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

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.