Upadacitinib holds favourable risk–benefit profile for RA treatment
Use of the Janus kinase (JAK) inhibitor upadacitinib in the treatment of rheumatoid arthritis (RA) yields significant improvements in signs, symptoms and physical function, in addition to inhibiting radiographic progression as compared with placebo, according to the results of the phase III SELECT-COMPARE trial.
Moreover, upadacitinib has an overall safety profile that is similar to that of the tumour necrosis factor (TNF) inhibitor adalimumab, except for higher rates of herpes zoster and creatinine phosphokinase (CPK) elevations on the JAK inhibitor.
Overall, the benefit–risk ratio of upadacitinib at a dose of 15 mg is favourable, the authors said.
In SELECT-COMPARE, 1,629 RA patients (mean age, 54 years; 79.31 percent female; mean disease duration, 8 years) with inadequate response to methotrexate were randomized to receive once-daily upadacitinib 15 mg (n=651), placebo (n=651) or adalimumab 40 mg (n=327).
Results for the primary endpoints were better with upadacitinib vs placebo, with greater proportions of patients meeting the American College of Rheumatology (ACR)20 response criteria (71 percent vs 36 percent; p≤0.001) and Disease Activity Score-28 for Rheumatoid Arthritis with C-reactive protein (DAS28CRP)<2.6 (29 percent vs 6 percent; p≤0.001) at week 12. Moreover, radiographic progression at week 26 was less and seen in fewer patients treated with the active drug (p≤0.001). [Arthritis Rheumatol 2019;doi:10.1002/art.41032]
Upadacitinib also showed superiority over adalimumab in terms of week-12 ACR50 (45 percent vs 29 percent) and DAS28CRP≤3.2 (45 percent vs 29 percent), pain on the visual analogue scale (–32.1 vs –25.6) and physical function (health assessment questionnaire-disability index score, –0.60 vs –0.49; p-all≤0.01) at week 12. These improvements were maintained through 26 weeks.
At week 26, significantly more patients in the upadacitinib group achieved low disease activity or were on remission compared with those in the placebo or adalimumab group (p≤0.001).
Adverse events (AEs), such as serious infections, were similar between the JAK and TNF inhibitors. The highest number of patients who discontinued treatment due to AEs and serious AEs was seen with adalimumab. However, herpes zoster and CPK elevations occurred more frequently with upadacitinib. There were three malignancies, five major adverse cardiovascular events and four deaths recorded, none of which occurred with the JAK inhibitor.
In total, 91 percent of patients completed week 26. Patients who had failed to show an improvement of ≥20 percent in tender and swollen joint counts from baseline to weeks 14, 18 or 22 were given rescue treatment: placebo to upadacitinib (47 percent), upadacitinib to adalimumab (19 percent) and adalimumab to upadacitinib (24 percent).
“One limitation of the trial was that the duration of the placebo-controlled period was 26 weeks, with rescue treatment provided starting at week 14. [This means that] not all patients remained on their randomized treatment assignment for the entire 6 months,” the authors pointed out.
“In addition, upadacitinib monotherapy was not assessed vs adalimumab with background methotrexate,” they added.
The authors stressed that integrated analyses of the present and the previous four pivotal trials of upadacitinib should help further the understanding of the potential use and safety of the JAK inhibitor in the RA population. [Arthritis Rheumatol 2016;68:2867-2877; Arthritis Rheumatol 2016;68:2857-2866; Lancet 2018;391:2503-2512; Lancet 2018;391:2513-2524]