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Results were based on the phase 4 MIRROR trial, which analyzed differences in treatment response for concomitant therapy compared with placebo in adults with uncontrolled gout.
At month 6, patients with gout receiving pegloticase (KRYSTEXXA) injection plus methotrexate had a 32% increase in response rate when compared with placebo. Results also confirm significantly lower infusion-related reactions incidence, an increase in complete resolution of 1 or more tophus, and lower immunogenicity, according to a study published in Arthritis & Rheumatology.1
“The publication of this data coupled with the recently expanded labeling provides clinicians the opportunity to evolve how we care for patients with uncontrolled gout,” said Suneet Grewal, MD, co-author and rheumatologist at East Bay Rheumatology Medical Group, Inc., in a statement. “Our patients often live with the impact of uncontrolled gout for 10 to 15 years before seeing a specialist. They have significant comorbidities like hypertension and chronic kidney disease, as well as inflammation and damage from urate crystals formed because of chronically elevated uric acid levels. These insights should encourage more clinicians to focus on care that rapidly reduces the urate burden and will change the course of disease for more patients.”
In July 2022, the US Food and Drug Administration (FDA) expanded labeling of pegloticase co-administered with methotrexate based on results of the phase 4, multicenter, randomized, double-blind, placebo-controlled, parallel-group MIRROR trial, which analyzed differences in treatment response for concomitant therapy compared with placebo in adults with uncontrolled gout.
Patients were randomized 2:1 for 52-weeks to receive pegloticase (8 mg biweekly) and oral folic acid (1 mg/day) with either oral methotrexate (15 mg/week) or placebo. The primary endpoint was the proportion of serum uric acid (sUA) responders (as defined by sUA <6 mg/dL 80% or more of the time during month 6).
Of the 152 patients included in the trial, 100 received pegloticase plus methotrexate and 52 were placed in the pegloticase plus placebo cohort. Most patients (n = 135) were male, White (n = 105, 69.1%), and had tophi (n = 115, 75.7%) with a mean age of 54.7 years and disease duration of 13.9 years. All patients reported 1 or more gout flares within the last 12 months. A significantly higher treatment response was reported at month 6 in those receiving methotrexate (n = 71, 71%) when compared with placebo (n = 20, 38.5%; [95%CI: 16.3−48.3%], p<0.0001).
Most patients experienced 1 or more adverse events (AE) in both the pegloticase plus methotrexate group (n = 78/96, 81.3%) and the pegloticase plus placebo cohort (n = 47/49, 95.9%). AEs were similar between both groups, with the most common being gout flare (66.7% vs 69.4%, respectively). However, infusion reaction (IR) rate was significantly lower in those receiving methotrexate co-therapy (4.2%) when compared with the placebo group (30.6%, p<0.001). Anti-drug antibody positivity showed similar trends. Serious AEs were comparable between the groups (8.3% in the methotrexate cohort and 10.2% in the placebo cohort).
SU management post pegloticase treatment was not evaluated and investigators did not address the pegloticase treatment duration in patients who had intolerance to xanthine oxidase inhibitors, which limited the study. Although methotrexate should be avoided in patients with an estimated glomerular filtration rate (eGFR) <30 ml/min, up to half of patients with gout have chronic kidney disease (CKD). Future studies of other immunomodulating therapies with pegloticase may be beneficial for patients with advanced CKD. Finally, 6-month results may not be long enough to observe the full therapeutic benefit of co-therapy. However, future analysis at week 52 will provide more details.
“These results confirm superiority of pegloticase plus methotrexate co-therapy to pegloticase monotherapy in terms of both treatment efficacy and safety in uncontrolled gout management,” investigators concluded. “Based on these findings, this trial strongly supports methotrexate co-administration with pegloticase in uncontrolled gout patients.”
Botson JK, Saag K, Peterson J, et al. A Randomized Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled GOut Receiving Pegloticase (MIRROR RCT): Primary Efficacy and Safety Findings [published online ahead of print, 2022 Sep 13]. Arthritis Rheumatol. 2022;10.1002/art.42335. doi:10.1002/art.42335