Upadacitinib in Rheumatoid Arthritis: A Benefit–Risk Assessment Across a Phase III Program

Philip G. Conaghan (), Eduardo Mysler, Yoshiya Tanaka, Barbara Silva-Tillmann, Tim Shaw, John Liu, Ryan Ferguson, Jeffrey V. Enejosa, Stanley Cohen, Peter Nash, William Rigby and Gerd Burmester
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Philip G. Conaghan: University of Leeds, and National Institute for Health Research Leeds Biomedical Research Centre
Eduardo Mysler: Organización Médica de Investigación
Yoshiya Tanaka: University of Occupational and Environmental Health Japan
Barbara Silva-Tillmann: AbbVie Inc.
Tim Shaw: AbbVie Ltd
John Liu: AbbVie Inc.
Ryan Ferguson: AbbVie Inc.
Jeffrey V. Enejosa: AbbVie Inc.
Stanley Cohen: Metroplex Clinical Research Center
Peter Nash: Griffith University
William Rigby: Dartmouth-Hitchcock Medical Center
Gerd Burmester: Charité-Universitätsmedizin Berlin

Drug Safety, 2021, vol. 44, issue 5, No 2, 515-530

Abstract: Abstract Treating to a target of clinical remission or low disease activity is an important principle for managing rheumatoid arthritis (RA). Despite the availability of biologic disease-modifying antirheumatic drugs (bDMARDs), a substantial proportion of patients with RA do not achieve these treatment targets. Upadacitinib is a once-daily, oral Janus kinase (JAK) inhibitor with increased selectivity for JAK1 over JAK2, JAK3, and tyrosine kinase 2. The SELECT phase III upadacitinib clinical program comprised five pivotal trials of approximately 4400 patients with RA, including inadequate responders (IR) to conventional synthetic (cs)DMARDs or bDMARDs. This review aims to provide insights into the benefit–risk profile of upadacitinib in patients with RA. Upadacitinib 15 mg once daily, in combination with csDMARDs or as monotherapy, achieved all primary and ranked secondary endpoints in the five pivotal trials across csDMARD-naïve, csDMARD-IR, and bDMARD-IR populations. Upadacitinib 15 mg also demonstrated significantly higher rates of remission and low disease activity in all five pivotal trials, compared with placebo, methotrexate, or adalimumab. Labeled warnings of JAK inhibitors include serious infections, herpes zoster, malignancies, major cardiovascular events, and venous thromboembolic events. Short- and long-term integrated analyses showed that upadacitinib 15 mg was associated with increased risk of herpes zoster and creatine phosphokinase elevations compared with methotrexate and adalimumab but otherwise had comparable safety with these active comparators. This review suggests that upadacitinib 15 mg had a favorable benefit–risk profile. The safety of upadacitinib will continue to be monitored in long-term extensions and post-marketing studies.

Date: 2021
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DOI: 10.1007/s40264-020-01036-w

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