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

ABSTRACT 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. Trial registration number NCT05278663. KEY MESSAGES What is already known on this topic Because of the limited efficacy and safety concerns of current drug therapies, unmet medical needs remain for many patients with systemic lupus erythematosus (SLE), necessitating new, more efficacious drugs. There is strong evidence for the relationship between Toll-like receptor (TLR)7/8 and SLE pathophysiology, and two phase 1 clinical studies of E6742, a small molecular selective dual antagonist of TLR7/8, in healthy adults showed good tolerance without safety issues. What this study adds E6742 was well tolerated in this phase 1/2 clinical trial of patients with SLE, demonstrating a favorable safety profile and providing a markedly improved interferon gene signature and sufficient efficacy signals. How this study might affect research, practice or policy This study provides the first clinical evidence to suggest that E6742, as a first-in-class TLR7/8 inhibitor, may be beneficial for SLE. The study outcomes also support larger, longer-term clinical trials of E6742.