An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis
An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis
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DOI：
10.1002/hep.31046
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发表时间：
2020-04-27
期刊：
影响因子：
13.5
通讯作者：
Shah, Vijay H.
中科院分区：
文献类型：
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作者：
Arab, Juan P.;Sehrawat, Tejasav S.;Shah, Vijay H.
背景和目的白细胞介素-22对酒精相关性肝炎（AH）的炎症和肝再生受损具有有益作用。F-652是人白细胞介素-22和免疫球蛋白G2结晶片段的重组融合蛋白。本研究旨在评估F-652在中度和重度AH患者中的安全性和有效性信号。方法和结果进行了2期剂量递增研究。在第1天和第7天给药的F-652（10 μ g/kg、30 μ g/kg或45 μ g/kg）在3名中度（终末期肝病模型[MELD]评分：11-20）和重度AH（MELD评分：21-28）患者中进行了测试。安全性定义为无严重不良事件，疗效通过第28天和第42天的里尔评分、MELD评分变化以及血清胆红素和转氨酶进行评估。使用了三个独立的倾向匹配的对照患者队列。测量血浆细胞外囊泡和多种血清细胞因子以评估炎症和肝再生。入组了18例患者（9例中度和9例重度AH），66%为男性，平均年龄为48岁。首次给药后F-652的半衰期为61-85小时。未发生导致停药的严重不良事件。MELD评分和血清转氨酶在治疗后第28天和第42天较治疗前显著下降（P < 0.05）。第7天里尔评分≤ 0.45的患者比例为83%，而对照队列分别为6%、12%和56%。细胞外囊泡计数在第28天显著减少（P < 0.013）。在第28天和第42天，细胞因子炎症标记物下调，再生标记物上调。结论F-652在剂量高达45 μ g/kg时是安全的，并且与由里尔和MELD评分确定的高改善率相关，炎症标记物减少，肝再生标记物增加。这项研究支持需要进行随机安慰剂对照试验来测试F-652在AH中的疗效。
BACKGROUND AND AIMS Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH.APPROACH AND RESULTS A phase-2 dose-escalating study was carried out. F-652 (10 mu g/kg, 30 mu g/kg, or 45 mu g/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42.CONCLUSIONS F-652 is safe in doses up to 45 mu g/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.