Missing one of its co-primary endpoints could make it difficult for Karyopharm Therapeutics to score conventional approval for Xpovio in myelofibrosis, according to Jefferies analysts.
Karyopharm Therapeutics’ push to expand its multiple myeloma drug Xpovio into myelofibrosis has hit a speedbump. Tuesday, the biotech unveiled mixed results in a Phase 3 myelofibrosis study, with an investigational Xpovio regimen meeting just one of two primary endpoints.
Following the readout, the company’s shares dropped to $5.44 apiece at market close, an 18.3% decrease from its previous closing price.
Karyopharm nevertheless intends to engage with the FDA to discuss “the totality of the data” and see how that might shape up to a regulatory path forward for Xpovio in this indication, according to a Tuesday release. Jefferies, however, isn’t optimistic: “We see low chance of conventional FDA approval w/ current dataset,” analysts told investors in a note sent the same day.
Xpovio is an oral nuclear export inhibitor that was approved in 2019 in combination with dexamethasone for patients with relapsed or refractory multiple myeloma who have undergone at least four prior lines of therapy. Last year, the drug made $114.9 million. Karyopharm forecasts net U.S. product revenue to be between $115 million to $130 million this year.
In the Phase 3 SENTRY study, Karyopharm combined Xpovio with ruxolitinib, a JAK inhibitor that is marketed by Incyte under brand names such as Jakafi and Opzelura. The trial enrolled more than 350 patients with myelofibrosis and who had never been treated with JAK inhibitors. Comparators were given placebo plus ruxolitinib.
At 24 weeks, 50% of patients treated with the Xpovio combo achieved at least a 35% decrease in spleen volume, a key disease marker. At the same time point, 28% of comparators on ruxolitinib alone hit this endpoint, resulting in a statistically significant advantage for the Xpovio regimen.
Xpovio was able to sustain this benefit over time, with 47% of patients maintaining a 35% spleen volume reduction by 36 weeks, versus 23% in controls.
However, the Xpovio regimen failed to hit SENTRY’s other co-primary endpoint of symptom improvement, as measured by a change in the absolute total symptom score. Patients treated with Karopharm’s combo saw a 9.89-point improvement in the scale, versus 10.86 points in those who received ruxolitinib alone.
A key opinion leader consulted by RBC Capital Markets “did not seem as concerned about the trial not hitting on its symptom scale endpoint,” the firm told investors in a Tuesday note. The expert, RBC continued, pointed out that ruxolitinib’s symptomatic benefits “are so robust that . . . it may not be possible for any drug to hit on this endpoint.”
What interested the expert more were the survival signals that Karyopharm reported. The biotech touted “promising” overall survival (OS) outcomes in its Tuesday release, with the Xpovio- ruxolitinib combo reducing the risk of death from any cause by 57% versus controls. A posthoc analysis also showed that the spleen volume response could be predictive of overall survival.
While RBC’s key opinion leader has expressed “some caution” about whether this survival signal is real, he nevertheless “believes this would be a very meaningful finding if it plays out longer-term,” the firm said. A significant survival benefit, analysts added, would trump the symptom score miss.
Karyopharm intends to present its OS data to the FDA in building its case for Xpovio’s expansion into myelofibrosis, the biotech said on Tuesday, though it did not yet provide a specific timeline for when such a filing could occur.
