BioPharma, Policy

FDA turns down approval for Daiichi Sankyo leukemia drug

The outcome was not surprising, in light of a negative vote by an FDA expert panel last month, but an investigator in the study criticized the agency’s approach as being based on a poor understanding of acute myeloid leukemia.

The Food and Drug Administration has turned down approval for a drug to treat a form of leukemia, even as Japanese regulators gave it the green light. However, the approach the FDA took to the drug had drawn criticism from U.S. leukemia experts.

Tokyo-based Daiichi Sankyo said Friday that the FDA had issued a complete response letter for its application for the drug, quizartinib, in patients with relapsed or refractory acute myeloid leukemia who have mutations of a gene called FLT3. The company said it is reviewing the letter – which means the FDA has decided there are issues that preclude approval at the present time – and would determine the next steps. Meanwhile, the company said three days earlier that Japan’s Ministry of Health, Labor and Welfare had approved the drug under the brand name Vanflyta.

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The company did not provide further details on why the FDA rejected quizartinib, but the decision came despite the Phase III study used for approval, QuANTUM-R, achieving its primary endpoint of showing the drug provided superior overall survival to chemotherapy, as well as breakthrough therapy designation and priority review from the agency.

A competing drug, Astellas Pharma’s Xospata (gilteritinib) received accelerated approval for relapsed or refractory FLT3-positive AML in November 2018, based on a 138-patient interim analysis of the Phase III ADMIRAL study comparing it with chemotherapy. Subsequent data resulted in Xospata winning full approval. Another drug, Novartis’ Rydapt (midostaurin), is approved for previously untreated FLT3-mutated AML in combination with chemotherapy. FLT3 mutations are associated with a poor prognosis in the disease.

Last month, the FDA’s Oncologic Drugs Advisory Committee, or ODAC, voted 8-3 against recommending approval for quizartinib, citing issues like a higher rate of cardiac events, with a 1-2 percent risk of on-treatment death observed. Others included a large difference in the numbers of patients in the study and control arms who were randomized but not treated and who had their data censored for the primary endpoint of overall survival. According to a publication of the trial data in The Lancet earlier this month, four of the 245 patients randomized to quizartinib were not treated, while 28 of the 122 randomized to the chemotherapy arm were not.

Some leukemia experts criticized the FDA’s approach to the drug.

“In my view, this is the FDA making the perfect the enemy of the good,” said QuANTUM-R investigator Dr. Mark Levis, in an interview at the American Society of Clinical Oncology’s annual meeting earlier this month. Levis heads the hematologic malignancies program at Johns Hopkins University and had testified at the ODAC meeting, where he noted that he does paid consulting for Daiichi Sankyo but had no financial interest in the meeting’s outcome.

Levis suggested the cardiotoxicity issue was overblown. According to the briefing document used ahead of the ODAC meeting, the rate of QT prolongation was 26.6 percent in the quizartinib arm, and 2.1 percent in the chemotherapy arm. According to the published data, serious QT prolongation among patients taking quizartinib was rare, occurring in eight or 10 patients, and there were no life-threatening events. “I’m frustrated with the FDA – they have not done the field a service,” he said, noting that a cardiology expert in the meeting had said the cardiotoxicity was not as serious as the agency made it out to be. “The case they presented indicated they do not understand the disease.”

To be sure, relapsed and refractory AML patients are extremely sick and fragile and anecdotally have been known to die shortly after signing up to participate in clinical trials. In QuANTUM-R, 96 patients died between the two arms after starting treatment, with 40 of those deaths attributed to side effects.

Dr. Daniel DeAngelo, chief of the leukemia division at the Dana-Farber Cancer Institute, whose center also participated in QuANTUM-R, agreed. While QT prolongation was observed, he said a presentation at last year’s European Hematology Association meeting had already shown it to be manageable and not a deal-breaker. “You had a Phase III study that met its endpoint, yet ODAC voted it down,” DeAngelo said at the ASCO meeting.

Levis also took issue with how the committee interpreted the patient dropouts. Part of the problem was that the trial was unable to offer Celgene’s Vidaza (azacitidine) as an option in the control arm due to those drugs not being approved in Europe when QuANTUM-R started in May 2014. Many patients were thus randomized to the chemotherapy drug cytarabine, especially at low doses, which is an unattractive option, leading to many dropping out. By contrast, when ADMIRAL started more than a year later, patients did have the option of receiving Vidaza, considered a superior drug to cytarabine.

Photo: Ekkaluck, Getty Images