Karyopharm seeks FDA green light for myelofibrosis combo treatment
Application based mainly on positive data from ongoing Phase 3 clinical trial
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Karyopharm Therapeutics has submitted an application to the U.S. Food and Drug Administration (FDA) seeking approval of its oral therapy selinexor, in combination with Jakafi (ruxolitinib), for adults with myelofibrosis.
Jakafi, marketed by Incyte and Novartis, is already approved to treat intermediate-risk or high-risk myelofibrosis. Selinexor is cleared under the brand name Xpovio for the treatment of multiple myeloma and certain other blood cancers. Karyopharm is now seeking to expand selinexor’s approval to include its use with Jakafi for myelofibrosis.
The supplemental new drug application is based mainly on positive data from an ongoing global, Phase 3 clinical trial, called SENTRY (NCT04562389). That data showed that adding selinexor to Jakafi nearly doubled the proportion of patients who achieved a clinically meaningful reduction in spleen size, which often becomes enlarged in myelofibrosis. The combination also showed signs of improving overall survival, although longer follow-up is needed to confirm these findings.
“Today’s submission is an important step toward our goal of bringing the combination of selinexor plus ruxolitinib to patients with myelofibrosis who continue to face a significant unmet need,” Reshma Rangwala, MD, PhD, chief medical officer and head of research of Karyopharm, said in a company press release.
Karyopharm submitted the application through the FDA’s accelerated approval pathway, which allows treatments for serious conditions to be marketed based on preliminary evidence from clinical trials that they are likely to provide a clinical benefit. Additional trial data are generally needed to confirm the benefit and support full approval.
The company also requested priority review, which, if granted, could shorten the FDA review period from the standard 10 months to six months. Karyopharm expects to learn the FDA’s decision on whether the application has been accepted for review and the anticipated review timeline by the end of this year.
Jakafi, selinexor use different mechanisms
Myelofibrosis is a type of blood cancer in which excessive production of abnormal blood cells in the bone marrow is associated with inflammation and scarring, or fibrosis. This makes it harder for the bone marrow to produce healthy blood cells. The spleen typically compensates for abnormal blood cell production, leading to its enlargement.
Jakafi is an oral JAK inhibitor that blocks enzymes involved in blood cell production and growth that are overly active in myelofibrosis. The treatment can help shrink an enlarged spleen and ease other myelofibrosis symptoms. However, not all patients respond adequately, and about two-thirds don’t see significant reductions in spleen size.
Selinexor works differently. It blocks XPO1, a protein that carries regulatory proteins — including those that help suppress tumors — out of the cell’s nucleus, where DNA is stored. Blocking XPO1 causes these proteins to build up in the nucleus, where they can interfere with processes that cancer cells rely on to grow and survive.
Combo therapy shows potential survival benefit
The SENTRY trial is evaluating a once-weekly dose of selinexor (60 mg) plus Jakafi versus Jakafi plus placebo in adults with myelofibrosis who have not previously received a JAK inhibitor.
After 24 weeks (about six months), nearly half (49.8%) of patients given the combination had at least a 35% reduction in spleen volume, compared with 28% of those given Jakafi alone. The difference was statistically significant, meeting one of the trial’s main goals.
The trial’s other main goal was to assess changes in myelofibrosis symptoms. Symptoms lessened in both groups, but adding selinexor did not significantly ease them compared to using Jakafi alone.
Early findings also pointed to a potential survival benefit. After a median follow-up of about one year, patients whose spleen volume decreased by at least 35% tended to have a lower risk of death. The risk of death was also 57% lower among those given selinexor plus Jakafi than among those on Jakafi alone.
However, the survival findings remain preliminary, and longer follow-up is needed to clarify selinexor’s effects on survival.
We believe the strength of these data underscores the potential of this novel combination to deliver meaningful long-term benefits and fundamentally change the treatment of patients with myelofibrosis.
Exploratory findings also suggested selinexor might be affecting the underlying disease. After about six months, 32% of patients on the combination had at least a 20% drop in variant allele frequency (VAF) — the proportion of blood cells carrying a cancer-associated mutation — compared with 23.9% of those on Jakafi alone.
“The SENTRY trial generated compelling and consistent results, including rapid, deep and sustained spleen responses across a broad range of patients, together with a promising overall survival signal and important evidence of disease modification,” Rangwala said.
For accelerated approval, the FDA would need to agree that a reduction in spleen volume of at least 35% can serve as a surrogate endpoint — a measure expected to predict, but not yet prove, a real clinical endpoint — for overall survival.
Karyopharm also plans to continue following SENTRY participants to collect longer-term survival data, which would be used to confirm the treatment’s benefit and potentially support selexinor’s full approval.
“We believe the strength of these data underscores the potential of this novel combination to deliver meaningful long-term benefits and fundamentally change the treatment of patients with myelofibrosis,” Rangwala added.
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