Exposure–Response Analyses of Upadacitinib Efficacy in Phase II Trials in Rheumatoid Arthritis and Basis for Phase III Dose Selection

Abstract

The relationships between upadacitinib, an oral selective Janus kinase 1 inhibitor, plasma exposures, and its efficacy (assessed by the American College of Rheumatology 20%/50%/70% responses over time) in moderate-to-severe active rheumatoid arthritis (RA) were characterized using data from 574 patients, on background methotrexate and inadequate response to methotrexate or anti-TNF therapy, from two phase II trials conducted with twice-daily dosing of an immediate-release formulation. The developed time-continuous Markov models were used to simulate efficacy of once-daily (q.d.). regimens of upadacitinib extended-release incorporating sources of uncertainty. Upadacitinib plasma concentrations associated with 15 and 30 mg extended-release q.d. doses were predicted to achieve that plateau of response across RA subpopulations. Results from these analyses provided the rationale that supported selection and de-risked evaluation of upadacitinib extended-release doses for the first time in >4,000 patients in five large phase III trials.Upadacitinib (ABT-494) is a selective inhibitor of Janus kinase 1 (JAK1), an intracellular tyrosine kinase that mediates receptor signaling for several inflammatory cytokines. 1 The JAKs are a family of four tyrosine kinases (JAK1, 2, and 3, and tyrosine kinase 2) that function as heterodimers or homodimers (for JAK2) to mediate receptor signaling for almost 40 cytokines involved in inflammatory diseases as well as in hematopoiesis and normal immune function. 2 Selective inhibition of JAK1 has the potential to offer advantages over nonspecific inhibition of multiple JAKs by reducing inflammation while limiting the unwanted effects on hematopoiesis and normal immune responses. 3,4 Accordingly, upadacitinib has been or is being evaluated in several phase III studies in rheumatoid arthritis (RA), 5-10 psoriatic arthritis, 11,12 giant cell arteritis, 13 and Crohn's disease, 14,15 and phase II studies in atopic dermatitis, ulcerative colitis, and ankylosing spondylitis. [16][17][18] Upadacitinib was evaluated in two phase IIb studies in patients with RA who were inadequate responders to anti-TNF

Exposure–Response Analyses of Upadacitinib Efficacy and Safety in Phase II and III Studies to Support Benefit–Risk Assessment in Rheumatoid Arthritis

“…Upadacitinib (ABT‐494) is a selective Janus kinase (JAK)1 inhibitor being developed for the treatment of several inflammatory disorders, including rheumatoid arthritis (RA), ulcerative colitis, atopic dermatitis, Crohn's disease, psoriatic arthritis, axial spondyloarthritis, and giant cell arteritis . The JAKs are a family of tyrosine kinases (JAK1, 2, and 3 and tyrosine kinase 2) that mediate receptor signaling for several cytokines involved in inflammatory diseases as well as normal immune function .…”

“…; and with consistency across RA subpopulations and with UPA monotherapy or combination with conventional synthetic disease-modifying antirheumatic drugs.Upadacitinib (ABT-494) is a selective Janus kinase (JAK)1 inhibitor being developed for the treatment of several inflammatory disorders, including rheumatoid arthritis (RA), ulcerative colitis, atopic dermatitis, Crohn's disease, psoriatic arthritis, axial spondyloarthritis, and giant cell arteritis. [1][2][3][4][5][6][7][8][9][10][11][12][13] The JAKs are a family of tyrosine kinases (JAK1, 2, and 3 and tyrosine kinase 2) that mediate…”

“…17,18 Upadacitinib demonstrated robust efficacy and acceptable safety in two phase II and in five phase III studies in subjects with moderate to severe RA. [2][3][4][5][6]19 Upadacitinib pharmacokinetics were thoroughly characterized following the administration of the immediate-release and extended-release formulations through noncompartmental analyses in phase I studies 20,21 as well as through population pharmacokinetic analyses across phase I to III studies. 21,22 Upadacitinib is a nonsensitive substrate for metabolism by cytochrome P450 3A4 isozyme (CYP3A); ~30% of upadacitinib dose is recovered in urine and feces as metabolites.…”

Exposure–Response Analyses for Upadacitinib Efficacy and Safety in the Crohn's Disease CELEST Study and Bridging to the Extended‐Release Formulation

“…The relationships between upadacitinib plasma concentration and clinical efficacy end points were characterized using a continuous‐time Markov modeling approach, similar to the approach used previously to analyze the efficacy for upadacitinib in patients with RA . The relationships between upadacitinib plasma exposures and endoscopic end points (endoscopic response 25%, endoscopic response 50%, and endoscopic remission at week 12 of 16) were characterized using regression analyses.…”

“…achieved the plateau for efficacy with very limited benefit for the 30 mg over 15 mg q.d. regimen . However, in subjects with CD, upadacitinib doses higher than 30 mg q.d.…”