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].