A phase 3 trial of Regeneron’s LAG-3 inhibitor has missed its primary endpoint, leaving the biopharma reeling from the second failure of a key late-stage program in the past year.
The trial assessed fianlimab in combination with Regeneron’s PD-1 inhibitor Libtayo as a first-line treatment for unresectable locally advanced or metastatic melanoma. Progression-free survival (PFS) on the drug combination was statistically no better than on Merck & Co.’s PD-1 inhibitor Keytruda, causing the trial to miss its primary endpoint.
Median PFS was numerically longer with the fianlimab combination, at 11.5 months on the high dose, compared with 6.4 months on Keytruda. The statistical miss was driven by a late separation in the PFS curves, BMO Capital Markets analysts said in a note to investors after speaking with Regeneron.
“It is clear that while mPFS was improved with high-dose fianlimab combo treatment, separation from monotherapy treatment did not occur until later in the study, leading to the not statistically significant result,” the analysts said. “Somewhat encouragingly, [Regeneron’s investor relations] did note a trend in [overall survival] improvement.”
The p value was just the wrong side of statistical significance. But, as the analysts said, “close does not count.” The failure of Regeneron’s “defining catalyst” of the first half of the year puts fresh pressure on the company, according to the analysts, who said they were left “shaking our heads” by the latest flop.
Pressure began to ratchet up almost one year ago, when Regeneron and Sanofi reported the failure of one of two phase 3 trials of their IL-33 drug itepekimab in chronic obstructive pulmonary disease. The back-to-back misses for key pipeline projects “amp up the pressure” on the next 12 to 18 months of clinical development at Regeneron, the analysts said.
Regeneron has ways to salvage fianlimab. A phase 3 trial comparing the high-dose fianlimab combination to Bristol Myers Squibb’s LAG-3/PD-1 fixed-dose immunotherapy Opdualag is continuing. Regeneron sees showing an overall survival benefit over Opdualag and hitting the primary response rate endpoint of the head-to-head trial as paths back for fianlimab, Evercore ISI analysts said in a note to investors.
Yet both BMO and Evercore analysts removed fianlimab from their models in response to the phase 3 flop. It is possible that Regeneron will show fianlimab is noninferior to Opdualag, BMO analysts said, but that is no longer the base-case assumption. BMO and Evercore analysts forecast $1.8 billion and $900 million in risk-adjusted peak sales, respectively, in melanoma before removing fianlimab from their models.
With fianlimab now seen as a long shot, BMO analysts said “clean positive readouts” from Regeneron’s Factor XI program will be critical to regaining investor confidence. Regeneron is developing two Factor XI antibodies in a broad program, with initial pivotal data expected in 2027 and a series of readouts in the calendar for the coming years.
Phase 3 data on the cemdisiran-pozelimab combination are another catalyst, BMO analysts said. Results from pivotal trials of the combination in geographic atrophy and paroxysmal nocturnal hemoglobinuria are due this year.