FDA questions credibility of Daiichi data ahead of AdComm

FDA Building 2
The Japanese company added quizartinib to its pipeline through the $410 million takeover of Ambit. (FDA)

The FDA has questioned the reliability of the phase 3 results Daiichi Sankyo hopes will win it approval for quizartinib in acute myeloid leukemia (AML). Officials raised the concerns in a briefing document (PDF) to support an upcoming advisory committee meeting.

Daiichi filed for FDA approval on the strength of a phase 3 trial that linked FLT3 inhibitor quizartinib to a 1.5 month improvement in overall survival (OS) over chemotherapy. The FDA subsequently pushed the PDUFA action date for the drug back to late August to give it time to evaluate additional data filed by Daiichi.

It looks like the additional data failed to convince the FDA that the quizartinib approval will be a slam-dunk for Daiichi. The FDA outlined its concerns in its request to the independent experts on the panel that will assess quizartinib.

“FDA seeks input from the committee on whether the imbalance in early censoring and patients randomized but not treated between the arms on Study AC220-007, the inconsistency of the results across the stratification subgroups and the effects of subsequent therapies on the primary endpoint impact the interpretation of the study results to a degree that renders them unreliable,” the agency wrote in its briefing materials. 

The FDA made the request after analyzing differences between the treatment and control arms of the clinical trial. In the intention-to-treat population, 2% of patients were randomized to receive the study drug but not treated. Another 0.4% of the patients in the cohort were censored for the OS endpoint before week eight. In the control arm, 23% of patients were randomized but not treated, and 7% were censored for the OS endpoint.

Those differences led the FDA to state “the credibility of the results ... were challenged by multiple findings.” How the advisory committee rules on the credibility question when it meets tomorrow may shape the near-term prospects of quizartinib. 

The FDA also highlighted the divergent performance of patients who received low and high-intensity chemotherapy and differences between the use of post-study therapies as factors that may have muddied the results. Almost one-quarter of patients who received quizartinib underwent allogeneic hematopoietic stem cell transplantation, compared to 0% in the control arm.

Officials have concerns about the risks posed by quizartinib, too. The FDA said the drug prolonged QT to an extent “consistent with an increased risk of arrhythmias” and was linked to a higher rate of associated adverse events in the phase 3 trial. Across development of quizartinib, “the risk of on-treatment deaths due to cardiac events was estimated as 1-2%,” according to the FDA. 

The risk led the FDA to suggest the use of strategies to manage the cardiac risks posed by the drug, such as a boxed warning and recommendation to co-administer beta blockers to stop arrhythmias. That assumes quizartinib wins approval, something that is far from certain as it stands. The FDA wants the expert panel to help it determine whether the OS benefit “is sufficiently meaningful to outweigh the safety risks of therapy with quizartinib.”

Daiichi has a lot resting on the answer to that question. The Japanese company added quizartinib to its pipeline through the $410 million takeover of Ambit Biosciences and will face competition even if it gets a chance to try to recoup its investment, notably from Astellas’ Xospata and Novartis’ Rydapt.