Enpatoran, a Toll-like receptor 7/8 inhibitor, in moderate-to-severe systemic

# Enpatoran, a Toll-like receptor 7/8 inhibitor, in moderate-to-severe systemic lupus erythematosus: findings from Cohort B of a multicentre, international, double-blind, placebo-controlled dose-finding phase 2 trial *The Lancet 2026* Articles Enpatoran, a Toll-like receptor 7/8 inhibitor, in moderate-to- severe systemic lupus erythematosus: findings from Cohort B of a multicentre, international, double-blind, placebo-controlled dose-finding phase 2 trial Eric F Morand, Maria Dall’Era, Jorge Sanchez-Guerrero, David R Pearson, Victoria P Werth, Joerg Wenzel, Sanjeev Roy, Christine Kleinmond, Hans Gühring, Evridiki Sgouroudi, Lena Klopp-Schulze, Flavie Moreau, Ruth Fernandez-Ruiz, Richard Furie Summary Background Toll-like receptors (TLR) 7 and 8 (TLR7/8) are activators of innate and adaptive immunity contributing to Lancet 2026; 407: 1809–24 lupus pathogenesis. In Cohort B of WILLOW, a phase 2, randomised, placebo-controlled, double-blind, basket, dose- See Comment page 1761 finding study, enpatoran, an oral small molecule inhibitor of TLR7/8, was evaluated in participants with active Centre for Inflammatory systemic lupus erythematosus (SLE). Diseases, Monash University, Melbourne, VIC, Australia (Prof E F Morand PhD); Division Methods Participants were eligible if they were aged 18–75 years with moderate-to-severe SLE, with or without of Rheumatology, University of cutaneous manifestations, had a disease duration of at least 6 months, and were receiving a stable dose of medication California San Francisco School before the screening period. Participants were recruited from 132 centres in 22 countries. In Part 1, participants were of Medicine, San Francisco, CA, randomly allocated in a 1:2 ratio to receive either placebo or 100 mg enpatoran, both twice-daily. Following the USA (Prof M Dall’Era MD); Division of Rheumatology, enrolment of 60 participants, Part 2 was activated and additional participants were randomly allocated in a 1:1:1:1 ratio Mount Sinai Hospital and to 25 mg, 50 mg, or 100 mg of enpatoran or placebo, all twice-daily, for 24 weeks. Random allocation was stratified by Toronto Western Hospital, region, biomarker status, and hybrid Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease University of Toronto, Toronto, Activity Index score. The primary objective was to evaluate the dose–response relationship of enpatoran, using British ON, Canada (Prof J Sanchez-Guerrero MD); Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response rate at week 24, based on Department of Dermatology, multiple comparison procedure–modelling analysis. Study visits were scheduled from week 0 to week 24, followed by University of Minnesota, a 2-week safety follow-up period for participants who chose not to enter the long-term extension. From weeks 2 to 12, Minneapolis, MN, USA glucocorticoid doses were tapered to a prednisone-equivalent dose of no more than 5 mg/day, as clinically tolerated. (D R Pearson MD); Department of Dermatology, Perelman Adverse events were monitored continuously throughout the study; safety parameters (including physical examination, School of Medicine, University vital signs, and routine chemistry and haematology) were assessed at all study visits. The trial was registered at of Pennsylvania, Philadelphia, ClinicalTrials.gov (NCT05162586) and a long-term extension study is ongoing. PA, USA (Prof V P Werth MD); Corporal Michael J Crescenz VAMC, Philadelphia, PA, USA Findings Between May 4, 2022, and Feb 6, 2024, participants were screened for eligibility for WILLOW (Prof V P Werth); Department of cohorts A and B; 715 participants were screened and 354 were randomly allocated and included in the Cohort B Dermatology and Allergy, safety population (95 to placebo, 71 to 25 mg enpatoran, 74 to 50 mg enpatoran, and 114 to 100 mg enpatoran). Cluster of Excellence One patient allocated to the placebo group was found to be ineligible and was excluded from the full analysis set for ImmunoSensation³, University Hospital of Bonn, Bonn, the ecacy analyses. 335 (95%) of 353 participants were female, 18 (5%) were male, and median age was 41 years Germany (Prof J Wenzel MD); (IQR 33–51). At week 24, the study did not meet its primary objective of identifying a statistically significant dose– Ares Trading, Eysins, response relationship for enpatoran in BICLA response rate (p=0·14). BICLA response rates at week 24 were higher Switzerland, an affiliate of with all doses of enpatoran (25 mg: 41 [58%] of 71; odds ratio [OR] vs placebo 2·2 [95% CI 1·1–4·0], 50 mg: Merck (S Roy MD); Merck Healthcare, Darmstadt, 36 [49%] of 74; OR 1·5 [95% CI 0·8–2·8], and 100 mg: 56 [49%] of 114; OR 1·6 [95% CI 0·9–2·8]) versus placebo Germany (C Kleinmond PhD, (37 [39%] of 94). The most common treatment-emergent adverse event was diarrhoea, in four (6%) of 71, H Gühring MD, E Sgouroudi PhD, two (3%) of 74, and two (2%) of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, L Klopp-Schulze PhD); EMD Serono Research and and seven (7%) of 95 participants in the placebo group. Serious adverse events were reported in one (1%) of 71, Development Institute, three (4%) of 74, five (4%) of 114, and three (3%) of 95 participants treated with 25 mg, 50 mg, and 100 mg enpatoran Billerica, MA, USA, an affiliate and placebo, respectively. of Merck (F Moreau MSc, R Fernandez-Ruiz MD); Northwell, New Hyde Park, NY Interpretation In this study of participants with moderate-to-severe SLE, enpatoran improved BICLA response rates (Prof R Furie MD); Division of versus placebo; however, the primary objective of a statistically significant dose-dependent eect on disease activity Rheumatology, Northwell, based on BICLA response was not met. Enpatoran was well tolerated across all dose groups. Great Neck, NY, USA (Prof R Furie) Funding Merck Healthcare (Darmstadt, Germany). Correspondence to: Prof Eric F Morand, Centre for Inflammatory Diseases, Monash Copyright © 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 University, Melbourne, VIC 3168, license. Australia eric.morand@monash.edu Articles Research in context Evidence before this study Added value of this study Only two targeted therapies have been approved for systemic To our knowledge, the WILLOW study is the first placebo- lupus erythematosus (SLE) in the past 60 years, and unmet controlled clinical trial of TLR7/8 inhibition in SLE. It examined the needs remain to reduce the burden of disease and minimise the effect of TLR7/8 inhibition with enpatoran on both skin-related use of glucocorticoids, which are associated with cumulative and systemic disease activity and provides an overall picture of toxicities. Toll-like receptor (TLR) 7 and 8 (TLR7/8) are key the potential clinical benefit of enpatoran while augmenting upstream drivers of both interferon signalling and B-cell knowledge on the underlying mechanisms of disease. This global activation, which are known contributors to the pathogenesis phase 2 clinical trial substantiates earlier phase Ib evidence for of lupus; TLR7 is also implicated in glucocorticoid resistance. enpatoran in lupus. WILLOW enrolled a large and representative TLR7/8 inhibition demonstrated efficacy with glucocorticoid- sample of participants to receive standard of care therapy sparing potential in a preclinical model of lupus. Enpatoran is a alongside placebo or enpatoran 25 mg, 50 mg, or 100 mg BID. first-in-class oral small molecule TLR7/8 inhibitor under clinical Cohort B (reported here) included participants with moderate-to- investigation in lupus. severe active systemic manifestations of SLE, while Cohort A enrolled participants with cutaneous manifestations of CLE or SLE We searched PubMed on Aug 13, 2025, for clinical trials (findings reported separately). published in English on TLR7/8 inhibitors from database inception to the search date, using the following terms in the Implications of all the available evidence title or abstract: (“SLE” OR “systemic lupus erythematosus” OR Although the primary objective of identifying a statistically “CLE” OR “cutaneous lupus erythematosus” OR “lupus significant dose–response relationship was not met, systemic nephritis” OR “lupus”) AND (“TLR7/8” OR “TLR7” AND “TLR8” disease activity reduction was observed across enpatoran dose OR “Toll-like receptor 7/8”). Four early-phase trials of TLR7/8 groups, evidenced by improved British Isles Lupus Assessment inhibitors were identified. A phase 1/2 study of E6742 in SLE Group-based Composite Lupus Assessment (BICLA) response and phase 1 trial of MHV370 in healthy volunteers indicated rates at week 24 versus placebo. Moreover, clinically that TLR7/8 has a role in type I interferon pathway activation, meaningful treatment benefits of enpatoran were with promising preliminary efficacy and safety findings. In a demonstrated across multiple prespecified secondary and Phase 1b trial in patients with cutaneous lupus erythematosus exploratory clinical and biomarker outcomes. Rates of (CLE), afimetoran was well tolerated and associated with attainment of the composite endpoint of BICLA response plus reduced expression of TLR7/8 pathway-associated cytokines clinically meaningful glucocorticoid reductions improved across and interferon gene signature (IFN-GS). Initial safety data from all enpatoran groups compared with placebo. The effect of a phase 1 trial of enpatoran in healthy participants showed that enpatoran on type I interferon activity was demonstrated by a enpatoran was well tolerated with no dose-limiting adverse rapid reduction in IFN-GS emerging as early as week 2, events. In addition, a phase 1b study of enpatoran in maintained until the end of treatment. Enpatoran was well participants with active CLE and SLE demonstrated that a tolerated, with rates of treatment-emergent adverse events 100 mg twice daily dose improved systemic disease activity and similar to placebo and consistent with previous clinical studies. reduced IFN-GS in a dose-dependent manner, without Overall, these findings highlight the role of TLR7/8 activation in tolerability concerns. The available data supported further the IFN pathway in SLE, and the role of TLR7/8 inhibition in evaluation of enpatoran for participants with lupus in a phase 2 attenuating cutaneous and systemic disease activity in SLE, trial (WILLOW). supporting further investigation of enpatoran in phase 3 trials. Introduction treatment goals of reduced disease activity and Systemic lupus erythematosus (SLE) is a chronic glucocorticoid dose.4 However, in pooled analyses of autoimmune disease with complex pathophysiology and phase 3 clinical trials, belimumab and anifrolumab at involvement across multiple organs,1 characterised by 1 year achieved rates of lupus low disease activity state periods of flares and remission.2 Current treatment (LLDAS) of 17% and 30%, and 8% and 15% for remission, options for SLE commonly provide inadequate control of respectively.5,6 Attainment of treatment goals remains disease activity1 and are associated with cumulative challenging, highlighting a need for novel targeted toxicity.2 Glucocorticoid exposure contributes to the therapies. adverse long-term outcomes of active disease, including SLE is characterised by a loss of immune tolerance and permanent organ damage and death.3 the dysregulation of innate and adaptive immunity, as Only two targeted biologic therapies—belimumab, evidenced by autoantibodies to nucleic acids and which targets B-lymphocyte stimulator protein and B-cell activation of the type I interferon cytokine family.1,2 activating factor, and anifrolumab, a type I interferon Aberrant type I interferon and antibody production result receptor antagonist—have been approved for SLE in the in a cycle of localised and systemic inflammation that last 60 years.2 Clinical guidelines recommend twin contributes to irreversible organ damage.1 A type I 1810 Articles interferon gene signature (IFN-GS) is increased in blood Lupus Assessment (BICLA) response and further and tissue cells from people with SLE,1,7 interferon explore the ecacy; pharmacokinetics and activation has been observed in lesional and non-lesional pharmacodynamics; and safety of enpatoran compared skin in people with cutaneous lupus erythematosus with placebo. (CLE),8 and local tissue production of interferon in the skin and other organs drives systemic autoimmunity and Methods progression in SLE.9 Broadening SLE treatments beyond Study design and participants targeting interferon or B cells in isolation might improve WILLOW is a global phase 2, randomised, double-blind, disease control. placebo-controlled, basket, proof-of-concept, dose- The cause of autoantibody and interferon activation in finding, parallel study conducted across 132 centres in SLE is unknown. Toll-like receptors (TLRs) 7 and 8 22 countries, to evaluate the ecacy and safety of (TLR7/8) have specialised, upstream roles in both innate enpatoran in adults with CLE or SLE receiving standard and adaptive immune responses that potentially of care therapy. Full details of the Cohort B study design contribute to SLE pathogenesis.10 TLR7/8 entrain type I in participants with SLE are provided in the appendix See Online for appendix interferon expression in the innate immune response to (pp 6–12). Cohort B was separated into two parts, with viral nucleic acids,10 and are key drivers of interferon Part 1 designed to evaluate whether enpatoran showed activation.11 Aditionally, TLR7/8 signalling pathways play signs of a clinical signal in SLE and provide a basis for a central immunomodulatory role in the activation of adaptation of Part 2 to improve enpatoran dose-finding, myeloid cells, neutrophils, and B cells.10,12 In childhood- if needed. Part 1 randomly allocated participants to onset SLE, gain of function mutations that enhance TLR7 receive either placebo or enpatoran, and Part 2 compared signalling result in type I interferon expression and the placebo with three dierent doses of enpatoran. An aberrant survival of B-cell receptor-activated B cells.11,13 In additional 2-week safety follow-up included all addition, elevated interferon expression by keratinocytes participants not choosing to enter the long-term in CLE triggers the TLR7-dependent development of extension. From weeks 2 through to 12, glucocorticoid systemic autoimmunity.14 To validate that TLR7/8 has a doses were tapered to a prednisone-equivalent dose of key role in SLE pathogenesis a randomised clinical trial 5 mg per day or lower as clinically tolerated and of TLR7/8 inhibition was required. maintained to week 24. Enpatoran is a novel, oral small molecule inhibitor of Institutional review boards or independent ethics TLR7/8.15 TLR7/8 inhibition reduced inflammatory committees approved the protocol at each site (appendix cytokine production with glucocorticoid-sparing pp 6–8), and the study was monitored by an independent potential in preclinical models of lupus.16 Early phase 1 data and safety monitoring committee. Participants trials in healthy participants indicated that enpatoran provided written informed consent. All authors was well tolerated with no dose-limiting adverse events contributed to the preparation of the manuscript and and comparable pharmacokinetic and pharmacodynamic assume responsibility for the accuracy and completeness properties between Asian (Japanese) and White of the reported data and for the fidelity of the trial to the participants.15,17 In a phase 1b study of participants with protocol. It was registered at ClinicalTrials.gov active CLE and SLE, 100 mg enpatoran twice daily (NCT05162586) and is complete, with a separate improved Systemic Lupus Erythematosus Disease long-term extension study ongoing. Activity Index 2000 (SLEDAI-2K) scores compared with Full eligibility criteria are provided in the appendix placebo after week 4 (maintained to week 24), reduced (pp 7–10). In brief, adults aged from 18–75 years were IFN-GS, and was well tolerated.18 These data supported eligible for Cohort B if they had a documented diagnosis further investigation of TLR7/8 inhibition with of SLE (fulfilling Systemic Lupus International enpatoran in CLE or SLE. In a novel basket design, Collaborating Clinics [SLICC] criteria, or ≥4 American WILLOW enrolled two cohorts of participants treated College of Rheumatology [ACR] or European League with enpatoran or placebo. Cohort A enrolled Against Rheumatism [EULAR]/ACR 2019 criteria). They participants with cutaneous manifestations as CLE also had moderate-to-severe disease activity, as defined alone or as skin activity associated with SLE.19 In this by British Isles Lupus Assessment Group (BILAG) 2004 cohort, the primary endpoint was met, with enpatoran of 1A and greater or 2B; as well as either a Safety of demonstrating a dose–response relationship based on Estrogens in Lupus Erythematosus National reduction in cutaneous disease activity at week 16. Assessment–SLE Disease Activity Index (SELENA- Separation of treatment groups began as early as week 2, SLEDAI) score of 6 or greater or Cutaneous Lupus and clinically meaningful responses were observed Disease Area and Severity Index–Activity (CLASI-A) alongside substantial suppression of IFN-GS. Cohort B score of 8 or greater, or both; all of which which were enrolled participants with moderate-to-severe SLE, with adjudicated at screening. Participants had a disease or without cutaneous manifestations to explore the duration of 6 months or longer and were receiving a dose–response relationship of enpatoran in terms of stable dose of at least one of: an immunomodulator or British Isles Lupus Assessment Group-based Composite immunosuppressant for at least 8 weeks before the Articles screening period, or an oral or topical glucocorticoid for glucocorticoid dose during the study; Systemic Lupus at least 2 weeks before screening. Participant race and Erythematosus Responder Index (SRI)-4 response, sex data (female or male) were obtained from study attainment of LLDAS, or remission as defined by forms completed by the investigator. Key exclusion Definition of Remission in SLE (DORIS) criteria at criteria included primary diagnosis of a non-SLE week 24 (full definitions are presented in the appendix autoimmune disease, rheumatic or dermatological [p 6]); change from baseline in number of tender and disease, drug-induced lupus, or active lupus nephritis. swollen joints as assessed by the proportion of participants with 50% or greater reduction in 28-joint Randomisation and masking count at week 24; change from baseline in Physician Participants were randomised into treatment blocks Global Assessment of SLE disease activity at week 24; using randomly permuted blocks of 6 in Part 1 and blocks time to first moderate or severe BILAG flare and time to of 4 in Part 2, in a centralised web-based system. first SELENA-SLEDAI Flare Index(SFI) severe flare from Allocation was concealed from investigators and the day 1 through to week 24; and change from baseline to sponsor, with the block size known only to the sponsor’s week 24 in Functional Assessment of Chronic Illness statistician. In Part 1, participants were randomly Therapy (FACIT)-Fatigue score (5-point Likert scale with allocated in a 1:2 ratio to placebo twice daily or 100 mg higher scores indicating better quality of life). oral enpatoran twice daily. Once 60 participants were An endpoint adjudication committee reviewed masked enrolled in Part 1, Part 2 was activated, wherein data for the primary and secondary endpoints participants were randomly allocated in a 1:1:1:1 ratio to (eg, reduction of disease activity and lupus flares) to placebo or 25 mg, 50 mg, or 100 mg of oral enpatoran (all monitor the quality of the SLE assessments by twice daily) for 24 weeks. Randomisation was stratified investigators. according to region (Asia, North America and western Exploratory pharmacodynamic biomarker and Europe, and central and South America and rest of pharmacokinetic assessments of enpatoran (appendix world), biomarker status (high IFN-GS or positive RNA p 6) included change from baseline in serum IFNα autoantibodies vs low IFN-GS and negative RNA concentrations and whole blood IFN-GS from week 2 autoantibodies), and hybrid SELENA-SLEDAI score through to week 26, and enpatoran plasma concentrations (≥10 vs <10) at screening. Masked participant identifiers at the end of a dosing interval immediately before next for the analysis of pharmacokinetic samples prevented dosing (C ) in each dose group. trough association of treatment codes with clinical data. Exploratory prespecified ecacy outcomes in the Participants, study investigators, and the sponsor were subgroup of participants with cutaneous manifestations masked to study intervention assignment. (defined as CLASI-A score ≥8 at screening and baseline) were CLASI-50 response (≥50% improvement from Outcomes baseline score) at week 24; change in CLASI-A total score The primary objective was to evaluate the dose–response from baseline through to week 24; attainment of relationship of enpatoran in reducing disease activity, cutaneous remission (CLASI-A total score of 0 to 1, based on BICLA response rate at week 24 (defined as CLASI-A total score of 0 to 3, or the combination of meeting all of the following: BILAG 2004 improvement CLASI-A total score of 0 to 1 and Cutaneous Lupus [all A scores at baseline improved to B, C, or D, and all B Activity Investigator’s Global Assessment [CLA-IGA] scores improved to C or D at week 24]; no worsening in score of 0 to 1 at week 24). CLASI-70 response (defined as disease activity as measured by BILAG; no worsening of ≥70% improvement in CLASI-A from baseline) was total hybrid SELENA-SLEDAI score from baseline to prespecified as an exploratory endpoint with additional week 24; no worsening of ≥0·3 points in Physician statistical analysis defined post-hoc. Additional post-hoc Global Assessment of SLE disease activity score exploratory outcomes in participants with cutaneous compared with baseline [visual analogue scale from 0=no manifestations were BICLA response rate at week 24 and disease to 3=maximally severe disease). Prespecified SRI-4 response rate at week 24. Safety, including the exploratory subgroup analyses of the primary outcome frequency, nature, and severity of treatment-emergent assessed BICLA response rate at week 24 by IFN-GS adverse events, serious adverse events, adverse events of status (high vs low) and glucocorticoid dose (≥10 mg special interest, and laboratory variables including vs <10 mg daily prednisone-equivalent dose) at baseline. clinically important changes in QT interval corrected Prespecified secondary ecacy outcomes included the using Fridericia’s formula (QTcF), was a prespecified composite endpoint of BICLA response and clinically secondary outcome. meaningful glucocorticoid reduction in participants receiving prednisone-equivalent dose 10 mg per day or Procedures more at baseline (daily prednisone-equivalent dose During the 5–7-week screening period, participants reduced from ≥10 mg at day 1 to ≤5 mg by week 12, underwent an SLE diagnostic examination, including a sustained through to week 24); proportion of participants medication history, documentation of classification who had a clinically meaningful reduction in criteria, and chest imaging. Study visits were scheduled 1812 Articles from week 0 to week 24, followed by a 2-week safety enpatoran or placebo, with measurable data collected at follow-up period for participants who chose not to enter baseline and at least once post-dose, and without the long-term extension. From week 2 to week 12, important events aecting pharmacodynamics or glucocorticoid doses were tapered to a prednisone- pharmac okinetics. equivalent dose of no more than 5 mg/day, as clinically The protocol allowed for enrolment of up to tolerated. In Part 1, participants received either 100 mg 432 participants. To ensure 80% power for detecting an enpatoran or placebo twice daily; in Part 2 participants enpatoran dose–response relationship for BICLA received either 25 mg, 50 mg, or 100 mg of enpatoran or response rate at week 24 , we used a generalised multiple placebo twice daily. For both parts, participants self- comparison procedure-modelling (MCP-Mod) approach administered study medication (four tablets in the (a method testing multiple dose–response relationships morning and four in the evening) consisting of 25 mg while controlling the type I error rate). Candidate models enpatoran, matching placebo tablets, or a combination are described in the appendix (p 11). Part 1 needed to thereof depending on the assigned dose level). enrol 60 participants across two treatment groups (1:2 to Participants were requested to self-administer the tablets placebo twice daily or enpatoran 100 mg twice daily) and with one glass of water and no food restrictions, however Part 2 planned to enrol 280 participants across on scheduled visits participants were requested to wait four treatment groups (1:1:1:1 to placebo or 25 mg, 50 mg, until pre-dose assessments had been completed in the or 100 mg of enpatoran, all twice daily). Part 2 enrolment clinic. could be increased to 372 participants if dose adaptation BICLA response (BILAG 2004 status, SELENA-SLEDAI was deemed necessary based on the interim analysis of score, and physician global assessment of SLE disease Part 1 data. The inverse normal method was used to activity), 28-joint count, and SFI were recorded at all combine p-values from Part 1 and Part 2. A response rate study visits with the exception of week 2. SRI-4 and of 25% in the placebo group and a maximum response LLDAS were assessed by investigator every 4 weeks from rate of 50% for the highest enpatoran dose were assumed. week 4 to week 24. FACIT-Fatigue scores were patient- The global null hypothesis for the primary objective was reported during study visits at weeks 0, 4, 8, 12, 24, and 26. that there was no dierence in BICLA response at Investigator’s assessments of CLASI and CLA-IGA week 24 between treatment groups. Statistical outcomes were documented at all study visits. significance would be demonstrated at the one-sided Enpatoran plasma concentrations were measured 60 0·025 α level. min pre-dose at baseline and weeks 2, 4, 8, and 12; 1–2 Exploratory subgroup analyses of the primary endpoint and 4–6 h post-dose at baseline; 1–2 h post-dose at week 8, (BICLA response at week 24) and key secondary endpoint and anytime during the visit at weeks 16, 20, and 24. (SRI-4) were predefined. The subgroup analyses of Assessment of serum IFNα concentrations (at baseline BICLA and SRI-4 response for participants with and weeks 2, 4, 12, 16, and 24) was done with the Simoa cutaneous manifestations (appendix p 11) were defined platform (Rules-Based Medicine, Austin, TX, USA). post-hoc. All other exploratory endpoints were IFN-GS levels were measured (at baseline and weeks 2, 4, prespecified. 12, 16, 24, and 26) using the AutoImmune Profile (AIP)- Apart from the primary analysis, the results for IFN-1 assay (DxTerity Diagnostics, Torrance, CA and secondary and exploratory analyses were considered IQVIA Laboratories China, Beijing, China) and calculated indicative of a nominally positive eect (improvement by averaging the normalised gene expression values of with enpatoran vs placebo) when p-values crossed the HERC5, IFI27, IFIT1, and RSAD2. statistical significance threshold or when 95% CIs did Adverse events were monitored continuously not contain 0 for dierences or 1 for ratios. Where throughout the study; safety parameters (including presented, 95% CIs were calculated using the Clopper– physical examination, vital signs, and routine chemistry, Pearson method, and the Miettinen–Nurminen method and haematology) were assessed at all study visits. QTcF for the between-group dierences (appendix p 11). Odds was assessed using electrocardiogram measurements at ratios (ORs) were derived from logistic regression models screening at baseline (pre-dose and 1–2 h post-dose), at with stratification factors of region and biomarker status, weeks 2, 8, and 20 (1–2 h post-dose), and at week 24 (as and baseline score as covariates. For the analyses of soon as possible during the visit). BICLA and SRI-4 responses, SELENA-SLEDAI score was used as a covariate in place of baseline score. Screening Statistical analysis for subgroup eect was conducted using logistic Ecacy analyses were performed on the full analysis set, regression models with treatment group, subgroup, and defined as participants correctly randomised into Cohort treatment by subgroup interaction as categorical B. Skin-related endpoints were analysed in participants variables. with cutaneous manifestations. The safety analysis set Continuous endpoints were analysed using mixed- included all participants who had received one or more model with repeated measures with stratification region, doses of study treatment. Biomarker analyses were biomarker status, treatment, and analysis visit as conducted in participants receiving one or more doses of classification variables, baseline score (where applicable), Articles and baseline hybrid SELENA-SLEDAI total score as 715 participants were screened and 354 were randomly covariates, and treatment by analysis visit interaction. allocated and included in the Cohort B safety population Binary endpoints were summarised using descriptive (95 to placebo [21 in Part 1 and 74 in Part 2]; 71 to 25 mg statistics (counts and percentages). Due to the high enpatoran; 74 to 50 mg enpatoran; and 114 to 100 mg enrolment in central and South America and rest of the enpatoran [40 in Part 1 and 74 in Part 2]; figure 1). world, the analyses defined the factor of region as One participant randomly allocated to the placebo group three levels in ecacy models: North America and was found to not meet BILAG eligibility criteria for Europe, central and South America, and rest of the world, Cohort B after adjudication at screening and was excluded thus combining eastern Europe (considered a part of rest from the full analysis set; thus, 353 participants were of the world for stratification during randomisation) with included in the full analysis set for the ecacy analyses North America and western Europe. (94 to placebo twice daily; figure 1). A total of 194 (55%) of For binary response endpoints, early treatment 353 participants in the full analysis set for the ecacy discontinuations, the use of prohibited protocol analyses had at least one protocol deviation during the treatments (ie, new or increased immunosuppressives or study, most commonly (in >10% of participants) relating antimalarials), and protocol deviations in glucocorticoid to the visit schedule (55 [16%]), concomitant medication use, as determined by the endpoint adjudication use (54 [15%]), ecacy assessments (49 [14%]), or safety committee, were all considered indicative of non-response; reporting or procedures (40 [11%]). other reasons for missing data were also considered non- Baseline characteristics are shown in table 1; responses. In the analysis of the continuous secondary 335 (95%) of 353 of participants were female and 18 (5%) endpoint of change from baseline in CLASI-A at week 24, were male, and median age was 41 years (IQR 33–51). After missing data were assumed missing at random. adjudication, 95% of participants met BILAG criteria for Time to event was defined as the time from day 1 moderate-to-severe SLE at baseline. Of the 353 participants, (random allocation) to date of first occurrence of the most had joint involvement (326 [92%]) or mucocutaneous event. In case of discontinuation or study completion involvement (346 [98%]), and 254 (72%) had high IFN-GS without occurrence of the event, the event was censored at baseline. Overall, 301 participants (85%) were receiving at the last assessment visit. Time to event endpoints were systemic glucocorticoids, including 180 (51%) receiving a analysed using a stratified log rank test of distribution of daily prednisone-equivalent dose of 10 mg or above per time to the event with stratification factors of region, day; 297 (84%) and 204 (58%) participants were receiving biomarker status, and SELENA-SLEDAI score. antimalarials and immunosuppressants, respectively. Estimation of treatment eect and 95% two-sided CIs Cutaneous manifestations were present in were based on hazard ratios from a stratified Cox model 162 (46%) participants (41 in the placebo group, and 29, 38, of event hazard rate, with terms for treatment group, and and 54 for enpatoran 25 mg, 50 mg, and 100 mg, strata defined by randomisation stratification factors. A respectively), of whom 156 (96%) had manifestations in cumulative distribution function for time to event was other organ systems. estimated via Kaplan–Meier method by treatment group. The study did not meet its primary objective of Censoring was assumed non-informative for event. identifying a statistically significant dose–response All analyses were performed using SAS software relationship for enpatoran in BICLA response rate at version 9.4 or higher apart from the analysis of the week 24 (p=0·14; table 2). Observed BICLA response rates primary estimands using the MCP-Mod approach, which increased over time across all treatment groups, was performed using R version 4.1.3 or higher, and the reaching 58% (41 of 71) in the enpatoran 25 mg group pharmacokinetic parameters were derived using Phoenix (OR vs placebo 2·2 [95% CI 1·1–4·0]), 49% (36 of 74) in WinNonlin version 8.3 or higher (Certara, Princeton, NJ, the 50 mg group (OR 1·5 [95% CI 0·8–2·8]), and 49% USA). (56 of 114) in the 100 mg group (OR 1·6 [95% CI 0·9–2·8]), compared with 39% (37 of 94) with placebo at week 24 Role of the funding source (table 2, figure 2A). A larger treatment eect was observed The WILLOW study was sponsored by Merck Healthcare. in some predefined subgroups, including participants Authors employed by the study sponsor were involved in with high IFN-GS or participants with high systemic data collection, analysis, interpretation, writing of the glucocorticoid use equivalent to a daily prednisone dose manuscript and provided approval to submit. Medical 10 mg or more at baseline (table 2). Additionally, in a writing support was provided by Helen Beaumont and post-hoc analysis of 162 participants with cutaneous Nicole Jones on behalf of Amica Scientific (Macclesfield, manifestations of SLE, BICLA response rates increased UK), and was sponsored by Merck Healthcare over time (figure 2B) and were higher in all enpatoran (Darmstadt, Germany; funder ID: 10.13039/100009945). groups (25 mg: 17 [59%] of 29; OR 3·0 [95% CI 1·1–8·2]; p=0·015; 50 mg: 22 [58%] of 38; OR 3·3 [95% CI 1·3–8·4]; Results p=0·0066; and 100 mg: 27 [50%] of 54; OR 2·2 [95% CI Between May 4, 2022, and Feb 6, 2024, participants were 0·9–5·3]; p=0·034) compared with placebo (13 [32%] of screened for eligibility for WILLOW cohorts A and B; 41; figure 2C). 1814 Articles 715 patients assessed for eligibility 361 excluded 323 did not meet eligibility criteria 38 met eligibility criteria but did not undergo randomisation Part 1 Part 2 61 were randomly assigned in Part 1 293 were randomly assigned in Part 2 21 assigned to placebo 40 assigned to 100 mg 74 assigned to placebo 71 assigned to 25 mg 74 assigned to 50 mg 74 assigned to 100 mg enpatoran enpatoran enpatoran enpatoran 354 in combined randomly allocated population 95 in placebo cohort 71 in 25 mg enpatoran 74 in 50 mg enpatoran 114 in 100 mg enpatoran cohort cohort cohort Part 1 Part 1 1 discontinued trial 6 discontinued trial regimen regimen 1 lost to follow-up 1 withdrew 1 had adverse event 1 lost to follow-up 1 lack of efficacy 2 other Part 2 Part 2 Part 2 Part 2 15 discontinued trial 8 discontinued trial 9 discontinued trial 5 discontinued trial regimen regimen regimen regimen 6 withdrew 6 withdrew 5 had adverse events 2 withdrew 6 had adverse events 2 had adverse events 1 protocol 2 had adverse event 1 lost to follow-up non-compliance 1 protocol 1 lack of efficacy 3 others non-compliance 1 other 94 included in full analysis 71 included in full analysis 74 included in full analysis 114 included in full analysis set* set set set 95 included in safety 71 included in safety 74 included in safety 114 included in safety analysis set analysis set analysis set analysis set 71 included in 74 included in 114 included in pharmacokinetic analysis pharmacokinetic analysis pharmacokinetic set set analysis set Figure 1: WILLOW Cohort B trial profile BILAG=British Isles Lupus Assessment Group. *One participant who was randomised to placebo was excluded from the full analysis set for the efficacy analyses as they entered Cohort B incorrectly owing to an error in recording BILAG at screening. In participants receiving a prednisone-equivalent the 25 mg and 50 mg groups (table 2). Rates of clinically glucocorticoid dose of 10 mg or higher per day at meaningful glucocorticoid reduction alone were similar baseline (180 [51%] of 353), enpatoran was associated between treatment groups, consistent with enforcement with higher rates of the composite endpoint of BICLA of glucocorticoid taper in the study design (table 2). response plus clinically meaningful glucocorticoid In the full analysis set, a nominally significant reduction versus placebo, with nominal significance in improvement in SRI-4 response rate at week 24 was Articles observed in the enpatoran 100 mg group (77 [68%] of 114) versus placebo (20 [49%] of 41; OR 2·7 [95% CI versus placebo (50 [53%] of 94; OR vs placebo 1·9 1·1 to 7·0]; p=0·02; table 2). Overall, LLDAS attainment [95% CI 1·1 to 3·5]; p=0·012) (table 2). In a post-hoc rates were higher with all enpatoran doses analysis in participants with cutaneous manifestations, versus placebo, with nominal significance in the 50 mg SRI-4 response rates were improved with nominal enpatoran group (table 2). Remission rates at week 24 significance in the 50 mg enpatoran group (27 [71%] of 38) were low and similar between treatment groups. Rates Placebo 25 mg enpatoran 50 mg enpatoran 100 mg enpatoran Total (n=94)* (n=71) (n=74) (n=114) (n=353) Median age, years (IQR) 40 (34–51) 41 (32–49) 39 (29–48) 44 (36–53) 41 (33–51) Sex Female 87 (93%) 69 (97%) 69 (93%) 110 (96%) 335 (95%) Male 7 (7%) 2 (3%) 5 (7%) 4 (4%) 18 (5%) Race† American Indian or Alaska Native 27 (29%) 22 (31%) 18 (24%) 28 (25%) 95 (27%) Asian 26 (28%) 16 (23%) 20 (27%) 27 (24%) 89 (25%) Black or African American 3 (3%) 6 (8%) 6 (8%) 3 (3%) 18 (5%) White 35 (37%) 24 (34%) 29 (39%) 51 (45%) 139 (39%) More than one race 1 (1%) 0 0 2 (2%) 3 (1%) Other 2 (2%) 3 (4%) 1 (1%) 3 (3%) 9 (3%) Geographic region North America and Europe 17 (18%) 14 (20%) 16 (22%) 33 (29%) 80 (23%) Asia 21 (22%) 15 (21%) 18 (24%) 21 (18%) 75 (21%) Central/South America and rest of world 56 (60%) 42 (59%) 40 (54%) 60 (53%) 198 (56%) Time since SLE diagnosis, years (SD) 10·2 (7·8) 7·0 (6·9) 9·8 (7·8) 9·6 (6·6) 9·4 (7·3) Diagnosis of SLE and CLE 59 (63%) 45 (63%) 43 (58%) 69 (61%) 216 (61%) Biomarker status at baseline IFN-GS high 67 (71%) 54 (76%) 50 (68%) 83 (73%) 254 (72%) IFN-GS low 27 (29%) 17 (24%) 24 (32%) 31 (27%) 99 (28%) Hybrid SLENA-SLEDAI Hybrid SELENA-SLEDAI total, mean (SD) 11 (3·3) 11 (2·9) 10 (2·8) 11 (3·0) 11 (3·0) <10 33 (35·1) 20 (28·2) 23 (31·1) 34 (29·8) 110 (31·2) ≥10 61 (64·9) 51 (71·8) 51 (68·9) 80 (70·2) 243 (68·8) Hybrid SELENA-SLEDAI mucocutaneous score >0 91 (97%) 71 (100%) 71 (96%) 113 (99%) 346 (98%) Hybrid SELENA-SLEDAI musculoskeletal score >0 89 (95%) 64 (90%) 69 (93%) 104 (91%) 326 (92%) BILAG severity Mild (no BILAG A and no more than one B) 4 (4%) 3 (4%) 3 (4%) 7 (6%) 17 (5%) Moderate (at least two BILAG B and no A) 55 (59%) 45 (63%) 43 (58%) 62 (54%) 205 (58%) Severe (at least one BILAG A) 35 (37%) 23 (32%) 28 (38%) 45 (39%) 131 (37%) CLASI-A total score Mild (0–9) 69 (73%) 52 (73%) 48 (65%) 78 (68%) 247 (70%) Moderate (10–20) 21 (22%) 14 (20%) 24 (32%) 30 (26%) 89 (25%) Severe (≥21) 4 (4%) 5 (7%) 2 (3%) 6 (5%) 17 (5%) Concomitant therapy Systemic glucocorticoids 78 (83%) 63 (89%) 66 (89%) 94 (82%) 301 (85%) ≥10 mg dose‡ 51 (54%) 34 (48%) 36 (49%) 59 (52%) 180 (51%) Immunosuppressants 50 (53%) 42 (59%) 46 (62%) 66 (58%) 204 (58%) Antimalarials 80 (85%) 60 (85%) 60 (81%) 97 (85%) 297 (84%) Data are n (%) unless otherwise stated. BILAG=British Isles Lupus Assessment Group-based Composite Lupus Assessment. CLASI-A=Cutaneous Lupus Disease Area and Severity Index–Activity. CLE=cutaneous lupus erythematosus. IFN-GS=interferon gene signature. SLE=systemic lupus erythematosus. SELENA-SLEDAI=Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index. *One participant who was randomly allocated to placebo was excluded from the full analysis set for the efficacy analyses as they entered Cohort B incorrectly owing to an error in recording BILAG at screening. †Includes 172 of 353 participants who identified as Hispanic or Latino (47 [50%] of 94 in the placebo group; 37 [52%] of 71 in the 25 mg enpatoran group; 37 [50%] of 74 in the 50 mg enpatoran group, and 51 [45%] of 114 in the 100 mg enpatoran group). ‡Daily prednisone-equivalent dose. Table 1: Baseline characteristics in the full analysis set for the efficacy analyses 1816 Articles of attainment of SRI-4 response, LLDAS, and remission In exploratory analyses of 162 participants with increased over time across all enpatoran groups cutaneous manifestations of SLE at baseline, enpatoran (appendix p 13). reduced cutaneous disease activity and increased Placebo 25 mg enpatoran 50 mg enpatoran 100 mg enpatoran (n=94) (n=71) (n=74) (n=114) Primary efficacy outcome at week 24 (full analysis set) Detection of enpatoran dose–response relationship in BICLA ·· ·· ·· 0·14 response based on MCP-Mod*(parts 1 and 2 combined), p-value BICLA response rate at week 24 (supplementary analysis) Response rate 37 (39%) 41 (58%) 36 (49%) 56 (49%) Percentage difference in response rate (95% CI) ·· 18 (3 to 33) 9 (–6 to 24) 10 (–4 to 23) OR (95% CI) ·· 2·2 (1·1 to 4·0) 1·5 (0·8 to 2·8) 1·6 (0·9 to 2·8) p-value versus placebo† ·· 0·0088 0·10 0·052 Subgroup analyses of BICLA response rate at week 24 IFN-GS high (≥0·71) at baseline Response rate 31% (21 to 44) 61% (47 to 74) 52% (37 to 66) 49% (38 to 61) Percentage difference in response rate (95% CI) ·· 30% (12 to 46) 21% (3 to 38) 18% (2 to 33) OR (95% CI) ·· 3·4 (1·6 to 7·3) 2·4 (1·1 to 5·1) 2·1 (1·1 to 4·2) p-value versus placebo ·· 0·0013 0·026 0·027 High glucocorticoid use (daily prednisone-equivalent dose ≥10 mg) at baseline Response rate 37% (24 to 52) 68% (50 to 83) 61% (44 to 77) 53% (39 to 66) Percentage difference in response rate (95% CI) ·· 30% (9 to 49) 24% (2 to 43) 15% (–4 to 33) OR (95% CI) ·· 3·52 (1·4 to 8·8) 2·7 (1·1 to 6·4) 1·9 (0·9 to 4·0) p-value versus placebo ·· 0·0071 0·03 0·11 Secondary efficacy outcomes at week 24 (full analysis set)‡ BICLA response and glucocorticoid reduction§ Response rate 16/51 (31%) 20/34 (59%) 20/36 (56%) 28/59 (48%) OR (95% CI) ·· 3·3 (1·3 to 8·2) 2·8 (1·1 to 6·7) 2·1 (1·0 to 4·6) p-value versus placebo (one-sided) ·· 0·0056 0·013 0·034 Percentage difference in response rate (95% CI)¶ ·· 28% (6 to 47) 24% (3 to 44) 16% (–2 to 33) SRI-4 response§ Response rate 50/94 (53%) 44/71 (62%) 48/74 (65%) 77/114 (68%) OR (95% CI) ·· 1·5 (0·8 to 2·8) 1·7 (0·9 to 3·2) 1·9 (1·1 to 3·5) p-value versus placebo (one-sided) ·· 0·11 0·052 0·012 Percentage difference in response rate (95% CI)¶ ·· 9% (–7 to 24) 12% (–3 to 26) 14% (1 to 27) Attainment of LLDAS§ Response rate 23/94 (25%) 21/71 (30%) 32/74 (43%) 35/114 (31%) OR (95% CI) ·· 1·3 (0·6 to 2·6) 2·5 (1·3 to 4·9) 1·5 (0·8 to 2·8) p-value versus placebo (one-sided) ·· 0·24 0·0039 0·11 Percentage difference in response rate (95% CI)¶ ·· 5% (8 to 19) 19% (4 to 33) 6% (–6 to 18) Attainment of remission (DORIS criteria)§|| Response rate 10/94 (11%) 7/71 (10%) 8/74 (11%) 20/114 (18%) OR (95% CI) ·· 0·9 (0·3 to 2·6) 1·1 (0·4 to 2·9) 2·0 (0·9 to 4·6) p-value versus placebo (one-sided) ·· 0·56 0·44 0·049 Percentage difference in response rate (95% CI)¶ ·· –1 (–10 to 10) 0 (–9 to 11) 7 (–3 to 16) Clinically meaningful glucocorticoid reduction§ Number of participants with response 36/51 (71%) 28/34 (82%) 27/36 (75%) 41/59 (69%) OR (95% CI) ·· 2·1 (0·7 to 6·3) 1·2 (0·4 to 3·2) 0·9 (0·4 to 2·2) p-value versus placebo (one-sided) ·· 0·09 0·37 0·56 ≥50% reduction in tender and swollen (28-joint) count Number of participants with response 53/77 (69%) 39/54 (72%) 45/58 (78%) 68/86 (79%) Change from baseline in PGA of SLE disease activity Mean (SD) –0·9 (0·6) –1·0 (0·6) –1·1 (1·0) –1·1 (0·6) (Table 2 continues on next page) Articles Placebo 25 mg enpatoran 50 mg enpatoran 100 mg enpatoran (n=94) (n=71) (n=74) (n=114) (Continued from previous page) Change from baseline in FACIT-Fatigue score** Participants, n 79 63 65 101 Least squares mean (95% CI) 2·4 (0·4 to 4·4) 4·8 (2·5 to 7·0) 3·6 (1·4 to 5·8) 5·1 (3·3 to 6·9) Least squares mean difference (95% CI) ·· 2·3 (–0·5 to 5·2) 1·2 (–1·7 to 4·0) 2·6 (0·1 to 5·2) Exploratory subgroup analysis at week 24 (CLASI-A score ≥8 at screening and baseline) Change from baseline to week 24 in CLASI-A score** Participants, n 41 29 38 54 Least squares mean (95% CI) –45·2 –59·5 –75·6 –73·5 (–82·3 to –64·7) (–55·4 to –34·9) (–71·5 to –47·4) (–86·2 to –65·0) Least squares mean difference (95% CI) ·· –14·3 –30·4 –28·3 (–41·5 to –15·2) (–29·8 to 1·2) (–44·7 to –16·2) Attainment of remission at week 24 CLASI-A 0 to 1 7 (17%) 6 (21%)†† 13 (34%) 15 (28%) CLASI-A 0 to 3 12 (29%) 12 (41%)†† 23 (61%) 29 (54%) CLASI-A 0 to 1 and CLA-IGA 0 to 1 5 (12%) 6 (21%)†† 11 (29%) 15 (28%) SRI-4 response rate at week 24 (post-hoc analysis)‡‡ Response rate 20 (49%)†† 18 (62%)†† 27 (71%) 36 (67%) OR (95% CI) ·· 1·7 (0·7 to 4·7) 2·7 (1·1 to 7·0) 2·1 (0·9 to 5·0) p-value versus placebo (one-sided) ·· 0·13 0·02 0·039 Percentage difference in response rate (95% CI) ·· 13% (–11 to 35) 22% (1 to 42) 18% (–2 to 37) Unless otherwise stated, data are n (%) for response rates, % (95% CI) for subgroup analyses of BICLA response at week 24, n/N (%) for secondary efficacy outcomes, and differences in response rates are given as percentages versus placebo (95% CI). BILAG=British Isles Lupus Assessment Group-based Composite Lupus Assessment. CLASI- A=Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity. CLA-IGA=Cutaneous Lupus Activity-Investigator’s Global Assessment. CLE=cutaneous lupus erythematosus. DORIS=Definition of Remission in SLE. FACIT=Functional Assessment of Chronic Illness Therapy. IFN-GS=interferon gene signature score. LLDAS=lupus low disease activity state. MCP-mod=multiple comparison procedure-modelling. MMRM=mixed-model with repeated measures. OR=odds ratio. PGA=Physician Global Assessment. SRI-4=SLE Responder Index-4. SLE=systemic lupus erythematosus. SELENA-SLEDAI=Safety of Estrogen in Lupus Erythematosus National Assessment-SLE Disease Activity Index. *MCP-Mod adjusted for baseline hybrid SELENA–SLEDAI total score, region, and biomarker status. †Combined p-value from weighted inverse normal method. Treatment effect statistically significant if p≤0·025. ‡Except BICLA response plus clinically meaningful glucocorticoid reduction, which were assessed in participants receiving ≥10 mg/day prednisone equivalent dose of glucocorticoid at baseline. §ORs, 95% CIs, and p-values based on logistic regression with stratification factors of region, biomarker status, and SELENA-SLEDAI score as independent variables. 95% CI for ORs were calculated using the Wald method. ¶95% CI for difference in response rate calculated using non-stratified Miettinen–Nurminen method. ||If remission attainment was not evaluable, it was considered not attained. **Estimates and 95% CIs based on a an MMRM of the change from baseline, with region, biomarker status, treatment, and analysis visit as classification variables, baseline score and baseline hybrid SELENA- SLEDAI total score as covariates, and treatment by analysis visit interaction. ††Data missing for one participant. ‡‡ORs, 95% CI, and p-values were based on a logistic model with treatment group, baseline hybrid SELENA-SLEDAI total score, region, and biomarker status as independent variables. Crude percentage differences in response rate and 95% CI were computed using the non-stratified Miettinen–Nurminen method. Table 2: Primary and secondary efficacy outcomes (full analysis set) and exploratory subgroup analysis in participants with SLE and cutaneous manifestations (CLASI-A score ≥8 at screening and baseline) cutaneous remission rates. Higher CLASI-50 and Global Assessment [CLA-IGA] score 0–1; table 2; appendix CLASI-70 response rates were achieved at week 24 in p 16). participants receiving enpatoran versus placebo, with In the full analysis set, between 39 (72%) of 54 and nominal statistical significance (p-values for overall 68 (79%) of 86 participants receiving enpatoran had 50% or treatment eect 0·0002 and 0·015, respectively; figure 2D greater reduction from baseline in tender and swollen and E). The treatment dierence in CLASI-50 response 28-joint counts at week 24, compared with rate was observed as early as week 4 (from 11 [20%] of 54 53 (69%) of 77 participants in the placebo group (table 2). to 12 [32%] of 38 in the enpatoran groups No significant dierence between enpatoran and placebo versus five [12%] of 41 in the placebo group). CLASI-A was observed in change from baseline in Physician’s Global total score improved over time with enpatoran (figure 2F) Assessment of SLE disease activity at week 24. Improvement and at week 24, least squares mean changes from baseline in FACIT-Fatigue score was observed in the 100 mg in CLASI-A total score were greater with enpatoran than enpatoran group at week 24 (table 2 and appendix p 14). in the placebo group (table 2). Rates of cutaneous Moderate or severe BILAG flares were reported in remission at week 24 were higher with enpatoran than four (6%) of 71, five (7%) of 74, and placebo across definitions (CLASI-A total score 0–1, eight (7%) of 114 participants in the 25 mg, 50 mg, and CLASI-A total score 0–3, or combined CLASI-A total 100 mg enpatoran groups, respectively, and score 0–1 and Cutaneous Lupus Activity-Investigator 12 (13%) of 94 participants in the placebo group. Times 1818 Articles to first moderate or severe BILAG flare and severe SFI compared with placebo, with larger IQRs in the 25 mg flare are shown in the appendix (p 18). group, suggesting more variability in IFN-GS suppression All enpatoran doses rapidly reduced interferon-alpha at that dose (figure 3). Maximum suppression occurred and IFN-GS levels from baseline to end of treatment by week 2 and was maintained through to week 24. Figure 2: BICLA response and cutaneous responses over time and at week 24 (A) BICLA response over time 90 in the full analysis set (n=353). (B–F) Outcomes in the subgroup of participants with 70 SLE and cutaneous 60 manifestations (CLASI-A score ≥8 at screening and baseline [n=162]), including BICLA 40 response over time (B), BICLA 30 response at week 24 (C), CLASI-50 response at week 24 (D), CLASI-70 response at 10 week 24 (E), and percentage 0 change from baseline in 0 4 8 12 16 20 24 CLASI-A total score over time (F). BICLA=British Isles Lupus Assessment Group–based Composite Lupus Assessment. CLASI-A=Cutaneous Lupus Erythematosus Disease Area and Severity Index–Activity. OR=odds ratio. SELENA- SLEDAI=Safety of Estrogens in Lupus Erythematosus National Assessment- Systemic Lupus Erythematosus Disease Activity Index. *95% CIs were calculated using the Clopper– Pearson method, and the Miettinen–Nurminen method for the between-group differences; ORs and 95% CI are based on a logistic model with treatment group, baseline hybrid SELENA- SLEDAI total score, region, and biomarker status as independent variables. †Nominal p-value, one-sided. ‡ORs for between-group differences were based on a logistic model adjusted for region, biomarker status, baseline CLASI-A score, and hybrid SELENA-SLEDAI total scores, with Clopper–Pearson 95% CIs and p-values based on the likelihood ratio χ² test. §Least-square means and 95% CIs based on mixed- model with repeated measures modelling of change from baseline in CLASI-A total score until week 24, with region, biomarker status, treatment, and analysis visit as classification variables, baseline CLASI-A total score and baseline hybrid SELENA- SLEDAI total score as covariates, and treatment by analysis visit interaction. % ,esnopser ALCIB A B 0 4 8 12 16 20 24 Time (weeks) Time (weeks) –10 –20 –30 –40 –50 –60 –70 –80 –90 Time (weeks) Number of observations Placebo BID twice daily 25 mg BID twice daily 50 mg BID twice daily 100 mg BID twice daily enilesab morf egnahc naemserauqs tsaeL §)IC %59 ,%( 80 60 40 20 0 F 0 2 4 8 12 16 20 24 41 41 39 37 36 34 36 28 28 27 27 27 27 25 38 38 36 37 35 37 36 51 51 51 51 49 52 52 % ,esnopser ALCIB C Δ18% (–2 to 37)* Δ26% (4 to 46)* Δ27% (3 to 48)* 59 58 50 OR 3·0 OR 3·3 (1·1–8·2)* (1·3–8·4)* OR 2·2 (0·9–5·3)* 32 p=0·015† p=0·0066† p=0·034† Placebo twice 25 mg 50 mg 100 mg daily (n=41) enpatoran enpatoran enpatoran twice daily twice daily twice daily (n=29) (n=38) (n=54) % ,esnopser 05-IASALC D Nominal p-value for overall treatment effect: 0·0002 Δ40% Δ37% Δ17% 79 82 59 OR 5·4 OR 6·2 (2·0–14·8)‡ (2·4–15·9)‡ OR 2·3 42 (0·8–6·1)‡ Placebo twice 25 mg 50 mg 100 mg daily (n=41) enpatoran enpatoran enpatoran twice daily twice daily twice daily (n=29) (n=38) (n=54) 80 60 40 20 0 % ,esnopser 07-ISALC ot egnahC Placebo twice daily (n=94) Placebo twice daily (n=41) 25 mg enpatoran twice daily (n=71) 25 mg enpatoran twice daily (n=29) 50 mg enpatoran twice daily (n=74) 50 mg enpatoran twice daily (n=38) 100 mg enpatoran twice daily (n=114) 100 mg enpatoran twice daily (n=54) E Nominal p-value for overall treatment effect: 0·015 Δ25% Δ34% Δ15% 61 52 41 OR 4·3 Placebo twice daily (n=41) OR 2·1 (1·6–11·3)‡ O (1 R ·3 3 – · 7 1 ·6)‡ 25 mg enpatoran twice daily (n=29) 27 (0·7–2·1)‡ 50 mg enpatoran twice daily (n=38) 100 mg enpatoran twice daily (n=54) Placebo twice 25 mg 50 mg 100 mg daily (n=41) enpatoran enpatoran enpatoran twice daily twice daily twice daily (n=29) (n=38) (n=54) % ,esnopser ALCIB 90 70 50 30 10 100 80 60 40 20 0 Articles laboratory investigations (41 [12%]; table 3). There were A no dierences in herpes zoster rates between treatment 20·0 groups (two in all groups). Rates of grade 3 or higher or 17·5 serious treatment-emergent adverse events were lower in 15·0 the enpatoran groups than in the placebo group (six or fewer participants in each treatment group). 12·5 The most common treatment-related adverse event 10·0 was diarrhoea (four [6%] of 71, two [3%] of 74, and 7·5 two [2%] of 114 participants in the 25 mg, 50 mg, and 100 mg enpatoran groups, respectively, and 5·0 seven [7%] of 95 participants in the placebo group). 2·5 Other common treatment-related adverse events were 0 upper respiratory tract infections, urinary tract Day Day Day Day Day Day Day infections, nasopharyngitis, influenza, asymptomatic 1 15 29 85 113 169 183 Number of bacteriuria, and headache (table 3). Decreased observations lymphocyte count was more commonly reported in the Placebo 93 92 91 86 79 66 10 25 mg enpatoran 67 66 66 66 64 54 6 placebo group than with enpatoran, and enpatoran 50 mg enpatoran 74 73 72 70 65 54 2 treatment did not lead to lowering of blood lymphocyte 100 mg enpatoran 109 106 107 104 103 93 16 counts during the study (table 3 and appendix p 18). There were no clinically relevant changes in ECG parameters or QT interval, and QTcF values appeared unremarkable over time. The majority of participants with QTcF above 450 ms were receiving concomitant antimalarial medication with known potential for QT prolongation (appendix p 22). There were three adverse events of special interest in the 100 mg enpatoran group (one case of grade 2 tachycardia [considered treatment-related after adjudication] and two cases of grade 3 pneumonia), and one in the 25 mg enpatoran group (grade 1 atrioventricular block [considered treatment-related after adjudication]). There were three adverse events of special interest in the placebo group (grade 1 sinus arrythmia, grade 3 pneumonia, and grade 3 urinary tract infection). There were no clear between-group dierences in discon- tinuation rate due to treatment-emergent adverse events, and there were no deaths during the study. Figure 3: Changes from baseline in interferon-alpha (A) and IFN-GS levels (B) Discussion IFN-GS=interferon gene signature. This phase 2 study enrolled a large, representative 24 participants receiving enpatoran who did not enter the population of participants with SLE who had moderate- long-term extension stopped treatment at week 24 and to-severe disease activity despite receiving standard of were available for IFN-GS assessment for 2 weeks post care therapy, the majority of whom were using a 10 mg or treatment. In these participants, IFN-GS returned to near above per day prednisone-equivalent dose. Evidence of baseline levels by week 26. Dose-normalised enpatoran similar clinical benefit in terms of BICLA response was C was comparable across dose groups and study visits observed across all enpatoran dose groups at week 24 trough (day 15, 29, 57, and 85), suggesting linear and time- versus placebo, meaning no statistically significant dose– invariant pharmacokinetics (appendix p 20). response relationship was identified and therefore the Through the 24-week treatment period and 2-week primary objective was not met. Higher rates of the safety follow-up, the frequencies of treatment-emergent composite endpoint of BICLA response accompanied by adverse events (TEAEs) were similar between enpatoran clinically meaningful glucocorticoid reduction were 25 mg (43 [61%] of 71 participants), 50 mg (47 [64%] of 74), achieved with enpatoran groups compared with placebo. 100 mg (70 [61%] of 114), and placebo (61 [64%] of 95) Some of the secondary and exploratory ecacy results groups (table 3). In the 354 participants in the safety also suggested that inhibition of TLR7/8 with enpatoran population, TEAEs occurred most commonly in the oered reductions in systemic and cutaneous disease system organ classes of infections and infestations activity in participants with SLE. Enpatoran treatment (139 [39%]), gastrointestinal disorders (55 [16%]), and eects were greatest in subgroups of participants with 1820 )RQI( seulav etulosba fo naideM L/gn ,ahpla-norefretni B 4·5 4·0 3·5 3·0 2·5 2·0 1·5 1·0 0·5 Day Day Day Day Day Day Day 1 15 29 85 113 169 183 Number of observations Placebo 93 93 92 87 81 73 10 25 mg enpatoran 67 66 67 66 66 59 6 50 mg enpatoran 74 73 71 71 66 64 2 100 mg enpatoran 110 106 107 104 104 101 16 )RQI( seulav etulosba fo naideM elacs raenil ,SG-NFI Placebo twice daily (n=93) 25 mg enpatoran twice daily (n=67) 50 mg enpatoran twice daily (n=74) 100 mg enpatoran twice daily (n=110) Articles Placebo (n=95) 25 mg enpatoran 50 mg enpatoran 100 mg enpatoran (n=71) (n=74) (n=114) Any adverse event 61 (64%) 43 (61%) 47 (64%) 70 (61%) Any treatment-related adverse event 19 (20%) 13 (18%) 19 (26%) 22 (19%) Grade ≥3 adverse event 6 (6%) 1 (1%) 3 (4%) 5 (4%) Grade ≥4 adverse event 1 (1%) 0 0 0 Serious adverse event 3 (3%) 1 (1%) 3 (4%) 5 (4%) Adverse event leading to study drug discontinuation 6 (6%) 2 (3%) 5 (7%) 3 (3%) Adverse event leading to death 0 0 0 0 Any adverse event of special interest* 3 (3%) 1 (1%) 0 3 (3%) Adverse events with an incidence of ≥5% in any group† Gastrointestinal disorders Diarrhoea 7 (7%) 4 (6%) 2 (3%) 2 (2%) Infections and infestations Upper respiratory tract infection 6 (6%) 7 (10%) 9 (12%) 8 (7%) Urinary tract infection 9 (9%) 2 (3%) 5 (7%) 11 (10%) Nasopharyngitis 4 (4%) 2 (3%) 6 (8%) 10 (9%) Influenza 6 (6%) 5 (7%) 2 (3%) 5 (4%) Asymptomatic bacteriuria 2 (2%) 4 (6%) 3 (4%) 2 (2%) Herpes zoster 2 (2%) 2 (3%) 2 (3%) 2 (2%) Laboratory investigations Lymphocyte count decreased 5 (5%) 1 (1%) 2 (3%) 1 (1%) Nervous system disorders Headache 4 (4%) 2 (3%) 7 (10%) 3 (3%) Data are number of participants (%). *Adverse events considered to be of special interest were severe infections (grade ≥3), seizure (any grade), clinically significant cardiac arrythmia, or serotonin syndrome. †Headings and subheadings are the system organ classes and preferred terms, respectively, in the Medical Dictionary for Regulatory Activities version 27.1. Table 3: Adverse events in the safety population cutaneous manifestations, high IFN-GS, or those with clinical response and a phase 3 trial of anifrolumab receiving high doses of glucocorticoids at baseline. While confirmed the clinical eectiveness of targeting improvement in some specific systemic symptoms interferon in SLE.25,26 Here, the demonstration that (eg, tender and swollen joint counts) were not indicative TLR7/8 inhibition with enpatoran rapidly and of significant improvements with enpatoran compared consistently reduced interferon-alpha levels and type I with placebo, BICLA response is a stringent endpoint IFN-GS from as early as week 2 until the end of treatment requiring improvement across all baseline disease in all participants confirms the role of TLR7/8 in activity, which could not be attributed to cutaneous interferon pathway activation in SLE. Furthermore, response alone. BICLA response rates were enhanced in participants From a mechanistic perspective, inhibiting TLR7/8 with high IFN-GS at baseline compared with the overall provides a novel approach to reducing SLE disease study population. Additional, longer-term studies would activity. The triad of interferon activation, autoreactive be necessary to formally evaluate IFN-GS and the B-cell activation, and glucocorticoid resistance is a associated role of RNA autoantibodies as tandem hallmark of SLE. TLR7 activation leads not only to biomarkers of response to TLR7/8 inhibition. Participant secretion of type I interferon and other cytokines, but numbers post-week 24 were low owing to enrolment into also autoreactive B-cell activation,20,21 while interferon the ongoing long-term extension; however, in those pathway (and specifically TLR7) activation has been evaluable, IFN-GS levels returned to near baseline levels found to confer glucocorticoid resistance in SLE.22 Early 2 weeks after enpatoran was discontinued. Such rapid data in support of TLR7/8 in interferon activation in SLE reversal of the biological eect suggests that the drive to include a phase 1/2 study of E6742, which reduced activation of the interferon pathway via TLR7/8 is IFN-GS and pro-inflammatory cytokine levels in intrinsic in patients with SLE; this reversal might also be participants with SLE,23 and a phase 1 study of afimetoran, beneficial from a treatment safety perspective. Similar which inhibited IFN-GS expression in participants with eects on interferon-alpha and IFN-GS were observed in CLE.24 In a phase 2 study, reductions in interferon-alpha participants with cutaneous manifestations of CLE or levels with litifilimab in patients with SLE were correlated SLE in Cohort A.19 Articles Cutaneous manifestations of lupus are seen not only in enpatoran safety profile was consistent with phase 1 and CLE but are also highly prevalent in people living with phase 1b studies and Cohort A of WILLOW.15,18 SLE and are intrinsically linked to systemic activity.8,9 The limitations of this phase 2 study include the small Type I interferon-driven skin inflammation in SLE might sample size of participants in some subgroups, the precede and perpetuate wider systemic inflammatory absence of formal involvement of people with lived responses and exacerbate disease progression.8,9 In experience of lupus in the study design and conduct, and murine models, skin inflammation triggered the exploratory nature of supportive outcomes. upregulation of type I interferon signalling, Additionally, approximately 40% of the participants were autoimmunity and antibody production, systemic White, with only 5% of participants being Black or immune responses in multiple organs, and SLE-like African American; this probably reflects the high level of pathology,21,27–29 findings replicated in rare cases of people recruitment from central and South America and rest of born with gain of function mutations of TLR7.11,13 In the world (56%) compared with north America and Europe current study, 46% of participants had SLE with active (23%) and Asia (21%), which is greater than that reported cutaneous manifestations at screening and baseline in other phase 2 and 3 studies in SLE.25,26 Further analysis despite treatment, highlighting the frequency of in larger trials is required to accurately determine the refractory skin involvement in SLE. In these participants, potential eect of race on outcomes with enpatoran. clinically meaningful reductions in systemic activity However, the overall ecacy, safety, and biomarker were achieved with all doses of enpatoran compared with findings oer valuable insights to advance our placebo. More than 90% of the subgroup with cutaneous understanding of the pathogenesis of SLE and support manifestations also had manifestations in other organ the continued clinical evaluation of enpatoran. systems, which suggests that the higher BICLA response In this phase 2 trial of the novel oral TLR7/8 inhibitor rates with enpatoran observed in these participants is not enpatoran in participants with SLE and moderate-to- solely attributable to isolated improvement in the high disease activity, the primary objective of identifying mucocutaneous domain. These findings are in line with a significant dose–response relationship for enpatoran the evidence of mechanistic links between cutaneous in terms of BICLA response was not met. However, manifestations and systemic involvement, relevant for clinically meaningful treatment benefits of enpatoran the underlying biology of TLR7/8 in lupus. were demonstrated across multiple prespecified Worsening mental health, physical health, and fatigue secondary and exploratory clinical and biomarker are associated with skin symptoms in CLE and SLE that outcomes, particularly in participants with cutaneous are often resistant to treatment.8,30 In participants with manifestations, and enpatoran was well tolerated. cutaneous manifestations of moderate-to-severe SLE, Treatment eects were particularly evident in 59–82% of participants receiving enpatoran had 50% or participants with cutaneous manifestations, high greater improvement in skin symptoms (CLASI-50), IFN-GS or high glucocorticoid doses at baseline, and and 41–61% had 70% or greater improvement enpatoran elicited high rates of clinically meaningful (CLASI-70). Furthermore, enpatoran reduced cutaneous improvement of skin manifestations. Moreover, activity as early as week 2–4 and improved cutaneous enpatoran-mediated downmodulation of interferon- remission rates compared with placebo across alpha and IFN-GS in all study participants confirms the three dierent measures. These subgroup results are role of the TLR7/8 pathway in type I IFN pathway consistent with the benefits reported in Cohort A of activation in SLE. Phase 3 trials are warranted to fully WILLOW, which was restricted to participants with define the ecacy and safety of enpatoran in the cutaneous manifestations of CLE or SLE, wherein the treatment of people living with SLE. primary outcome was met and improved rates of Contributors CLASI-50 and CLASI-70 responses were observed.19 In EFM and DRP are chief investigators for the WILLOW trial. DRP, EFM, participants with cutaneous manifestations of SLE in JS-G, JW, MD, RF, SR, and VPW conceptualised the trial. FM was responsible for the statistical plan and statistical analyses, including Cohort B, patterns of dose response are being directly accessing and verifying the underlying data reported in the investigated and additional population pharmacometric manuscript. CK, DRP, EFM, JS-G JW, MD, RF, RF-R, SR, and VPW modelling analyses are ongoing to fully characterise the contributed to participant recruitment and data collection. DRP, EFM, dose–response relationship for these outcomes. Taken CK, ES, FM, HG, LK-S, RF-R, and SR accessed and verified the underlying data. EFM prepared a first draft of the manuscript. together, the results from WILLOW Cohort A and All authors had full access to all the data in the study and had final Cohort B demonstrate that enpatoran has potential in responsibility for the decision to submit for publication. managing systemic as well as cutaneous manifestations Declaration of interests of lupus. EFM has received research funding from AbbVie, Amgen, AstraZeneca, Enpatoran was well tolerated across all doses during Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech- the 24-week treatment period and 2-week follow-up. Homan La Roche, GSK, Janssen, Novartis, Takeda, and Union Chimique Belge (grant or contracts with Monash University); consulting Rates of treatment-emergent adverse events were similar fees from AstraZeneca, Biogen, Bristol Myers Squibb, Calabetta, between the enpatoran and placebo groups, with no Cullinan, DragonFly, Eli Lilly, EMD Serono, Galapagos, evidence for more severe events with enpatoran. The GlaxoSmithKline, Novartis, Orna, Remegen, Quell, UCB, and Zenas; 1822 Articles payment or honoraria for lectures, presentations, speakers bureaus, 6 Parodis I, Lindblom J, Levy RA, et al. Attainment of remission and low manuscript writing or educational events from AstraZeneca, EMD disease activity after treatment with belimumab in patients with Serono, and Viatris; support for attending meetings or travel from systemic lupus erythematosus: a post-hoc analysis of pooled data from AstraZeneca and EMD Serono; stock or stock options from Dragonfly; five randomised clinical trials. Lancet Rheumatol 2024; 6: e751–61. and patents planned, issued, or pending for AstraZeneca and Monash 7 Rönnblom L, Eloranta ML. The interferon signature in University (WO2022074123A1 [treatment of flares in lupus]; autoimmune diseases. Curr Opin Rheumatol 2013; 25: 248–53. WO2021184080A1 [compositions and methods for treating lupus]; 8 Billi AC, Ma F, Plazyo O, et al. Nonlesional lupus skin contributes WO2023044530A1 [methods of treatment]; WO2021094378A1 [type I to inflammatory education of myeloid cells and primes for interferon inhibition in systemic lupus erythematosus]; cutaneous inflammation. Sci Transl Med 2022; 14: eabn2263. WO2023057369A2 [treatment of lupus]). MD’E serves as an advisor for 9 Psarras A, Alase A, Antanaviciute A, et al. Functionally impaired Aurinia, AstraZeneca, GSK, and Genentech, and participates in data plasmacytoid dendritic cells and non-haematopoietic sources of type I interferon characterize human autoimmunity. Nat Commun monitoring committees for Janssen and Cabaletta. JS-G has received 2020; 11: 6149. consulting fees from Biogen and EMD Serono. DRP has received grants 10 Bender AT, Tzvetkov E, Pereira A, et al. TLR7 and TLR8 or clinical trials support from Daiichi Sankyo, EMD Serono, and dierentially activate the IRF and NF-κB pathways in specific cell Priovant Therapeutics; and has received consulting fees from Biogen, types to promote inflammation. Immunohorizons 2020; 4: 93–107. EMD Serono, and Pfizer. VPW has received consulting fees from Merck 11 Al-Azab M, Idiiatullina E, Liu Z, et al. Genetic variants in UNC93B1 Healthcare (Darmstadt, Germany) and serves as an investigator or predispose to childhood-onset systemic lupus erythematosus. advisor for AstraZeneca and Biogen; and University of Pennsylvania Nat Immunol 2024; 25: 969–80. (Philadelphia, PA, USA) holds the copyright for the Cutaneous Lupus 12 Wang T, Kuley R, Hermanson P, et al. Immune complexes- Erythematosus Disease Area and Severity Index. JW has received mediated activation of neutrophils in systemic lupus erythematosus research funding from Almirall, AstraZeneca, BMS, GSK, Incyte, and is dependent on RNA recognition by toll-like receptor 8. Spirig; consulting fees from Actelion, AstraZeneca, Bayer, Biogen, BMS, Front Immunol 2024; 15: 1515469. GSK, Incyte, Janssen, and Merck; honoraria from Merck Healthcare 13 Brown GJ, Cañete PF, Wang H, et al. TLR7 gain-of-function genetic (Darmstadt, Germany) for advisory activities; is a member of theDFG- variation causes human lupus. Nature 2022; 605: 349–56. funded Cluster of Excellence ImmunoSensation³–EXC 2151– 390873048; 14 Martens JWS, Liu J, Maz M, Kahlenberg JM. The role of skin- and has participated on advisory boards for Actelion, AstraZeneca, Bayer, derived IFN-kappa in the development of systemic autoimmunity. Biogen, BMS, GSK, Incyte, Janssen, and Merck. SR is an employee of J Immunol 2022; 208 (supp 1): 108.01. Ares Trading (Eysins, Switzerland), an aliate of Merck. CK, ES, LK-S, 15 Port A, Shaw JV, Klopp-Schulze L, et al. Phase 1 study in healthy and HG are employees of Merck Healthcare (Darmstadt, Germany). participants of the safety, pharmacokinetics, and FM and RF-R are employees of EMD Serono Research and Development pharmacodynamics of enpatoran (M5049), a dual antagonist of toll- Institute (Billerica, MA, USA), an aliate of Merck. RF has received like receptors 7 and 8. Pharmacol Res Perspect 2021; 9: e00842. honoraria from Merck Healthcare (Darmstadt, Germany) for advisory 16 Deshmukh A, Pereira A, Geraci N, et al. Preclinical evidence for the activities. All other authors declare no competing interests. glucocorticoid-sparing potential of a dual toll-like receptor 7/8 inhibitor in autoimmune diseases. J Pharmacol Exp Ther 2024; Data sharing 388: 751–64. Any requests for additional data by qualified scientific and medical 17 Klopp-Schulze L, Gopalakrishnan S, Yalkinoglu Ö, et al. Asia- researchers for legitimate research purposes will be subject to Merck inclusive global development of enpatoran: results of an ethno- Healthcare’s (Darmstadt, Germany) Data Sharing Policy. All requests bridging study, intrinsic/extrinsic factor assessments and disease should be submitted in writing to Merck Healthcare’s data sharing trajectory modeling to inform design of a phase II multiregional portal. When Merck Healthcare has a co-research, co-development, or clinical trial. Clin Pharmacol Ther 2024; 115: 1346–57. For more on data sharing portal co-marketing or co-promotion agreement, or when the product has been 18 Witte T, Fernandez-Ruiz R, Abramova N, et al. Enpatoran, a first-in- see https://www.merckgroup. out-licensed, the responsibility for disclosure might be dependent on the class, selective, orally administered toll-like receptor 7/8 inhibitor, in com/en/research/our-approach- agreement between parties. Under these circumstances, Merck systemic and cutaneous lupus erythematosus: results from a to-research-and-development/ Healthcare will endeavour to gain agreement to share data in response randomised, placebo-controlled phase Ib study. Lupus Sci Med 2025; healthcare/clinical-trials/ 12: e001705. to requests. commitment-responsible-data- 19 Morand EF, Werth VP, Wenzel J, et al. Ecacy and safety of sharing.html Acknowledgments enpatoran, a Toll-like receptor 7/8 inhibitor, in patients with skin We thank the study participants and sta, along with Dominika Weinelt, manifestations of cutaneous lupus erythematosus or systemic lupus Yulia Dyachkova, and Genevieve Jehl for roles in study conduct and erythematosus: findings from Cohort A of a multicentre, analysis. Medical writing support was provided by Helen Beaumont and international, double-blind, placebo-controlled, dose-finding Nicole Jones on behalf of Amica Scientific (Macclesfield, UK) and was phase 2 trial. 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J Exp Med 1997; 186: 1451–59. 1824 --- [PDF原文](https://sci-net.xyz/storage/8010893/93bee40ee68f6c5c423564fcd45e8b72e1f719bc545809c9638aa6890d9932a1/Enpatoran-a-Toll-like-receptor-7-8-inhibitor-in-moderate-to-severe-systemic-lupus-erythematosus.pdf) DOI: 10.1016/S0140-6736(26)00463-0