Switching Adalimumab, Upadacitinib May Provide Long-Term RA Benefit

Roy Fleischmann, MD

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Patients with rheumatoid arthritis (RA) switching from upadacitinib (RINVOQ) to adalimumab (HUMIRA)—or vice versa—may experience clinically relevant improvements in their disease management over 5 years, according to new data.¹

New long-term analysis from the SELECT-COMPARE trial showed that a majority of patients who did not at least completely respond to either the JAK inhibitor upadacitinib or TNF-alpha inhibitor adalimumab for the treatment of their RA were able to achieve Clinical Disease Activity Index (CDAI) scores indicating remission after switching to the other therapy long-term. The findings validate the strategy of switching therapies based on mechanism of action in patients with RA who may struggle to respond to their initial targeted therapy option.

Such theories of treatment strategy have already been considered—albeit at shorter treatment durations considering lesser-efficacious outcomes, like a Brazil-based meta-analysis published last year.²

Led by Roy Fleischmann, MD, of the Metroplex Clinical Research Center at University of Texas Southwestern Medical Center, investigators behind the phase 3 SELECT-COMPARE are assessing once-daily 15 mg upadacitinib versus 40 mg adalimumab, administered every other week, both with concomitant methotrexate in patients with RA and inadequate response to lone methotrexate. In the ongoing trial, patients who did not achieve a specified clinical response by 26 weeks were switched to the targeted therapy.¹

The team had already observed clinical and functional benefit based on the mechanism-of-action switch at both 6 and 12 months; this latest assessment reviewed outcomes at 5 years. Clinical remission of RA remains the main therapeutic target for this patient population, the team wrote, with low disease activity serving as a key alternative for those unable to achieve remission.

“As a result of the complexity of the disease, patients with RA may require multiple trials of medications with different mechanisms of action (MoAs) to achieve their treatment goal,” Fleischmann and colleagues wrote. “However, despite the number of currently approved advanced therapies with different MoAs available for patients with RA, including (biologic DMARDs), multiple clinical trials and post-marketing reports have shown that a minority of patients achieve remission or low disease when assessed using the CDAI or the Simplified Disease Activity Index, metrics favored by the American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) for assessing disease activity in RA.”

SELECT-COMPARE was designed to begin as a double-blind, placebo-controlled trial for 26 weeks, followed by an active comparator assessment up to week 48—then an open-label extension for either dose for ≤10 years. Eligible patients were ≥18 years old with active RA per ≥6 swollen joints and ≥6 tender joints, hsCRP ≥5 mg/L, and evidence of erosive disease, on a stable dose of methotrexate.

The current assessment evaluated efficacy up to 228 weeks post-treatment switch using outcome measures of CDAI-based low disease activity (≤10) and remission (≤2.8), as well as the C-reactive protein based 28-joint Disease Activity Score (DAS28[CRP] ≤3.2 and ≤2.6). They additionally sought 20%, 50%, and 70% improvement per ACR response criteria (ACR 20/50/70), and percent change from baseline in ACR core components of physical function, disease activity, self-assessed pain, inflammation and affected joint counts.

Investigators additionally observed safety through week 264, with treatment-emergent adverse events (TEAEs) summarized in patients who switched by week 26, by events per 100 patient-years.

The assessment included 252 patients switched from upadacitinib to adalimumab, and 159 switched from adalimumab to upadacitinib based on no or incomplete response by week 26. Among the upadacitinib-to-adalimumab arm, 228 entered the long-term extension, and 140 completed 228 weeks of therapy post-switch. In the latter group, 141 entered the long-term extension, and 101 completed the 228 weeks.

Among patients switched from adalimumab to upadacitinib due to non-response, 40 (76.9%) achieved CDAI low disease activity at week 228; another 17 (32.7%) achieved CDAI remission. Another 29 (58.0%) achieved DAS28(CRP) <2.6, and 38 (76.0%) achieved DAS(CRP) <3.2.

Among patients switched to adalimumab, 51 (72.9%) achieved low disease activity and 20 (28.6%) achieved remission. Another 35 (50.0%) achieved DAS28(CRP) <2.6, and 52 (74.3%) achieved DAS28(CRP) <3.2.

ACR20, 50, and 70 were achieved by 90.4%, 64.7%, and 44.2% of patients switched to upadacitinib at week 228, respectively. The same levels were met by 80.6%, 59.2%, and 42.3% of patients switched to adalimumab in the same period, respectively.

Regarding safety, the overall exposure-adjusted TEAE rate at week 264 was lower among patients switched to upadacitinib (165.0 per 1000; 95% CI, 154.6 – 175.9) than those switched to adalimumab (205.7 per 1000; 95% CI, 196.0 – 215.7). No new safety signals were identified with either agent.

Investigators concluded their findings provide clarity in a gap of knowledge on the long-term outcomes of ACR-recommended strategies behind mechanism-of-action switching to treat RA. Though the findings support the hypothesis of switching from a biologic DMARD to a TNF inhibitor—and vice versa—in patients failing to response to either therapy, the data are limited by the meta-analysis nature of research. The study did not include in-class switch arms, which warrant further analysis into the prescription strategy.

“To the best of our knowledge, however, SELECT-COMPARE is the first study to report clinical outcomes in patients switching to a TNF inhibitor after insufficient response to a JAK inhibitor, as well as a bidirectional immediate switch between a JAK inhibitor and a TNF inhibitor, with outcomes reported up to 5 years,” they wrote.

References

1. ^{Fleischmann R, Blanco R, Van den Bosch F, et al. Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE. Rheumatol Ther. Published online March 18, 2024. doi:10.1007/s40744-024-00658-1}
2. ^{Kunzmann K. Switch from TNF Inhibitors to Biosimilars Provides Consistent Rheumatoid Arthritis Outcomes. HCPLive. Published September 20, 2023. https://www.hcplive.com/view/switch-tnf-inhibitors-biosimilars-consistent-rheumatoid-arthritis-outcomes}