Onyx Pharmaceuticals Inc.’s NDA and clinical development program for the investigational multiple myeloma drug Kyprolis (carfilzomib) could be a textbook example of an appropriate accelerated approval plan, satisfying all of the criteria that have been laid out by FDA’s Oncologic Drugs Advisory Committee, panel members said at their June 20 meeting.

Although Onyx sought approval on the basis of one single-arm, Phase II trial, rather than a randomized study generally preferred by FDA and ODAC, this was acceptable given the lack of viable treatment options for heavily pre-treated patients with relapsed/refractory myeloma, committee members said.

Furthermore, the status of the company’s confirmatory trial plans was viewed favorably by the panel. Onyx already has fully enrolled one Phase III trial, and enrollment in another randomized, confirmatory study is expected to begin soon.

These factors, coupled with a 22% response rate and an acceptable toxicity profile in a heavily pre-treated population, led 11 of 12 ODAC members to conclude that carfilzomib had a favorable risk benefit/profile in the relapsed/refractory setting Also see "Onyx’s Kyprolis Sails Through FDA Panel, Boosted By Confirmatory Trial Plans" - Pink Sheet, 20 June, 2012..

A fully enrolled Phase III confirmatory trial, with plans to begin another randomized study soon, were viewed favorably by ODAC members weighing accelerated approval.

“I feel that this application fulfilled the criteria for what we should see for accelerated approval – an unmet need, a drug with, I felt given the setting, a good response rate and certainly a very good duration of response,” committee Chairman Wyndham Wilson, National Cancer Institute, said. “The toxicity profile was really very reasonable given the degree of prior therapy here.”

The fact that the 792-patient, randomized ASPIRE confirmatory trial has been fully enrolled “is in Onyx’s favor,” Wilson added.

The panel’s vote boosts the chances that FDA will grant accelerated approval by the drug’s July 27 user fee date, rather than holding up approval until data from ASPIRE are reported.

Favorable comments by FDA and ODAC on the advanced stage of Onyx’s confirmatory study program should give sponsors a roadmap for navigating the accelerated approval pathway in oncology, where FDA has tightened the approval requirements in an attempt to improve clinical programs and expedite the confirmatory study process.

FDA Briefing Documents Cast A Negative Tone

Onyx is seeking accelerated approval of carfilzomib, a second-generation proteasome inhibitor, based upon the results of Study PX-171-003, a single-arm, Phase II trial of 266 patients.

Subjects were required to have received prior treatment with Millennium Pharmaceuticals Ltd.’s first-generation proteasome inhibitor Velcade (bortezomib) and either of Celgene Corp.’s two immunomodulatory agents – Thalomid (thalidomide) or Revlimid (lenalidomide). Patients also must have received an alkylating agent, either alone or in combination with other multiple myeloma treatments, and an anthracycline, either alone or in combination with other treatments unless not clinically indicated. The median number of prior therapies for patients in the study was five.

Advisory Committee Vote

11-0, with one abstention, that carfilzomib has a favorable risk/benefit assessment for use in treating patients with relapsed and refractory multiple myeloma who have received at least two prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent

Carfilzomib was associated with an overall response rate of 22.9% and a median duration of response of 7.8 months.

However, FDA briefing documents released before the ODAC meeting questioned whether the lone, single-arm trial provided sufficient evidence demonstrating carfilzomib’s benefit over other available therapies in the relapsed/refractory population. “Since carfilzomib produced an ORR of only 22% in the primary efficacy study, it may not provide an advantage over available therapy,” the documents stated.

The briefing documents also raised concerns about serious cardiac, pulmonary and hepatic toxicities seen in the study and highlighted the difficulty of ascertaining whether such events in a single-arm trial are drug-related Also see "Safety Concerns Weigh On Onyx’s Carfilzomib In Multiple Myeloma" - Pink Sheet, 18 June, 2012..

Given the tone of the agency’s briefing documents and the NDA’s reliance upon a single-arm trial, it would not have been surprising had ODAC concluded that carfilzomib’s approval should await confirmatory efficacy and safety data from ongoing Phase III trials.

At a February 2011 meeting on general issues related to accelerated approval and the difficulties of completing confirmatory trials, ODAC said sponsors should seek approval based upon randomized, rather than single-arm, studies, although it made an exception for indications with small patient populations or where drug activity is high. ODAC’s view confirmed the direction in which the agency was already moving in encouraging sponsors to conduct randomized trials for accelerated approval Also see "Accelerated And Accompanied: Oncology Drugs Should Use Randomized Trials, FDA Panel Says" - Pink Sheet, 8 February, 2011..

Given the preference for randomized trials expressed by ODAC and FDA, Onyx’s decision to file for accelerated approval on the basis of a single-arm study was viewed as a risky strategy Also see "Oncology NDAs Based On Single-Arm Studies Run Risk Of FDA Refusal To File" - Pink Sheet, 1 May, 2011..

Confirmatory Trial Plans Are A Plus

However, when it submitted its NDA, Onyx had one big advantage in its favor – two ongoing Phase III trials Also see "Onyx Files Carfilzomib For Accelerated Approval With Two Phase III Trials Ongoing" - Pink Sheet, 28 September, 2011..

At the same 2011 meeting where it emphasized the need for randomized studies, ODAC said sponsors should conduct two confirmatory trials in most cases, and those studies should be ongoing, or at least in an advanced stage of development, at the time of accelerated approval. This recommendation was aimed at addressing the problems with confirmatory trials that either were never completed or were delayed for an extended period of time Also see "FDA Will Make Advisory Committee Review Of Accelerated Approvals An Annual Event" - Pink Sheet, 14 February, 2011..

Onyx is currently conducting the ASPIRE study under a Special Protocol Assessment. The randomized Phase III trial is testing a combination of lenalidomide and dexamethasone, with or without carfilzomib, in 792 relapsed multiple myeloma patients who received one to three prior therapies. The primary endpoint is progression-free survival. The study is fully enrolled, and a final analysis is expected in mid-2014.

Another ongoing study, FOCUS, was designed pursuant to recommendations from the European Medicines Agency and is aimed at gaining global approval. The randomized trial is comparing carfilzomib to corticosteroids and optional low-dose cyclophosphamide in relapsed/refractory patients who have received three or more lines of therapy. The primary efficacy endpoint is overall survival. More than half of the targeted 302 patients had been enrolled as of March 2012; final analysis is projected for mid-2014.

Onyx also recently announced plans for a head-to-head confirmatory study against bortezomib in an earlier disease setting. The ENDEAVOR trial will evaluate the combination of carfilzomib and low-dose dexamethasone against a bortezomib/dexamethasone combination in 888 patients who have disease that relapsed after at least one, but not more than three, prior therapeutic regimens. Enrollment is expected to begin in July, according to ClinicalTrials.gov. The primary endpoint is progression-free survival.

The advanced stage of Onyx’s confirmatory trials program, including the existence of an SPA, stood in contrast to the less developed, post-approval plans for Seattle Genetics Inc.’s lymphoma treatment Adcetris (brentuximab) when it went before ODAC in July 2011.

At that meeting, Office of Oncology Drug Products Director Richard Pazdur (now director of the Office of Hematology and Oncology Products) took Seattle Genetics to task for failing to discuss with the agency a comprehensive development program for the antibody drug conjugate, including the design of trials that could provide the confirmatory evidence under accelerated approval Also see "Adcetris Review Adds Some Clarity To Principles For Accelerated Approval" - Pink Sheet, 25 July, 2011..

Seattle Genetics ultimately agreed to conduct two randomized trials simultaneously to confirm brentuximab’s clinical benefit – these were studies the company had planned to conduct in the front line setting. FDA granted brentuximab accelerated approval in August Also see "Seattle Genetics Commits To Simultaneous Confirmatory Trials For Adcetris" - Pink Sheet, 19 August, 2011..

Pazdur Signals His Approval …

The advanced stage of Onyx’s confirmatory trial plans resonated with ODAC members and Pazdur, whose remarks at the meeting portrayed a far more positive view of the sufficiency of the carfilzomib clinical data and the risk/benefit profile than was suggested in the agency’s briefing documents, indicating a difference of opinion between the office director and the clinical reviewer.

Pazdur acknowledged the shortcomings of single-arm trials but sought to put the carfilzomib data into perspective relative to bortezomib, which received accelerated approval in 2003 and later converted to regular approval.

The existence of a completely enrolled, randomized study “gives us a lot of confidence,” FDA’s Pazdur said.

“One of the things that we had confidence in is … the response rate that’s being presented here is quite similar to what we saw with bortezomib; in fact it’s in a more refractory disease population,” Pazdur said. “Bortezomib went on in confirmatory trials to show clinical benefit.”

Unlike other applications for accelerated approval based upon single-arm trials, “we already have a ... completely enrolled randomized study, so it gives us a lot of confidence in this,” he said.

… As Does ODAC’s Chairman

Wilson said he believed that ODAC’s requirements for accelerated approval, as discussed in February 2011, had been met here. Committee members at that meeting “recommended that even for accelerated approval that a randomized study be done. However, I think that we all recognized that there are settings in which a single-arm trial can be done if, in fact, it is done in a setting in which there is no other standard therapy, and I think that’s the case here,” he said.

“The other recommendation was that confirmatory trials be planned and ideally under way at the time that accelerated approval was granted by FDA. And in the current case the confirmatory trial, which is being done under a SPA, is actually not only … under way but it’s actually completed enrollment,” he said. “So I do think that from the recommendations that came out of the ODAC … that the current submission does fulfill some of the basic endpoints or timeline issues that were recommended.”

Wilson said he believed the 18% ORR in patients who were refractory to bortezomib in their most recent line of treatment suggested carfilzomib has a mechanism that works somewhat differently than the first-generation proteasome inhibitor. “That actually is a very compelling argument that this drug is actually adding something to a drug that is already out there. I think the toxicity spectrum of this, for those of us that treat cancer patients, especially those that have had as much therapy as these have, really is not of major concern so far.” He said he believed the single-arm Phase II study showed a “pretty convincing signal” that is likely to be confirmed in the Phase III trials.

“I think it’s important that there is a Phase III trial that’s ongoing and one that’s due to start,” committee member Ralph Freedman, M.D. Anderson Cancer Center, agreed, suggesting that this should serve as a model for future sponsors seeking accelerated approval.

Committee member Deborah Armstrong, Johns Hopkins University, said she believed the clinical responses seen in the single-arm Phase II trial “are real and, probably even more important, are meaningful in this population.”

With one confirmatory trial having completed accrual and a second study planned in an earlier treatment setting, “I don’t know that we’ll actually get true confirmation in this population ever, but I think based on what’s available for these patients … this is definitely improving the therapeutic armamentarium.”

Onyx’s Myeloma Drug Kyprolis Fits ODAC’s View On Accelerated Approval

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