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

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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.