Purpose

To determine whether emixustat hydrochloride (emixustat) reduces the rate of enlargement of geographic atrophy (GA) compared with placebo in subjects with age-related macular degeneration (AMD) and to evaluate the safety and tolerability of emixustat over 24 months of treatment.

Design

Multicenter, randomized, double-masked, placebo-controlled, phase 2b/3 clinical trial.

Participants

Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.25 to 18 mm² were enrolled.

Methods

Subjects were randomized (1:1:1:1) to emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for 24 months. Visits included screening, baseline, and months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, and 25.

Main Outcome Measures

The primary efficacy end point was the mean annual growth rate of total GA area in the study eye, as measured by a central reading center using fundus autofluorescence (FAF) images. The change from baseline in normal luminance best-corrected visual acuity (NL-BCVA) was a secondary efficacy end point.

Results

Of 508 randomized subjects, 320 completed the study. Demographics and baseline characteristics were comparable between treatment groups. On average, GA lesions in the study eye grew at a similar rate in each group (emixustat: 1.69 to 1.84 mm²/year; placebo: 1.69 mm²/year; P ≥ 0.81). Changes in NL-BCVA were also comparable between groups. Subjects with a larger low luminance deficit (LLD) at baseline (≥20 letters) demonstrated a more rapid growth of GA over 24 months. No relationship was observed between the risk-allele status of the AMD-associated single-nucleotide polymorphisms tested and the growth rate of GA. The most common adverse events in emixustat-treated subjects were delayed dark adaptation (55%), chromatopsia (18%), visual impairment (15%), and erythropsia (15%).

Conclusions

Emixustat did not reduce the growth rate of GA in AMD. The most common adverse events were ocular in nature and likely related to the drug’s mechanism of action. Data gained from this study over a 2-year period add to the understanding of the natural history of GA and the baseline characteristics affecting the growth rate of GA.

中文翻译：

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依米司他盐酸盐用于继发于年龄相关性黄斑变性的地理萎缩 ：一项随机临床试验

目的

为了确定与年龄相关性黄斑变性（AMD）的受试者相比，安慰剂盐酸盐（emixustat）与安慰剂相比是否能降低地理萎缩（GA）的扩大率，并评估emixustat在治疗24个月内的安全性和耐受性。

设计

多中心，随机，双掩蔽，安慰剂对照的2b / 3期临床试验。

参加者

继发于AMD的GA，视敏度得分至少为35个字母以及总面积为1.25至18 mm ^2的GA患者。

方法

受试者被随机分配（1：1：1：1）接受emixustat 2.5 mg，5 mg，10 mg或安慰剂治疗，每天口服一次，持续24个月。随访包括筛查，基线和第1、2、3、6、9、12、15、18、21、24和25个月。

主要观察指标

主要功效终点是研究眼中总GA面积的年均增长率，这是由中央阅读中心使用眼底自发荧光（FAF）图像测得的。次要功效终点是正常亮度最佳矫正视力（NL-BCVA）相对于基线的变化。

结果

在508名随机受试者中，有320名完成了研究。治疗组之间的人口统计学和基线特征相当。平均而言，每组研究眼中的GA病变以相似的速度增长（混血抑制剂：1.69至1.84 mm ² /年；安慰剂：1.69 mm ² /年；P≥0.81）。两组之间NL-BCVA的变化也相当。在基线（≥20个字母）处具有较大的低亮度不足（LLD）的受试者表现出24个月内GA的增长更快。测试的与AMD相关的单核苷酸多态性的风险等位基因状态与GA的增长率之间没有关系。在接受emixustat治疗的受试者中，最常见的不良事件是延迟暗适应（55％），色盲（18％），视力障碍（15％）和红血球（15％）。

结论

Emixustat并没有降低AMD中GA的增长率。最常见的不良事件本质上是眼部的，可能与药物的作用机制有关。从这项研究中获得的为期2年的数据增加了对GA的自然历史以及影响GA增长率的基线特征的了解。