258 First-in-human results from a phase 1 single- and multiple-ascending dose study in healthy participants assessing the safety, pharmacokinetics, and pharmacodynamics of the interleukin-17A inhibitor JNJ-81241459

Background: Interleukin (IL)-17A is a clinically validated target for the treatment of several systemic autoimmune diseases. Multiple biologic IL-17A inhibitors are approved to treat psoriasis and other inflammatory diseases. Orally delivered therapeutics targeting IL-17A have the potential to benefit broader patient populations than injectable biologics. JNJ-81241459 is a targeted orally administered small molecule that binds to IL-17A, inhibiting its function. Methods: This double-blind, placebo-controlled Phase 1 study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of JNJ-81241459 in healthy volunteers. In Part 1, participants were randomized to receive a single dose of JNJ-81241459 (n=6) or placebo (n=2) in one of 5 escalating dose cohorts. In Part 2, participants were randomized to one of 4 multiple ascending dose cohorts and received JNJ-81241459 (n=8) or placebo (n=2) for 14 days. Results: Following administration of single oral doses under fasted conditions, mean Cmax and area under the curve (AUC) increased in a dose-dependent manner. Dose-dependent increases in an indirect measure of target engagement were observed, reflecting a blockade of IL-17A binding to its receptor. Following 14 days of dosing, observed mean AUCtau and Ctrough approached projected predicted efficacious exposure levels in the multi-ascending dose cohorts. Exposures in all cohorts were lower than the no observable adverse effect level (NOAEL) exposures determined in animal toxicity studies. There were no serious adverse events (AEs) or severe AEs; no clinically significant or consistent alterations in safety laboratory parameters, vital signs, or electrocardiograms; and no treatment-related discontinuations. Conclusion: These results suggest JNJ-81241459 is well tolerated at doses providing projected efficacious exposure levels and support clinical development of JNJ-81241459 for the treatment of psoriasis and other systemic inflammatory diseases.