POS1153 SAFETY AND EFFICACY OF MONTHLY DOSING OF PEGLOTICASE (EVERY 4 WEEKS) WITH METHOTREXATE CO-ADMINISTRATION IN PATIENTS WITH UNCONTROLLED GOUT: PHASE 4 FORWARD OPEN-LABEL TRIAL

<h2>Abstract</h2><h3>Background:</h3> Pegloticase, when co-administered with methotrexate (MTX) decreases pegloticase immunogenicity, thus increasing SU-lowering response rate and decreasing infusion reaction (IR) risk in patients (pts) with uncontrolled gout [1]. However, the current treatment regimen of infusions administered every 2 weeks for >2 hours can be burdensome on pts. The recent results from the AGILE trial demonstrated the safety and efficacy of a shorter infusion time (60 min) of pegloticase with MTX coadminitration [2]. In addition to a shorter infusion time, decreasing the frequency of pegloticase to a single monthly (Q4W) IV dose will further improve treatment logistics, pt adherence and infusion efficiency. <h3>Objectives:</h3> To report PK, safety, and efficacy of 2 pegloticase doses (16 and 30 mg) infused Q4W up to 6 months with MTX coadministration. <h3>Methods:</h3> This Phase 4, multicenter, open-label study (FORWARD I, NCT04762498) enrolled pts with uncontrolled gout (serum uric acid [sUA] ≥6 mg/dL, ULT failure/intolerance, ≥1 gout symptom [1 tophus, ≥2 flares in 12 months, gouty arthropathy]). Key exclusion criteria were MTX contraindication, serious bacterial infection, G6PD deficiency, and eGFR <40 ml/min/1.73 m². Pts underwent a 4-week oral MTX run-in (15 mg/wk with 1 mg/d folic acid) followed by a pegloticase+MTX treatment period from Day 1 through Week 24 (6 infusions). Approximately 10-20 pts per dose cohort were planned. Pts were enrolled into the 16-mg cohort, and following 4- and 8-week efficacy and safety data reviews from this cohort, the 30-mg cohort enrolment was initiated. Pts who remained on treatment through Week 24 could continue into the optional 24-week extension period through Week 48 visit (up to 12 infusions), (Figure 1). The co-primary endpoints included the proportion of Month 6 responders (pts achieving and maintaining sUA <6 mg/dL for at least 80% of the time at Month 6), and the time to first sUA ≥6 mg/dL after first achieving sUA <6 mg/dL, from the first pegloticase infusion until Week 24. Secondary endpoints were PK parameters, proportion of pts with sUA <6 mg/dL, area under sUA concentration vs time curve from Day 1 to Week 24 and Day 1 to Week 48, proportion of pts with sustained sUA< 6 mg/dL at Week 24 and 48, and pegloticase immunogenicity. Adverse events (AEs) of interest were monitored. <h3>Results:</h3> Of the 51 pts who received Q4W pegloticase with MTX co-administration, 25 were enrolled in the 16-mg cohort and 26 in the 30-mg cohort. Overall, 72.0% and 69.2% of pts completed treatment through Week 24; 70.6% of the pts continued in the optional extension phase (17 in 16 mg and 19 in 30 mg), and 94.1% and 68.4% of these pts completed Week 48. The Month 6 sUA-lowering response (co-primary endpoint) was achieved in 68.0% [95% CI: 46.5, 85.1] in the 16-mg cohort and 73.1% [95% CI: 52.2, 88.4] pts in the 30-mg cohort. Overall, 8 pts in each cohort (32.0% in 16-mg and 30.8% in 30-mg) had an sUA ≥ 6 mg/dL after achieving sUA < 6 mg/dL from first infusion until Week 24, with median time (Q1, Q3) to this event of 50.5 (11.5, 86.5) and 22.5 (18.5,82.0) days. Of the 36 pts who continued into the extension period, 88.2% (15/17) and 68.4% (13/19) were sUA responders during Month 12 in the 16-mg and 30-mg cohorts. The median proportion of time pts sustained sUA < 6 mg/dL was 100% from Day 1 to Week 24 or Day 1 to Week 48 for both cohorts. The IR rate including anaphylaxis at Week 48 treatment period was 16.0% in the 16-mg cohort and 11.5% in the 30-mg cohort. No IRs occurred after Week 24 consistent with MIRROR RCT (pegloticase Q2W dosing with MTX coadminstration). Pegloticase standard stopping rule (sUA > 6 mg/dL at 2 consecutive visits) was not implemented until enrollment was complete in the 16-mg cohort. Also, 1 pt in the 30-mg cohort with IR was dosed despite meeting this rule. If the discontinuation criteria had been properly applied, the IR rate would be ~8% in both groups. Major adverse cardiac events (MACE; edema, peripheral edema, transient ischemic attack) identified by standardized MedDRA query (SMQ) search occurred in 8.0% and 3.8% of pts, respectively (Table 1); however, upon further review, these were not considered by the Sponsor to be MACE. <h3>Conclusion:</h3> These data demonstrate the feasibility of Q4W increased-dose pegloticase while maintaining safety and efficacy comparable to pegloticase 8 mg Q2W in MIRROR RCT. PK analysis is underway to choose the appropriate dose for the phase 3 confirmatory trial. <h3>REFERENCES:</h3> [1] Botson JK et al. <i>Arthritis Rheumatol</i> 2023;75:293-304. [2] Troum O, et al. [Abstract]. <i>Arthritis Rheumatol.</i> 2024;76(suppl 9). Figure 1Study Schema of FORWARD OL Study Table 1Primary and secondary endpoints and safety dataPegloticase 16 mg Q4W + MTX(n = 25)Pegloticase 30 mg Q4W + MTX(n = 26)Primary/Secondary Efficacy Endpoints (ITT Analysis Set*)Month 6 sUA respondersResponder, n (%)17 (68.0)19 (73.1)95% CI (Clopper-Pearson exact method)(46.5, 85.1)(52.2, 88.4)Time to first sUA ≥ 6 mg/dL after first achieving sUA <6 mg/dL from the first pegloticase infusion until Week 24Median time for patients with events (Q1, Q3), days50.5 (11.5, 86.5)22.5 (18.5,82.0)Kaplan-Meier estimate median time (95% CI)NE (98.00,NE)NE (100, NE)TEAEs (Safety Analysis Set**), n (%)Any TEAEs20 (80.0)22 (84.6)Related to MTX5 (20.0)3 (11.5)Related to pegloticase11 (44.0)8 (69.2)Rheumatology CTC Grade ≥3 TEAEs4 (16.0)0Serious TEAEs3 (12.0)0TEAEs of special interestIR or anaphylaxis^†4 (16.0)3 (11.5)MACE by SMQ (edema, peripheral edema, transient ischemic attack)^‡2 (8.0)1 (3.8)Gout Flares18 (72.0)20 (76.9)ITT, intent-to-treat; NE, non-evaluable; MACE, major adverse cardiac events; sUA, serum urate; TEAE, treatment-emergent adverse events; SMQ, standardized MedDRA query*At least one scheduled assessment on Day 1**≥1 dose of pegloticase+MTX† 1 patient with anaphylaxis in 16-mg cohort; none in 30-mg.‡ Not considered MACE by the Sponsor. <h3>Acknowledgements:</h3> This study was funded by Amgen, Inc. Medical writing and editing support provided by Swati Ghatpande, PhD, employee of and stockholder in Amgen, Inc. <h3>Disclosure of Interests:</h3> Orrin Troum AbbVie, Amgen, Horizon (now Amgen, Inc.), Novartis, Pfizer Inc, Sanofi-Genzyme, 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 AbbVie, Amgen, Horizon (now Amgen, Inc.), Lilly, and Novartis, Compensation for intellectual property from Horizon, Study site/principal investigator research grants: from Horizon (now Amgen, Inc.), Allena, Olatec, and Radius Health. Compensation for intellectual property from Horizon, Fang Fang Amgen Inc., Amgen Inc., Katie Obermeyer Amgen Inc., Amgen Inc., Afroz Mohammad 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.