Mixed survival data force clinical hold on studies of Oncopeptides' Pepaxto

Shares in Oncopeptides fell as much as 26% on Thursday after the company said the FDA placed a partial clinical hold on studies of the peptide-drug conjugate Pepaxto (melphalan flufenamide) due to "large differences" in overall survival (OS) observed in the Phase III OCEAN trial in patients with relapsed refractory multiple myeloma.

Pepaxto gained accelerated FDA approval in February to treat multiple myeloma patients who had received at least four prior lines of therapy, with Oncopeptides also looking to see if the drug can provide benefit earlier in the disease course. The OCEAN study, initiated in 2017, is comparing Pepaxto head-to-head against Bristol Myers Squibb's Pomalyst (pomalidomide) in 495 patients with relapsed refractory multiple myeloma who have received two to four prior treatment lines.

In May, Oncopeptides announced top-line OCEAN results indicating that its drug was non-inferior to Pomalyst on the primary endpoint of progression-free survival (PFS), with a hazard ratio (HR) of 0.817 favouring Pepaxto and a median PFS that was 41% higher than for Pomalyst, based on an independent review committee (IRC) assessment. The company reported revised numbers on Thursday, saying the primary endpoint of superior PFS has now been met after the IRC reassessed data from 29 trial participants, finding a HR of 0.792 and PFS improvement of 39% relative to Pomalyst.

OS data favoured Pomalyst

However, Oncopeptides also disclosed Thursday that for the trial's key secondary goal of OS, the HR was 1.104 in favour of Pomalyst. The drugmaker suggested that further analyses point to "striking efficacy differences…across different patient populations" leading to "substantial HR differences between pre-specified subgroups in both directions," which may explain the OS findings.

According to Oncopeptides, the differences in OS prompted the FDA to request a partial clinical hold pending further investigation. The company said that it will co-operate with the regulator to perform the necessary analysis to understand the benefit/risk profile of Pepaxto and to identify what patients benefit from treatment in earlier lines of therapy.

Accelerated approval at risk?

Pepaxto's accelerated approval earlier this year calls for the drug to be used in combination with dexamethasone in fifth-line or later adult patients whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.

The authorisation was based on findings from the Phase II HORIZON study, in which the overall response rate (ORR) was 23.7% in a subset of patients who had received at least four prior lines of treatment and were triple-class refractory. Oncopeptides noted that in the OCEAN study, the ORR was 32.5% for Pepaxto and 26.9% for Pomalyst, revised from earlier figures of 32.1% and 26.5%, respectively.

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