Upadacitinib proves long-term efficacy in RA

Upadacitinib remains effective through 5 years in patients with rheumatoid arthritis (RA) who have inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), with no new safety signals, as shown by the results of the phase III long-term extension (LTE) of SELECT-NEXT.

“Results remained consistent with earlier analyses of SELECT-NEXT,” the researchers said. “Overall, the long-term benefit-risk profile for upadacitinib in RA remains favourable.”

In this study, RA patients on stable csDMARDs were randomly assigned to receive upadacitinib 15 mg once daily (QD), 30 mg QD, or placebo for 12 weeks. Then, those on placebo were switched to upadacitinib 15 mg QD or 30 mg QD in the LTE phase, while the rest continued their original dose.

Blinding continued until switching upadacitinib dose from 30 to 15 mg QD due to approval of the 15-mg dose. The earliest switch occurred at week 168. The researchers then reported efficacy and treatment-emergent adverse events (TEAEs) through 5 years.

Of the participants, 611 (92 percent) entered the LTE phase, and 271 (44 percent) ceased treatment by year 5, mainly due to AEs (16 percent).

Five-year clinical outcomes improved or were sustained. Of the patients treated with upadacitinib 15 and 30 mg QD, 51 percent and 43 percent attained Clinical Disease Activity Index remission, and 75 percent and 66 percent achieved Disease Activity Score in 28 joints based on C-reactive protein <2.6, respectively. [J Rheumatol 2024;51:663-672]

There was also an increase in the number of patients who achieved ≥20-, 50,- or 70-percent improvement in the American College of Rheumatology criteria responses from week 60 through year 5. Of note, these results persisted irrespective of initial randomization to upadacitinib or placebo.

Safety profile

With regard to safety, TEAEs did not differ significantly from those seen in earlier analyses and other SELECT studies. Malignancies (excluding nonmelanoma skin cancer), major adverse cardiovascular events, and venous thromboembolic events were rare, and no new safety signals appeared.

“This analysis of patients with moderate-to-severe RA despite treatment with csDMARDs found upadacitinib continued to be efficacious across multiple RA disease activity measures including achievement of low disease activity and remission through 260 weeks,” the researchers said. [Lancet 2018;391:2513-2524; Lancet 2019;393:2303-2311]

“Long-term efficacy results were generally comparable between patients initially randomized to upadacitinib 15 mg or 30 mg, and those who switched from placebo to [the study drug] at week 12, [but] slightly greater responses were observed with the 15-mg dose for some endpoints,” they added.

Additionally, the safety profile of upadacitinib through year 5 reflected that with earlier analyses of SELECT and with an integrated phase III safety analysis of the study drug in RA. [Lancet 2018;391:2503-2512; Ann Rheum Dis 2021;80:304-311]

Of note, three of the five deaths in the current study were due to COVID-19, “likely because the onset of the COVID-19 pandemic during the last 2 years of the study,” according to the researchers.

Upadacitinib is a selective JAK inhibitor designed for greater selectivity of JAK1 over JAK2, JAK3, and tyrosine kinase 2. It has been tested across a range of patient populations with RA, including those naïve to methotrexate (MTX) or with inadequate response to MTX and DMARDs. [BMC Rheumatol 2018;2:23]