Merck KGaA Advances Lupus Drug Despite Trial Setback

Merck Shares Data Supporting Enpatoran’s Phase 3 Progression

Merck KGaA has disclosed data supporting its decision to advance its lupus drug, enpatoran, into phase 3 development, despite a recent setback in one patient cohort. The German pharmaceutical company had tested the oral TLR7/8 inhibitor enpatoran in the phase 2 WILLOW study, which assessed the drug's efficacy across two lupus subtypes.

Peter Guenter, Merck’s CEO of healthcare, revealed in October 2024 that the trial's primary endpoint was met in a cohort comprising patients with either cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) with organ-specific involvement. He described this portion of the study as providing “very strong and unambiguous proof of concept in cutaneous lupus.” However, detailed data were not initially disclosed.

Mixed Results and Subsequent Data Release

Merck encountered concerns regarding enpatoran’s viability in March 2025 when the drug failed to meet the primary endpoint in the second trial cohort focused exclusively on patients with SLE. Nonetheless, the company highlighted “promising responses” in predefined subgroups, advocating continued development of the therapy.

In response, Merck has now released the detailed data from the successful CLE cohort to substantiate its commitment to enpatoran’s advancement. The drug demonstrated a clinically meaningful improvement by week 16, measured by the CLE Disease Area and Severity Index. By week 24, 91.3% of treated patients achieved a 50% or greater improvement from baseline, and 60.9% showed a 70% or greater improvement, compared to 38.5% and 11.5%, respectively, in the placebo group.

Importantly, enpatoran was well-tolerated, exhibiting a manageable safety profile consistent with prior studies and with no new safety signals reported, according to Merck.

Company Statements and Future Plans

Jan Klatt, Head of Development Unit Neurology & Immunology at Merck Healthcare, commented: “We are encouraged by the WILLOW results, where we observed clinically meaningful efficacy with a favorable safety profile in people living with lupus rash.” He added that discussions with global health authorities regarding a phase 3 program for enpatoran are currently underway.

Scientific Rationale and Pipeline Context

Merck leveraged data from the CLE cohort to reinforce the rationale behind targeting toll-like receptors 7 and 8, which are linked to severe lupus cases. The drug showed a rapid and sustained reduction in interferon gene signature scores starting from week 2 through week 24.

Enpatoran is also being evaluated for idiopathic inflammatory myopathies and represents one of Merck’s two most advanced candidates in its neurology and immunology pipeline. The other candidate, cladribine, is currently in phase 3 trials as a treatment for generalized myasthenia gravis.

Highlights

• Merck KGaA is advancing the oral TLR7/8 inhibitor enpatoran into phase 3 for lupus despite mixed phase 2 results.
• Phase 2 WILLOW study met the primary endpoint in the cohort including cutaneous lupus erythematosus (CLE) patients.
• By week 24, over 91% of patients in the CLE cohort achieved ≥50% improvement on the CLE Disease Area and Severity Index versus 38.5% on placebo.
• Enpatoran showed a favorable safety and tolerability profile with no new safety concerns.
• Merck is engaged in discussions with global regulators for a phase 3 lupus program.
• The drug demonstrated a rapid reduction in interferon gene signature scores, supporting its mechanism of action.
• Enpatoran is among Merck’s leading neurology and immunology pipeline candidates, alongside cladribine in phase 3 for myasthenia gravis.