BioPharma

FDA panel votes to delay Karyopharm myeloma drug’s approval amid safety concerns

Shares of the company were down more than 12 percent in premarket trading on the Nasdaq Wednesday. They had already fallen 46 percent Friday after the release of AdCom briefing documents.

A Food and Drug Administration decision on a drug for the blood cancer multiple myeloma will be delayed due to concerns about toxicity and also difficulty interpreting data from the clinical trial.

The FDA’s Oncologic Drugs Advisory Committee voted 8 to 5 in favor of delaying the decision whether or not to approve Karyopharm Therapeutics’ selinexor in combination with the steroid dexamethasone until results of the randomized Phase III trial are available.

Shares of Newton, Massachusetts-based Karyopharm were down more than 12 percent in premarket trading on the Nasdaq Wednesday. They had already fallen 46 percent Friday due to skeptical statements about clinical trial data the company had submitted in the advisory committee briefing documents. Advisory committees, or AdComs, are panels of outside experts the FDA convenes when it needs additional expertise to help it decide whether or not to approve a drug. AdCom votes are not binding in approval decisions, but the FDA usually follows them.

The company had been seeking accelerated approval for selinexor with dexamethasone in multiple myeloma patients based on the Phase IIb STORM study in patients who were “triple-class” refractory to at least three therapies, including a proteasome inhibitor, an immunomodulating drug and a CD38-targeting monoclonal antibody. With the AdCom vote, the FDA’s decision will instead be delayed until results of the Phase III BOSTON study are available.

Despite the unfavorable outcome, SVB Leerink gave Karyopharm’s stock an “outperform” rating, with a $14 price target. Analyst Jonathan Chang wrote that the arguments posed by one AdCom panelist who voted in favor of recommending accelerated approval were “particularly persuasive.” In particular, Chang wrote that the panelist said there is precedence on other approved myeloma drugs on safety and efficacy, while historical response rates for dexamethasone alone cited in the briefing documents are “highly unlikely” to be achieved today. Moreover, randomizing patients in such a late-line treatment setting would not be realistic, feasible or ethical, according to Chang.

Selinexor is a selective inhibitor of nuclear export, or SINE drug. It works by binding with and inhibiting XPO1, a nuclear export protein, designed to lead to the accumulation of tumor-suppressing proteins inside cell nuclei. This, in turn, is meant to restart their tumor suppressor function.

The main issues raised in the briefing documents last week were that STORM was a single-arm study, toxicity and dose selection. The single-arm design made it difficult to interpret the data, which showed 25.4 percent of 122 patients responding to the combination. Because historical studies have shown that 10-27 percent of patients respond to dexamethasone, and in a Phase I study selinexor did not demonstrate single-agent efficacy, it is difficult to show whether the drug had an effect in STORM.

There was also significant toxicity associated with the drug. All the patients experienced side effects that occurred during treatment, with two-thirds of them experiencing serious side effects. Most patients required a dose modification due to toxicity, and more than a quarter discontinued treatment due to side effects. The documents also highlighted that a randomized, controlled trial of selinexor in acute myeloid leukemia showed that overall survival was worse for the patients who received the drug than for those who did not.

However, a spokesperson for the company wrote in an email that it is difficult compare the leukemia trial, SOPRA, to the myeloma study because they had different designs and dealt with different diseases and patient characteristics. Moreover, the series side effects in STORM were consistent with the safety profile in triple-class refractory myeloma patients, who are heavily pretreated and have underlying morbidities. He wrote that the two reported treatment-related deaths – one from pneumonia and one from sepsis – were included in the presentation of the STORM data at the American Society of Hematology meeting in December. However, pneunomia is the most common reported infection in myeloma, he noted, and occurred in 11.4 percent of patients in the study.

In terms of criticism over dose selection, the AdCom stated that the dose used in STORM, 45 milligrams per square meter of body area – approximately 80 milligrams total – was better tolerated in the Phase I study than a higher dose. But it was still not well-tolerated given the high rate of side effects and treatment discontinuation. Nevertheless, the company did not evaluate lower doses, which may have been better tolerated.

Photo: FDA, Flickr