Adcom gives Karyopharm a second chance with selinexor

Incredibly, a US FDA panel has left the door open for approval of Karyopharm’s selinexor in multiple myeloma, despite concerns about safety.

Policy and regulation

The approval of Karyopharm Therapeutics’ selinexor in multiple myeloma has been delayed on worries about its efficacy and, more importantly, safety. But a US FDA advisory committee stopped short of rejecting the project outright yesterday in a vote that was closer than had been expected.

After damning briefing documents highlighted an increased death rate with selinexor in a different use, acute myeloid leukaemia, some might wonder what a drug needs to do to get a definitive thumbs-down. Karyopharm’s stock fell 20% in premarket trading this morning, but it could have been much worse.

In the end, panellists voted 8-5 that a decision on selinexor be delayed until the Boston trial yields results, due by the end of this year or early in 2020. The study is testing selinexor plus Velcade and dexamethasone, versus Velcade and dexamethasone alone, in multiple myeloma patients who have received one to three prior therapies.

Stormy panel

Boston is therefore looking at a less severe population than the single-arm, open-label Storm trial on which selinexor’s accelerated approval filing was based. Storm evaluated selinexor plus dexamethasone in patients who had received at least three prior therapies, and found a 25.4% objective response rate (Karyopharm hopes to Storm the multiple myeloma market, 1 May 2018).

Friday’s pre-panel documents questioned how much of this was down to selinexor, given that high-dose dexamethasone has led to response rates of 10-27% in historical studies. Boston could give a clearer answer on this, given that it includes an active comparator.

More worrying was the safety profile of Karyopharm’s project: all patients in Storm experienced at least one treatment-emergent adverse event, leading to death in 8% of cases. There was also a high rate of dose modifications and discontinuations due to adverse events.

Results from the Sopra study in AML raised further concerns. Notably this did include a control arm, in which patients received best supportive care or chemotherapy. Overall survival was numerically worse with selinexor than control, which the FDA’s briefing documents put down to the agent's toxicity.

Karyopharm had not previously disclosed these results, instead merely saying in 2017 that the Sopra trial had been stopped for lack of efficacy.

Despite these issues, the company now has another bite at the cherry with selinexor. Panellists in favour of the project’s approval pointed to the severity of late-line multiple myeloma and the lack of other options, both of which could work in the company’s favour.

The closeness of yesterday’s vote suggests that, remarkably, Karyopharm could still snatch victory from the jaws of defeat. But it still needs to get a result – and show an acceptable safety profile – with selinexor in Boston.

Notable trials of selinexor
Study Setting Design Trial ID Data
Boston Multiple myeloma (1-3 prior treatments) Selinexor + Velcade + dex vs Velcade + dex NCT03110562 YE2019/2020
Storm Multiple myeloma (penta/quad-refractory)  Single-arm, selinexor + dex NCT02336815 25.4% ORR
Sopra Relapsed AML Selinexor vs physician's choice chemo NCT02088541 Median OS 94 days, vs 170 days for control
Dex: dexamethasone. Source: EvaluatePharma,

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