BENEFIT–RISK ANALYSIS OF UPADACITINIB VERSUS ADALIMUMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS AND HIGHER OR LOWER RISK OF CARDIOVASCULAR DISEASE

Background: An integrated benefit-risk profile analysis of upadacitinib (UPA) across the SELECT RA program, including a head-to-head study of UPA 15 mg vs adalimumab (ADA; SELECT-COMPARE), demonstrated that UPA had a favorable benefit-risk profile. However, there is a need to better understand the benefits-risks of UPA in patients at higher or lower risk of cardiovascular (CV) disease. Objectives: To evaluate the short- and long-term benefit-risk profile of UPA 15 mg relative to ADA among patients with RA and an inadequate response to MTX (MTX-IR) with a lower risk (<65 years of age and no CV risk factors) or higher risk (≥65 years of age and/or ≥1 CV risk factor) of CV disease, focusing on risk definitions from the European Medicines Agency. Methods: Data are from the SELECT-COMPARE phase 3 study, in which patients received UPA 15 mg, placebo (PBO), or ADA 40 mg, with all patients on background MTX. Within the first 26 weeks (wks), patients with an insufficient response were switched from PBO to UPA, UPA to ADA, or ADA to UPA; all patients still on PBO at wk 26 were switched to UPA. CV risk factors used to identify high-risk patients included prior history of a CV event, hypertension, diabetes mellitus, current or former smoker, age ≥65 yrs, elevated baseline LDL-C, and lowered baseline HDL-C. In this post hoc analysis, safety and efficacy were evaluated up to wk 264 in lower and higher CV risk groups separately. Safety data are reported as the differences in exposure-adjusted event (E) rates per 100 patient-years (PY) for patients receiving UPA or ADA, with assignment of treatment-emergent adverse events based on drug exposure at the time of event. Efficacy data are reported as differences between the proportion of patients achieving efficacy outcomes (based on non-responder imputation) for those receiving UPA or ADA. In patients who achieved DAS28(CRP) <2.6 by wk 26, the Kaplan-Meier method was used to analyze the time from wk 26 visit to loss of response, which was defined as the earliest date at which response was lost (ie, higher disease activity than the remission threshold) at two consecutive visits or discontinuation of the study drug due to lack of efficacy. Results: A total of 211 patients were identified in the lower-risk group (UPA, n=129; ADA, n=82) and 767 patients in the higher-risk group (UPA, n=522; ADA, n=245). The rates of most adverse events of interest were generally similar between UPA and ADA in either the lower- or higher-risk group (Figure 1). Consistent with previous reports, higher rates of herpes zoster (HZ) were observed with UPA than ADA. Notably, rates of malignancy excluding nonmelanoma skin cancer (NMSC), MACE, and VTE were comparable between UPA and ADA. In the high-risk group specifically, the rate of malignancy excluding NMSC was 0.7 vs 1.0 E/100 PY with UPA and ADA, respectively, while MACE was 0.4 vs 0.3 E/100 E/PY and VTE was 0.3 vs 0.5 E/100 PY through wk 264. Across all efficacy endpoints, UPA showed better outcomes compared to ADA in both the short-term (wk 26) and long-term (wk 264) (Figure 2). At wk 26, DAS28(CRP) <2.6 was attained by 21% and 12% more patients with UPA than ADA in the lower- and higher-risk groups, respectively (nominal P=. 003 and P< .001). UPA treatment also led to numerically better DAS28(CRP) <2.6 responses at wk 264 in both risk groups compared to ADA. Patients who achieved DAS28(CRP) <2.6 by wk 26 showed numerically better maintenance of response up to wk 264 with UPA vs ADA in both the lower-risk (70% vs 55%) and higher-risk (69% vs 59%) groups, although sample size was limited. Conclusion: In both short- and long-term analyses, UPA 15 mg treatment led to comparable safety risks and better efficacy outcomes relative to ADA regardless of baseline CV risk status, except HZ which was higher with UPA. Thus, the overall benefit-risk profile was found to be favorable for UPA vs ADA independent of the risk groups, although the benefits were more apparent in younger patients without CV risk factors. REFERENCES: [1] Conaghan PG et al. Drug Saf 2021;44:515-30. [2] Smolen JS et al. Ann Rhum Dis 2023;82:3-18. Acknowledgements: AbbVie and the authors thank the patients, study sites, and investigators who participated in this clinical trial (NCT02629159). AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing, and approval of the publication. All authors had access to relevant data and participated in the drafting, review, and approval of this publication. No honoraria or payments were made for authorship. Yanna Song of AbbVie provided statistical support. Medical writing support was provided by Matthew Eckwahl, PhD, of AbbVie. Disclosure of Interests: Gerd R. Burmester AbbVie, BMS, Lilly, Galapagos, Janssen, MSD, Pfizer, Roche, Sanofi, and UCB, AbbVie, BMS, Lilly, Galapagos, Janssen, MSD, Pfizer, Roche, Sanofi, and UCB, Eduardo Mysler AbbVie, Amgen, Astra Zeneca, Novartis, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Sanofi, HiBio, and Alpine Immunology, AbbVie, Amgen, Astra Zeneca, Novartis, Lilly, Pfizer, Roche, BMS, Sandoz, GSK, Janssen, Sanofi, HiBio, and Alpine Immunology, Peter C. Taylor Consultant for AbbVie, Galapagos, Gilead, Lilly, Pfizer, Biogen, Fresenius, GlaxoSmithKline, Janssen, Nordic Pharma, UCB, Acelyrin Inc; participation on Data Safety Monitoring Boards for Immunovant, Moonlake, Sanofi-Aventis, and Kymab, Galapagos, Lars Erik Kristensen Pfizer, AbbVie, Amgen, UCB, Celgene, BMS, Sanofi, Biogen, Forward Pharma, MSD, Novartis, Eli Lilly, and Janssen, Novo Nordisk, Eli Lilly, Merck, Novartis, and UCB, Pfizer, AbbVie, Amgen, UCB, Celgene, BMS, Sanofi, Biogen, Forward Pharma, MSD, Novartis, Eli Lilly, and Janssen pharmaceuticals, Novartis, Eli Lilly, Janssen, UCB, and Pfizer, Stephen Hall AbbVie, BMS, Lilly, Janssen, Pfizer, UCB, and Novartis, AbbVie, BMS, Lilly, Janssen, Pfizer, UCB, and Novartis, Bettina Wick-Urban AbbVie, AbbVie, Andrew Garrison AbbVie, AbbVie, Tianming Gao AbbVie, AbbVie, Nasser Khan AbbVie, AbbVie, Sander Strengholt AbbVie, AbbVie, Roy Fleischmann AbbVie, Amgen, Arthrosi, AstraZeneca, Biogen, BMS, Boehringer-Ingelheim, Cyxone, Dren Bio, Flexion, Galapagos, Galvani, Genentech, Gilead, GSK, Immunovant, ImmuneMed, InventisBio, Janssen, Kinska, Lilly, Monte Rosa, Novartis, Pfizer, Priovant, Recor, Roche, Sanofi-Aventis, and Vyne, AbbVie, Amgen, Arthrosi, AstraZeneca, Biogen, BMS, Boehringer-Ingelheim, Cyxone, Dren Bio, Flexion, Galapagos, Galvani, Genentech, Gilead, GSK, Immunovant, ImmuneMed, InventisBio, Janssen, Kinska, Lilly, Monte Rosa, Novartis, Pfizer, Priovant, Recor, Roche, Sanofi-Aventis, and Vyne DOI: 10.1136/annrheumdis-2024-eular.1416 Keywords: Randomized controlled trial, Comorbidities, Targeted synthetic drugs, Disease-modifying Drugs (DMARDs), Cardiovascular diseases Citation: , volume 83, supplement 1, year 2024, page 770Session: Rheumatoid arthritis (Poster View)

Randomized controlled trial, Comorbidities, Targeted synthetic drugs, Disease-modifying Drugs (DMARDs), Cardiovascular diseases