POS0536 SAFETY, PHARMACOKINETICS, BIOMARKER, AND EFFICACY OF E6742, A DUAL ANTAGONIST OF TOLL-LIKE RECEPTOR 7 AND 8, IN A FIRST-IN-PATIENT PHASE1/2 STUDY IN SYSTEMIC LUPUS ERYTHEMATOSUS

<h3>Background:</h3> E6742 is a novel, first-in-class, orally available, small molecule inhibitor of toll-like receptors (TLR) 7 and 8. Based on preclinical evidence, E6742 inhibits the activation of TLR7 and TLR8 which promote autoimmune response in systemic lupus erythematosus (SLE). The safety results from previous Phase 1 studies in healthy adults demonstrated that E6742 has an adequate safety and tolerability profile. <h3>Objectives:</h3> To evaluate the safety, tolerability, pharmacokinetics (PK), biomarker, and efficacy of E6742 in a Phase 1/2, randomized, double-blind, placebo-controlled study in patients with SLE for the first time (NCT05278663). <h3>Methods:</h3> SLE patients received 100 mg E6742 or placebo twice daily in cohort 1, and 200 mg E6742 or placebo twice daily in cohort 2. In each cohort, patients were randomized to either E6742 or placebo in a ratio of 2:1 and received multiple oral administrations of E6742 or placebo for 12 weeks. <h3>Results:</h3> A total of 12 patients (8 for E6742 100 mg, 4 for placebo) were enrolled in the cohort 1 and subsequently 14 patients (9 for E6742 200 mg, 5 for placebo) were enrolled in the cohort 2; in total, 26 patients received the study drug. Of the 26 patients, 24 patients completed 12-week treatment. Demographic and baseline characteristics were generally balanced between placebo and E6742 groups. For safety profile, the primary endpoint, E6742 demonstrated a favorable safety profile and was well tolerated vs placebo. The proportion of patients with any treatment-emergent AEs (TEAEs) was 58.8 % in the E6742 group (37.5% for 100 mg, 77.8% for 200 mg) and 66.7% in the placebo group, respectively. Furthermore, no TEAEs of Grade 3, Grade 4, or deaths were observed in the study. PK parameters were similar to levels of healthy adults with no specific concern. Interferon gene signature (IGS) were immediately downregulated by E6742 (at both 100 mg and 200 mg) treatment and recovered after the end of treatment. For the exploratory endpoint, despite a short treatment duration of 12 weeks, improved clinical signals were observed. Dose-dependent improvement was observed in British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) at Week 12 (33.3% for placebo, 37.5% for 100 mg, 57.1% for 200 mg, respectively). Moreover, therapeutic effects with E6742 were also showed in other symptoms, including skin inflammation (Cutaneous Lupus Erythematosus Disease Area and Severity Index-Activity [CLASI-A] scores), arthritis (tender/swollen joint counts), and serological indicators such as anti-double-stranded DNA antibody and complement levels. <h3>Conclusion:</h3> E6742 was well tolerated in patients with SLE and demonstrated a favorable safety profile. In addition, E6742 provided a markedly improved IGS response, and sufficient efficacy signals regardless the short treatment duration. These results provide the first clinical evidence to suggest that E6742 as a first-in-class TLR7/8 inhibitor, could potentially be beneficial for SLE, and support the longer-term, larger clinical trials of E6742. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> Authors thank all the investigators involved in this clinical study of E6742. This work was supported by the Japan Agency for Medical Research and Development (AMED) under grant Cyclic Innovation for Clinical Empowerment (CiCLE) program [grant number: JP19pc0101038]. <h3>Disclosure of Interests:</h3> Mari Aoki Eisai Co., Ltd., Yoshiya Tanaka Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers, Pfizer, Taiho, Mitsubishi-Tanabe, Eisai, Chugai, Taisho, Atsushi Kumanogoh Asahi Kasei, Astellas, Eisai, GlaxoSmithKline, Chugai, Eli Lilly, Boehringer-Ingelheim, Pfizer, Bristol-Myers Squibb, Eisai, Chugai, Tatsuya Atsumi AbbVie, Alexion, Asahi-Kasei, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Janssen, Novartis, Boehringer-Ingelheim, Mitsubishi-Tanabe, Pfizer, Taiho, UCB, GlaxoSmithKline, AstraZeneca, Boehringer-Ingelheim, Novartis, Otsuka, Eisai, GlaxoSmithKline, Tomonori Ishii Astellas, Chugai, Janssen, Ono, Sanofi, Eisai, Asahi Kasei, Fumitoshi Tago Eisai Co., Ltd., Kazuaki Watanabe Eisai Co., Ltd., Shintaro Yamamuro Eisai Co., Ltd., Shizuo Akira Eisai, Eisai, Chugai, Otsuka.