It's not all roses for onyx. Looks like there are some concerns.
FDA “Very Concerned” About Carfilzomib’s Safety
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 news).
At that meeting, the committee will review data related to Onyx Pharmaceutical’s (NASDAQ:ONXX) application to have carfilzomib (Kyprolis) 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.
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.
The original poster is reposting the staff findings which caused so many to disastrously short ONXX ahead of the FDA panel meeting. The key summation point, "the risks of carfilzomib may not outweigh its benefits" was misread by many to mean the reverse: that the risks did outweigh the benefits. In fact, Bloomberg and others, in reporting the story, omitted the crucial "not" from the phrase, thereby making rejection seem like a foregone conclusion. The poster seems to be clinging to the this discredited (and costly) misinterpretation.
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 (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 (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, errata, and draft question (all PDFs) for the FDA advisory committee.