Background/Purpose: The MIRROR RCT trial examined pegloticase (PEGylated uricase) safety and efficacy with methotrexate (MTX) vs placebo (PBO) as co-therapy. Sustained urate-lowering rate during Month 6 (primary endpoint) was significantly higher in the MTX vs PBO group (71.0% vs 38.5%) with lower infusion reaction (IR) rate (4.2% vs 30.6%) and otherwise similar safety profile.¹ Both findings were related to higher pegloticase exposure and lower anti-PEG antibody incidence in the MTX group.² Here we report MIRROR RCT findings through treatment Month 12.

Methods: Pegloticase efficacy, safety, pharmacokinetics (PK), and immunogenicity were examined when blinded MTX (oral 15 mg/wk) or PBO was given as co-therapy to pegloticase (8 mg biweekly infusion) for 52 wks in uncontrolled gout patients (pts; serum uric acid [sUA]≥7 mg/dL, ULT failure/intolerance, ≥1 gout symptom [1 tophus, ≥2 flares in 12 months, gouty arthropathy]). Key exclusion criteria included MTX contraindication, immunosuppressant use, G6PD deficiency, and eGFR 2. After a 2-wk tolerance test, pts were randomized 2 MTX:1 PBO, initiating blinded MTX/PBO 4 wks before pegloticase infusion 1. Month 12 efficacy endpoints were proportion of responders (sUA < 6 mg/dL for ≥80% of Wks 48-52; intent-to-treat population [ITT], all randomized pts), proportion with resolution of ≥1 tophus (ITT), and time to sUA monitoring discontinuation (2 consecutive pre-infusion sUA >6 mg/dL after Wk 2; modified ITT [mITT], ≥1 pegloticase dose). AEs and lab values were monitored (safety population, ≥1 pegloticase dose).

Results: Response rate during Month 12 was 60.0% (60/100) vs 30.8% (16/52) in the MTX vs PBO group (difference: 29.1% [13.2%, 44.9%], p< 0.001). 22.9% (22/96) of the MTX and 63.3% (31/49) of the PBO group met sUA discontinuation criteria, with median (95% CI) time to discontinuation not estimable (NE, too few discontinuations to estimate) (NE, NE) in MTX pts and 69 days (29, 401) in PBO pts (p < 0.0001). Of pts with tophi at baseline, 53.8% (28/52) vs 31.0% (9/29) had complete resolution of ≥1 tophus at Wk 52 (difference: 22.8% [1.2%, 44.4%], p = 0.048), which was higher than Wk 24 (34.6% [18/52] vs 4/29 [13.8%]). PK and immunogenicity findings were consistent with those thru Month 6,² indicating higher pegloticase exposure and lower immunogenicity in the MTX group. Safety profile was similar between treatment groups, with all IRs occurring within 24 wks. Neither ALT (MTX: +0.6 ± 23.3 U/L, PBO: +2.5±14.4 U/L) nor AST (MTX: +1.5±22.1 U/L, PBO: +1.5 ± 11.0 U/L) meaningfully changed from baseline at Wk 52 and few pts experienced elevated (2xULN) ALT (2 MTX [2.2%], 1 [2.0%] PBO) or AST (4 MTX [4.3%], 1 [2.0%] PBO). eGFR remained stable during treatment (Wk 52 change from baseline MTX: +4.6 ± 10.8 ml/min/1.73m², PBO: +1.1 ± 16.6 ml/min/1.73m²).

Conclusion: MIRROR RCT 12-month safety and efficacy further support MTX as co-therapy to pegloticase and showed no IRs after treatment Month 6. The proportion of pts with tophus resolution was higher at Wk 52 than Wk 24, suggesting continued therapeutic benefit beyond Month 6 in some pts.

References
1. Botson J et al. Ann Rheum Dis 2022;81 (Suppl 1):112
2. Xin Y et al. Ann Rheum Dis 2022;81 (Suppl 1):910

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/12-month-findings-of-the-randomized-double-blind-placebo-controlled-multicenter-efficacy-and-safety-study-of-methotrexate-to-increase-response-rates-in-patients-with-uncontrolled-gout-receiving-pe/