Safety, Tolerability, and Pharmacokinetics of IMU-935, a Novel Inverse Agonist of Retinoic Acid Receptor-Related Orphan Nuclear Receptor γt: Results From a Double-Blind, Placebo-Controlled, First-in-Human Phase 1 Study.

Retinoic acid receptor-related orphan nuclear receptor (ROR)γt regulates the transcription of interleukin-17 and other cytokines implicated in inflammatory and autoimmune diseases. We assessed the safety, tolerability, and pharmacokinetics (PK) of IMU-935, an inverse agonist of RORγt, in a first-in-human phase 1 study. This was a double-blind, placebo-controlled trial that randomly assigned healthy subjects single ascending doses (25-400 mg) or multiple ascending doses (150 mg once or twice daily for 14 days) of IMU-935 or placebo. Dose escalation was determined by the safety, tolerability, and PK. Twenty-four and 70 subjects received placebo or IMU-935, respectively. Of the 70 subjects who received IMU-935, 59 received a single dose and 11 received multiple doses. Treatment-emergent adverse events (TEAEs) occurred in 21 subjects (88%) and 58 (83%) given any dose of placebo or IMU-935, respectively. Treatment-related TEAEs occurred in 6 (30%) and 25 (42%) subjects given a single dose of placebo and IMU-935, respectively. All treatment-related TEAEs were mild except for 2 moderate TEAEs and 1 moderate TEAE in the IMU-935 group and placebo group, respectively. No treatment-related discontinuations or serious adverse events occurred. The PK of IMU-935 were dose proportional with a half-life of ≈24 hours. In conclusion, IMU-935 was safe with no dose-limiting toxicities and had a PK profile that supports once-daily dosing.