Sanofi has reported mixed phase 3 data on amlitelimab, further muddying the prospects of a molecule tipped to generate blockbuster sales. But, with hits among the misses, the French drugmaker plans to file for approvals in atopic dermatitis around the world this year.
Investor excitement about the program was punctured when Sanofi shared data from the first phase 3 study of the anti-OX40 ligand antibody in September. While that trial hit its primary and key secondary endpoints, efficacy fell short of analyst expectations and the bar set by Sanofi and Regeneron’s Dupixent. Yet Sanofi talked up the Coast 1 data and set its sights on replicating the results in a second, near-identical Coast 2 trial.
Friday, Sanofi shared data from the second study, revealing the trial met the primary endpoint as assessed for the U.S. but missed on other key measures. Neither amlitelimab regimen was significantly better than placebo on co-primary endpoints analyzed for the European market. People who used rescue medication were automatically classed as nonresponders in the U.S. analysis, but not the EU version, Sanofi explained.
The U.S. primary endpoint data were roughly in line with the results of the first study, with significantly more people meeting the validated investigator global assessment scale for atopic dermatitis (vIGA-AD) response criteria on amlitelimab than placebo at Week 24. Sanofi reported similar vIGA-AD response rates regardless of whether patients received amlitelimab every four or every 12 weeks.
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A secondary U.S. endpoint that looked at the proportion of patients with a 75% or greater improvement in the eczema area and severity index total score (EASI-75) was comparable across the two studies, too. Generally, differences between the amlitelimab and placebo vIGA-AD and EASI-75 data were smaller in the second trial than in the first study, but, under the U.S. analysis, the gaps remained statistically significant.
The vIGA-AD response rates on amlitelimab under the EU analysis were similar across the two trials. The response rate per the EU analysis on the four-week regimen was around two percentage points higher in the second trial than the first study, but a similar amount lower on the 12-week dose. The key difference was the placebo response rate, which shot up more than 8 percentage points and caused the failure.
Amlitelimab performed numerically better than placebo on EASI-75, the co-primary endpoint in the EU analysis, but the vIGA-AD failure prevented Sanofi from claiming statistical success under its hierarchical testing procedures. The EASI-75 endpoint was nominally significant under the EU analysis.
Last week, Sanofi’s head of R&D, Houman Ashrafian, Ph.D., told attendees at the J.P. Morgan Healthcare Conference that hitting the primary endpoint in the second trial is “obviously the most important thing.” The failure to fully meet that core objective was compounded by a miss on a secondary endpoint in the U.S. analysis. The endpoint, which hit in the first trial, assessed vIGA-AD and skin redness.
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Despite the setback, Sanofi committed to seeking approvals “based on the totality of data.” The company shared the Coast 2 data alongside results from Shore, another phase 3 trial. Shore looked at the same amlitelimab regimens and endpoints as the Coast studies, but allowed patients to take medium-potency background topical corticosteroids with or without topical calcineurin inhibitors.
Ashrafian said allowing background therapies “is germane to how atopic dermatitis is practiced today.” Under those conditions, both amlitelimab regimens beat placebo on the vIGA-AD and EASI-75 endpoints under the U.S. and EU analyses. Response rates for both endpoints were generally higher in Shore than in Coast 1 and 2 across all arms, including the placebo cohorts.
Sanofi also shared a preliminary analysis from its Atlantis phase 2 open-label study. The data offer early support for the company’s argument that amlitelimab’s mechanism of action means responses to the antibody will deepen over time. Between Week 24, when the Coast and Shore primary endpoints were assessed, and Week 52, the vIGA-AD and EASI-75 responses increased in the Atlantis trial.
Data from Estuary, a phase 3 trial with a 52-week randomized double-blind period, are due in the second half of the year. Deepening responses over time would bolster Sanofi’s attempts to position the antibody as an effective drug that is more convenient than existing treatments and is particularly appropriate for treatment-naive patients, some of whom the company believes could achieve disease remission.
