Safety, Tolerability, and Pharmacokinetics of an Oral Small Molecule Inhibitor of IL-17A (LY3509754): A Phase I Randomized Placebo-Controlled Study.

Autor: Datta-Mannan A; Eli Lilly and Company, Indianapolis, Indiana, USA., Regev A; Eli Lilly and Company, Indianapolis, Indiana, USA., Coutant DE; Eli Lilly and Company, Indianapolis, Indiana, USA., Dropsey AJ; Eli Lilly and Company, Indianapolis, Indiana, USA., Foster J; Eli Lilly and Company, Bracknell, Berkshire, UK., Jones S; Eli Lilly and Company, Indianapolis, Indiana, USA., Poorbaugh J; Eli Lilly and Company, Indianapolis, Indiana, USA., Schmitz C; Eli Lilly and Company, San Diego, California, USA., Wang E; Eli Lilly and Company, Indianapolis, Indiana, USA., Woodman ME; Eli Lilly and Company, Indianapolis, Indiana, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2024 May; Vol. 115 (5), pp. 1152-1161. Date of Electronic Publication: 2024 Jan 31.
DOI: 10.1002/cpt.3185
Abstrakt: For some patients with psoriasis, orally administered small molecule inhibitors of interleukin (IL)-17A may represent a convenient alternative to IL-17A-targeting monoclonal antibodies. This first-in-human study assessed the safety, tolerability, pharmacokinetics (PKs), and peripherally circulating IL-17A target engagement profile of single or multiple oral doses of the small molecule IL-17A inhibitor LY3509754 (NCT04586920). Healthy participants were randomly assigned to receive LY3509754 or placebo in sequential escalating single ascending dose (SAD; dose range 10-2,000 mg) or multiple ascending dose (MAD; dose range 100-1,000 mg daily for 14 days) cohorts. The study enrolled 91 participants (SAD, N = 51 and MAD, N = 40) aged 21-65 years (71% men). LY3509754 had a time to maximum concentration (T max ) of 1.5-3.5 hours, terminal half-life of 11.4-19.1 hours, and exhibited dose-dependent increases in exposure. LY3509754 had strong target engagement, indicated by elevated plasma IL-17A levels within 12 hours of dosing. Four participants from the 400-mg (n = 1) and 1,000-mg (n = 3) MAD cohorts experienced increased liver transaminases or acute hepatitis (onset ≥ 12 days post-last LY3509754 dose), consistent with drug-induced liver injury (DILI). One case of acute hepatitis was severe, resulted in temporary hospitalization, and was classified as a serious adverse event. No adverse effects on other major organ systems were observed. Liver biopsies from three of the four participants revealed lymphocyte-rich, moderate-to-severe lobular inflammation. We theorize that the DILI relates to an off-target effect rather than IL-17A inhibition. In conclusion, despite strong target engagement and a PK profile that supported once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated.
(© 2024 Eli Lilly and Company. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
Externí odkaz: