Ritlecitinib.

PF-06651600 is under investigation in clinical trial NCT02974868 (Study To Evaluate The Efficacy And Safety Profile Of PF-06651600 And PF-06700841 In Subjects With Alopecia Areata).|Ritlecitinib is an orally available small-molecule inhibitor of tyrosine-protein kinase JAK3 (Janus kinase 3; JAK3) with potential immunomodulatory and anti-inflammatory activities. Upon administration, ritlecitinib selectively and irreversibly binds to JAK3 and prevents the activation of the JAK-signal transducers and activators of transcription (STAT) signaling pathway. This may decrease the production of certain pro-inflammatory cytokines and prevent both an inflammatory response and the inflammation-induced damage caused by certain immunological diseases. By selectively targeting JAK3, PF-06651600 may spare interleukin (IL)-6 signaling, as well as other JAK1-dependent immunoregulatory cytokines such as IL-10, IL-27, and IL-35, which may offer a safety benefit compared to non-selective JAK inhibitors. JAK kinases are intracellular enzymes involved in signaling pathways affecting hematopoiesis, immunity and inflammation.
Ritlecitinib, a dual JAK3/TEC inhibitor, was granted FDA breakthrough status for treating alopecia areata (autoimmune-induced hair loss) in September 2018. Promising phase 3 trial results in alopecia areata were reported by Pfizer in August 2021, placing it in competition with Lilly/Incyte’s Olumiant. It is also used in clinical studies to treat vitiligo, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Ritlecitinib achieved high JAK3 selectivity via covalent interaction with a unique cysteine residue (Cys909) in the catalytic domain.