Novel Ophthalmic Product for Corneal Infections and Injuries

Biolytx Pharmaceuticals Corp. is developing a peptide, BP001, derived from the human endogenous host defense protein CAP37, as a novel multi-target ophthalmic product for corneal infections and injuries. The standard-of-care for corneal infections is topical administration of antibiotics that may be accompanied by topical steroids, to limit the destructive effect of the resulting corneal inflammation. The efficacy of antibiotics is limited by the alarming increase of resistant bacteria, and the use of steroids is limited by their potential adverse effects (recrudescent infection, increased intraocular pressure). BP001 has multiple beneficial effects and is developed as a new product to mitigate these limitations. It is bactericidal, restores the sensitivity of resistant Pseudomonas aeruginosa to fluoroquinolones, promotes corneal re-epithelialization, and based on our recent results, is predicted to be anti-inflammatory through inhibition of a toll-like receptor. Interestingly, we recently observed that the composition of the buffer used to prepare BP001 greatly affects its bactericidal properties in vitro. Building on this observation, our specific aims in this phase I application are to 1) develop and optimize an ophthalmic formulation of BP001 to potentiate the effective killing of P. aeruginosa, and 2) demonstrate the benefit of using the optimized formulation for treatment of bacterial keratitis with BP001 alone and in combination with ofloxacin. We will use the Quality by design (QbD) approach to develop a formulation that meets critical quality attributes, defined as (a) enhances the bactericidal potency (at least 10-fold compared to the original saline solution, (b) does not irritate the eye, (c) enhances retention of the solution in the eye to maximize the effect of BP001 at the site of action, and d) does not interfere with the bactericidal potency of ofloxacin when used in combination. Measured outcomes will be viscosity, minimum bactericidal concentrations, and synergistic effects of BP001 and ofloxacin prepared in formulations and tested on sensitive and resistant strains of P. aeruginosa. We will then use the formulation optimized in aim 1 to evaluate enhancement of BP001 bactericidal activity in vivo. We will conduct dose-responses of BP001 and ofloxacin in saline and formulation, and a dose-response of the BP001/ofloxacin combination treatment prepared in formulation, using a mouse model of bacterial keratitis induced by a resistant strain of P. aeruginosa. At the conclusion of phase I, we expect to have developed a formulation that enhances BP001 bactericidal effects and supports efficient clearing of bacterial keratitis induced by a resistant P. aeruginosa isolate by the BP001/ofloxacin combination. In phase II, we will demonstrate wound healing and anti-inflammatory effects of BP001, in mouse models of keratitis and corneal abrasion, using the formulation optimized in phase I. Completion of this project will advance the development of a new class of drug with multi-targeted effects for corneal infections and injuries.Narrative: Once corneal integrity is breached, prompt treatment is required to halt the development of infections and harmful sequelae such as ulceration, perforation, scarring and loss of vision. No currently available treatment is able to address both the problem of antimicrobial resistance and the problem of re- epithelialization of the cornea. Our product has the ability to treat vision-threatening bacterial keratitis by restoring antibiotic sensitivity and promoting corneal healing, thereby addressing the major inadequacies of current treatment options and is of relevance to the mission of both NEI and NIAID.