Merck KGaA has announced positive results from Cohort A of its Phase 2 WILLOW study evaluating enpatoran, an investigational oral TLR7/8 inhibitor, in patients with cutaneous lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) with active lupus rash. The findings were presented at the 16th International Congress on Systemic Lupus Erythematosus (LUPUS 2025) in Toronto.
The WILLOW study utilized a unique basket design with two distinct cohorts. Cohort A, which focused on patients with CLE or SLE with active lupus rash, successfully met its primary endpoint, demonstrating a dose-response relationship and clinically meaningful improvement in Cutaneous Lupus Erythematosus Disease Area and Severity Index Activity (CLASI-A) scores at Week 16 (p = 0.0002).
At Week 24, up to 91.3% of patients receiving enpatoran achieved a CLASI-50 response (≥50% improvement from baseline), and up to 60.9% achieved a CLASI-70 response (≥70% improvement), compared with 38.5% and 11.5%, respectively, in the placebo group. The drug was well-tolerated with a manageable safety profile consistent with previous studies.
"Lupus can make navigating everyday life difficult. The skin manifestation, known as lupus rash, often comes with persistent itching, which can lead to scarring and hair loss. This can significantly impact the physical, emotional and social well-being of those living with lupus, underscoring the urgent need for effective treatments," said Jan Klatt, Head of Development Unit Neurology & Immunology for the Healthcare business of Merck.
However, results were mixed across the study's two cohorts. While Cohort A showed clear success, Cohort B—which evaluated enpatoran's effect on systemic disease activity in SLE patients using the BICLA response endpoint—did not meet its primary endpoint of dose response. Despite this setback, Merck reported "promising efficacy results" in prespecified subpopulations within Cohort B. Full data from this cohort will be presented at the European Alliance of Associations for Rheumatology Congress (EULAR 2025).
Novel Mechanism of Action Targets Key Disease Drivers
Enpatoran represents a potential first-in-class oral therapy for lupus that selectively blocks the activation of Toll-like receptors (TLR)7 and TLR8, which play a significant role in lupus pathogenesis and are associated with severe manifestations of the disease.
Treatment with enpatoran in Cohort A led to a rapid reduction in interferon gene signature scores beginning at Week 2, which was maintained through Week 24. This confirms the involvement of the TLR7/8 pathway in interferon activation in CLE and supports the drug's proposed mechanism of action.
Principal investigator Prof. Eric Morand of Monash University and Monash Health commented, "These new findings offer promising evidence that, with enpatoran, we may be able to advance outcomes, which remain suboptimal for most patients. 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."
Study Design and Patient Population
The WILLOW study (NCT05162586) is a global, multicenter, randomized, placebo-controlled Phase 2 trial evaluating three doses of enpatoran taken twice daily (25 mg, 50 mg, and 100 mg) versus placebo plus standard of care over 24 weeks.
The study's innovative basket design included two distinct patient populations:
- Cohort A: Patients with CLE or SLE with active lupus rash, evaluated using the CLASI-A score
- Cohort B: Patients with active SLE, evaluated using the BICLA response endpoint
This approach allowed researchers to assess both organ-specific disease activity (skin manifestations) and systemic disease activity in different lupus populations.
Development Plans Moving Forward
Despite the mixed results across cohorts, Merck remains committed to the development of enpatoran. The company confirmed that discussions with health authorities regarding a global Phase 3 program are already underway, based primarily on the positive results from Cohort A.
During Merck's Q4 earnings call, Chief Financial Officer Helene von Roeder expressed optimism about the therapy's future: "Even though the SLE did not meet the primary endpoint, the previous success of the CLE cohort and the previous success of certain, predefined populations in the SLE cohort, make us optimistic about the potential for further development."
Addressing Significant Unmet Needs
Lupus erythematosus is a chronic autoimmune disease that disproportionately affects women and people of color. The disease can manifest in various forms, with SLE and CLE being two primary types. Symptoms range from mild to life-threatening and often include fatigue, joint pain, rashes, and organ involvement.
Skin manifestations of lupus, particularly lupus rash, can cause significant physical discomfort and emotional distress. Current treatment options for lupus have limitations in terms of efficacy and side effects, highlighting the need for new therapeutic approaches.
If approved, enpatoran could offer a novel oral treatment option for patients with lupus, potentially addressing significant unmet needs in this patient population. According to GlobalData, diagnosed prevalent cases of SLE in the seven major markets (US, France, Germany, Italy, Spain, UK, and Japan) are projected to increase from 0.55 million in 2021 to 0.58 million in 2031, with sales of enpatoran potentially reaching $85 million by 2030 if approved.
The development of enpatoran aligns with Merck's broader commitment to neurology and immunology, where the company has significant R&D and commercial experience, particularly in multiple sclerosis. Merck's current pipeline also includes potential therapies for other neuroinflammatory and immune-mediated diseases, including generalized myasthenia gravis (gMG).
