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
Objective 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,...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-07-01
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| Series: | ACR Open Rheumatology |
| Online Access: | https://doi.org/10.1002/acr2.70059 |
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| Summary: | Objective 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. Methods 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. Results 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. Conclusion 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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| ISSN: | 2578-5745 |