Safety, Pharmacokinetics, Biomarker Response, and Efficacy of E6742, a Dual Antagonist of Toll-Like Receptors 7 and 8, in a First-in-Patient, Randomized, Double-Blind, Phase 1/2 Study in Systemic Lupus Erythematosus

Objectives To evaluate the safety, tolerability, pharmacokinetics (PK), biomarker response, and efficacy of E6742 in a phase 1/2 study in patients with systemic lupus erythematosus (SLE). Methods Two sequential cohorts of SLE patients were enrolled and randomized to 12 weeks of twice-daily treatment with E6742 (100 or 200 mg; n = 8 or 9) or placebo (n = 9). Results The proportion of patients with any treatment-emergent adverse events (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. No Common Terminology Criteria for Adverse Events ≥ Grade 3 TEAEs occurred. PK parameter levels were similar between SLE patients and healthy adults in previous phase 1 studies. The interferon gene signature (IGS) and levels of proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α) after ex-vivo challenge with a Toll-like receptor 7/8 agonist were immediately decreased by E6742 treatment. Dose-dependent improvements in the British Isles Lupus Assessment Group-based Composite Lupus Assessment response were observed at Week 12 in the E6742 (37.5% for 100 mg; 57.1% for 200 mg) and placebo (33.3%) groups. E6742 also had therapeutic effects on other symptoms, including skin inflammation, arthritis, and levels of anti-double-stranded DNA antibodies and complements. Conclusions E6742 had a favorable safety profile and was well tolerated, with marked IGS responses and sufficient efficacy signals in patients with SLE. These results provide the first clinical evidence to support E6742 in the treatment of SLE, and support larger, longer-term clinical trials. ### Competing Interest Statement COMPETING INTERESTS: YT has received grants from Mitsubishi-Tanabe, Eisai, Chugai, and Taisho; speaker fees and/or honoraria from Eli Lilly, AstraZeneca, Abbvie, Gilead, Chugai, Behringer-Ingelheim, GlaxoSmithKline, Eisai, Taisho, Bristol-Myers Squibb, Pfizer, and Taiho. AK has received grants from Chugai; consulting fees from Eisai; speaker fees and/or honoraria from Asahi Kasei, Astellas, Eisai, GlaxoSmithKline, Chugai, Eli Lilly, Boehringer-Ingelheim, Pfizer, and Bristol-Myers Squibb. TA has received grants from GlaxoSmithKline; consulting fees from GlaxoSmithKline, AstraZeneca, Boehringer-Ingelheim, Novartis, Otsuka, and Eisai; speaker fees and/or honoraria from 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, and UCB. TI has received grants from Asahi Kasei; consulting fees from Eisai; speaker fees and/or honoraria from Astellas, Chugai, Janssen, Ono, and Sanofi. FT, MA, and SY are employees of Eisai. SA has received grants from Chugai, and Otsuka; consulting fees from Eisai. ### Clinical Trial NCT05278663 ### Funding Statement This work was supported by the Japan Agency for Medical Research and Development (AMED) under the Cyclic Innovation for Clinical Empowerment (CiCLE) grant program (grant number: JP19pc0101038). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: 1. Hospital of the University of Occupational and Environmental Health Japan Institutional Review Board of Hospital of the University of Occupational and Environmental Health Japan gave ethical approval for this work. 2. Japan Community Health Care Organization Chukyo Hospital Institutional Review Board of Japan Community Health Care Organization Chukyo Hospital gave ethical approval for this work. 3. Daido Hospital Institutional Review Board of Daido Clinic gave ethical approval for this work. 4. Institutional Review Board of Matsuyama Red Cross Hospital of Matsuyama Red Cross Hospital gave ethical approval for this work. 5. Hokkaido University Hospital Institutional Review Board of Hokkaido University Hospital gave ethical approval for this work. 6. Tohoku University Hospital Institutional Review Board of Tohoku University Hospital gave ethical approval for this work. 7. Tokyo Metropolitan Hospital Organization Tokyo Metropolitan Tama Medical Center Institutional Review Board of Tokyo Metropolitan Tama Medical Center gave ethical approval for this work. 8. National Hospital Organization Kyushu Medical Center Institutional Review Board of National Hospital Organization Kyushu Medical Center gave ethical approval for this work. 9. Osaka University Hospital Institutional Review Board of Osaka University Hospital gave ethical approval for this work. 10. St. Lukes International Hospital Institutional Review Board of St. Lukes International Hospital gave ethical approval for this work. 11. Certified Review Board of National Center for Global Health and Medicine of National Center for Global Health and Medicine gave ethical approval for this work. 12. Juntendo university Hospital institutional review board of Juntendo University Hospital gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors