FDA accelerated approval sought for myelofibrosis combo therapy

Karyopharm Therapeutics said it is on track to file an application this month seeking U.S. Food and Drug Administration (FDA) accelerated approval of its oral therapy selinexor, when combined with Jakafi (ruxolitinib), for adults with myelofibrosis.

Accelerated approval is a pathway that allows treatments for serious conditions to be marketed based on preliminary evidence of their efficacy in clinical trials, with full approval contingent on additional clinical trial data confirming the therapy’s benefits. Karyopharm said it will request FDA priority review, which shortens the review period to six months from the standard 10 months. The company said it also plans to advance regulatory activities with its partners to support potential regulatory filings outside the U.S.

“Our planned submission under the accelerated approval pathway represents the beginning of an important new chapter for Karyopharm and an important milestone for the myelofibrosis community,” Richard Paulson, Karyopharm’s president and CEO, said in a company press release.

Jakafi, marketed by Incite and Novartis, is approved to treat intermediate- or high-risk myelofibrosis. Selinexor is cleared for use, under the brand name Xpovio, to treat multiple myeloma and certain other blood cancers.

“If approved, selinexor plus Jakafi would become the first combination treatment for myelofibrosis, introducing a novel therapeutic mechanism for the treatment of this disease,” Paulson said. “Our planned submission follows productive engagements with the FDA,” he said, adding that the company looks forward to “continuing to work closely” with the agency.

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Spleen shrinkage as evidence of efficacy

Clinical trial data showed that the combination treatment resulted in sustained reductions in the size of the spleen, which often becomes enlarged in myelofibrosis. The company said the FDA considered this a “reasonably likely surrogate [outcome] to predict overall survival,” meaning it can be used as preliminary evidence of the combination’s efficacy.

Myelofibrosis forms when the bone marrow produces an excess of abnormal blood cells, causing inflammation and tissue scarring (fibrosis). This makes it difficult for the bone marrow to produce healthy blood cells. The spleen typically tries to compensate for abnormal blood cell formation, becoming enlarged.

The selinexor-Jakafi combination treatment is intended to target cancer cells through two different mechanisms.

Jakafi is an oral JAK inhibitor, meaning it works by suppressing a group of enzymes known as JAKs that are involved in the production and growth of blood cells. Because these enzymes are overly active in myelofibrosis, blocking them is expected to reduce myelofibrosis symptoms, including an enlarged spleen. However, about two-thirds of myelofibrosis patients who take JAK inhibitors don’t see significant reductions in spleen size.

Selinexor works by blocking XPO1, a protein that transports regulatory proteins — including those involved in tumor suppression — out of a cell’s nucleus, where all DNA is stored. These regulatory proteins accumulate in the nucleus, where they can suppress signaling pathways essential for cancer cell growth and survival.

The planned application is based mainly on positive data from an ongoing global, Phase 3 clinical trial, called SENTRY (NCT04562389). That study is testing how well selinexor plus Jakafi works as a first-line treatment compared with a placebo plus Jakafi in adults with myelofibrosis who have never received JAK inhibitors.

Top-line data showed that significantly more participants on the combination treatment achieved a 35% reduction in spleen volume after about six months (49.8% vs. 28%), meeting one of the trial’s main goals.

Early survival data, after about one year, also suggested a 57% lower risk of death with the combo compared with Jakafi alone. But because these survival results are preliminary, more follow-up data are needed to clarify the effects of selinexor plus Jakafi on survival.

“Together with the continued scientific engagement we are seeing across the myelofibrosis community, we believe the strength and consistency of the SENTRY data reinforce the potential of selinexor to fundamentally change the treatment of patients with myelofibrosis,” Paulson said.

Karyopharm is also continuing SENTRY-2 (NCT05980806), a global Phase 2 trial testing two selinexor doses in combination with Jakafi. Enrollment in the first, 60 mg dose group is complete, with 29 participants, while enrollment continues in the second, 40 mg dose group. Top-line data from the 60 mg group are expected later this year.