame numerous speed bumps to secure its first-ever approval as a fifth-line treatment for multiple myeloma in 2019, and about a year later, the FDA cleared the drug for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), too. However, the FDA rescinded that accelerated nod in DLBCL in May of this year. Now, hopes of propelling the drug forward in endometrial cancer—where the company had to rework its trial plans in 2022—appear dimmer, as well. Karyopharm’s stock price has taken a beating since late Thursday and was down more than 68% around 9:30 am ET on Friday, July 31. "While disappointed by these unexpected results, we believe they advance the scientific understanding of XPO1 inhibition for tens of thousands of endometrial cancer patients worldwide. We are deeply committed to further investigating these data," Reshma Rangwala, M.D., Ph.D., Karyopharm’s chief medical officer and head of research, said in a July 30 statement. "While the results we are announcing today fell short of our expectations, they do not diminish our confidence in the broader potential of selinexor and benefit of XPO1 inhibition," added CEO Richard Paulson. "We remain focused on maximizing our opportunity in myelofibrosis and continuing to build on our profitable multiple myeloma business.” On that latter point, news of the miss in the late-stage endometrial cancer study—dubbed XPORT-EC-042—dovetailed with the announcement that Karyopharm plans to file its investigational combo of Xpovio and Incyte and Novartis’ Jakafi (ruxolitinib) for a U.S. accelerated approval in myelofibrosis in August, with hopes of securing a priority review. If the regimen were to win approval, it would become the first FDA-sanctioned combination therapy for adult myelofibrosis patients, Karyopharm pointed out in a release. The company reported mixed results on the combo this past spring, with the phase 3 trial meeting one of two primary endpoints. Namely, the Xpovio regimen charted a statistically significant improvement in spleen volume reduction of 35% or more compared to a Jakafi-and-placebo control, with spleen responses observed in 50% of patients on the study drug regimen versus 28% in the control arm. But the study missed on a co-primary endpoint around patient-reported symptom scores at 24 weeks compared to baseline. In Thursday’s release, Karyopharm said it is plotting its submission on the heels of “productive engagements” with the FDA, which included written feedback that spleen volume reduction of 35% or more “appears to qualify as a reasonably likely surrogate endpoints (RLSE) to predict overall survival and can be used to support an sNDA under the accelerated approval pathway.” Karyopharm added that it plans to use overall survival data from a long-term follow-up of its phase 3 Sentry trial to confirm that clinical benefit. While the company is hopeful about Xpovio’s prospects in myelofibrosis, this could be the end of the road for the oncology drug in endometrial cancer, where the FDA had already given Xpovio the side eye as a maintenance treatment once before. Three weeks after announcing a phase 3 win for its drug for advanced or recurrent endometrial cancer patients who had responded to front-line chemotherapy back in 2022, Karyopharm revealed that a meeting with the FDA had made it clear that the parties “had differing views on the study significance and overall clinical benefit” of Xpovio’s phase 3 Siendo study. That prompted Karyopharm to launch a new study in TP53 wild-type patients, which ended in a flop.