U.S. Food and Drug Administration (FDA) staff members appear to have substantial concerns related to the safety of car­filz­o­mib.

The FDA this morning published its internally prepared briefing document for this Wednesday's meeting of the agency's Oncologic Drugs Advisory Committee (ODAC) (see related Beacon ^[1] news).

At that meeting, the committee will review data related to Onyx Pharma­ceutical's (NASDAQ:ONXX) application to have carfilzomib ^[2] (Kyprolis ^[3]) approved as a new treat­ment for re­lapsed / refractory multiple myeloma.

The FDA report released this morning states that the agency's staff is "very concerned" about "severe toxicities, including deaths" that have been observed in association with the use of car­filz­o­mib.

Because the source of the toxicities is uncertain, and because -- according to the FDA staff -- car­filz­o­mib may not offer an efficacy advantage over existing myeloma ther­a­pies, the FDA believes "the risks of car­filz­o­mib may not outweigh its benefits."

Onyx's stock is trading down about 2 per­cent at midday while the over­all stock market is relatively unchanged.

Safety Concerns

In its briefing document, the FDA staff lays out three primary areas of concern related to car­filz­o­mib's safety.

First, the staff notes that a total of up to nine deaths due to heart-related issues occurred during car­filz­o­mib Phase 2 trials involving 526 myeloma patients.   Overall, 23 per­cent of the patients in the trials experienced heart-related side effects of any degree of severity, including congestive heart failure, cardiac arrest, or irregular heart rhythm.

It should be noted that Onyx and the FDA apparently disagree on how many deaths during the car­filz­o­mib trials should be attributed to heart-related causes.  Onyx reported only four such deaths in a summary of the trial data it provided the FDA.  The agency, however, identified up to five addi­tional deaths that it believes are likely to have been heart-related.

Second, the FDA analysis of car­filz­o­mib trial data reveals that 70 per­cent of myeloma patients in car­filz­o­mib's trials had lung-related side effects such as shortness of breath, blood clots in the lung, and fluid accumulation in the lungs.  Most of the lung-related side effects, however, were mild or mod­er­ate.

Finally, the FDA staff report notes that two deaths due to liver-related issues occurred during the car­filz­o­mib Phase 2 trials.

Based on these and other safety-related data, the FDA report concludes that "there are a number of patients with re­lapsed multiple myeloma who are at high risk of developing life-threatening" heart-related side effects if treated with car­filz­o­mib.

In addi­tion, the FDA report char­ac­ter­izes the lung-related side effects among car­filz­o­mib-treated patients as "significant."  It also considers the same to be true -- albeit "to a lesser extent" -- for the liver-related side effects observed during car­filz­o­mib's trials.

The FDA criticism of car­filz­o­mib's safety will come as a surprise to many who have followed the drug during its devel­op­ment.  Until recently, discussions about the drug's safety have focused on the levels of periph­eral neu­rop­athy (pain and tingling in the extremities) observed among patients taking the drug.

In particular, car­filz­o­mib was believed to cause less periph­eral neu­rop­athy than Velcade ^[4] (bor­tez­o­mib), a drug similar to car­filz­o­mib that already is approved by the FDA as a treat­ment for myeloma.  As a result, car­filz­o­mib was often char­ac­ter­ized as a "safer version of Velcade."

Other Important Aspects Of The FDA Advisory Committee Meeting Materials

The FDA staff report also contains several other items that are likely to receive attention during Wednesday's advisory committee meeting.

In regard to car­filz­o­mib's efficacy, the FDA reports that the over­all response rate for the drug is approx­i­mately 22 per­cent.  This is the response rate among the same re­lapsed / refractory patients for whom Onyx would like the FDA to approve car­filz­o­mib.

The FDA staff does have some concerns, however, related to the calculation of this response rate.

One concern is that almost all patients who received car­filz­o­mib during its clinical trials also received relatively small amounts of dexamethasone ^[5] (Decadron) to counteract infusion-related side effects.  Dexamethasone by itself has anti-myeloma properties and is routinely used in com­bi­na­tion with other myeloma treat­ments.  Thus, the FDA notes in its report that the agency cannot tell exactly how much of the response rate it has calculated for car­filz­o­mib is due to car­filz­o­mib alone, and how much is due to dexa­meth­a­sone.

In addi­tion, the FDA report notes that the calculation of car­filz­o­mib's over­all response rate is based on a comparatively small number of patients.  A total of 266 patients were enrolled in the car­filz­o­mib trial for which Onyx submitted data for review by the FDA.  However, only 69 of those patients were unresponsive to, or intolerant of, treat­ments from among the key categories of already approved myeloma treat­ments.  As a result, the FDA's esti­mate of car­filz­o­mib's response rate is based on the experience of this relatively small number of patients.

Despite the concerns the FDA expressed about car­filz­o­mib’s safety and efficacy in the agency’s briefing document, the FDA has not built substantial skepticism into the question it has drafted for its advisory committee to vote on at the end of this Wednesday's meeting.  The FDA has simply asked the committee to vote on whether the risk-benefit assess­ment for car­filz­o­mib is favorable for the targeted re­lapsed / refractory multiple myeloma population.

For addi­tional in­­for­ma­tion, see the FDA briefing document ^[6], errata ^[7], and draft question ^[8] (all PDFs) for the FDA advisory committee.