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. 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. 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 (Cmin) below the quantitation limit (BQL), and the median Cmin was higher (1.03 µg/mL vs. BQL) than pegloticase monotherapy trials. 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. ClinicalTrials.gov, NCT03635957 . Registered on 17 August 2018.

中文翻译：

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甲氨蝶呤提高接受聚乙二醇化酶治疗的未受控制的痛风患者的缓解率的多中心疗效和安全性研究 (MIRROR)：开放标签研究长期扩展期间的 12 个月疗效、安全性、免疫原性和药代动力学结果


出版物表明，免疫调节联合疗法可提高接受聚乙二醇化酶治疗的不受控制/难治性痛风患者的反应率。 MIRROR 开放标签试验显示，6 个月聚乙二醇化酶 + 甲氨蝶呤联合治疗的反应率为 79%，而已确定的聚乙二醇化酶单药治疗的反应率为 42%。此处提供了长期疗效/安全性数据。未控制的痛风患者（尽管进行降尿酸治疗[ULT]、ULT 不耐受或功能限制性痛风石，血清尿酸 [SU] ≥ 6 mg/dL 且 SU ≥ 6 mg/dL）被纳入。免疫功能低下、G6PD 缺乏、严重肾脏疾病或有甲氨蝶呤禁忌症的患者被排除在外。聚乙二醇化酶治疗前 4 周和治疗期间口服甲氨蝶呤（15 毫克/周）和叶酸（1 毫克/天）。检查了 12 个月的应答率（第 12 个月期间 SU < 6 mg/dL，≥ 80%）、SU 相对于基线的 52 周变化以及扩展安全性。对接受 ≥ 1 次聚乙二醇酶输注的患者进行了疗效分析。检查药代动力学 (PK)/抗药物抗体 (ADA) 并将其与功效/安全性结果相关。纳入 14 名患者（均为男性，49.3 ± 8.7 岁，13.8 ± 7.4 年痛风病史，治疗前 SU 9.2 ± 2.5 mg/dL）。 3 名患者无反应并在 24 周前停止研究治疗，1 名患者在 24 周时按照方案退出研究（在治疗延长修订之前入组），10 名患者在第 52 周仍留在研究中。在这 10 名患者中，8 名完成了 52聚乙二醇化酶 + 甲氨蝶呤治疗数周，并且是 12 个月的反应者。 其余两名患者在第 24 周时停用聚乙二醇化酶 + 甲氨蝶呤（达到治疗目标）并留在研究中接受观察（由医生酌情开出别嘌呤醇）；其中一名患者在 12 个月后仍然是有反应者。第 52 周时，SU 相对于基线的变化为 − 8.2 ± 4.1 mg/dL（SU 1.1 ± 2.4 mg/dL，n = 10）。痛风发作在治疗早期很常见，但在治疗期间逐渐减少（第 1-12 周，13/14 [92.9%]；第 36-52 周，2/8 [25.0%]）。一名患者从败血症（严重 AE）中康复。两名无反应者出现了高 ADA 滴度；与聚乙二醇化酶单药治疗试验相比，谷浓度 (Cmin) 低于定量限 (BQL) 的患者较少，且中位 Cmin 较高（1.03 µg/mL 与 BQL）。聚乙二醇化酶 + 甲氨蝶呤联合疗法在 12 个月内具有良好的耐受性，SU 持续降低，痛风发作逐渐减少，并且没有新的安全问题。抗体/PK 研究结果表明，甲氨蝶呤可减弱 ADA 的形成，同时治疗反应率较高。 ClinicalTrials.gov，NCT03635957。注册日期：2018 年 8 月 17 日。