FDA Denies Appeal; Pepaxto to be Withdrawn

FDA has denied an Oncopeptides appeal seeking to stop a CBER request for the company to voluntarily withdraw its accelerated-approval multiple myeloma drug Pepaxto (melphalan flufenamide). This looks to be one of the first tests of the modified authority FDA was granted in 2022 under the Food and Drug Omnibus Reform Act to use “expedited procedures” to force an accelerated-approval product from the market when a drug sponsor’s confirmatory data fail to demonstrate a clinical benefit.

FDA’s earlier request to withdraw the drug came after a confirmatory trial (OCEAN) demonstrated a worse overall survival and failed to verify clinical benefit. Pepaxto was originally approved 2/2021, and at FDA’s request, Oncopeptides ceased marketing it 10/2021, the company said at the time. The withdrawal request followed a 9/23/2022 Oncologic Drugs Advisory Committee vote of 14 to 2 against whether the benefit-to-risk profile of Pepaxto was favorable in adult patients with relapsed or refractory multiple myeloma.

In a briefing document released in advance of the meeting, FDA reviewers said the OCEAN trial did not meet the prespecified primary endpoint — progression-free survival (PFS) superiority of melphalan flufenamide compared to pomalidomide (see story). FDA dismissed revised PFS data the company submitted showing a marginal PFS significance because it considered unconfirmed progression as events in the PFS analysis.

In a 2/23 “final decision” memo, FDA concluded that the “grounds for withdrawing approval have been met because: (1) the confirmatory study conducted as a condition of accelerated approval did not confirm Pepaxto’s clinical benefit and (2) the available evidence demonstrates that Pepaxto is not shown to be safe or effective under its conditions of use.”

The memo addressed the failed confirmatory trial, saying that “(c)ontrary to the agreed-upon, pre-specified statistical analysis plan, the sponsor subsequently performed a reanalysis of the data reassessing 29 patients from the control arm who had unconfirmed disease progression and concluded that the primary endpoint was achieved with a 1.9-month median improvement in PFS, despite a notable detrimental effect on OS [overall survival] that remained after their reanalysis.”

FDA noted that Oncopeptides argued in its appeal that Pepaxto should remain on the market for a subset of the currently indicated patient population based on the evidence that it provided in post-hoc analyses submitted to FDA. CDER did not agree with the sponsor’s post-hoc reanalysis of the PFS data, and disagreed with the company’s argument that “immune modulatory drugs such as pomalidomide are associated with a dissociation between PFS and OS,” the memo said.

The memo concluded that Pepaxto should not remain on the market while an additional study is conducted to assess the safety and efficacy of the drug, “whether for a narrower patient population or otherwise.”