Real transparency on FDA rejections

There has been a pleasant surprise for investors hoping that the FDA's release in July of an "initial batch" of fairly uncontentious complete response letters relating to subsequently approved drugs would be followed by something more substantial. On Thursday the agency published 89 live CRLs, relating to unapproved projects, and promised to continue doing so "promptly" for future rejections.

The latest batch of CRLs includes Replimune's oncolytic virus vusolimogene oderparepvec, but perhaps the most contentious concerns Daiichi Sankyo/Merck & Co's now withdrawn filing for patritumab deruxtecan. The published CRL reveals that Daiichi was already told in mid-2024 that Herthena-Lung02 might be insufficient to serve as a confirmatory trial.

The CRL, dated 26 June 2024, states that Herthena-Lung02 had failed to meet a prespecified interim PFS boundary, and recommends that Daiichi meet the FDA "to discuss alternative trial(s) that may verify clinical benefit after a potential accelerated approval".

At the time Daiichi put the patri-dxd rejection down to manufacturing deficiencies, and stated that the CRL "did not identify any issues with the efficacy or safety data submitted in the application". Technically that's correct, since Herthena-Lung02 wouldn't have comprised part of the supporting data package for a filing that sought accelerated approval.

But clearly the problem turned out to be important, even as three months later Herthena-Lung02 was toplined positive for PFS at subsequent analysis. The filing ended up being pulled when Herthena-Lung02 revealed a bust on overall survival at this year's ASCO.

Revelations

The patri-dxd CRL is one of 11 relating to seven oncology projects, excluding generics, among the 89 newly published CRLs. The FDA says these concern letters issued from 2024 to the present, all relating to filings that haven't yet resulted in approval or were withdrawn.

However, the stash doesn't appear to be complete. The period in question also included CRLs for Regeneron's linvoseltamab, Daiichi Sankyo/AstraZeneca's Datroway, Pfizer's Talzenna and Roche's Columvi, but for unknown reasons these don't appear among the 89.

Newly published CRLs relating to novel oncology projects

Source: US FDA.

While the rejection of Replimune's vuso-vec has an especially high profile, it's reassuring to learn that what's shown in the CRL backs that company's disclosures about the heterogeneity of the phase 1/2 population, and problems around contribution of components in a confirmatory phase 3 trial. 

Some had speculated that this filing had been blocked by Vinay Prasad, who was then newly appointed as head of the FDA's CBER division, and Replimune's share price has waxed and waned as Prasad subsequently departed and was then reinstated in his post.

However, Stat has revealed that it was the FDA's director of oncology, Richard Pazdur, who intervened to block vuso-vec, while Prasad apparently played no substantive role in the CRL. As it stands currently Replimune has scheduled a type A meeting – designed for urgent dispute resolution – with the FDA to discuss the vuso-vec filing.

Meanwhile, Jiangsu HengRui and Elevar’s camrelizumab and rivoceranib combo received two pairs of CRLs in the past 18 months, the first relating to third-party manufacturing but the second for undisclosed reasons. The published CRLs say the second was due to failure to resolve the prior manufacturing concerns, and add that rivoceranib can't be approved until camrelizumab is. 

In July the FDA published CRLs relating to drugs that did end up being approved during 2020-24, and these included six novel oncology products. Similarly to that disclosure, the latest CRLs include numerous redactions, and the FDA says it will continue in future to remove confidential commercial information and trade secrets – but not company names.