Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials

Abstract

Introduction This integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug. Methods Safety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020. Results A total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg ( N = 907) or 30 mg ( N = 921) for 2504.6 PY of exposure or adalimumab ( N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon. Conclusions Upadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib. Trial Registration Numbers SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-021-00410-z.

Effectiveness and Safety of JAK Inhibitors in Autoinflammatory Diseases: A Systematic Review

“…In general JAKi show a heterogenous risk of infectious complications. For example, a known class effect for JAKi is an elevated risk of herpes zoster ( 67 – 70 ). In one recent study, serious infections were more frequent with tofacitinib at a dose of 10 mg twice daily compared to TNF inhibition ( 71 ), which contradicts some available evidence pointing to a similar risk of serious infections under JAKi compared to other biological disease-modifying antirheumatic drugs (bDMARDs) ( 72 , 73 ).…”

The cardiometabolic conditions of psoriatic disease

“…However, in the interim analysis of tofacitinib in PsA patients in the OPAL Balance trial (3 year, open-label extension study of tofacitinib in PsA), there was no evidence of an increased risk of CV events ( 86 ). Similarly, in an integrated analysis of 2 randomized, placebo-controlled phase 3 trials with upadacitinib in PsA, including one trial with adalimumab, rates of MACE were similar across treatment groups ( 87 ). It has been reported that TNFi induce body composition changes in IRD with weight and fat mass gain, especially in the central abdominal region ( 88 ).…”

Janus kinase inhibitors for hidradenitis suppurativa: expanding the therapeutic toolbox

“…4 Herpes zoster may be more common with JAK inhibitors than with biologics, with rates of 3Á8-6Á7 per 100 patient-years with upadacitinib, another JAK1 inhibitor, compared with 0Á1 with biweekly adalimumab in patients with psoriatic arthritis. 7 Possibly more concerning are cytopenias, reported with JAK inhibitors affecting JAK2, related to its transmission of erythropoietin, thrombopoietin and haematopoietic cell development cytokines. 8 More data could clarify whether the risk of thrombocytopenia with INCB054707 is restricted to higher doses.…”

“…Common adverse effects with JAK inhibitors for other dermatoses include upper respiratory tract infections and nasopharyngitis, in as many as 10% of patients 4 . Herpes zoster may be more common with JAK inhibitors than with biologics, with rates of 3·8–6·7 per 100 patient‐years with upadacitinib, another JAK1 inhibitor, compared with 0·1 with biweekly adalimumab in patients with psoriatic arthritis 7 …”