Introduction
Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease that primarily involves the lining of synovial joints and can cause progressive disability [1]. Research efforts are now targeting Janus kinases (JAK)-signal transducer and activator of transcription proteins (STAT) signaling cascade as a therapeutic strategy [2]. EMA (European Medicines Agency) and Pharmaceuticals and Medical Devices Agency have approved four oral, small molecule JAK inhibitors, tofacitinib, baricitinib, upadacitinib, and filgotinib for the treatment of RA [3],[4],[5]. These agents differ in their in vitro selectivity profile for JAK subtypes. Newer generations of JAK inhibitors are more selective, specifically targeting inhibition of JAK1 while avoiding potential undesirable effects of inhibiting downstream signaling from JAK2 and JAK3 [3],[6],[7].
Filgotinib is an oral, once-daily, potent JAK1 preferential inhibitor [8], which has demonstrated clinical improvement in RA and was granted marketing approval in European Union and Japan for treatment of moderate to severe RA in adults. Filgotinib has met all the primary endpoints, ACR20 at Week 12 or Week 24, in its Phase 3 clinical trials, FINCH 1, FINCH 2, and FINCH 3 [9],[10]. These studies showed that filgotinib was well tolerated and highly efficacious in patients with moderately to severely active RA, by reducing the signs and symptoms of disease, improving function, and slowing the progression of joint destruction. Filgotinib also showed clinical benefit in ulcerative colitis [11],[12] and is currently being investigated for treatment of other chronic inflammatory diseases such as Crohn’s disease [13]. GS-829845, the major circulating metabolite of filgotinib, is also a JAK1 preferential inhibitor and approximately 10-fold less potent than the parent compound [8],[14],[15]. This report describes exposure-efficacy and exposure-safety analyses for filgotinib and its major active metabolite, GS-829845, based on population pharmacokinetic (PopPK) model-derived PK exposures and efficacy and safety data from three Phase 3 studies (FINCH 1, FINCH 2, and FINCH 3) and two Phase 2 studies (DARWIN 1 and DARWIN 2) in patients with moderate to severe RA to support dose recommendation [9],[10],[16],[17],[18].