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

Abstract

AbstractRetinoic 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.