enpatoran (M5049) / EMD Serono - LARVOL DELTA

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

EMD Serono Presents Results on Efficacy and Safety of Enpatoran in Systemic Lupus Erythematosus (SLE) at EULAR 2025 (Businesswire) - P2 | N=456 | WILLOW (NCT05162586) | Sponsor: EMD Serono Research & Development Institute, Inc. | "Cohort B of the Phase 2 study indicates all doses of enpatoran were associated with higher BICLA response rates compared with placebo, though the primary endpoint of BICLA dose-response relationship at Week 24 was not met; Data show encouraging efficacy in a large subgroup of SLE patients with active cutaneous manifestations at baseline, including improved response rates in key disease activity measurements; Enpatoran was well-tolerated and exhibited a manageable safety profile consistent with previous studies, with no new safety signals identified."

P2 data • Systemic Lupus Erythematosus

EMD Serono Presents Positive Phase 2 Data for Enpatoran Demonstrating Reduction in Disease Activity in Patients with Cutaneous Lupus Erythematosus (CLE) and Systemic Lupus Erythematosus (SLE) with Active Lupus Rash (Businesswire) - P2 | N=456 | WILLOW (NCT05162586) | Sponsor: EMD Serono Research & Development Institute, Inc. | "Results will be presented at the 16th International Congress on Systemic Lupus Erythematosus (LUPUS 2025), taking place May 21-24 in Toronto...Cohort A met its primary endpoint, demonstrating a dose-response relationship and showing a clinically meaningful improvement in CLASI-A scores at Week 16 (p = 0.0002). Additionally, 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....On Cohort B of the WILLOW study, promising efficacy results were observed in prespecified subpopulations, even though the primary endpoint of dose response was not met. The full readout from this cohort will be presented at the European Alliance of Associations for Rheumatology Congress (EULAR 2025)."

P2 data • Cutaneous Lupus Erythematosus • Lupus • Systemic Lupus Erythematosus

Toll-like receptor 8 activation induces a neutrophil inflammatory phenotype: therapeutic implications for the utility of toll-like receptor 8 inhibition. (PubMed, J Leukoc Biol) - "Expression of NFKBIZ was induced by TLR8 in neutrophils in vitro and found to also be reduced by enpatoran in patients with COVID-19, suggesting it may be useful as a marker for TLR8-activated neutrophils and for identifying candidate diseases and patients that may benefit from treatment with a TLR7/8 inhibitor. Overall, our findings provide new insights into TLR8 and neutrophil biology that have therapeutic implications in autoimmune diseases and immune-mediated inflammation."

IO biomarker • Journal • Immunology • Infectious Disease • Inflammation • Inflammatory Arthritis • Lupus • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • Systemic Lupus Erythematosus • CXCL8 • TLR7 • TLR8

Merck KGaA fails midphase lupus trial, says totality of data support further development (FierceBiotech) - P2 | N=456 | WILLOW (NCT05162586) | Sponsor: EMD Serono Research & Development Institute, Inc. | "One of Merck KGaA’s leading immunology assets has flunked a phase 2 lupus trial. Despite the primary endpoint miss, Merck has concluded further development is warranted in light of responses seen in subgroups and a recent win in another form of the disease...Merck tested its oral TLR7/8 inhibitor enpatoran in two forms of lupus....Thursday, Merck revealed the systemic lupus erythematosus (SLE) cohort was less successful. The SLE arm missed its primary endpoint, which assessed responses on a composite scale after 24 weeks of daily dosing."

P2 data • Systemic Lupus Erythematosus

Toll-Like Receptor 7 Promotes Periodontal Inflammation and Alveolar Bone Resorption Through the NF-κB Signaling Pathway. (PubMed, J Periodontal Res) - "TLR7 is upregulated in periodontitis and may promote the progression of the disease by activating the NF-κB signaling pathway, potentially serving as a therapeutic target. The findings reveal a novel role for TLR7 in periodontitis and highlight the TLR7-NF-κB axis as a key pathway in disease pathogenesis, with broader implications for understanding and treating inflammatory conditions."

IO biomarker • Journal • Dental Disorders • Inflammation • Osteoporosis • Periodontitis • TLR7

A TQT Study to Investigate the Effect of Enpatoran on Cardiac Repolarization in Healthy Participants (clinicaltrials.gov) - P1 | N=40 | Completed | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Active, not recruiting ➔ Completed

Trial completion

The WILLOW Study With M5049 in SLE and CLE (SCLE and/or DLE) (WILLOW) (clinicaltrials.gov) - P2 | N=456 | Completed | Sponsor: EMD Serono Research & Development Institute, Inc. | Active, not recruiting ➔ Completed

Trial completion • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

A TQT Study to Investigate the Effect of Enpatoran on Cardiac Repolarization in Healthy Participants (clinicaltrials.gov) - P1 | N=40 | Active, not recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Recruiting ➔ Active, not recruiting

Enrollment closed

Study of M5049 in DM and PM Participants (NEPTUNIA) (clinicaltrials.gov) - P2 | N=40 | Recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Dec 2024 ➔ Apr 2025 | Trial primary completion date: Jul 2024 ➔ Apr 2025

Trial completion date • Trial primary completion date • Dermatomyositis • Immunology • Myositis

Safety, Pharmacokinetics, Clinical Efficacy and Exploratory Biomarker Results from a Randomized, Double-Blind, Placebo-Controlled Phase 1b Study of Enpatoran in Active Systemic and Cutaneous Lupus Erythematosus (SLE/CLE) (ACR Convergence 2024) - P1, P2 | "Enpatoran was well tolerated up to the highest evaluated dose of 150 mg BID for 24 weeks and demonstrated favorable safety and PK profiles in the first clinical study in SLE and CLE. The numerical reduction in SLEDAI-2K scores with enpatoran 100 mg BID and suppression of IFN-GS suggest a pharmacological effect. Enpatoran is being evaluated in a larger cohort of patients with SLE and/or CLE in an ongoing Phase II study (WILLOW; NCT05162586).Medical writing support was provided by Bioscript Group."

Biomarker • Clinical • IO biomarker • P1 data • PK/PD data • Cutaneous Lupus Erythematosus • Immunology • Infectious Disease • Inflammatory Arthritis • Lupus • Novel Coronavirus Disease • Pneumonia • Respiratory Diseases • 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 | Not yet recruiting ➔ Recruiting

Enrollment open • Renal Disease

Cell damage shifts the microRNA content of small extracellular vesicles into a Toll-like receptor 7-activating cargo capable to propagate inflammation and immunity. (PubMed, Cell Commun Signal) - "Our results demonstrate that miR203a is just one paradigmatic TLR7-activating miRNA among the hundreds released by UV-irradiated keratinocytes, which altogether trigger pDC activation in psoriatic conditions. This represents the first evidence that cell damage shifts the miRNA content of sEVs towards a TLR7-activating cargo capable to propagate inflammation and immunity, offering strong support to the physiological role of systemic miRNA-based cell-to-cell communication."

IO biomarker • Journal • Dermatology • Immunology • Inflammation • Psoriasis • CD8 • MIR203A • TLR7

Asia-inclusive drug development leveraging principles of ICH E5 and E17 guidelines: Case studies illustrating quantitative clinical pharmacology as a foundational enabler. (PubMed, Clin Transl Sci) - "Herein, we describe recent case examples of model-informed Asia-inclusive global clinical development in the EMD Serono portfolio, as applied to the ataxia telangiectasia and Rad3-related inhibitors, tuvusertib and berzosertib (oncology), the toll-like receptor 7/8 antagonist, enpatoran (autoimmune diseases), the mesenchymal-epithelial transition factor inhibitor tepotinib (oncology), and the antimetabolite cladribine (neuroimmunological disease). Through these case studies, we illustrate pragmatic approaches to ethnic sensitivity assessments and the application of a model-informed drug development toolkit including population pharmacokinetic/pharmacodynamic modeling and pharmacometric disease progression modeling and simulation to enable early conduct of Asia-inclusive MRCTs. These examples demonstrate the value of a Totality of Evidence approach where every patient's data matter for de-risking ethnic sensitivity to inter-population variations in drug- and..."

Journal • Review • Ataxia • Cerebral Hemorrhage • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency • ATR

A TQT Study to Investigate the Effect of Enpatoran on Cardiac Repolarization in Healthy Participants (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany | Not yet recruiting ➔ Recruiting

Enrollment open

Effect of Renal Impairment on Enpatoran Pharmacokinetics (clinicaltrials.gov) - P1 | N=40 | Not yet recruiting | Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

New P1 trial • Renal Disease