Safety, Tolerability, Efficacy, Pharmacokinetics, and Pharmacodynamics of Afimetoran, a Toll-Like Receptor 7 and 8 Inhibitor, in Patients With Cutaneous Lupus Erythematosus: A Phase 1b Randomized, Double-Blind, Placebo-Controlled Study.

Publication date: Jul 01, 2025

There is an unmet need for safe and effective oral treatments for cutaneous lupus erythematosus (CLE). Afimetoran is an investigational, first-in-class, orally bioavailable, selective small molecule inhibitor of Toll-like receptors (TLRs) 7 and 8. We investigated the safety, tolerability, efficacy, pharmacokinetics, and pharmacodynamics of afimetoran in patients with CLE. In this Phase 1b, randomized, double-blind, placebo-controlled study (NCT04493541), patients with CLE received afimetoran (30 mg once daily) or a placebo, in addition to select background medications, over 16 weeks. Safety and tolerability were mainly reported through adverse events (AEs). Pharmacokinetics were determined using plasma concentration-time data. Pharmacodynamic biomarkers and efficacy (CLE Disease Area and Severity Index-Activity [CLASI-A] scores) were exploratory end points. Thirteen patients were randomized (afimetoran, n = 8; placebo, n = 5), and 12 patients completed treatment (1 discontinued afimetoran [COVID-19 infection]). Afimetoran demonstrated a favorable safety profile compared with placebo (patients with AEs: 62. 5% vs 80. 0%), with mainly mild-to-moderate AEs. Plasma concentrations exceeded the projected targeted 24-hour 90% inhibition concentration, supporting once- daily dosing. Pharmacodynamic analyses showed a rapid response to afimetoran by week 1 maintained throughout and beyond treatment, with reduced expression of TLR7/8 pathway-associated cytokines. All patients who received afimetoran had a change in the interferon-1 gene signature (P < 0. 0001) at week 16, with five of eight patients demonstrating a >50% improvement in CLASI-A scores. These findings support afimetoran’s potential as a once daily oral treatment for patients with CLE and suggest a possibly substantial therapeutic benefit, warranting further clinical investigation of afimetoran for lupus.

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