Safety and Efficacy of Pegloticase and Methotrexate in Gout

Pegloticase (PEGylated uricase) is an excellent option for patients with refractory, uncontrolled, or tophaceous gout. Use of pegloticase is often hindered by development of antidrug antibodies, which are associated with lower rate of urate lowering response and higher risk of infusion reaction.

Mithu Maheswaranathan, MD

Credit: Duke Health

The MIRROR randomized controlled trial (RCT) compared pegloticase in combination with methotrexate versus placebo (PBO) in terms of efficacy and safety, finding pegloticase plus methotrexate (MTX) 15mg weekly resulted in significantly higher rate of sustained urate-lowering response through month 6 of treatment (71% vs 38.5%, respectively). Additionally, patients on pegloticase/MTX combination therapy had a lower rate of infusion reaction (2.4% vs 30.6%) than patients receiving pegloticase monotherapy.¹

A recent phase 4 randomized, double-blinded, PBO-controlled study provided an update on longitudinal safety and efficacy data as a follow-up to the MIRROR RCT.² Patients received pegloticase 8 mg intravenous infusion every 2 weeks and were randomized 2:1 to receive pegloticase with blinded methotrexate (15 mg weekly) or PBO for a total of 1 year. Adult patients with uncontrolled gout, defined as serum uric acid level (sUA) ≥7 mg/dL, oral urate-lowering therapy failure or intolerance, and at least 1 ongoing gout symptom (1 or more tophi, 2 or more flares in the year prior to screening, and/or chronic gouty arthritis) were enrolled.Patients with methotrexate contraindication or intolerance were among those excluded from this trial.

The trial’s primary efficacy endpoint evaluated proportion of treatment responders through month 6 (sUA <6 mg/dL for at least 80% of weeks 20 – 24). Secondary endpoints included proportion of treatment responders during month 12 (sUA <6 mg/dl for at least 80% of weeks 48 – 52) and the proportion of patients with detectable tophi at baseline with complete resolution of ≥1 tophi at week 52.

They also measured pegloticase serum concentrations and anti-drug antibodies. Treatment safety and tolerability were assessed, and tophi were photographed and classified as measurable or unmeasurable. “Complete response” was defined as 100% tophus area reduction in measurable tophi and unmeasurable tophi no longer visible.

The study included 152 patients who were predominantly male (89%) and White (69%). The study found significantly more patients in the MTX group, vs PBO, having sustained lowering of urate levels during month 6 (71% vs 38.5%; P <.0001). This response rate was significantly higher in patients cotreated with methotrexate vs PBO by month 12 (60% vs 30.8%). Fewer patients on methotrexate met the serum urate discontinuation criteria vs PBO (22.9% vs 63.3%; P <.001).

Additionally, a higher proportion of patients on MTX (vs PBO) had complete resolution of one or more tophi (53.8% vs 31%; P = .048). When evaluating immunogenicity, they found a higher proportion of PBO patients did not have “evaluable” pegloticase concentrations; the MTX group had higher pegloticase serum concentrations and lower immunogenicity. There was a higher proportion of new anti-PEG antibodies in the placebo group compared to the methotrexate group (58.3% vs 31.6%), and development of new anti-PEG antibodies was associated with lower treatment response rate and higher rate of infusion reactions. Of note, no infusion reactions were observed after week 24 in either treatment group.

Ultimately, this follow-up of the MIRROR RCT demonstrates significant benefits of coadministration of methotrexate with pegloticase, maintaining the initial findings from observations through 6 months. Patients who are cotreated with MTX have higher urate-lowering response rates through month 12 and lower infusion reaction rates (regardless of anti-PEG antibody status).

While optimal duration of pegloticase therapy is unknown, this study provides support for continued therapeutic benefit of pegloticase beyond month 6 and benefits of concomitant methotrexate administration with pegloticase.

References:

1. _{^{Botson JK, Saag K, Peterson J, et al. A randomized, placebocontrolled study of methotrexate to increase response rates in patients with uncontrolled gout receiving pegloticase: primary efficacy and safety findings. Arthritis Rheumatol 2023;75:293–304}}
2. _{^{Gorter A, Bakker MM, Ten Klooster PM. The impact of health literacy: associations with disease activity and medication prescription in patients with rheumatoid arthritis. Rheumatology, 2023}}