Target Occupancy and Functional Inhibition of JAK3 and TEC Family Kinases by Ritlecitinib in Healthy Adults: An Open-Label, Phase1 Study.

Abstract

Ritlecitinib is a small molecule in clinical development that covalently and irreversibly inhibits Janus kinase3 (JAK3) and the TEC family of kinases (BTK, BMX, ITK, TXK, and TEC). This phase1, open-label, parallel-group study assessed target occupancy and functional effects of ritlecitinib on JAK3 and TEC family kinases in healthy participants aged 18-60years who received 50 or 200mg single doses of ritlecitinib on day1. Blood samples to assess ritlecitinib pharmacokinetics, target occupancy, and pharmacodynamics were collected over 48hours. Target occupancy was assessed using mass spectroscopy. Functional inhibition of JAK3-dependent signaling was measured by the inhibition of the phosphorylation of its downstream target signal transducer and activator of transcription5 (pSTAT5), following activation by interleukin15 (IL-15). The functional inhibition of Bruton's tyrosine kinase (BTK)-dependent signaling was measured by the reduction in the upregulation of cluster of differentiation69 (CD69), an early marker of B-cell activation, following treatment with anti-immunoglobulinD. Eight participants received one 50mg ritlecitinib dose and 8 participants received one 200mg dose. Ritlecitinib plasma exposure increased in an approximately dose-proportional manner from 50 to 200mg. The maximal median JAK3 target occupancy was 72% for 50mg and 64% for 200mg. Ritlecitinib 50mg had >94% maximal target occupancy of all TEC kinases, except BMX (87%), and 200mg had >97% for all TEC kinases. For BTK and TEC, ritlecitinib maintained high target occupancy throughout a period of 48hours. Ritlecitinib reduced pSTAT5 levels following IL-15- and BTK-dependent signaling in a dose-dependent manner. These target occupancy and functional assays demonstrate the dual inhibition of the JAK3- and BTK-dependent pathways by ritlecitinib. Further studies are needed to understand the contribution to clinical effects of inhibiting these pathways.