LBA0001 EFFICACY AND SAFETY OF UPADACITINIB IN PATIENTS WITH GIANT CELL ARTERITIS (SELECT-GCA): A DOUBLE-BLIND, RANDOMIZED CONTROLLED PHASE 3 TRIAL

Background: Advanced targeted therapies for giant cell arteritis (GCA) are limited, and glucocorticoids (GCs) remain a primary treatment option. Interleukin-6 (IL-6) and interferon gamma (IFN-γ) have been strongly implicated in the pathogenesis of GCA. Upadacitinib (UPA), an oral and selective JAK inhibitor approved across multiple inflammatory diseases, is a strong inhibitor of the JAK-dependent cytokines IL-6 and IFN-γ and has the potential to treat GCA. Objectives: To assess the efficacy and safety of UPA vs placebo (PBO), in combination with a GC taper regimen, in patients with GCA. Methods: SELECT-GCA is a double-blind, randomized PBO-controlled phase 3 trial conducted in 24 countries, consisting of two 52-week periods. Results from the first 52-week period (primary analysis) are reported here, in which patients received either UPA 7.5 mg or 15 mg (UPA7.5 or UPA15) once daily in combination with a 26-week GC taper regimen or PBO with a 52-week GC taper regimen. Eligible patients were aged ≥50 yrs, diagnosed with new-onset or relapsing GCA, and had received prior GCA treatment with ≥40 mg prednisone or equivalent daily before baseline (BL) and were taking prednisone ≥20 mg daily at BL. Patients with prior exposure to JAK inhibitors, inadequate response or exposure to IL-6 inhibitors within 4 weeks before BL, or chronic use of systemic GCs were excluded. The primary endpoint was sustained remission, defined as the absence of signs or symptoms of GCA from week 12 through week 52 and adherence to the protocol-defined GC taper regimen. Secondary endpoints included sustained complete remission (defined as achievement of sustained remission with normalization of ESR and CRP), disease flare-related endpoints, several patient-reported outcomes including FACIT-Fatigue, and cumulative GC exposure. Exposure-adjusted treatment-emergent adverse events (TEAEs) were documented through 52 weeks. Results: A total of 428 patients were randomized and treated (PBO, N=112; UPA7.5, N=107; UPA15, N=209). BL characteristics were balanced across treatment groups, with 70% and 30% of patients having new-onset and relapsing GCA, respectively. The primary endpoint of sustained remission at week 52 was achieved with UPA15 vs PBO (46% vs 29%, P=.0019). Additionally, the study met 9 out of 11 multiplicity-controlled secondary endpoints with UPA15 including achievement of sustained complete remission from week 12 through week 52 (37% vs 16%, P<.0001). UPA15 resulted in a decreased risk for flare through 52 weeks relative to those receiving PBO (Figure). Additionally, UPA15 led to significantly greater improvements in FACIT-Fatigue scores from BL to week 52 (least-squares mean change: UPA15, 1.7; PBO, -2.4; P=.0036). Cumulative GC exposure over 52 weeks was significantly lower with UPA15 vs PBO (median exposure of 1615 mg vs 2882 mg, P<.0001). Across most endpoints, UPA7.5 showed numerically better efficacy compared to PBO but did not reach statistical significance. Safety outcomes over 52 weeks were generally similar among the UPA groups and PBO (Table), with numerically higher rates of serious infections and MACE observed in the PBO group and no MACE reported in the UPA groups. Rates of herpes zoster, lymphopenia, anemia, and nonmelanoma skin cancer (NMSC) were numerically higher with UPA15 than PBO. Rates of VTE were comparable across treatment groups. Rates of serious TEAEs and malignancy, excluding NMSC, were similar between UPA15 and PBO. Four treatment-emergent deaths were reported: two in the PBO group and two in the UPA15 group (one of which was attributable to COVID-19 and the other was adjudicated as an unexplained cause). Conclusion: UPA15 combined with a 26-week GC taper demonstrated superior efficacy and reduced GC use compared to PBO with a 52-week GC taper. No new safety signals were identified with UPA as compared to its known safety profile [1]. Overall, UPA15 provided a favorable benefit-risk profile and represents a potential new oral targeted therapy for patients with GCA. REFERENCES: [1] Burmester GR et al. RMD Open 2023:9:e002735. Acknowledgements: AbbVie and the authors thank the patients, study sites, and investigators who participated in this clinical trial (NCT03725202). AbbVie funded this trial 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. Medical writing support was provided by Matthew Eckwahl, PhD, of AbbVie. We also thank Yang Yang, Charles Phillips, and Aditi Kadakia, of AbbVie, for their contributions. Disclosure of Interests: Daniel Blockmans GSK, Roche, Sara K Penn AbbVie, AbbVie, Arathi Setty AbbVie, AbbVie, Wolfgang Schmidt AbbVie, Chugai, Medac, Novartis, Roche, and Sanofi, Advisory board member for AbbVie, Chugai, GlaxoSmithKline, Novartis, Roche, Fresenius Kabi, and Sanofi, AbbVie, GlaxoSmithKline, Novartis, and Sanofi, Andrea Rubbert-Roth AbbVie, Amgen, BMS, Chugai, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Roche, and Sanofi, AbbVie, Amgen, BMS, Chugai, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Roche, and Sanofi, Ellen-Margrethe Hauge Novo Nordic, Novartis, AbbVie, Sanofi, Sobi, MSD, and UCB, Novartis, AbbVie, and Sobi; advisory board for SynACT Pharma, Independent Research Fund Denmark, Novo Nordic Foundation, Danish Rheumatism Association, Aarhus University, Danish Regions Medicine Grants, Galapagos, AbbVie, Roche, and Novartis, Helen Keen Roche and eTherapeutic Guidelines Australia, Board member of Australian Rheumatology Association, Roche, Abbvie, Sun, Emerald, Novartis, Biogen, Sanofi, and Syneos, Tomonori Ishii AbbVie, Asahi Kasei Pharma, Astellas, Ayumi Pharmaceutical, BMS, Chugai Pharmaceutical, Daiichi-Sankyo, Eisai, Janssen, Mitsubishi Tanabe, Ono Pharmaceutical, Pfizer, and Sanofi, Nader Khalidi Travel support from Astra Zeneca, Advisory Board fees from Roche, BMS, Sanofi, and Abbvie, Meng Liu AbbVie, AbbVie, Weihan Zhao AbbVie, AbbVie, Ivan Lagunes AbbVie, AbbVie, Ana Romero AbbVie, AbbVie, Peter K Wung AbbVie, AbbVie, Peter A. Merkel Royalties from UpToDate, AbbVie, AstraZeneca, Boeringher-Ingelheim, BMS, ChemoCentryx, CSL Behring, Dynacure, EMDSerono, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Regeneron, Sparrow, Takeda, and Talaris, AbbVie, AstraZeneca, Boeringher-Ingelheim, BMS, ChemoCentryx, Eicos, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi, and Takeda.