A Phase 3 Multicenter, Randomized, Vehicle-Controlled Clinical Study to Evaluate the Safety and Efficacy of an Ophthalmic Emulsion of Nintedanib in Pterygium Patients

一项评估尼达尼布眼用乳剂在翼状胬肉患者中的安全性和有效性的 3 期多中心、随机、载体对照临床研究

• 批准号: 10076453
• 负责人: rong yang
• 金额: $ 70万
• 依托单位: CLOUDBREAK THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10076453
• 关键词: Address; Adverse effects; Affect; Anxiety; Appearance; Blood Vessels; Chronic; Clinical; Clinical Research; Clinical Trials; Conjunctival Pterygium; Cornea; Development; Disease; Disease Progression; Dose; Drug vehicle; Electroretinography; Emulsions; Excision; Eye; Eyedrops; FDA approved; Fibroblast Growth Factor; Formulation; Goals; Grant; Growth; Human; Hyperemia; Individual; KDR gene; Laboratories; Left; Length; Lesion; Life; Marketing; Measures; Medical; Microscopic; Modeling; Monkeys; No-Observed-Adverse-Effect Level; Operative Surgical Procedures; Ophthalmology; Oral; Oryctolagus cuniculus; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phase; Phase II Clinical Trials; Phase III Clinical Trials; Physiologic Intraocular Pressure; Platelet-Derived Growth Factor; Population; Product Approvals; Quality of life; Questionnaires; Randomized; Recurrence; Risk; Safety; Signs and Symptoms; Small Business Innovation Research Grant; Surveys; Symptoms; Testing; Tissues; Vascular Endothelial Growth Factors; Visual impairment; base; capsule; conjunctiva; design; idiopathic pulmonary fibrosis; improved; inhibitor/antagonist; irritation; meetings; novel; novel therapeutics; ocular surface; phase III trial; prevent; primary endpoint; reduce symptoms; safety assessment; safety study; secondary endpoint; small molecule; standard of care; success; treatment duration; treatment effect

Pterygium is a common ocular surface disease with abnormal fibrovascular growth on the cornea that affects about 10 million individuals in the US. Later-stage disease impairs vision and early to middle stage disease causes worry and anxiety about eye appearance in patients. The current standard of care is surgical removal of lesion tissue. However, rapidly growing lesions recur in about 10% of patients after surgery. There is no approved drug to treat pterygium. We address this unmet medical need with a topical ocular drug. Our goal is to develop a pharmacological treatment for pterygium by targeting the well-established angiogenic and fibrotic pathogenesis of the disease to improve pterygium signs and symptoms, to stop disease progression and reduce the need for surgery. We formulated a topical eye drop of nintedanib (CBT-001), a small molecule multikinase inhibitor (MKI) that targets key pterygia pathogenic pathways: VEGF, PDGF and FGF. In a Phase 2 clinical trial, partially supported by a NEI Fast-track grant, we demonstrated that nintedanib eye drop substantially reduced pterygia vascularity and conjunctival hyperemia, significantly reduced lesion size and lessened patients’ worry about eye appearance. Those are the key factors that influence patients’ decision to seek surgery. Now we intend to test nintedanib in an improved emulsion formulation in two Phase 3 clinical trials and to seek product approval after a successful end of Phase 2 (EOP2) meeting with FDA. The Aims of this Phase IIb application are: Aim 1, to evaluate the ocular and systemic safety of the nintedanib ophthalmic emulsion in nonclinical models to qualify for long-term (12 mo) use in humans. We use the same metrics and apply the same criteria as applied previously, to include all of (i) no significant in-life ocular or systemic clinical observations; (ii) no significant ocular irritation, change of intra-ocular pressure or electroretinogram; (iii) no significant microscopic observations in ocular or non-ocular tissues; (iv) quantification of no-observed-adverse-effect-level (NOAEL). In Aim 2, we will assess safety and efficacy in a Phase 3 clinical study in primary, recurrent (including impending recurrence) pterygium patients during 12-month BID repeat ocular dosing of nintedanib ophthalmic emulsion. For safety, the goal is to show that we meet established FDA safety criteria for chronic use of an eye drop product in humans. For efficacy, the goal is to prevent the progression of pterygium lesion on the cornea, to reduce pterygium-induced hyperemia and vascularity, and reduce patients’ worry about their eye appearance. These goals are set based on discussions with doctors, patients, and FDA officials. If nintedanib ophthalmic emulsion is shown to be safe and efficacious in Phase 3 trials and is marketed, this disease-modifying therapy will change the Standard of Care by significantly improving the treatment of millions of pterygium patients by relieving symptoms and signs of the disease, preventing progression of the lesion, reducing the need for surgical interventions, and lowering the risk of post-surgical disease recurrence.

翼状胬肉是一种常见的眼表疾病，其角膜纤维血管异常生长， 在美国大约有1000万人晚期疾病损害视力，早期至中期疾病 引起患者对眼睛外观的担心和焦虑。目前的治疗标准是手术切除 病变组织。然而，大约10%的患者在手术后会复发快速生长的病变。没有 治疗翼状胬肉的药物我们用一种局部眼用药物来解决这种未满足的医疗需求。 我们的目标是开发一种药物治疗翼状胬肉的目标是明确的血管生成 及纤维化发病机制，改善翼状胬肉体征和症状，停止疾病 并减少对手术的需求。我们配制了尼达尼布（CBT-001）局部滴眼液， 小分子多激酶抑制剂（MKI），靶向关键翼状胬肉致病途径：VEGF、PDGF和 FGF.在部分由NEI快速通道资助支持的II期临床试验中，我们证明了尼达尼布 滴眼液可明显减轻翼状胬肉血管及结膜充血，明显减轻病变 减轻患者对眼睛外观的担忧。这些都是影响患者预后的关键因素 决定寻求手术。现在，我们打算在两个III期试验中测试尼达尼布在改良乳剂中的应用 临床试验，并在与FDA成功结束2期（EOP 2）会议后寻求产品批准。 本IIb期申请的目的是：目的1，评价尼达尼布的眼部和全身安全性 眼用乳剂在非临床模型中的应用，以符合人类长期（12个月）使用的条件。我们使用相同的 指标，并应用与先前应用的相同的标准，以包括所有的（i）没有显著的活体眼部或 全身性临床观察;（ii）无显著的眼部刺激、眼内压变化或 视网膜电图;（iii）眼部或非眼部组织中无显著显微镜观察结果;（iv）定量 无明显不良作用水平（NOAEL）。 在目标2中，我们将在一项3期临床研究中评估原发性、复发性（包括 尼达尼布眼用重复眼部给药12个月BID期间的翼状胬肉患者 凝乳是否安全性方面，我们的目标是证明我们符合FDA制定的长期使用眼睛的安全标准 在人体内滴药对于疗效，目标是防止角膜上翼状胬肉病变的进展， 减少由钾引起的充血和血管增生，减少患者对眼睛的担忧 外观.这些目标是根据与医生、患者和FDA官员的讨论制定的。 如果尼达尼布眼用乳剂在III期试验中显示安全有效并已上市， 疾病改善疗法将通过显著改善数百万人的治疗来改变护理标准， 翼状胬肉患者的症状和体征，防止病变进展， 减少手术干预的需要，并降低手术后疾病复发的风险。