Carfilzomib On Track For End-of-Year Submission After Surprising Top-line Phase II Results

Onyx's next-generation proteasome inhibitor shows a 24% response rate, 7.4 month durable response as a salvage therapy in multiple myeloma.

Onyx Pharmaceuticals is on track to submit its next-generation proteasome inhibitor carfilzomib by the end of the year in multiple myeloma after its performance in heavily pretreated patients exceeded expectations in the Phase IIb 003-A1 trial.

Top-line data released July 26 showed a 7.4 month duration of response and an overall response rate (partial response or greater) of 24 percent, the primary endpoint. The clinical benefit rate (minimal response or greater) was 36 percent.

Onyx went into the study hoping for a response rate in the high teens and responses that lasted four to six months, CEO Anthony Coles said during a same-day analysts call. "Quite frankly the drug exceed our expectations," Coles said. Patients like those in the A1 study generally have an anticipated 11 percent response rate with median survival of six to 10 months.

Buoyed by the findings, the company plans to meet with the FDA as soon as possible to discuss filing an NDA by the end of the year, with a possible launch in mid-2011 based on submission for accelerated approval and a six-month review.

The results cleared even the "investor bar," which had set durability of response at six months or more and a response rate trending toward 20 percent, JP Morgan analyst Cory Kasimov said in a same-day note. The data provides "meaningfully greater confidence" in Onyx's accelerated approval strategy, as well as in the outcome of Phase III studies, Kasimov said.

Indeed, investors demonstrated their confidence in carfilzomib by boosting the value of Onyx stock over 20 percent by the end of the day. The stock closed at $26.04, up $4.54 or 21.12 percent compared to $21.50 the day before.

If granted accelerated approval, Onyx plans to submit results of the international Phase III ASPIRE study, which began enrolling earlier this month under a Special Protocol Assessment from FDA, as the confirmatory trial required for full approval. ASPIRE is testing lenalidomide (Celgene's Revlimid ) plus dexamethasone against the combination with carfilzomib added in 700 relapsed patients, those who have experienced one to three prior treatments, a slightly less difficult-to-treat population.

The company indicated it might go the accelerated approval route after it released promising data from the ongoing A1 trial at the American Society of Hematology meeting in New Orleans last December (Also see "Carfilzomib Multiple Myeloma Data Do New Onyx Parent Proud At ASH '09" - Pink Sheet, 7 Dec, 2009.). Full data from A1 likely will be presented at this year's ASH meeting in Orlando.

The open-label, single-arm study evaluated 266 patients with relapsed and refractory MM who were refractory to the last treating regimen and who had also received two or more prior therapies, including Velcade , either thalidomide or Revlimid, an alkylating agent, glucocorticoids and an anthracycline. Refractive disease was defined as a response of 25 percent or less or progression during therapy or within 60 days after completion of therapy. Patients in the study had experienced a median of five regimens including 13 drugs.

One piece of information to come is an analysis of the entire intent to treat population, data that could alter downward the study's objective response rate, Robert W. Baird analyst Raymond Christopher cautions in a July 26 note. Christopher also questions whether patients who failed Takeda/Millennium's first-in-class proteasome inhibitor Velcade (bortezomib) should have been re-challenged with that drug before being considered "refractory" for inclusion in the study.

Talking to the multiple myeloma experts, "the feeling is [that] once we refract each of the drugs, we always refract each of the drugs," Ted Love, Onyx head of R&D, asserted during the call. But, "even in patients who have not demonstrated refractiveness to Velcade ... the issue really is do they respond to our drug?" he said.

Love pointed to the results of the 004 Phase II study presented last month at the American Society of Clinical Oncology meeting in Chicago, which compared Velcade-naive and Velcade-experienced patients treated with carfilzomib and found activity in both groups, with "a very impressive response" in the Velcade-naive group. In that study, the single-agent overall response rate was 55 percent and the time to progression was 11.5 months, Love said. Data from that study will be submitted with the carfilzomib NDA, he said.

During the call, Coles and Love were thoroughly quizzed on the Velcade issue, including how many patients had failed Velcade as their last treatment before the study. The primary focus was to be sure patients had relapsed after their last Avastin treatment, said Love, adding that for many patients, Velcade would have been part of that regimen. Love later acknowledged that one patient had been allowed into the study without having failed Velcade and that the oversight had been accounted for in the analysis. "Our numbers actually discount that event," he said.

Carfilzomib's Safety Profile Is A Differentiator

Typical of a first-in-class drug Velcade, approved in 2007, validated its target, the proteasome, as an oncology target and was welcomed heartily as an addition to the oncologic armamentarium, in this case as a tool against hematological cancers. Velcade had $1.4 billion in 2009 sales, a market share Onyx aims to dent.

But also typical of first-in-class, Velcade's approach to proteasome regulation is comparatively indiscriminate, and it is associated with off-target side effects such as neuropathy. Millennium and others in the industry, including Onyx, are working to overcome its shortcomings with more refined drugs (Pharmaceutical Approvals Monthly, April 2010).

Unlike Velcade, carfilzomib has shown little cross-reactivity with other catalytic sites on the proteasome, potentially limiting effects such as neuropathy. Safety data presented at ASH on the first 141 patients showed a peripheral neuropathy rate of only 0.7 percent, Michael Kauffman, Onyx's chief medical officer, said on the call. "We haven't seen anything substantially different than that going forward," he added. The second key point is that long-term treatment with carfilzomib doesn't appear to exacerbate the peripheral neuropathy treatment-experienced patients had coming into the study, he said.

[Editor's note: This paragraph was updated July 28 to correct an earlier posting error.]

- Shirley Haley ([email protected])