A Phase I/II Trial for Intravitreous Treatment of Severe Ocular von Hippel-Lindau Disease Using a Combination of the PDGF Antagonist E10030 and the VEGF Antagonist Ranibizumab (16-EI-0159)

目的：Von Hippel-Lindau（VHL）病是一种常染色体显性遗传疾病，其中在肾脏、肾上腺、胰腺、脑、脊髓、眼、内耳、附睾和阔韧带中发生具有特定组织病理学的多种良性和恶性肿瘤和囊肿。这种疾病在美国影响了大约7,000人。视网膜毛细血管瘤（RCH）是最常见的，往往是最早的表现VHL疾病，并可能导致显着的视力丧失。在一些这样的眼睛中，尽管积极治疗，RCH的不可阻挡的进展导致失明和眼球痨。血管内皮生长因子（VEGF）是血管生成和血管通透性的有效介质，其水平已显示在VHL蛋白（pVHL）缺陷的多种细胞类型中升高。 血小板衍生生长因子（PDGF）在血管生成过程中对未成熟新血管的稳定具有重要作用，其在pVHL缺陷细胞系中上调并在其他pVHL缺陷肿瘤中表达。在先前的两项I期研究中，单独抗VEGF治疗对眼部VHL疾病无有益作用。本研究的目的是在患有严重眼部VHL疾病的受试者中研究联合研究性治疗与连续玻璃体内注射E10030（一种PDGF-B拮抗剂）和雷珠单抗（一种VEGF-A拮抗剂）的安全性和可能疗效。 研究人群：患有重度眼部VHL疾病的三名受试者将在一只眼睛中接受联合研究治疗，并将随访104周。 设计图：在这项I/II期、单中心、前瞻性、开放标签、非随机、非对照、单组试验中，合格参与者的一只眼睛将接受研究产品E10030（一种PDGF-B拮抗剂）和雷珠单抗（一种VEGF-A拮抗剂）治疗。受试者将接受联合试验性治疗，包括从基线至基线每四周玻璃体内注射E10030（1.5 mg，0.05 mL）和雷珠单抗（0.5 mg，0.05 mL）， 第16周（共5次治疗），然后每8周一次，直至第48周（自基线起共9次治疗）。所有参与者将被随访104周。 结局指标：本研究的主要结局将是联合研究治疗的安全性，通过至第52周报告的不良事件（AE）表格进行评估。次要结局将包括第104周时的AE列表，以及第52周和第104周时研究眼的以下指标：在没有其他消融治疗的情况下，至少有一个RCH尺寸缩小的受试者比例（通过眼底照相和荧光素血管造影FA评估）;经历中度视力丧失的参与者比例（定义为电子视力伊娃测试较基线损失15个字母）;视力的平均变化; RCH大小变化（通过眼底照相和FA测量）;渗出变化（通过眼底照相、光学相干断层扫描OCT和FA测量）;视网膜前增生、纤维化或视网膜牵拉的变化（通过OCT和眼底摄影评估）;接受RCH消融治疗或眼科手术的受试者比例;成功消融治疗RCH的受试者比例;以及出现一个或多个新RCH的参与者的比例。 于二零二一财政年度，该试验仍处于分析状态。 初步结果的分析已经完成，手稿已经提交并暂时接受出版。 这篇论文发表了。

Objective: Von Hippel-Lindau (VHL) disease is an autosomal dominant heritable disorder in which multiple benign and malignant neoplasms and cysts of specific histopathologies develop in the kidney, adrenal gland, pancreas, brain, spinal cord, eye, inner ear, epididymis and broad ligament. The disease affects about 7,000 individuals in the United States. Retinal capillary hemangiomas (RCH) are the most common and often the earliest manifestation of VHL disease and may lead to significant vision loss. In some such eyes, inexorable progression of RCH leads to blindness and phthisis bulbi despite aggressive treatment. Levels of vascular endothelial growth factor (VEGF), a potent mediator of angiogenesis and vascular permeability, have been shown to be elevated in multiple cell types deficient in the VHL protein (pVHL). Platelet-derived growth factor (PDGF), which has an important role in stabilization of immature new vessels during angiogenesis, is upregulated in pVHL-defective cell lines and expressed in other pVHL-defective tumors. Anti-VEGF therapy alone had no beneficial effect on ocular VHL disease in two previous phase 1 studies. The objective of this study is to investigate the safety and possible efficacy of combination investigational treatment with serial intravitreal injections of E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist, in participants with severe ocular VHL disease. Study Population: Three participants with severe ocular VHL disease will receive the combination investigational treatment in one eye and will be followed for 104 weeks. Design: In this phase I/II, single-center, prospective, open label, non-randomized, uncontrolled, single group trial, one eye of eligible participants will be treated with investigational products, E10030, a PDGF-B antagonist, and ranibizumab, a VEGF-A antagonist. Participants will receive combination investigational treatment consisting of intravitreal injections of E10030 (1.5 mg in 0.05 mL) and ranibizumab (0.5 mg in 0.05 mL) every four weeks from baseline through Week 16 (totaling five treatments) and then every eight weeks through Week 48 (totaling nine treatments from baseline). All participants will be followed for 104 weeks. Outcome Measures: The primary outcome for the study will be safety of the combination investigational treatment, assessed by tabulation of adverse events (AE) reported through Week 52. Secondary outcomes will include tabulation of AEs at Week 104, and the following measures in the study eye at Week 52 and 104: the proportion of participants experiencing reduction in size of at least one RCH in the absence of other ablative treatment (assessed by fundus photography and fluorescein angiography FA); the proportion of participants experiencing moderate vision loss (defined as a loss of 15 letters from baseline on Electronic Visual Acuity EVA testing); mean change in visual acuity; change in size of RCH (measured by fundus photography and FA); change in exudation (measured by fundus photography, optical coherence tomography OCT and FA); change in epiretinal proliferation, fibrosis or retinal traction (assessed by OCT and fundus photography); proportion of participants undergoing ablative treatment of RCH or ocular surgery; proportion of participants with successful ablative treatment of RCH; and the proportion of participants with appearance of one or more new RCH. In fiscal year 2021, the trial remains in analysis status. The analysis of primary results has been completed, and a manuscript has been submitted and provisionally accepted for publication. This paper was published.