enpatoran (M5049) / EMD Serono - LARVOL DELTA

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

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

New P1 trial

The WILLOW Study With M5049 in SLE and CLE (SCLE and/or DLE) (WILLOW) (clinicaltrials.gov) - P2 | N=532 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Trial completion date: Aug 2024 ➔ Dec 2024 | Trial primary completion date: Jul 2024 ➔ Nov 2024

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

Human Red Blood Cells Express Toll-like Receptor 7 and Bind Single Stranded RNA (ATS 2024) - "To determine if RBC binding of RNA40 was TLR7 mediated, we incubated RBCs with RNA-40 in the presence of TLR7 inhibitors (ODN 2088, Enpatoran) and excess receptor (TLR7 -Fc chimera)... We demonstrate that human RBCs express TLR7 and bind ssRNA. Moreover, we demonstrate that membrane localization of TLR7 is increased during SARS-CoV2-associated sepsis, suggesting that RBCs may participate in the host immune response during viral infection. Ongoing studies will be required to elucidate the role of RBC TLR7 in modulating the innate immune response during viral infection."

IO biomarker • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation • Novel Coronavirus Disease • Respiratory Diseases • Septic Shock • TLR7 • TLR9

The WILLOW Study With M5049 in SLE and CLE (SCLE and/or DLE) (WILLOW) (clinicaltrials.gov) - P2 | N=532 | Active, not recruiting | Sponsor: EMD Serono Research & Development Institute, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus

Efficacy evaluation of B cell targeting drugs and the involved mechanism of action study in humanized BAFF transgenic SLE mice model (IMMUNOLOGY 2024) - "At week 25 of age, B6-hBAFF mice developed lupus nephritis.Belimumab, a BAFF antibody administrated to BAFF transgenic mice demonstrated the effectively reduced serum antibody levels after 16 weeks of dosing. Only the BTK inhibitor Orelabrutinib significantly eliminated serum Igs levels. Enpatoran exhibited a similar ability to Orelabrutinib in reducing T follicular helper cell and plasma cell populations spleen and lymph nodes.In summary, the humanized BAFF transgenic SLE model proves to be a valuable tool for preclinical efficacy studies in SLE treatment and understanding pathogenesis."

Late-breaking abstract • Preclinical • Glomerulonephritis • Immunology • Inflammatory Arthritis • Lupus • Lupus Nephritis • Nephrology • Systemic Lupus Erythematosus • TLR7

Enpatoran: Data from P2 WILLOW trial (NCT05162586) for cutaneous lupus erythematosus in Q3 2024 (EMD Serono) - Q4 23 IR Roadshow in Paris: Data from P2 WILLOW trial (NCT05162586) for systemic lupus erythematosus in Q4 2024

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

Safety evaluation from an ongoing randomized, double-blind, multiple-ascending dose phase Ib study of enpatoran versus placebo in patients with active systemic or cutaneous lupus erythematosus (SLE/CLE) (LUPUS 2024) - P1, P2 | "Conclusions Based on a review of blinded data, no new safety signals were identified to the cut-off date in the first clinical study of enpatoran in SLE/CLE. The phase II proof-of-concept WILLOW study is evaluating the safety and efficacy of enpatoran in a larger cohort of patients with SLE and/or CLE (NCT05162586)"

Clinical • P1 data • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Systemic Lupus Erythematosus • TLR7

Asia-Inclusive Global Development of Enpatoran: Results of an Ethno-Bridging Study, Intrinsic/Extrinsic Factor Assessments and Disease Trajectory Modeling to Inform Design of a Phase II Multiregional Clinical Trial. (PubMed, Clin Pharmacol Ther) - P1, P2 | "Aldehyde oxidase (AOX) is considered to be a key contributor to enpatoran metabolism, and a literature review indicated no relevant ethnic differences in AOX function based on in vitro and clinical PK data from marketed drugs metabolized by AOX, supporting the conclusion of low ethnic sensitivity for enpatoran. Taken together, the inclusion of Asian patients in MRCTs including WILLOW was informed based on a Totality of Evidence approach."

Journal • P2 data • Cutaneous Lupus Erythematosus • Immunology • Inflammatory Arthritis • Lupus • Metabolic Disorders • Myositis • Systemic Lupus Erythematosus • TLR8