enpatoran (M5049) / EMD Serono - LARVOL DELTA

Clinically meaningful thresholds for percent change in CLASI-A scores in adults with cutaneous manifestations of lupus: A post-hoc analysis of Phase 2 WILLOW study (AAD 2026) - P2 | " Post-hoc analyses used pooled data from the WILLOW Phase 2 enpatoran trial in patients with SLE or CLE (NCT05162586)... This evidence suggests the clinically meaningful threshold for percent change in CLASI-A from baseline is 60%–70%. Additional studies using other outcome anchors can further refine clinically meaningful improvement endpoints for CLASI-A. *Victoria Werth and Benjamin F. Chong are joint first authors"

Clinical • P2 data • Retrospective data • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

Therapeutic Approaches for Cutaneous Lupus Erythematosus: a Changing Landscape of Clinical Trials. (PubMed, J Inflamm Res) - "Existing SLE drugs such as belimumab and anifrolumab have shown potential promise as a treatment for CLE, and a Phase III CLE clinical trial for anifrolumab is ongoing. Other emerging therapies such as deucravacitinib, litifilimab, and enpatoran have been successful with skin-related endpoints in Phase II CLE trials...As CLASI has become an accepted primary endpoint for clinical trials, drug development is shifting to prioritize cutaneous outcomes and to use endpoints that measure skin-specific effects. This targeted approach represents a fundamental change that may ultimately increase FDA-approved therapies specifically for CLE and expand treatment options for patients with CLE."

Journal • Review • Cutaneous Lupus Erythematosus • Dermatology • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Safety and efficacy of enpatoran in lupus: Results from the first 48 weeks of the phase II WILLOW long-term extension study (EULAR 2026) - No abstract available

Clinical • P2 data • Immunology • Inflammatory Arthritis • Lupus

Efficacy of enpatoran on arthritis outcomes in participants with active cutaneous manifestations of SLE: A post-hoc analysis of Cohort B of the phase II WILLOW study (EULAR 2026) - No abstract available

Clinical • P2 data • Retrospective data • Immunology • Inflammatory Arthritis • Rheumatology

A Study of Enpatoran in Participants With Cutaneous Manifestations of Lupus With or Without Systemic Disease (ELOWEN-2) (clinicaltrials.gov) - P3 | N=202 | Not yet recruiting | Sponsor: EMD Serono Research & Development Institute, Inc.

New P3 trial • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

ELOWEN-1: A Study of Enpatoran in Participants With Cutaneous Manifestations of Lupus With or Without Systemic Disease (clinicaltrials.gov) - P3 | N=202 | Not yet recruiting | Sponsor: EMD Serono Research & Development Institute, Inc.

New P3 trial • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Enpatoran, a Toll-Like Receptor 7/8 Inhibitor, in Skin Manifestations of Cutaneous Lupus Erythematosus or Systemic Lupus Erythematosus: Pooled Safety Data from the Phase 2 WILLOW Trial (LUPUS 2026) - P2 | "Decreased lymphocyte count was more common with placebo (n=4; 5.9%) than enpatoran 25 mg BID (n=1; 1.9%), 50 mg BID (n=2; 3.1%) or 100 mg BID (n=2; 2.5%). No clinically relevant between-group differences were observed in other laboratory parameters, vital signs, or electrocardiogram findings including QTcF.Abstract S1:04 Figure 1Abstract S1:04 Table 1Pooled safety data from WILLOW cohorts A and B for participants with CLE/SLE and cutaneous manifestationsa Conclusions Enpatoran was well tolerated across all doses in participants with cutaneous manifestations of lupus at baseline in the WILLOW study, consistent with the overall study population and other previous studies of enpatoran, with no new safety concerns identified."

Clinical • P2 data • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TLR7

Design of a Phase 3, Randomised, Double-Blind, Placebo-Controlled Parallel Study to Evaluate the Efficacy and Safety of Enpatoran in Cutaneous Manifestations of Lupus With or Without Systemic Disease (LUPUS 2026) - P2 | "Randomisation will be stratified by factors including region, systemic disease severity (none/mild or moderate/severe [BILAG >=1A/2B]) and cutaneous disease severity (CLASI-A 8–9 or >=10).Results The primary objective will be to demonstrate the efficacy of enpatoran for reducing cutaneous disease activity by achieving CLASI-70 response at Week 24; secondary endpoints include BICLA response at Week 24 in the subpopulation of participants with moderate to severe SLE to assess efficacy across all affected organs, and safety/tolerability in the overall population ( figure 1).Abstract PO:11:286 Figure 1Phase 3 study design and primary/key secondary endpoints Conclusions This novel phase 3 trial design aims to benefit a broader group of participants than conventional CLE or SLE trials, by evaluating enpatoran in participants with cutaneous manifestations of lupus with or without systemic disease. This approach has the potential to transform the lupus treatment..."

Clinical • IO biomarker • P3 data • Cutaneous Lupus Erythematosus • Discoid Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TLR7

Psoriatic microRNAs induce NK cell activation via an innate immune crosstalk abrogated by the Toll-like receptor 7/8 antagonist Enpatoran. (PubMed, J Transl Med) - No abstract available

Journal • Immunology

TLR7 inhibition limits cardiac ischemic injury by disrupting ITGAM-dependent immune-endothelial interaction. (PubMed, bioRxiv) - "Pharmacological inhibition of TLR7 with enpatoran reduced myocardial inflammation and infarct size and improved cardiac function in a mouse model of I/R injury when administered before, during, or shortly after ischemia...Mechanistically, TLR7 activation induced Itgam expression in endothelial cells and leukocytes and promoted their adhesion via ITGAM-ICAM1 interaction under physiological shear stress, whereas ITGAM neutralization disrupted this interaction, reduced immune cell infiltration, and limited ischemic injury. These findings define a TLR7-ITGAM signaling axis as a key driver of endothelial-leukocyte crosstalk in myocardial I/R injury and support TLR7 inhibition as a promising therapeutic strategy to mitigate acute myocardial infarction."

IO biomarker • Journal • Cardiovascular • Inflammation • Myocardial Infarction • Myocardial Ischemia • Reperfusion Injury • ICAM1 • ITGAM • TLR7

What's New in Cutaneous Lupus Erythematosus: Guidelines, Biologics, and Beyond. (PubMed, J Clin Aesthet Dermatol) - "Ongoing therapeutic innovation, guided by mechanistic insights and strengthened by the development of standardized outcome measures, is transforming the CLE landscape and advancing the goal of precision-based, durable disease control."

Journal • Review • CNS Disorders • Cutaneous Lupus Erythematosus • Dermatology • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Rheumatology • Systemic Lupus Erythematosus

Effect of Renal Impairment on Enpatoran Pharmacokinetics (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Trial completion date: Apr 2026 ➔ Jul 2026

Trial completion date • Renal Disease

A Study of Enpatoran in Participants With Cutaneous Manifestations of Lupus With or Without Systemic Disease (Elowen-2) (clinicaltrials.gov) - P3 | N=202 | Not yet recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

New P3 trial • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus

Can Phagocytosis, Neutrophil Extracellular Traps, and IFN-α Production in Systemic Lupus Erythematosus Be Simultaneously Modulated? A Pharmacological Perspective. (PubMed, Int J Mol Sci) - "Preliminary data show that Toll-like receptors 7/8 (TLR 7/8) inhibition (e.g., Enpatoran) may reduce interferon-α (IFN-α) production by monocytes and NET formation by neutrophils. Our hypothesis is that future therapies combining compounds that modulate the three cellular processes might result in a better disease management as current therapies."

Journal • Review • Immunology • Inflammatory Arthritis • Lupus • Psychiatry • Systemic Lupus Erythematosus • IFNA1

Elowen-1: A Study of Enpatoran in Participants With Cutaneous Manifestations of Lupus With or Without Systemic Disease (clinicaltrials.gov) - P3 | N=202 | Not yet recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

New P3 trial • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Update on cutaneous lupus erythematosus pathogenesis, diagnosis and management. (PubMed, J Eur Acad Dermatol Venereol) - "Antimalarials, particularly hydroxychloroquine, remain the cornerstone of systemic therapy. Second-line or third-line agents such as methotrexate, retinoids, dapsone, thalidomide and lenalidomide are recommended in refractory cases. Biological therapies, including belimumab and anifrolumab, are approved in the setting of SLE. Promising results from recent trials of targeted therapies including inhibitors of plasmacytoid dendritic cells, TLR7/8 and TYK2 are paving the way for novel treatment strategies in CLE."

Journal • Review • Cutaneous Lupus Erythematosus • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TLR7 • TYK2

Remission from cutaneous manifestations of lupus with enpatoran, a first-in-class oral small molecule toll-like receptor 7/8 inhibitor: pooled post-hoc exploratory analysis from a randomized placebo-controlled Phase II study (ACR Convergence 2025) - P2 | "Patients receiving enpatoran achieved higher rates of CLASI-50/70 response, CLA-IGA and CLASI-A remission vs placebo. Findings support further investigation of enpatoran efficacy and safety in patients with lupus and active cutaneous manifestations."

Clinical • P2 data • Retrospective data • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • TLR7

Enpatoran, a first-in-class, selective, orally administered toll-like receptor 7/8 inhibitor, in systemic and cutaneous lupus erythematosus: results from a randomised, placebo-controlled phase Ib study. (PubMed, Lupus Sci Med) - P1 | "Enpatoran was well tolerated and demonstrated favourable safety and PK profiles in patients with SLE and CLE. Although preliminary, the SLE disease activity and biomarker results support the therapeutic targeting of TLR7/8 for lupus."

Biomarker • Clinical • IO biomarker • Journal • P1 data • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TLR7

TARGETING MONOCYTE TLR8 AS AN ANTI-INFLAMMATORY THERAPY IN DECOMPENSATED ADVANCED CHRONIC LIVER DISEASE (AASLD 2025) - "Treatment of dACLD monocytes, using either the specific TLR8 inhibitor CU-CPT9a or the dual TLR7/8 inhibitor Enpatoran, reduced expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α. Our comprehensive immunophenotyping data demonstrate monocyte activation as a key regulator of SI in dACLD and identifies TLR8 activity as a driver of this process, with elevated monocyte TLR8 expression and serum TLR8 ligand activity observed in dACLD patients. Crucially, the TLR8 pathway is druggable, highlighting this as a tractable therapeutic target to abrogate SI in dACLD."

IO biomarker • Metastases • Hepatology • Inflammation • CD63 • CD8 • CD9 • IL1B • IL6 • TLR7 • TLR8 • TNFA

Efficacy and safety of first-in-class oral small molecule toll-like receptor 7/8 inhibitor enpatoran in patients with lupus erythematosus and active cutaneous manifestations: Results of the Phase II WILLOW study (EADV 2025) - P2 | "Cohort A of WILLOW showed a significant dose response with enpatoran in change from BL in CLASI- A vs placebo at Week 16 in pts with CLE and/or SLE with predominantly active lupus rash. In both cohorts, more pts receiving enpatoran than placebo had CLASI-50/70 responses. Reduced IFN-GS levels support TLR7/8 involvement in IFN pathway activation, a hallmark of lupus."

Clinical • IO biomarker • P2 data • Cutaneous Lupus Erythematosus • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TLR7

Effect of Renal Impairment on Enpatoran Pharmacokinetics (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Trial completion date: Dec 2025 ➔ Apr 2026 | Trial primary completion date: Dec 2025 ➔ Apr 2026

Trial completion date • Trial primary completion date • Renal Disease

Study of M5049 in DM and PM Participants (NEPTUNIA) (clinicaltrials.gov) - P2 | N=40 | Terminated | Sponsor: EMD Serono Research & Development Institute, Inc. | Active, not recruiting ➔ Terminated; Based on interim analyses for futility

Trial termination • Dermatomyositis • Immunology • Myositis

The Willow LTE Study With M5049 in Participants With SCLE, DLE and/or SLE (WILLOW LTE) (clinicaltrials.gov) - P2 | N=379 | Active, not recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Recruiting ➔ Active, not recruiting | Trial completion date: Apr 2025 ➔ Aug 2028 | Trial primary completion date: Apr 2025 ➔ Aug 2028

Enrollment closed • Trial completion date • Trial primary completion date • Cutaneous Lupus Erythematosus • Discoid Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Study of M5049 in DM and PM Participants (NEPTUNIA) (clinicaltrials.gov) - P2 | N=40 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Dermatomyositis • Immunology • Myositis

Randomised, placebo-controlled Phase II study of oral enpatoran, a first-in-class toll-like receptor 7/8 inhibitor, in systemic lupus erythematosus (EULAR 2025) - P2 | "At BL, most pts had musculoskeletal (92.4%) or mucocutaneous (98.0%) involvement; 85.3% of pts were receiving systemic GC (51.0% a prednisone-equivalent dose ≥10 mg/day). In this Phase II study, enpatoran was well tolerated and exhibited nominally significant improvements in measures of SLE disease activity through Wk24 vs pbo. Enpatoran-mediated downmodulation of IFN-GS confirms the involvement of the TLR7/8 pathway in type I IFN pathway activation in SLE."

Clinical • IO biomarker • Late-breaking abstract • P2 data • Cutaneous Lupus Erythematosus • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Musculoskeletal Diseases • Systemic Lupus Erythematosus • TLR7 • TLR8