Accelerated path closes for Moderna/Merck’s immunotherapy

Only last month Moderna was hoping for a quick green light for its personalised neoantigen immunotherapy mRNA-4157, but that hope evaporated today. The company disclosed during its R&D day that the FDA “has not been supportive” of accelerated approval in adjuvant melanoma based on current data on the Merck-partnered project – which includes a recent three-year update from its phase 2 trial, Keynote-942.

The news came amid a broader shake-up in which the group slashed R&D spending by $1.1bn a year and discontinued five assets, including two in oncology: mRNA-5671, a KRAS antigen-specific project, and mRNA-2752, an mRNA encoding Ox40L, IL-23 and IL-36γ.

Moderna, which says it now expects to break even in 2028, saw its stock open down 18% this morning.

Melanoma knockback

The FDA’s issue with mRNA-4157 is unclear but it’s possible that, with the melanoma sector already well served, the agency is waiting for a clear overall survival benefit.

The last update from Keynote-942, at ASCO this year, found that mRNA-4157 plus Keytruda reduced the risk of recurrence or death by 49% versus Keytruda alone. There was also a trend towards improved overall survival with the combination.

During its second-quarter earnings call Moderna highlighted three things that would be needed for accelerated approval: durability (which it believed it had already shown); substantial recruitment into a phase 3 trial; and manufacturing readiness.

The pivotal melanoma study, Interpath-001, is “substantially enrolled”, Moderna said today, so it seems unlikely that the issue lies there.

Notably, like Keynote-942, Interpath-001 also has a primary endpoint of recurrence-free survival, with OS only a secondary. 

As well as melanoma, Moderna and Merck are testing mRNA-4157 in pivotal trials in NSCLC and cutaneous squamous cell carcinoma.

Moderna’s move out of KRAS, meanwhile, comes not long after Novartis threw in the towel with its G12C inhibitor opnurasib. Unlike many other KRAS projects, mRNA-5671 had been designed to present KRAS antigens to a patient’s immune system, covering the four most common mutations (G12C, G12D, G12V and G13D). Other KRAS “cancer vaccines” in development include Gritstone’s Slate-KRAS.