France's big pharmaceutical company Sanofi has halted development of "amlitelimab," a candidate treatment for atopic dermatitis. It completed three global phase 3 trials but still abandoned its filing for approval, a rare move in the late clinical stage.
The market's attention now turns to corporations studying the same target (OX40L. In Korea, IMBiologics(493280) is representative.
IMBiologics does not see Sanofi's decision as a failure of the mechanism targeting OX40L. It says only the limits of a monoclonal antibody were exposed, and that a bispecific antibody aimed at another target as well could yield sufficiently different results. Clinical data to be released next year are expected to be the first test of this company strategy.
The company said, "In autoimmune diseases, the causes and immune responses are complex, so it is hard to expect sufficient effect by suppressing only a single mechanism," and added, "Considering the safety issues raised in prior candidates, we plan to further tighten patient selection criteria and monitoring in the clinic."
◇ Harder than a phase 3 win: "leapfrogging Dupixent"
Sanofi judged that amlitelimab did not show enough advantage to replace the standard treatment "Dupixent."
There was no head-to-head trial comparing amlitelimab with Dupixent. The industry largely views Sanofi's decision as closer to failing to prove superiority rather than establishing inferiority.
In fact, amlitelimab met key endpoints in two global phase 3 trials (COAST 1 and SHORE). In a long-term follow-up study (ESTUARY), it confirmed that the drug's effect persisted even after stopping treatment.
The problem was the third phase 3 (COAST 2). It passed U.S. approval criteria but ran into hurdles under European and Japanese standards.
Europe and Japan assess whether the proportion of patients whose skin is almost clear (vIGA-AD 0/1) and the proportion with at least a 75% reduction in skin lesions (EASI-75) exceed certain thresholds, but amlitelimab did not clear that bar.
Safety also left some unease. Among 3,778 total trial participants, two cases of Kaposi sarcoma were reported. Kaposi sarcoma is a rare vascular tumor that mainly appears when infection with a specific virus (HHV-8) coincides with immune suppression.
Both patients had preexisting risk factors, and Kaposi sarcoma did not occur during trial conduct. Sanofi did not attribute causality to amlitelimab but stated in its release, "After reviewing both efficacy and safety data, we decided to stop development."
Kaposi sarcoma has also been reported with another antibody that modulates the OX40 signaling pathway. Kyowa Kirin, which had been developing "rocatinlimab," terminated all trials early this year after confirmed and suspected cases of Kaposi sarcoma emerged. At the time, Kyowa Kirin said, "We cannot rule out a potential mechanistic association with OX40 pathway modulation."
Unlike amlitelimab, which targets OX40L, rocatinlimab targets the OX40 receptor. With the same rare tumor repeatedly reported in two candidates with different mechanisms, later developers now face the task of demonstrating long-term safety as well as efficacy.
◇ Limits of monoclonal antibodies… IMBio says "a bispecific is the breakthrough"
IMBiologics interprets the Sanofi case instead as supporting evidence for its bispecific antibody strategy.
The company explained, "Amlitelimab had advantages in that its effect lasted long and the dosing interval was extended, but the speed at which effects appeared and the overall efficacy fell short of expectations," adding, "We believe that while maintaining the long-term immunoregulatory function handled by OX40L, simultaneously blocking another inflammatory pathway can boost both the initial treatment effect and overall efficacy."
IMBiologics has licensed out the OX40L-based bispecific antibodies "IMB-101" and "IMB-102" to U.S.-based Navigator Medicine. Of these, IMB-102 is being developed with atopic dermatitis as the indication, like amlitelimab. The company is targeting entry into a phase 1 trial next year.
The basis the company presents is preclinical data. In its own rodent atopic model, the OX40L antibody underlying IMB-102 reduced disease by 31%. Under the same conditions, amlitelimab achieved only a 13% reduction. The company attributes the efficacy gap to a different epitope—the position where the antibody binds to OX40L. However, there is no guarantee that results in rodents will be reproduced as is in humans.
To this, the company adds another antibody, aiming to further raise the initial treatment response while maintaining OX40L's long-term immunoregulatory effect. The antibody is the subject of a pending patent and has not yet been disclosed.
The company said, "IMB-102 is being developed to surpass Dupixent in both efficacy and dosing convenience," adding, "While preserving the advantage of long-lasting effect shown by amlitelimab, we plan to differentiate it with dosing once every three months."
◇ "IMB-101" takes the first test… first report card next year
The candidate that will first gauge the success or failure of the company's strategy is IMB-101. It is being developed with hidradenitis suppurativa as the indication.
Partner Navigator Medicine is conducting a phase 2a trial in 150 patients with moderate to severe hidradenitis suppurativa at 41 sites across eight countries, including the United States, Germany and Poland. Dosing began for the first patient in Mar., and the goal is to analyze the primary endpoint in Sept. next year.
In phase 1 results disclosed in May, as the dose increased, inflammation-related biomarkers decreased, and no serious adverse events were reported. However, because the study involved healthy adults, whether the same efficacy and safety will be confirmed in actual patients is a separate question. Addressing concerns about Kaposi sarcoma is also a task for this trial.
The most conscious comparator for the company is Sanofi's "brivekimab." Like IMB-101, it is a bispecific antibody that simultaneously blocks OX40L and TNF-α.
In a phase 2a trial for hidradenitis suppurativa, brivekimab recorded a HiSCR50 (the proportion of patients with ≥50% reduction in inflammatory nodules and abscesses) of 66.7%, surpassing the standard treatment Humira (58.9%). It is being viewed as the first clinical evidence that the strategy of simultaneously suppressing two inflammatory pathways can be effective in actual patients.
By contrast, there is a structural difference from IMB-101. Derived from a camelid antibody, brivekimab showed anti-drug antibodies (ADAs) in more than 80% of patients in phase 1. As the body recognizes the drug as a foreign substance and mounts an immune response, there is concern that efficacy could wane with long-term dosing.
According to IMBiologics, IMB-101 recorded a 3.3% rate of treatment-related adverse events (TRAEs) in phase 1a, and its immunogenicity was also low. However, since the results were obtained from different clinical trials, a direct comparison of superiority is difficult.
The company aims to secure efficacy on par with or better than brivekimab while further extending the dosing interval. Brivekimab is administered every two weeks, but the development goal for IMB-101 is to extend the interval to 8–12 weeks.
The company said, "Our partner is also conducting a phase 1 trial in Australia for the subcutaneous formulation candidate 'NAV-242,' which has an improved half-life for IMB-101," adding, "In the first half of next year, we expect to be able to confirm whether a dosing interval of more than eight weeks is feasible."