Replimune’s fight with the FDA deepens

Replimune’s long-running saga with the US regulator took a turn for the worse last week, with the FDA issuing its oncolytic virus vusolimogene oderparepvec with its second complete response letter, again refusing to approve it on the basis of data from the Ignyte trial.

This time around the drama was heightened by the FDA publishing the CRL after market on Friday, the day of vuso-vec's PDUFA date, before Replimune issued its own press statement. This move is tied to the agency's transparency drive, which has seen previous CRLs published retrospectively in an effort to highlight regulatory concerns that until now companies have been able to play down or even omit, without any comeback.

In this case, the dispute appears to centre on conflicting interpretations of previous guidance, with the FDA's letter claiming that the company had been told as long ago as 2021 that Ignyte was inadequate to support approval. Approximately five hours after the FDA’s publication Replimune issued a press release that for its part sharply criticised the regulator. 

Here the company stated that the rejection was “not because the medicine failed, but because the system did”, accusing the FDA of inconsistency. On Monday investors trashed Replimune's stock, sending it down 65%.

Single-arm trial

At the core of the dispute is the adequacy of Ignyte, a single-arm study of vuso-vec (also known as RP1). 

The FDA states that it communicated concerns about the adequacy of Ignyte in 2021, and maintains that these issues were not sufficiently addressed either in the initial application or in the response to the first CRL. Replimune, however, claims that it did not receive such feedback in recent interactions, and notes that its submission was accepted, granted breakthrough therapy designation, and given priority review.

After receiving its first rejection, last July, Replimune and the FDA held a type A meeting, designed for urgent dispute resolution, and the company said an accelerated approval pathway had not been determined. Nevertheless, it resubmitted the BLA, relying on updated results from the same Ignyte trial, along with a subset of patients from the Ignyte-3 study. 

This seemed too little to resolve the issues raised in the first CRL, and the second CRL has made this abundantly clear. Among the issues flagged, the FDA noted that Ignyte-3 has so far only treated about 10% of its intended patient population, and has had limited follow-up on the duration of response. 

The agency also cited reliance on investigator-assessed outcomes and difficulties interpreting progression-free survival, due to the absence of prespecified analyses and insufficient control of type 1 error. Replimune maintains that the FDA’s new review team, of which the company claims it was unaware before the CRL, did not clearly signal that this data package would be insufficient.

The FDA further noted inconsistencies in response criteria, noting that the methodology used in the Ignyte trial was not aligned with Recist v1.1, which introduced variability and potential bias in tumour response assessment. Replimune said it had provided detailed analyses to address this, but it seems these were insufficient for the regulator.

Key points of dispute

Source: FDA CRL & OncologyPipeline.