Karyopharm investors seemed as surprised as anyone by a positive result from the Storm study of selinexor. The data, in heavily pretreated multiple myeloma, should be enough to give the company a foothold in an increasingly crowded market.
But to really make a mark in multiple myeloma Karyopharm will need to move selinexor into earlier therapy lines – and data from the Boston trial, in patients who have received one to three prior treatments, will not be available until next year.
A win here would be needed for selinexor to achieve the peak $725m US multiple myeloma sales forecast by Leerink analysts, who believe that only $215m of these will come from the penta-refractory population studied in Storm. Jittery shareholders, who deserted Karyopharm yesterday ahead of the readout from part two of the phase IIb Storm trial – only to pile back in when the data were reported after the markets closed – face another nervous wait.
In the meantime, Karyopharm believes that the single-arm Storm trial will be enough for accelerated approval in penta-refractory patients before using Boston, if positive, to support full approval in patients relapsing after at least one prior therapy.
Company executives and investigators from the Storm trial noted on a conference call today that there were few options for this very sick population, which might spur the agency to look favourably on selinexor. Patients in Storm had failed on various approved multiple myeloma therapies including Celgene’s Revlimid and Johnson & Johnson’s Darzalex.
Selinexor’s novel mechanism – it is a first-in-class XPO1 inhibitor – could help its positioning as a therapy of last resort. And oral delivery could give the project a convenience advantage over potential challengers from the CAR-T arena, including BCMA-targeting agents such as Bluebird/Celgene’s bb2121 and Nanjing Legend Biotech’s LCAR-B38M.
“Selinexor could be universally applicable – unlike CAR-T,” said Sundar Jagannath of the Mount Sinai School of Medicine, a researcher on the Storm trial. On the conference call he suggested that patients might receive selinexor in the community setting while awaiting CAR-T therapy, pointing out that, at best, his centre was only able to treat one CAR-T patient per month.
Another Storm investigator, Paul Richardson of the Dana-Farber Cancer Institute, added that selinexor might also prove an important option in patients who have progressed on CAR-T.
Some Karyopharm investors might be wishing that they had shown more nerve ahead of the readout, which showed a 25.4% objective response rate with selinexor plus dexamethasone, better than the 20% seen in part one (Upcoming events – Karyopharm and Aveo hope data can satisfy US regulators, March 23, 2018).
A slightly shorter median duration of response was recorded in part two, 4.4 months versus five months in part one – but this was clinically meaningful, said Dr Richardson.
The Leerink analysts wrote that a response rate of 20-21% or over should be enough for approval in penta-refractory patients.
Lack of safety therefore seems like the only potential stumbling block. Karyopharm did not give detailed safety data, but said that adverse events were in line with previous results, which included gastrointestinal and haematological toxicity. The company said nausea, vomiting and lost appetite could be controlled with supportive care and dose modification, and Dr Richardson added that selinexor’s side-effect profile was “real but manageable”.
Karyopharm’s chief executive, Michael Kauffman, admitted that the 18% discontinuation rate in part one of Storm was higher than that seen with other multiple myeloma agents used in earlier lines of therapy, but added that this was to be expected in the sicker penta-refractory population, and should come down with better management of selinexor’s side effects.
Still, this could become more important if the project does move into earlier use, and is no doubt something that investors will be watching for when the Boston trial reports.
Karyopharm is also studying selinexor in diffuse large B-cell lymphoma, with top-line results due from the Sadal trial by the end of the year, and liposarcoma.
But the Boston study, evaluating selinexor in combination with Velcade and dexamethasone, will be its big test. Maybe investors will be more confident this time as readout approaches.
|Study||Setting||Trial ID||Data due|
|Storm||Multiple myeloma (penta-refractory)||NCT02336815||Reported|
|Sadal||Diffuse large B-cell lymphoma||NCT02227251||Year end 2018|
|Boston||Multiple myeloma (1-3 prior treatments)||NCT03110562||2019|