抗白细胞介素33片段抗原结合区RO7303359在年龄相关性黄斑变性继发地理萎缩中的I期研究

IF 3.2 Q1 OPHTHALMOLOGY

Ophthalmology science Pub Date : 2025-04-20 DOI:10.1016/j.xops.2025.100800

Joel A. Pearlman MD, PhD , Veeral S. Sheth MD, MBA , Arshad M. Khanani MD, MA , Vahan B. Indjeian PhD , Flavia Brunstein MD, PhD , Denison Kuruvilla PhD , Mauricio Maia PhD , Randall Dere , Ling Ma PhD , Hao Chen PhD , Seema Datta PhD , Jeffrey R. Willis MD, PhD , Henry E. Wiley MD

{"title":"抗白细胞介素33片段抗原结合区RO7303359在年龄相关性黄斑变性继发地理萎缩中的I期研究","authors":"Joel A. Pearlman MD, PhD , Veeral S. Sheth MD, MBA , Arshad M. Khanani MD, MA , Vahan B. Indjeian PhD , Flavia Brunstein MD, PhD , Denison Kuruvilla PhD , Mauricio Maia PhD , Randall Dere , Ling Ma PhD , Hao Chen PhD , Seema Datta PhD , Jeffrey R. Willis MD, PhD , Henry E. Wiley MD","doi":"10.1016/j.xops.2025.100800","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Design</h3><div>Phase I, open-label, multicenter, single-dose, dose-escalation study.</div></div><div><h3>Participants</h3><div>Patients with GA secondary to AMD.</div></div><div><h3>Methods</h3><div>Patients received a single intravitreal (IVT) injection of RO7303359 (dose range, 1–20 mg).</div></div><div><h3>Main Outcome Measures</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>In this trial (<span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> 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.</div></div><div><h3>Financial Disclosure(s)</h3><div>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</div></div>","PeriodicalId":74363,"journal":{"name":"Ophthalmology science","volume":"5 5","pages":"Article 100800"},"PeriodicalIF":3.2000,"publicationDate":"2025-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Phase I Study of the Anti-interleukin 33 Fragment Antigen-Binding Region RO7303359 in Geographic Atrophy Secondary to Age-Related Macular Degeneration\",\"authors\":\"Joel A. Pearlman MD, PhD , Veeral S. Sheth MD, MBA , Arshad M. Khanani MD, MA , Vahan B. Indjeian PhD , Flavia Brunstein MD, PhD , Denison Kuruvilla PhD , Mauricio Maia PhD , Randall Dere , Ling Ma PhD , Hao Chen PhD , Seema Datta PhD , Jeffrey R. Willis MD, PhD , Henry E. Wiley MD\",\"doi\":\"10.1016/j.xops.2025.100800\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Purpose</h3><div>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.</div></div><div><h3>Design</h3><div>Phase I, open-label, multicenter, single-dose, dose-escalation study.</div></div><div><h3>Participants</h3><div>Patients with GA secondary to AMD.</div></div><div><h3>Methods</h3><div>Patients received a single intravitreal (IVT) injection of RO7303359 (dose range, 1–20 mg).</div></div><div><h3>Main Outcome Measures</h3><div>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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusions</h3><div>In this trial (<span><span>ClinicalTrials.gov</span><svg><path></path></svg></span> 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.</div></div><div><h3>Financial Disclosure(s)</h3><div>Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</div></div>\",\"PeriodicalId\":74363,\"journal\":{\"name\":\"Ophthalmology science\",\"volume\":\"5 5\",\"pages\":\"Article 100800\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-04-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Ophthalmology science\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2666914525000983\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Ophthalmology science","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2666914525000983","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}

引用次数: 0

摘要

目的：白细胞介素（IL） 33是一种有效的促炎细胞因子，是年龄相关性黄斑变性（AMD）病理生理的潜在靶点。本研究评估了靶向IL-33/血清刺激-2 （ST2）途径的抗IL-33片段抗原结合区（Fab） RO7303359在AMD继发地理萎缩（GA）患者中的作用。I期，开放标签，多中心，单剂量，剂量递增研究。参与者：继发于AMD的GA患者。方法玻璃体内单次注射RO7303359（剂量范围：1 ~ 20mg）。主要结局指标主要目的是评估RO7303359的安全性和耐受性。次要目标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。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和细胞间粘附分子1。结果37例患者入组剂量队列。RO7303359单次IVT剂量高达20mg显示出可接受的安全性，有轻度眼部不良事件报告。药代动力学分析显示，ivt给药的Fab的剂量比例暴露在预期范围内。未观察到治疗后出现的抗药物抗体。对房水PD生物标志物水平变化的评估未能证明其对IL-33/ST2通路活性的明显影响。结论在该试验（ClinicalTrials.gov标识号，NCT04615325）中，RO7303359表现出可接受的安全性和PK谱，但使用水相PD生物标志物对IL-33/ST2通路缺乏明显的影响，导致GA的开发中断。需要进一步的工作来评估IL-33/ST2通路在AMD病理生理中的相关性。财务披露专有或商业披露可在本文末尾的脚注和披露中找到。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Phase I Study of the Anti-interleukin 33 Fragment Antigen-Binding Region RO7303359 in Geographic Atrophy Secondary to Age-Related Macular Degeneration

Purpose

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.

Design

Phase I, open-label, multicenter, single-dose, dose-escalation study.

Participants

Patients with GA secondary to AMD.

Methods

Patients received a single intravitreal (IVT) injection of RO7303359 (dose range, 1–20 mg).

Main Outcome Measures

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.

Results

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.

Conclusions

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.