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
Orrin Troum (1), John K. Botson (2), Fang Fang (3), Katie Obermeyer (3), Afroz S. Mohammad (3), Supra Verma (3), Brian Lamoreaux 3)
Affiliation(s):
1. Division of Rheumatology, University of Southern California Keck School of Medicine, and Providence Saint John’s Health Center, Santa Monica, CA, USA
2. Orthopedic Physicians Alaska, Anchorage, AK
3. Amgen, Inc., Thousand Oaks, CA
Introduction: 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 infusion regimen administered every 2 weeks for >2 hours can be burdensome on pts. Decreasing the frequency of pegloticase to a single monthly (Q4W) IV dose will further improve treatment logistics, adherence and efficiency. Here, we report safety and efficacy of 2 pegloticase doses (16 and 30 mg) infused Q4W up to 6 months with MTX coadministration.
Methods: 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 through Week 24 (6 infusions). Approximately 10-20 pts per dose cohort were planned. Pts were enrolled into the 16-mg cohort, and following initial safety review, the 30-mg cohort enrollment was initiated. Pts who remained on treatment through Week 24 could continue into the optional extension period through Week 48 (up to 12 infusions), (Figure). 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. Key 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, and pegloticase immunogenicity.
Results: Of the 51 pts who received treatment, 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 was achieved in 68.0% [95% CI: 46.5, 85.1] in the 16-mg cohort and 73.1% [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. 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% at Week 24 and 48 for both cohorts. The IR rate including anaphylaxis at Week 48 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 coadministration). Major adverse cardiac events identified by standardized MedDRA query (SMQ) search occurred in 8.0% and 3.8% of pts, respectively (Table).
Conclusion: 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 analyses are underway to choose the appropriate dose for the phase 3 confirmatory trial.
References:
1. Botson JK et al. Arthritis Rheumatol 2023;75:293-304.
Disclosures
O.M. Troum has received consultant fees from AbbVie, Amgen, Bristol-Myers Squibb, Horizon,* Lilly, and Pfizer; speaker fees from AbbVie, Amgen, Horizon,* Novartis, Pfizer Inc, Sanofi-Genzyme; and research support from AbbVie, Amgen, Bristol Myers Squibb, CorEvitas, Horizon,* Novartis, and Sanofi-Genzyme. J.K. Botson has received research support (study site/principal investigator) from Horizon,* Allena, Olatec, and Radius Health, consulting/speaker fees from AbbVie, Amgen, Horizon,* Lilly, and Novartis, and compensation for intellectual property from Horizon.* F. Fang, K. Obermeyer, A.S. Mohammad, S. Verma, and B. LaMoreaux are employees of and stockholders in Amgen, Inc.
*now Amgen, Inc.
