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Objective To examine the efficacy and safety of pegloticase in combination with methotrexate in patients with uncontrolled gout in an exploratory, open-label clinical trial (NCT03635957) prior to a randomized, controlled trial. Methods A multicenter, open-label, efficacy and safety study of pegloticase with methotrexate cotreatment was conducted in patients with uncontrolled gout. Patients were administered oral methotrexate (15 mg/week) and folic acid (1 mg/day) 4 weeks prior to and throughout pegloticase treatment. The primary study outcome was the proportion of responders, defined as sUA <6 mg/dL for ≥80% of the time during month 6 (weeks 20, 22, and 24). All analyses were performed on a modified intent-to-treat population, defined as patients who received ≥1 pegloticase infusion. Results Seventeen patients were screened and 14 patients (all men, average age: 49.3 ± 8.7 years) were enrolled. On Day 1, mean sUA was 9.2 ± 2.5 mg/dL and 12 of the 14 patients had visible tophi. At the 6 month timepoint, 11/14 (78.6%, 95%CI 49.2-95.3%) met the responder definition, with 3 patients discontinuing after meeting protocol-defined treatment discontinuation rules (pre-infusion sUA values greater than 6 mg/dL at 2 consecutive scheduled visits). All patients tolerated methotrexate. No new safety concerns were identified. Conclusion In this study, an increased proportion of patients maintained therapeutic response at 6 months when treated concomitantly with methotrexate and pegloticase when compared to the previously reported 42% using pegloticase alone. These results support the need for a randomized study of methotrexate or placebo with pegloticase to validate these open label findings.

Objective To assess efficacy, safety, pharmacokinetics, and immunogenicity of pegloticase plus methotrexate (MTX) versus pegloticase plus placebo cotreatment for uncontrolled gout in a randomized, placebo‐controlled, double‐blind trial. Methods This study included adults with uncontrolled gout, defined as serum urate ≥7 mg/dl, oral urate‐lowering therapy failure or intolerance, and presence of ongoing gout symptoms including ≥1 tophus, ≥2 flares in the past 12 months, or gouty arthritis. Key exclusion criteria included MTX contraindication, current immunosuppressant use, G6PDH deficiency, and estimated glomerular filtration rate <40 ml/minute/1.73 m2. Patients were randomized 2:1 to 52 weeks of pegloticase (8 mg biweekly) with either oral MTX (15 mg/week) or placebo. The primary end point was the proportion of treatment responders during month 6 (defined as serum urate <6 mg/dl for ≥80% of visits during weeks 20–24). Efficacy was evaluated in all randomized patients (intent‐to‐treat population), and safety was evaluated in all patients receiving ≥1 blinded MTX or placebo dose. Results A total of 152 patients were randomized, 100 to receive pegloticase plus MTX, 52 to receive pegloticase plus placebo. Significantly higher treatment response occurred during month 6 in the MTX group versus the placebo group (71.0% [71 of 100 patients] versus 38.5% [20 of 52 patients], respectively; between‐group difference 32.3% [95% confidence interval 16.3%, 48.3%]) (P < 0.0001 for between‐group difference). During the first 6 months of pegloticase plus MTX or pegloticase plus placebo treatment, 78 (81.3%) of 96 MTX patients versus 47 (95.9%) of 49 placebo patients experienced ≥1 adverse event (AE), most commonly gout flare (64 [66.7%] of 96 MTX patients and 34 [69.4%] of 49 placebo patients). Reports of AEs and serious AEs were comparable between groups, but the infusion reaction rate was considerably lower with MTX cotherapy (4.2% [4 of 96 MTX patients, including 1 patient who had anaphylaxis]) than with placebo cotherapy (30.6% [15 of 49 placebo patients, 0 who had anaphylaxis]) (P < 0.001). Antidrug antibody positivity was also lower in the MTX group. Conclusion MTX cotherapy markedly increased pegloticase response rate over placebo (71.0% versus 38.5%) during month 6 with no new safety signals. These findings verify higher treatment response rate, lower infusion reaction incidence, and lower immunogenicity when pegloticase is coadministered with MTX.

OBJECTIVETo compare fenofibric acid (FA) + statin to respective monotherapies on the prevalence of metabolic syndrome and its diagnostic components in patients with mixed dyslipidemia.RESEARCH DESIGN AND METHODSPost hoc analysis of over 2,000 metabolic syndrome patients administered either FA + low- or moderate-dose statin; FA alone; or low-, moderate-, or high-dose statin alone.RESULTSFA + low- or moderate-dose statin combination therapy reduced the presence of metabolic syndrome (35.7 or 35.9%, respectively) more than low-, moderate-, or high-dose statin monotherapy (15.5, 16.6, or 13.8%, respectively), mostly due to improvements in triglycerides and HDL cholesterol levels. Mean glucose levels slightly decreased with FA monotherapy, slightly increased with statin monotherapy, and were essentially unchanged with FA + statin. FA with or without statin also reduced non-HDL cholesterol, apolipoprotein B, total cholesterol, VLDL cholesterol, and high-sensitivity C-reactive protein.CONCLUSIONSFA + statin in patients with mixed dyslipidemia reduces the prevalence of metabolic syndrome.

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