A Multicentre, Efficacy and Safety Study of Methotrexate to Increase Response Rates in Patients With Uncontrolled Gout Receiving Pegloticase (MIRROR): 12-Month Efficacy, Safety, Immunogenicity, and Pharmacokinetic Findings of an Open-label Study

Abstract Background: Publications suggest immunomodulation co-therapy improves responder rates in uncontrolled/refractory gout patients undergoing pegloticase treatment. The MIRROR open-label trial showed a 6-month pegloticase+methotrexate co-therapy responder rate of 79%, compared to an established 42% pegloticase monotherapy responder rate. Longer-term efficacy/safety data are presented here.Methods: Uncontrolled gout patients (serum urate [SU]≥6 mg/dL and SU≥6 mg/dL despite urate-lowering therapy [ULT], ULT intolerance, or functionally-limiting tophi) were included. Patients with immunocompromised status, G6PD deficiency, severe kidney disease, or methotrexate contraindication were excluded. Oral methotrexate (15 mg/week) and folic acid (1 mg/day) were administered 4-weeks before and during pegloticase therapy. Twelve-month responder rate (SU<6 mg/dL for ≥80% during Month 12), 52-week change from baseline in SU, and extended safety were examined. Efficacy analyses were performed for patients receiving ≥1 pegloticase infusion. PK/anti-drug antibodies (ADAs) were examined and related to efficacy/safety findings. Results: Fourteen patients were included (all male, 49.3 ± 8.7 years, 13.8 ± 7.4 year gout history, pre-therapy SU: 9.2 ± 2.5 mg/dL). Three patients were non-responders and discontinued study treatment before 24-weeks, one patient exited the study per-protocol at 24-weeks (enrolled prior to treatment extension amendment), and 10 remained in study through Week 52. Of the 10, 8 completed 52-weeks of pegloticase+methotrexate and were 12-month responders. The remaining two discontinued pegloticase+methotrexate at Week 24 (met treatment goals) and stayed in study under observation (allopurinol prescribed at physicians’ discretion); one remained a responder at 12-months. At 52-weeks, change from baseline in SU was -8.2 ± 4.1 mg/dL (SU: 1.1 ± 2.4 mg/dL, n=10). Gout flares were common early in treatment but progressively decreased while on therapy (Weeks 1-12: 13/14 [92.9%], Weeks 36-52: 2/8 [25.0%]). One patient recovered from sepsis (serious AE). Two non-responders developed high ADA titres; fewer patients had trough concentrations (Cmin) below quantitation limit (BQL) and median Cmin was higher (1.03 mg/mL vs. BQL) than in pegloticase monotherapy trials.Conclusions: Methotrexate+pegloticase co-therapy was well-tolerated over 12-months, with sustained SU lowering, progressive gout flare reduction, and no new safety concerns. Antibody/PK findings suggest methotrexate attenuates ADA formation, coincident with higher treatment response rates.Trial registration: ClinicalTrials.gov: NCT03635957, registered 17 August 2018, https://clinicaltrials.gov/ct2/show/NCT03635957