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

翼状胬肉是一种常见的眼表疾病，在角膜上有异常的纤维血管生长，影响 美国约有1000万人。晚期疾病损害视力，早至中期疾病 引起患者对眼睛外观的担忧和焦虑。目前的护理标准是手术切除。 病变组织。然而，约10%的患者手术后会复发快速生长的皮损。没有 批准用于治疗翼状胬肉的药物。我们通过外用眼科药物来解决这一未得到满足的医疗需求。 我们的目标是开发一种通过靶向成熟的血管生成来治疗翼状胬肉的药物疗法。 且病机纤维化，能改善翼状胬肉的体征和症状，阻止疾病的发展 进展和减少手术的需要。我们配制了九替达尼滴眼液(CBT-001)， 小分子多激酶抑制剂(MKI)靶向翼状胬肉的关键致病途径：血管内皮生长因子、PDGF和 成纤维细胞生长因子。在一项由NEI Fast-Track赠款部分支持的第二阶段临床试验中，我们证明了九替达尼布 滴眼液显著减少翼状胬肉的血管和结膜充血，明显减轻病变 大小和减轻患者对眼睛外观的担忧。这些都是影响患者健康的关键因素 决定寻求手术。现在我们打算在两个阶段3中测试一种改进的乳剂配方中的奈替达尼。 临床试验，并在与FDA的第二阶段(EOP2)会议成功结束后寻求产品批准。 此IIb期应用的目的是：目标1，评估九替丹尼的眼部和全身安全性 非临床模型的眼用乳剂有资格在人类身上长期(12个月)使用。我们使用的是相同的 指标，并应用与之前应用的相同标准，以包括以下所有内容：(I)在生活中没有显著的眼部或 系统的临床观察；(Ii)无明显眼刺激、眼压变化或 视网膜电信号；(3)眼或非眼组织未见明显的显微镜观察；(4)定量 未观察到的不良反应水平(NOAEL)。 在目标2中，我们将在第三阶段临床研究中评估初发、复发(包括 即将复发)翼状胬肉患者在重复滴眼九替达尼布12个月期间 乳剂。在安全性方面，我们的目标是表明我们符合FDA制定的长期使用眼睛的安全标准 在人体中丢弃产品。在疗效方面，目标是防止翼状胬肉在角膜上的损害进展， 减少翼状胬肉引起的充血和血管，减少患者对眼睛的担忧 外表。这些目标是根据与医生、患者和FDA官员的讨论制定的。 如果九替达尼眼用乳剂在3期试验中被证明是安全有效的，并在市场上销售，这 疾病修正疗法将显著改善数百万人的治疗，从而改变护理标准 通过缓解疾病的症状和体征，防止病变的进展， 减少手术干预的需要，降低手术后疾病复发的风险。

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.