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: 9903520
• 负责人: jinsong ni
• 金额: $ 73.91万
• 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 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903520
• 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，其角膜纤维血管异常生长， 在美国的百万人。晚期疾病损害视力，目前的标准治疗是手术治疗 切除病变组织。然而，约10%的患者在手术后复发。因为没有 为了治疗翼状胬肉，我们建议用局部眼部药物来解决这种未满足的医疗需求。 我们已经配制了一种局部滴眼液尼达尼布，这是一种小分子多激酶抑制剂（MKI）， 翼状胬肉发病机制中的生长因子。宁芙是一种活性药物成分， Ofev®，FDA批准的特发性肺纤维化口服治疗药物。我们已经表明，我们的公式化 尼达尼布（CBT-001）在兔角膜缝合模型中抑制角膜新生血管形成，并导致 免疫缺陷小鼠眼睛上生长的人翼状胬肉病变组织的消退。这些结果 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 我们成功地向FDA提交了IND申请，并已被批准进行临床试验， 美方我们的监管策略采用505（B）2途径，参考现有的人体安全性、药代动力学 Ofev®的非临床研究结果。我们的私人天使投资200万美元，使我们能够完成所有的 IND支持临床前研究，并将部分支持拟议的临床试验。 该快速通道申请的I期目的是：（1）评价眼部和全身安全性和耐受性 以及在单次局部眼部施用CBT-001眼用后对翼状胬肉血管分布的影响 （2）测定CBT-001的全身药代动力学，并选择合适的治疗方案。 在原发性高血压患者中，CBT-001眼用溶液单次局部眼部给药后的最高安全剂量 翼状胬肉患者。我们的II期目的是：（1）评价CBT-001在原发性高血压患者中的眼部和全身安全性。 和复发性翼状胬肉患者在TID期间和之后，28天重复眼部给药;（2）评估 TID期间和之后，CBT-001在原发性和复发性翼状胬肉患者中的28天重复眼部给药。我们 将确定CBT-001是否能够（i）减轻角膜血管异常的关键翼状胬肉症状 通过使用标准化的5点翼状胬肉充血分级量表分析眼睛照片来测量角膜和结膜的厚度;（ii） 通过测量角膜病变长度、宽度和眼部照片中翼状胬肉面积来稳定或消退病变;（iii） 提高患者的生活质量;（iv）改善翼状胬肉病变引起的散光。 本两年研究计划的项目里程碑是完成2a期多中心、随机、 评价CBT-001的安全性、有效性和药代动力学的媒介物对照、剂量递增研究 翼状胬肉患者的眼用溶液。如果CBT-001被证明是临床安全有效的， 批准上市后，它可以通过减少翼状胬肉患者的 减少手术次数，降低术后疾病复发的风险。