LB0004 RANDOMISED, PLACEBO-CONTROLLED PHASE II STUDY OF ORAL ENPATORAN, A FIRST-IN-CLASS TOLL-LIKE RECEPTOR 7/8 INHIBITOR, IN SYSTEMIC LUPUS ERYTHEMATOSUS

Background: Current treatments for lupus (including systemic lupus erythematosus [SLE] and cutaneous lupus erythematosus [CLE]) offer inadequate disease control and may be associated with cumulative toxicity. Toll-like receptors (TLR) 7 and TLR8 have functions in innate and adaptive immunity implicated in SLE pathogenesis. Gain-of-function mutations in TLR7 were identified in patients (pts) with SLE, and TLR7/8 signalling pathways play a central role in regulating interferon (IFN) induction. Preclinical data suggest TLR7/8 activation may mediate glucocorticoid (GC) resistance. Enpatoran is a first-in-class, oral small molecule TLR7/8 inhibitor. WILLOW (NCT05162586) is a Phase II randomised double-blind placebo (pbo)-controlled dose-finding parallel adaptive study in adults with SLE or CLE receiving standard of care (SoC) to evaluate the efficacy and safety of enpatoran. In Cohort A of WILLOW, enpatoran demonstrated a significant dose response in change from baseline (BL) in Cutaneous Lupus Disease Area and Severity Index-Activity (CLASI-A) vs pbo at Week (wk) 16 in CLE or SLE with active lupus rash. Objectives: Report results from WILLOW Cohort B in pts with active SLE despite SoC. Methods: Pts with SLE of moderate to high disease activity (British Isles Lupus Assessment Group [BILAG] 2004 ≥1A or 2B), and hybrid SELENA-SLEDAI ≥6 and/or CLASI-A ≥8 were enrolled. In Part 1, 60 pts were randomised 1:2 to pbo or enpatoran 100 mg twice daily (BID). Part 2 was then activated, with pts randomised 1:1:1:1 to SoC plus pbo, enpatoran 25 mg BID, 50 mg BID or 100 mg BID for 24 wks. The primary objective was to evaluate the dose-response relationship of enpatoran in reducing disease activity, based on the BILAG-based Composite Lupus Assessment (BICLA) response rate at Wk24. Five dose-response models were tested using one-sided Multiple Comparison Procedure-Modelling methodology to control for multiplicity (all for dose vs BICLA response at Wk24). Secondary and exploratory endpoints included change in type I IFN gene signature (IFN-GS) level, BICLA response with clinically meaningful GC reduction, and BICLA response rate and CLASI-A improvement ≥50%/70% (CLASI-50/70) in pts with CLASI-A score ≥8 at BL. Treatment-emergent adverse events (TEAEs) were recorded. Results: 354 pts were randomised; 353 were evaluated for efficacy (pbo n=94; enpatoran 25 mg BID n=71; 50 mg BID n=74; 100 mg BID n=114). 94.9% of pts were female; median age was 41 years. 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). No statistically significant dose-response relationship for enpatoran was identified; all doses were associated with higher BICLA response rates vs pbo (Table 1) with a nominally significant improvement in the 25 mg BID group at Wk24 (nominal p=0.0088). The largest treatment effect occurred in subgroups with high IFN-GS or prednisone-equivalent dose ≥10 mg at BL. Compared with pbo, type I IFN-GS was significantly reduced for all enpatoran doses as early as Wk2 and maintained to Wk24. Higher rates of BICLA response combined with clinically meaningful GC reduction were observed in all enpatoran groups vs pbo (58.8%, 55.6% and 47.5% vs 31.4%). In pts with CLASI-A score ≥8 at BL (pbo n=41; enpatoran 25 mg BID n=29; 50 mg BID n=38; 100 mg BID n=54), BICLA response rates were higher for enpatoran than pbo, and up to 81.5%/60.5% of pts receiving enpatoran had CLASI-50/70 responses, vs 41.5%/26.8% for pbo, respectively at Wk24. There was no clinically meaningful difference in rates of TEAEs between enpatoran and pbo (range: 61%-64%), including the most frequently reported TEAEs, which were infections and infestations. There was no apparent dose-dependent increase in TEAEs, including severe TEAEs, with enpatoran (Table 2). Conclusion: 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. REFERENCES: NIL . Acknowledgements: The authors wish to thank Dominika Weinelt for their support with the study conduct and analysis. Medical writing support was provided by Nicole Jones on behalf of Amica Scientific, Macclesfield, UK, and sponsored by Merck Healthcare KGaA, Darmstadt, Germany. Disclosure of Interests: Eric Morand Consulting fees, speaker honoraria and appeared on scientific advisory boards for AstraZeneca, Biogen, Bristol Myers Squibb, DragonFly, Eli Lilly, EMD Serono, GlaxoSmithKline, Novartis, Remegen, Quell, UCB, and Zenas (arrangements are direct with author)., Research funding from AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Genentech-Hoffman La Roche, GSK, Janssen, Novartis, Takeda, and Union Chimique Belge (grants/contracts with Monash University), Maria Dall'Era Maria Dall'Era serves as an advisor for Aurinia, AstraZeneca, GSK and Genentech, and participates in data monitoring committees for Janssen and Cabaletta., Jorge Sanchez-Guerrero Jorge Sanchez-Guerrero is a consultant for Biogen Inc. and EMD Serono., David Pearson Consultant for Biogen Inc., Merck & Co., and Pfizer Inc., Received grant and/or clinical trials support from Daiichi Sankyo Inc., EMD Serono Inc., and Priovant Therapeutics., Victoria P. Werth Consultant for Merck Healthcare KGaA. The University of Pennsylvania owns the copyright for the CLASI., Jörg Wenzel Received honoraria from Merck Healthcare KGaA for advisory activities., Sanjeev Roy Employee of Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA., Christine Kleinmond Employee of Merck Healthcare KGaA, Darmstadt, Germany., Ruth Fernandez-Ruiz Employee of Merck Healthcare KGaA, Darmstadt, Germany., Lena Klopp-Schulze Employee of Merck Healthcare KGaA, Darmstadt, Germany., Hans Gühring Employee of Merck Healthcare KGaA, Darmstadt, Germany., Flavie Moreau Employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA., Richard A. Furie Received honoraria from Merck Healthcare KGaA for advisory activities. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.

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