Efficacy of a RARγ selective agonist eye drop formulation on improvement of tear production and corneal fluorescein staining in the BTX‐B mouse model of dry eye disease

Abstract

PurposeMultiple studies have demonstrated the potential beneficial effects of retinoids on dry eye disease. Retinoic acid receptors (RAR) α, β and γ are widely distributed in ocular tissues. In vitro data suggest that the beneficial effects of retinoids on ocular health are mediated via RARγ (Kimura 2015). The purpose of this study was to evaluate the in vivo effects of palovarotene (PVO), a RARγ selective agonist, in a dry eye animal model.MethodsThe efficacy of a PVO ocular formulation was tested in the botulinum toxin type B (BTX‐B) mouse model which involves injection of BTX‐B into the lacrimal gland of the right eye with contralateral control. Eye drop formulations at 3 doses of PVO (low, mid, high) with vehicle, were administered by daily topical instillation for 28 consecutive days and compared to current standard of care, Restasis®. Endpoints included ophthalmic examinations, tear production measurement (TPM) by phenol red‐impregnated cotton threads, corneal fluorescein staining (CFS) using a scoring system of 0 to 4, and histopathology.ResultsAt Day 28 post BTX‐B injection, the mean (SD) TPM and CFS score in the untreated group were 1.5 (0.3) mm and 2.0 (0.7), respectively. In comparison, PVO eye drop treatment significantly improved dry eye signs (p<.0001) at all doses tested – TPM was increased by 132, 166 and 188% at low, mid and high dose, respectively, while CFS score was decreased by 70, 85 and 85%, respectively. PVO treatment effects were greater than Restasis® (113% increase in TPM, 50% decrease in CFS). All PVO doses were tolerated for 28 days. Histopathology evaluation revealed no effects on the Meibomian glands.ConclusionsThese results indicate a beneficial therapeutic effect of PVO in the BTX‐B animal model and support further development of a PVO ocular formulation for the treatment of human dry eye disease.