Pearlman Joel A, Sheth Veeral S, Khanani Arshad M, Indjeian Vahan B, Brunstein Flavia, Kuruvilla Denison, Maia Mauricio, Dere Randall, Ma Ling, Chen Hao, Datta Seema, Willis Jeffrey R, Wiley Henry E
Retinal Consultants Medical Group, Sacramento, California.
University Retina and Macula Associates, Lemont, Illinois.
Ophthalmol Sci. 2025 Apr 20;5(5):100800. doi: 10.1016/j.xops.2025.100800. eCollection 2025 Sep-Oct.
Interleukin (IL) 33 is a potent proinflammatory cytokine and a potential target in age-related macular degeneration (AMD) pathophysiology. This study evaluated RO7303359, an anti-IL-33 fragment antigen-binding region (Fab) targeting the IL-33/serum stimulation-2 (ST2) pathway, in patients with geographic atrophy (GA) secondary to AMD.
Phase I, open-label, multicenter, single-dose, dose-escalation study.
Patients with GA secondary to AMD.
Patients received a single intravitreal (IVT) injection of RO7303359 (dose range, 1-20 mg).
The primary objective was to evaluate the safety and tolerability of RO7303359. The secondary objectives included assessing pharmacokinetics (PK), immune response, and pharmacodynamic (PD) biomarker activity. Pharmacodynamic biomarkers assessed in aqueous humor included CC motif chemokine ligand 2, CXC motif chemokine ligand 10, IL-6, and intercellular adhesion molecule 1.
Thirty-seven patients enrolled in the dose cohorts. Single IVT doses of RO7303359 demonstrated an acceptable safety profile up to 20 mg, with mild ocular adverse events reported. Pharmacokinetics analysis revealed dose-proportional exposure within expected ranges for an IVT-administered Fab. No treatment-emergent antidrug antibodies were observed. Evaluation of changes in aqueous humor PD biomarker levels failed to demonstrate a discernible effect on IL-33/ST2 pathway activity.
In this trial (ClinicalTrials.gov identifier, NCT04615325), while RO7303359 exhibited acceptable safety and PK profiles, absence of demonstrable effects on the IL-33/ST2 pathway using aqueous PD biomarkers resulted in discontinuation of development in GA. Further work is needed to evaluate the relevance of the IL-33/ST2 pathway in the pathophysiology of AMD.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
白细胞介素（IL）-33是一种强效促炎细胞因子，是年龄相关性黄斑变性（AMD）病理生理学中的一个潜在靶点。本研究评估了RO7303359，一种靶向IL-33/血清刺激因子2（ST2）通路的抗IL-33片段抗原结合区（Fab），用于治疗继发于AMD的地图样萎缩（GA）患者。
I期、开放标签、多中心、单剂量、剂量递增研究。
继发于AMD的GA患者。
患者接受一次玻璃体内（IVT）注射RO7303359（剂量范围为1-20mg）。
主要目的是评估RO7303359的安全性和耐受性。次要目的包括评估药代动力学（PK）、免疫反应和药效学（PD）生物标志物活性。在房水中评估的药效学生物标志物包括CC基序趋化因子配体2、CXC基序趋化因子配体10、IL-6和细胞间黏附分子1。
37名患者入组剂量队列。单次IVT剂量的RO7303359在高达20mg时显示出可接受的安全性，报告了轻度眼部不良事件。药代动力学分析显示，IVT给药的Fab在预期范围内呈剂量比例暴露。未观察到治疗中出现的抗药抗体。房水PD生物标志物水平变化的评估未能证明对IL-33/ST2通路活性有明显影响。
在本试验（ClinicalTrials.gov标识符，NCT04615325）中，虽然RO7303359表现出可接受的安全性和PK特征，但使用房水PD生物标志物对IL-33/ST2通路未显示出明显作用，导致GA治疗开发中断。需要进一步开展工作来评估IL-33/ST2通路在AMD病理生理学中的相关性。
专有或商业披露信息可在本文末尾的脚注和披露中找到。
