Development of a safe and effective topically administered pharmacotherapy to treat acute corneal pain

ABSTRACT The corneal epithelium in the eye is richly innervated, and is thus very painful when injured. There are currently no FDA-approved treatments specifically for corneal pain, and those treatment options that are used are associated with significant side effects. For example, NSAIDs may induce corneal melt which can lead to vision loss, and topical steroids may cause increased intraocular pressure (IOP) and delayed corneal wound healing. There is therefore a significant unmet clinical need for a novel pharmaceutical agent that can serve as an efficacious topical therapy with little or no side effects. Based on initial data generated by Vyluma, topical pregabalin has the potential to meet this need. Pregabalin is currently approved as an oral analgesic for the treatment of neuropathic pain, and the literature indicates that oral pregabalin is effective in treating acute corneal pain, though safety for this indication is inconclusive. Vyluma is in the process of developing a topical pregabalin formulation (NVK032) that can be administered locally to the eye, and the goal of this study is to further develop this formulation as a non-NSAID, non-steroid and non-anesthetic molecule to be a safe and effective topically administered pharmacotherapy to treat acute corneal pain. To achieve this goal, this study includes 3 specific aims. Specific Aim #1 will be a pharmacodynamic dose identification study to identify the minimum effective dose of NVK032 to treat acute corneal pain in a rat model. This aim will involve optimizing the formulation parameters (e.g., pH, osmolarity, viscosity) of NVK032, and performing an ophthalmic pain study in rats which measures pain by counting paw eye wipes in response to ophthalmic capsaicin (chemically induced pain). Six treatment groups (negative control, positive control, and 4 different NVK032 concentrations) will be compared in order to establish a minimum and maximum effective concentration of NVK032. Specific Aim #2 will be identification of the appropriate NVK032 formulation with maximum efficacy in a rat model. This aim will involve preclinical formulation development of NVK032, and a rat ophthalmic pain study to compare 5 treatment groups (negative control, positive control, or NVK032 in 1 of 3 vehicles: balanced salt solution, viscous solution, or semi-solid) in order to provide evidence regarding whether viscosity influences efficacy of NKV032. Specific Aim #3 will be performance of ocular and systemic pharmacokinetic (PK) studies in rabbits. This aim will involve preclinical formulation development of NVK032, followed by repeat-dose ocular/systemic PK studies to compare the 3 vehicles evaluated in Aim 2 in both healthy and injured rabbits so as to calculate PK parameters such as maximum serum concentration and concentration in the eye (ocular and systemic Cmax), area under the curve, and time to peak drug concentration. These studies will lead to a better understanding of the topical administration of NVK032 for the treatment of corneal pain, which will support development of NVK032 as an effective and safe therapy for this indication.