Kidney Safety Findings in Patients with Uncontrolled Gout Treated with Pegloticase with and Without Methotrexate

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Background: Pegloticase is a PEGylated uricase approved for the treatment of uncontrolled gout. Methotrexate (MTX) coadministered with pegloticase attenuates anti-drug antibody formation, leading to higher response rates and markedly reduced infusion reaction risk compared with pegloticase+placebo (PBO). MTX is cleared via the kidneys, limiting its use in patients (pts) with CKD. Also, pts with uncontrolled gout have a high comorbidity burden (CVD, CKD). We report the renal safety findings of MTX in pts enrolled in the pivotal MIRROR RCT. Methods: Pts (N=152) with uncontrolled gout (SU ≥7 mg/dL, oral ULT failure/intolerance, and tophi, ≥2 flares/yr, and/or gouty arthritis) received up to 52 wks of pegloticase (8 mg infusion Q2W) with either 15 mg oral MTX/wk or PBO and 1mg folic acid daily; pts with eGFR <40 ml/min/1.73 m2 were excluded. First infusion (Day 1) occurred after a 2-wk MTX tolerance period (Wk -6 to Wk -4) and a 4-wk MTX/PBO run-in (Wk -4 to Day 1). Baseline (BL) was prior to MTX exposure (Wk -6). Albuminuria was graded based on urine albumin-creatinine ratio (UACR) values (A1: <30 mg/g, A2: 30–299 mg/g, A3: ≥300 mg/g). We report safety data from on-treatment pts receiving ≥1 pegloticase dose. Results: While pts with eGFR < 40 ml/min/1.73m2 were excluded, the distribution of pts with BL stage 3 CKD (eGFR<60) were similar in MTX and PBO groups (33.3% vs 30.8%). During the 52-wk tx period, renal function was stable in both groups (Wk 52 eGFR change from BL: MTX: +4.6±1.4 [n=58], PBO: +1.1±4.2 [n=16]). CKD stage remained stable or improved in most pts (MTX: 93.1% [n=58], PBO: 93.8% [n=16]). Albuminuria grade was not negatively impacted by MTX (grade improvement [MTX: 10.9% vs PBO: 12.5%] or stable [83.6% vs 81.3%]). MTX-associated adverse events (GI disorders, skin disorders, infections) were similar between the 2 groups. More pts in the MTX vs PBO group had transient ALT levels >ULN (13.6% vs 6.3%; no >2 x ULN or above in either group), but ALT and AST levels remained stable from BL to Wk 52. Mild hematological AEs (Grade 1 leukopenia and Grade 2 anemia) occurred in 1 pt in the MTX group (none in PBO group). Conclusion: MTX safety data from MIRROR RCT indicate that low-dose MTX was generally well tolerated among uncontrolled gout pts with no observed adverse impact on renal function. Funding: Commercial Support - Amgen, Inc.

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