Study Describes Long-Term Safety of Upadacitinib Across Indications in Rheumatology

Gerd Burmester, MD

Credit: Gerd Burmester on X

Findings from a recent study are providing clinicians with important insight into the long-term integrated safety profile of upadacitinib 15 mg across indications in rheumatology.¹

Assessed in the context of active comparators based on data from the SELECT program, the study found a generally consistent safety profile for upadacitinib across clinical trials in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA), with no new safety risks identified with long-term treatment. With a few exceptions, rates of treatment-emergent adverse events (TEAEs) were generally similar between upadacitinib 15 mg and active comparators in RA and PsA.¹

“Safety observed with JAK inhibition to date has highlighted the need to further characterize the long-term safety profile of individual JAK inhibitors across diverse patient populations,” Gerd Burmester, MD, professor of medicine and director of the department of rheumatology and clinical immunology at Charité - University Medicine Berlin, and colleagues wrote.¹

An oral Janus kinase (JAK) inhibitor, upadacitinib first earned US Food and Drug Administration (FDA) approval in 2019 for the treatment of adults with moderately to severely active RA who have an inadequate response or intolerance to methotrexate. The decision was supported by data from the SELECT clinical program—a collection of 5 registrational phase 3 trials including more than 4400 patients with RA.² Upadacitinib now boasts FDA approvals across other rheumatic and gastroenterological conditions, although its long-term safety profile across diverse patient populations has not been explored.

To describe the long-term integrated safety profile of upadacitinib 15 mg across indications for different rheumatic conditions, investigators compiled safety data from 11 phase 3 trials across RA, PsA, AS, and nr-axSpA. TEAEs with an onset on or after the first dose of the study drug and ≤ 30 days after the last dose of the study drug for upadacitinib 15 mg and methotrexate, or ≤ 70 days for adalimumab, were coded using MedDRA version 26.0.¹

TEAEs were summarized for RA (pooled upadacitinib 15 mg, adalimumab, and methotrexate), PsA (pooled upadacitinib 15 mg and adalimumab), AS (pooled upadacitinib 15 mg), and nr-axSpA (upadacitinib 15 mg) and presented as exposure-adjusted event rates per 100 patient-years. Deaths, cardiovascular events, VTEs, and gastrointestinal perforations were adjudicated by blinded, independent committees using pre-specified definitions.¹

In total, 4998 patients (RA, n = 3209; PsA, n = 907; AS, n = 596; nr-axSpA, n = 286) received ≥ 1 dose of upadacitinib 15 mg, totaling 15,895.8 patient-years of exposure, with the majority of exposure from RA studies. Investigators noted the rate of adverse events leading to discontinuation of the study drug was generally similar across treatment groups and diseases, although adverse events leading to discontinuation of upadacitinib 15 mg treatment varied widely. The most frequently reported adverse events were pneumonia (RA; n = 22/459), COVID-19 (PsA; n = 7/121), headache (AS; n = 3/42), and worsening axial spondyloarthritis and pulmonary embolism (nr-axSpA; both n = 2/20).¹

Investigators also noted rates of serious infection and opportunistic infection were generally similar across treatment groups and diseases, but the rate of serious infection was greater with upadacitinib 15 mg versus adalimumab in PsA. COVID-19 pneumonia was both the most common serious infection and serious adverse event with upadacitinib 15 mg treatment for all diseases. Additionally, herpes zoster and elevated creatinine phosphokinase were reported more often with upadacitinib 15 mg versus active comparators in RA and PsA, with upadacitinib 15 mg showing similarly elevated rates of herpes zoster across all diseases.¹

Rates of malignancy excluding nonmelanoma skin cancer were generally similar across treatment groups and diseases, although greater rates of nonmelanoma skin cancer were observed with upadacitinib 15 mg versus active comparators in RA and PsA. Similar rates of MACE and VTE were observed across treatment groups and diseases. Rates of extra-musculoskeletal manifestations, including uveitis and inflammatory bowel disease, were generally low across PsA, AS, and nr-axSpA with UPA 15 mg treatment, with the highest number of events reported for uveitis in AS. The most common cause of death across all diseases was COVID-19/COVID-19 pneumonia.¹

References:

1. ^{Burmester GR, Cohen SB, Deodhar A, et al. SAFETY OF UPADACITINIB ACROSS RHEUMATOID ARTHRITIS, PSORIATIC ARTHRITIS, AND AXIAL SPONDYLOARTHRITIS ENCOMPASSING 15,000 PATIENT-YEARS OF CLINICAL TRIAL DATA. Annals of the Rheumatic Diseases. https://doi.org/10.1136/annrheumdis-2024-eular.809}
2. ^{Kunzmann, K. FDA Approves Upadacitinib for Inadequately Treated Rheumatoid Arthritis. HCPLive. August 16, 2019. Accessed June 24, 2024. https://www.hcplive.com/view/fda-approves-upadacitinib-for-inadequately-treated-rheumatoid-arthritis}