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Merck KGaA (Merck)’s investigational lupus therapy enpatoran will be advancing to Phase III trials after meeting the primary endpoint in one cohort but missing it in another.
While the drug met the primary endpoint in cohort A, which included patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE), it missed the primary endpoint in cohort B, which enrolled SLE patients through the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) to determine systemic disease activity.
Despite the mixed results, Merck will advance the lupus asset to Phase III trials, confirmed Jan Klatt, head of the development unit of neurology and immunology.
Klatt confirmed: “We are encouraged by the WILLOW results, where we observed clinically meaningful efficacy with a favourable safety profile in people living with lupus rash. Based on these results, discussions with health authorities on a global Phase III programme with enpatoran are underway.”
The Germany-based biotech was investigating the oral, novel toll-like receptor (TLR)7 and TLR8 inhibitor in the Phase II WILLOW trial (NCT05162586). The trial investigated three doses, 25mg, 50mg or 100mg twice-daily enpatoran, compared to placebo.
Cohort A data shows benefit of TLR7/8 mechanism
In the study, cohort A saw a clinically meaningful improvement in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) scores after 16 weeks of treatment.
After 16 weeks of treatment, 91.3% of patients receiving enpatoran achieved a CLASI-50 response, and up to 60.9% achieved a CLASI-70 response, compared with 38.5% and 11.5%, respectively, in the placebo group.
Treated patients in cohort A also saw a rapid reduction in interferon gene signature scores beginning at just two weeks, with response maintained, confirming the involvement of the TLR7/8 pathway in interferon activation.
Principal investigator and Monash Health's head of rheumatology Eric Morand said: “The data from the WILLOW study further our understanding of TLR7/8 inhibition in SLE and CLE, which is a novel mechanism of action that may offer new hope for patients.”
Meanwhile, despite Merck stating it had seen "promising signs of efficacy in the prespecified subpopulations" from the lupus drug in cohort B, the primary endpoint of dose-response was not met.
In cohort A, enpatoran was well-tolerated with a manageable safety profile consistent with previous studies, with no new safety signals identified.
Merck said that data from cohort A will be presented at the 16th International Congress on Systemic Lupus Erythematosus (LUPUS 2025), taking place on 21-24 May in Toronto, Canada. Data from cohort B will be presented at the European Alliance of Associations for Rheumatology Congress (EULAR 2025) taking place 11-14 June in Barcelona, Spain.