Phase 1 Iontophoretic Delivery of Dexamethasone for Tx of Anterior Scleritis

摘要 非感染性巩膜炎是眼壁（巩膜）的炎性疾病。其估计 美国的患病率为50，000。巩膜炎通常是管理与口服非甾体类 炎性药物、全身皮质类固醇和/或全身免疫抑制剂 毒品在三级医疗机构中，大多数患者需要长期治疗，包括全身治疗。 皮质类固醇和/或免疫抑制。即使在系统性疾病的背景下， 巩膜炎通常会导致治疗方案。对于这种高影响孤儿疾病， 避免全身副作用的有效局部给药治疗方案 是非常可取的。 该提案要求提供资金，用于对离子电渗疗法进行初步评估， 地塞米松治疗非感染性、非坏死性巩膜炎，在IND下进行。 Eyegate Pharma正在开发一种离子电渗输送系统， 磷酸地塞米松滴眼液（40 mg/mL）滴眼，靶向 葡萄膜炎和干眼症的迹象。地塞米松是一种众所周知的皮质类固醇， 几十年来可用于眼部和全身给药的其他制剂。我们 认为离子电渗皮质类固醇递送可能有效治疗 巩膜炎，因为它提供了一种通过结膜下递送药物的方式 血管丛，迅速清除眼药水。现有证据表明， 离子电渗递送的地塞米松可能对巩膜炎有效，包括： 全身性皮质类固醇和长效皮质类固醇的有效性 巩膜炎的巩膜，皮质类固醇滴眼液部分有效。没有 在42名葡萄膜炎患者中发生了发育限制性不良事件， 105名干眼患者参加了评价离子电渗递送 地塞米松。 拟议的研究-第一阶段，但不是第一次在人类-将旨在评估安全性 地塞米松离子导入治疗前巩膜炎的耐受性 剂量变化研究。将入组并治疗4例患者。剂量为 将增加下一组，否则根据剂量发生率终止研究- 限制每一剂量的毒性。本研究的主要目的是确定一系列 看起来安全和可耐受的剂量。第二个目标是提供一个初步的 基于观察到的治疗应答和比例的疗效评估 需要抢救治疗如果结果是有利的， 计划进行第二阶段研究。

ABSTRACT Non-infectious scleritis is an inflammatory disease of the eye wall (sclera). Its estimated US prevalence is 50,000. Scleritis typically is managed with oral non-steroidal inflammatory drugs, systemic corticosteroids, and/or systemic immunosuppressive drugs. In tertiary settings, most patients require long-term therapy, including systemic corticosteroids and/or immunosuppression. Even in the context of systemic disease, scleritis often drives the treatment regimen. For this high impact orphan disease, an effective locally administered treatment regimen that avoided systemic side effects would be very desirable. This proposal requests funding for an initial evaluation of iontophoretic delivery of dexamethasone for non-infectious, non-necrotizing scleritis, conducted under IND. Eyegate Pharma is developing an iontophor-etic delivery system to deliver dexamethasone phosphate ophthalmic solution (40 mg/mL) to the eye, targeting the indications of uveitis and dry eyes. Dexamethasone is a well-known corticosteroid, available in other formulations for ocular and systemic delivery for decades. We consider iontophoretic corticosteroid delivery as likely to be effective for treatment of scleritis, because it provides a means of delivering drug past the subconjunctival vascular plexus, which rapidly clears eyedrops. Available evidence suggesting that iontophoretically delivered dexamethasone may be effective for scleritis includes: effectiveness of systemic corticosteroids and depot corticosteroids placed adjacent to the sclera for scleritis, and partial effectiveness of corticosteroid eyedrops. No development-limiting adverse events have been encountered in 42 uveitis patients and 105 dry eye patients enrolled in studies evaluating iontophoretic delivery of dexamethasone. The proposed study-phase 1, but not first-in-human-will aim to assess the safety and tolerability of iontophoretic delivery of dexamethasone for anterior scleritis in a dose-varying study. Sets of four patients will be enrolled and treated. The dose for the next set will be increased or else the study terminated based on the incidence of dose- limiting toxicity at each dose. The primary objective of this study is to identify a range of doses that appear safe and tolerable. The secondary objective is to provide a preliminary assessment of efficacy based on observed responses to treatment and the proportion requiring rescue therapy. If results are favorable, further development of the approach in phase 2 studies is planned.