Karyopharm gets an Xpovio blow

Like other myelofibrosis hopefuls before it, Karyopharm has produced mixed data from the Sentry trial of Xpovio. The study hit on one co-primary endopoint – spleen volume reduction – but failed on symptom improvement.

The company still hopes for FDA approval, bolstered by what it called a “promising” signal on overall survival. But investors were less impressed, with Karyopharm’s stock falling 13% on Tuesday morning.

The cash-strapped group therefore looks unlikely to be able to raise money from the public markets, but it’s assuaged its most pressing need for funds, also announcing a $30m private placement. However, the money will only keep it going until the third-quarter, so merely kicks Karyopharm’s problems slightly down the road.

Standing Sentry

The big problem now is whether Xpovio is approvable in first-line myelofibrosis based on Sentry, which compared a combination with Jakafi, versus Jakafi alone.

The first co-primary endpoint was the proportion of patients with a 35% or greater spleen volume reduction (SVR35) at 24 weeks. Here, the result was emphatic, with 50% in the combination arm hitting this metric, versus 28% in the control cohort. A benefit was maintained at 35 weeks.

The other co-primary endpoint was change in total symptom score from baseline to week 24. This endpoint has proven tricky for other myelofibrosis contenders, and this also proved the case for Xpovio. There was no difference here between the combination and control; in fact, Jakafi alone was numerically ahead with a 10.86-point improvement, versus a 9.89-point improvement for Xpovio plus Jakafi.

Data from Sentry trial of Xpovio in first-line myelofibrosis

Note: *co-primary endpoint; **nominal p value. TSS=total symptom score. Source: company presentation.

On a call to discuss the data Sentry’s lead investigator, Mount Sinai’s Dr John Mascarenhas, played down the importance of symptom improvement, saying that Jakafi is already “quite potent” in reducing symptom burden, and has set a high bar to clear. He contended that spleen volume reduction wasn’t just a regulatory endpoint, but also a surrogate for improved survival.

And here, Karyopharm believes it has a trump card. The company highlighted an early analysis of OS, a secondary endpoint, showing a 57% reduction in the risk of death with the combo versus Jakafi alone.

Still, Mascarenhas dodged a question of how a spleen volume reduction at 35 weeks had already translated into an OS benefit of this magnitude. In any case, Karyopharm will continue to follow OS to maturity, although execs wouldn’t say when more data on this endpoint might be available.

As for adverse events, Xpovio plus Jakafi was linked with more grade 3 or higher adverse events – the company didn’t break these out, but low-grade adverse events were largely gastrointestinal or haematologic. The combo was also associated with a higher rate of discontinuations, although Karyopharm characterised the safety profile as “manageable” and said any toxicity was outweighed by its benefits.

Poor precedent

It will now be up to the FDA to decide whether this is indeed the case. The precedent doesn’t look great for Karyopham: AbbVie’s Bcl-2/Bcl-XL inhibitor navitoclax succeeded on SVR35 when combined with Jakafi, but the combo was numerically worse than Jakafi on TSS, and the project ended up being discontinued. 

Meanwhile, Novartis bought MorphoSys for €2.7bn on the promise of the latter’s BET inhibitor pelabresib, despite a Jakafi combo failing to beat Jakafi alone on TSS; the project appeared to have done enough on subgroup analyses to secure the Swiss group’s buy-in. That was until a US filing had to be abandoned in 2024, largely because of toxicity, though a new phase 3 study is now starting.

Karyopharm will hope the OS signal is enough to set apart Xpovio, a CRM1-mediated nuclear export inhibitor that’s already approved for second-line and relapsed/refractory multiple myeloma, and has an accelerated nod for late-line diffuse large B-cell lymphoma.