A Phase 2a Multicenter, Randomized, Vehicle-Controlled, Dose Escalating Study to Evaluate the Safety, Efficacy and Pharmacokinetics of CBT-001 Ophthalmic Solution in Pterygium Patients

一项 2a 期多中心、随机、载体对照、剂量递增研究，旨在评估 CBT-001 眼用溶液在翼状胬肉患者中的安全性、有效性和药代动力学

• 批准号: 9789897
• 负责人: jinsong ni
• 金额: $ 80.91万
• 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 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789897
• 关键词: Address; Affect; Area; Astigmatism; Blood Vessels; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Conduct Clinical Trials; Conjunctival Pterygium; Controlled Study; Cornea; Disease; Dose; Drug Kinetics; Excision; Eye; Eye diseases; Eyedrops; FDA approved; Fibroblast Growth Factor; Funding; Growth; Growth Factor; Human; Hyperemia; Image; Immune; Individual; Legal patent; Length; Lesion; Marketing; Masks; Measures; Medical; Methods; Modeling; Mus; Operative Surgical Procedures; Ophthalmic Solutions; Oral; Oryctolagus cuniculus; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Pharmacotherapy; Phase; Platelet-Derived Growth Factor; Privatization; Quality of life; Questionnaires; Randomized; Reading; Recurrence; Research; Risk; Safety; Standardization; Surgical sutures; Symptoms; Testing; Time; Tissues; United States National Institutes of Health; Vascular Endothelial Growth Factors; Vision; Visual impairment; Width; capsule; conjunctiva; follow-up; idiopathic pulmonary fibrosis; improved; inhibitor/antagonist; irritation; neovascularization; novel; ocular surface; off-patent; open label; preclinical study; small molecule; standard of care; vascular abnormality

Pterygium is an 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 the current standard of care is surgical removal of lesion tissue. However, lesions recur in about 10% of patients after surgery. Because there is no approved drug to treat pterygium, we propose to address this unmet medical need with a topical ocular drug. We have formulated a topical eye drop nintedanib, a small molecule multikinase inhibitor (MKI) that targets growth factors implicated in pterygium pathogenesis. Nintedanib is the active pharmaceutical ingredient of Ofev®, an FDA-approved oral treatment for idiopathic pulmonary fibrosis. We have shown that our formulated nintedanib, CBT-001, suppresses cornea neovascularization in a rabbit corneal suture model and causes regression of human pterygium lesion tissue grown on the eyes of immune-deficient mice. These results have enabled us to globally file the method of use patent of nintedanib for pterygium treatment. We have successfully submitted our IND application to FDA and have been approved to proceed with a clinical trial in the US. Our regulatory strategy takes the 505(b)2 path by referencing existing human safety, pharmacokinetics and non-clinical study results of Ofev®. Our private angel funding of $2 million enabled us to complete all the IND-enabling pre-clinical studies and will partially support the proposed clinical trial. The Phase I Aims of this Fast Track application are to: (1) Evaluate ocular and systemic safety and tolerability as well as effect on pterygium vascularity after a single topical ocular administration of CBT-001 ophthalmic solution in primary pterygium patients; (2) Determine systemic pharmacokinetics of CBT-001 and select the highest safe dose after a single topical ocular administration of CBT-001 ophthalmic solution in primary pterygium patients. Our Phase II Aims are to: (1) Evaluate ocular and systemic safety of CBT-001 in primary and recurrent pterygium patients during and after TID, 28 day repeat ocular dosing; (2) Assess the efficacy of CBT-001 in primary and recurrent pterygium patients during and after TID, 28 day repeat ocular dosing. We will determine whether CBT-001 can (i) reduce the key pterygium symptom of abnormal vascularity on cornea and conjunctiva by analyzing eye photos using a standardized 5-point Pterygium Hyperemia Grading Scale; (ii) stabilize or regress lesion by measuring corneal lesion length, width and area of pterygium in eye photos; (iii) improve the quality of life of patients; and (iv) improve astigmatism caused by pterygium lesion. The Project Milestone for this two-year Research Plan is to complete a Phase 2a multicenter, randomized, vehicle-controlled, dose escalating study to evaluate the safety, efficacy and pharmacokinetics of CBT-001 ophthalmic solution in pterygium patients. If CBT-001 proves to be clinically safe and efficacious and is approved for marketing, it may significantly improve the treatment of pterygium patients by reducing the number of surgical interventions and lower the risk of post-surgical disease recurrence.

翼状胬肉是一种眼表疾病，角膜上有异常纤维血管生长，影响约 10 美国有 100 万人。晚期疾病会损害视力，目前的护理标准是手术 去除病变组织。然而，约10%的患者术后病变会复发。因为没有 已批准治疗翼状胬肉的药物，我们建议通过局部眼部药物来解决这一未满足的医疗需求。 我们配制了一种外用滴眼剂尼达尼布，这是一种小分子多激酶抑制剂 (MKI)，针对 生长因子与翼状胬肉发病机制有关。尼达尼布是以下药物的活性成分 Ofev®，FDA 批准的一种治疗特发性肺纤维化的口服药物。我们已经证明我们制定的 nintedanib，CBT-001，抑制兔角膜缝合模型中的角膜新生血管形成并引起 免疫缺陷小鼠眼睛上生长的人类翼状胬肉病变组织的消退。这些结果有 使我们能够在全球范围内申请尼达尼布治疗翼状胬肉的使用方法专利。我们有 成功向 FDA 提交了 IND 申请，并已获批在美国进行临床试验 美国。我们的监管策略采用 505(b)2 路径，参考现有的人体安全性、药代动力学 Ofev®的非临床研究结果。我们的 200 万美元私人天使融资使我们能够完成所有 支持 IND 的临床前研究并将部分支持拟议的临床试验。 该快速通道应用的第一阶段目标是：(1) 评估眼部和系统安全性和耐受性 以及单次局部眼部施用 CBT-001 眼科药物后对翼状胬肉血管分布的影响 原发性翼状胬肉患者的解决方案； (2)测定CBT-001的全身药代动力学并选择 原发性单次局部眼部施用 CBT-001 滴眼液后的最高安全剂量 翼状胬肉患者。我们的 II 期目标是：(1) 评估 CBT-001 在初级临床中的眼部和全身安全性 以及 TID 期间和之后复发性翼状胬肉患者，28 天重复眼部给药； (2) 评估效果 CBT-001 在 TID 期间和之后用于原发性和复发性翼状胬肉患者，28 天重复眼部给药。我们 将确定 CBT-001 是否可以 (i) 减轻角膜血管异常的关键翼状胬肉症状 通过使用标准化 5 点翼状胬肉充血分级量表分析眼睛照片来检查结膜； (二) 通过测量眼睛照片中角膜病变长度、宽度和翼状胬肉面积来稳定或消退病变； (三) 提高患者的生活质量； (iv)改善翼状胬肉病变引起的散光。 这个两年研究计划的项目里程碑是完成 2a 期多中心、随机、 评估 CBT-001 安全性、有效性和药代动力学的媒介对照、剂量递增研究 翼状胬肉患者的眼药水。如果CBT-001被证明在临床上安全有效并且是 批准上市后，它可以通过减少翼状胬肉患者的治疗来显着改善 手术干预次数并降低术后疾病复发的风险。