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 during long-term extension 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. Pharmacokinetics (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 the 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 the 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 titers; fewer patients had trough concentrations (C_min) below the quantitation limit (BQL), and the median C_min was higher (1.03 µg/mL vs. BQL) than pegloticase monotherapy trials.

Conclusions: Pegloticase + methotrexate 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 on 17 August 2018.

Keywords: Gout; Methotrexate; Pegloticase; Tophi.

Fig. 1

Pre-infusion serum urate levels during the methotrexate run-in (4 weeks) and pegloticase + methotrexate treatment (up to 52 weeks) periods. In the 3 non-responders, serum urate (SU) increases above 6 mg/dL were noted at weeks 2 and 4, weeks 4 and 6, and weeks 8 and 10. Data points represent the mean values, and error bars represent standard error (includes patients on treatment, values below the lower limit of detection were set to 0). SU, serum urate

Fig. 2

Comparison of pegloticase exposure with methotrexate co-treatment in the current study (MIRROR OL) and as monotherapy in prior phase 3 trials. Blue circles represent responders, and red circles represent non-responders. The gray dotted line shows the limit of quantitation (LOQ) of pegloticase measurements (0.6 µg/mL). Data below LOQ (BQL) were imputed as 0.3 µg/mL

Fig. 3

Comparison of observed pegloticase concentrations in the current study (MIRROR OL, pegloticase + methotrexate co-therapy) and in a simulated PK profile of prior phase 3 trials (pegloticase monotherapy). Circles represent the observed data in MIRROR OL with non-responders in red and responders in blue. Simulated monotherapy pegloticase concentration over time is shown as the median concentration (black line) with 90% confidence intervals (gray-shaded area). The simulation was modeled using the time elapsed from the start of each infusion, pooling data from all 12 infusions administered to phase 3 pivotal trial participants. Values below the limit of quantitation were imputed as 0.3 μg/ml (dotted line)

Fig. 4

Proportion of patients on treatment experiencing gout flares during the pegloticase + methotrexate treatment period. The mean number of flares during weeks 0–12 and weeks 37–52 was 4.2 ± 2.3 (range 1 − 8) and 2.5 ± 0.7 (range 2 − 3), respectively

Fig. 5

Liver a, b and renal function c test results through the run-in (weeks − 4 to 0) and treatment (weeks 0 to 52) periods. Week − 4 values were measured prior to methotrexate exposure. Week 0 (day 1) values were measured prior to pegloticase exposure. The number of patients with liver function tests above the upper limits of normal and estimated glomerular filtration rate < 60 mL/min/1.73 m.² are also shown d. Error bars represent the standard deviation. ALT, alanine aminotransferase; AST, aspartate aminotransferase; eGFR, estimated glomerular filtration rate (calculated from serum creatinine measurements using the MDRD equation)