ABS0756 SHORTER INFUSION DURATION OF PEGLOTICASE COADMINISTERED WITH METHOTREXATE IN PATIENTS WITH UNCONTROLLED GOUT: SECONDARY AND EXPLORATORY ENDPOINTS OF THE AGILE TRIAL

<h2>Abstract</h2><h3>Background:</h3> Pegloticase, administered intravenously every 2 weeks over ≥2 hours, effectively lowers serum urate (SU) in patients (pts) with uncontrolled gout who have failed or cannot tolerate conventional urate-lowering therapies. Methotrexate (MTX) is recommended for coadministration with pegloticase [1] to decrease pegloticase immunogenicity, increase the SU-lowering response rate, and decrease infusion reaction (IR) risk [2]. The primary findings of the AGILE trial (NCT04511702) demonstrated the safety and efficacy of a shorter infusion time (60 min) of pegloticase with MTX coadministration [3]. <h3>Objectives:</h3> To report key secondary and exploratory findings of the 60-min cohort of AGILE. <h3>Methods:</h3> This Phase 4, multicenter, open-label study included pts with uncontrolled gout (SU ≥6mg/dL, oral urate-lowering therapy intolerance/inefficacy, and ≥1 of: ≥1 tophus, ≥2 gout flares/year, or gouty arthritis). Key exclusion criteria were MTX contraindication, serious bacterial infection, G6PD deficiency, eGFR <40 ml/min/1.73 m², or elevated liver function tests. Eligible pts underwent a 4-week oral MTX run-in (15 mg/week with 1 mg/day folic acid) followed by 24 weeks of pegloticase+MTX treatment (Day 1, first infusion). Initial cohorts were sequentially enrolled to receive 60-, 45-, or 30-min infusions to determine optimal duration for larger enrollment. The primary endpoint was the pegloticase+MTX IR rate (including anaphylaxis) of the most desirable infusion duration. Key secondary endpoints included SU-lowering response rate during Month 6 and rate of pegloticase discontinuation due to IR, anaphylaxis, or SU-response loss (2 consecutive pre-infusion SU >6mg/dL after Week 2). Key exploratory endpoints included the proportion of pts meeting individual SU discontinuation criteria (2 consecutive pre-infusion SU >6mg/dL) and the proportion of pts with SU <6mg/dL for each visit. These analyses included pts who received ≥1 pegloticase infusion (modified intent-to-treat [mITT]] and safety analysis sets). <h3>Results:</h3> Initial cohort enrollment started with ~10 pts in each cohort and proceeded sequentially from 60- to 45- to 30-min infusions. The 60-min cohort was chosen for further investigation based on the low IR rate. 116 pts made up the 60-min cohort (mITT) (90% men, mean [±SD] age: 55.2±11.3 years, BMI: 33.6±6.3 kg/m², eGFR: 76.5±19.4 ml/min/1.73m²; 12.0±10.4-year gout history, 66% had tophi, 7.0±7.1 flares in prior year, SU: 8.7±1.7 mg/dL). IR rate was 6.0% (95%CI: 2.5-12.0%; 7/116) in the 60-min group. The primary endpoint was met as the upper 95% CI bound for IR rate was <13% (a pre-specified threshold) and similar to the 4.2% (including anaphylaxis in 1%) in MIRROR RCT with 120-min infusions [2]. The proportion of SU responders at Month 6 (SU <6mg/dL for ≥80% of the time during Month 6) was 67.2% [95% CI: 57.9%, 75.7%] (Table 1). Between 82%-88% of pts on treatment had pre-infusion SU levels <6mg/dL post Day 1 through Week 2-24. 19% (22/116) of pts (95% CI: 12.3%, 27.3%) discontinued treatment (IR [n=4] including anaphylaxis [n=2], and SU discontinuation criteria met [n=19]; 1 patient discontinued due to both) (Table 2). Median time to event for the composite safety endpoint (discontinuation due to IRs or ARs or meeting SU discontinuation criteria) was not estimable using Kaplan-Meier method due to low number of pts with events. The incidence of anaphylaxis was low (1.7% [2/116]). All adjudicated IRs, including anaphylaxis, were mild or moderate (Rheumatology CTC grade 1 or 2). No pts had an adjudicated major adverse cardiac event during the study. Mean [±SD] change from baseline (Day 1, first infusion) in Physician Global Assessment of Gout score (range: 0 [excellent health] to 10 [very poor health]) was -2.4 (2.54) at Week 14 and -3.1 (2.60) at Week 24. Similarly, mean [±SD] change from baseline in Patient Global Assessment of Gout (range: 0-10), as measured by disability, was -2.0 (2.84) at Week 14 and -2.3 (3.19) at Week 24. <h3>Conclusion:</h3> With coadministration of MTX, shorter 60-min pegloticase infusions showed similar efficacy (response rates) and safety (IR, discontinuation) as MIRROR RCT. Additionally, patient-reported outcomes showed improvements consistent with prior pegloticase trials. Shorter infusion times will ease the logistical burden by receiving expeditious and efficient treatment for uncontrolled gout. <h3>REFERENCES:</h3> [1] Pegloticase [PI], Horizon Therapeutics USA, 2022. [2] Botson JK et al. <i>Arthritis Rheumatol</i> 2023;75:293-304. [3] Troum O et al. ACR 2024. Abstract 2012. Table 1Serum Urate < 6mg/dL Responders During Month 6mITT Analysis Set60-MinutePegloticase+MTX(N=116)Responder, n (%)78 (67.2)95% CI*(57.9, 75.7)Non-Responder^†, n (%)38 (32.8)Non-responder due to meeting stopping rule prior to Week 24, n (%)24 (20.7)Patients missing all data in analysis period, n (%)16 (13.8)mITT, modified intent-to-treat; MTX, methotrexate.*Clopper-Pearson exact method. The upper bound of the 95% was bounded at 100.†proportion of hours less than 80% counted as a non-responder. Any other patient was counted as a non-responder if only 1 SU value was available, or SU values were not collected during the month 6 period. Table 2Infusion Reactions Including Anaphylaxis at Week 24Safety analysis set, n(%)60-MinutePegloticase + MTX(N=116)IR including anaphylaxis related to pegloticase7 (6.0)95% CI *(2.5, 12.0)IR leading to treatment discontinuation, anaphylaxis, or meeting SU discontinuation criteria^†22 (19.0)95% CI(12.3, 27.3)≥1 IR leading to treatment discontinuation4 (3.4)95% CI(0.9, 8.6)≥1 anaphylaxis2 (1.7)95% CI(0.2, 6.1)Individual SU discontinuation criteria met19 (16.4)95% CI(10.2, 24.4)IR, infusion reaction; MTX, methotrexate*Clopper-Pearson exact method.^† 2 consecutive pre-infusion SU > 6mg/dL after Day 1. The stopping rule is defined while on treatment. <h3>Acknowledgements:</h3> This study was funded by Amgen, Inc. Medical writing and editing support is provided by Amy Cohen, PhD, and Swati Ghatpande, PhD, employees and stockholders of Amgen, Inc. <h3>Disclosure of Interests:</h3> Orrin Troum Speaker fees from AbbVie, Amgen, Horizon (now Amgen, Inc.), Novartis, Pfizer Inc, Sanofi-Genzyme, Consultant fees from AbbVie, Amgen, Bristol-Myers Squibb, Horizon (now Amgen, Inc.), Lilly, and Pfizer, Research support from AbbVie, Amgen, Bristol Myers Squibb, CorEvitas, Horizon, Novartis, and Sanofi-Genzyme, John Botson Consulting/speaker fees from AbbVie, Amgen, Horizon (now Amgen, Inc.), Lilly, and Novartis, Consulting/speaker fees from AbbVie, Amgen, Horizon (now Amgen, Inc.), Lilly, and Novartis, and compensation for intellectual property from Horizon, Research support (study site/principal investigator) from Horizon (now Amgen, Inc.), Allena, Olatec, and Radius Health, consulting/speaker fees from AbbVie, Amgen, Horizon (now Amgen, Inc.), Lilly, and Novartis, and compensation for intellectual property from Horizon, Fang Fang Amgen Inc., Amgen Inc., Katie Obermeyer Amgen Inc., Amgen Inc., Supra Verma Amgen Inc., Amgen Inc., Brian LaMoreaux Amgen Inc., Amgen Inc. © The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.