Ocular PK/PD of a Novel Non-Steroidal Anti-Inflammatory Compound in a Murine Model of Meibomian Gland Dysfunction

Abstract

Purpose : The long-term use of an efficacious and safe topical anti-inflammatory compound with a rapid onset of action for dry eye and other chronic ophthalmic inflammation mediated diseases presents an unmet medical need in ophthalmology. In this study, a murine allergic eye disease (AED) model of dry eye disease (DED) was used to evaluate mitigating effects of a class of anti-inflammatory compounds on DED progression. We hypothesize that compounds that engage and down-regulate disease-relevant pro-inflammatory pathways in our AED model have potential to treat ocular signs and symptoms of DED in human patients.

Methods : Female C57Bl/6 mice immunized against ovalbumin (OVA) were challenged with a topical OVA solution to induce inflammation and DED progression prior to treatment. A representative compound (compound A) from a novel class of Aerie anti-inflammatory compounds was evaluated in the AED model of DED. An ophthalmic solution of compound A, vehicle control, and a dexamethasone phosphate (positive control) solution was applied topically TID. Subjective masked and randomized clinical scoring of observable ocular inflammation was taken over the course of 4 days. Post-mortem tissue measurements of inflammation include flow cytometry of immune infiltrate, qPCR analysis of inflammatory biomarkers within Meibomian Gland (MG), and ELISA assays for inflammatory biomarkers.

Results : Topical administration of Compound A and the positive control dexamethasone phosphate significantly reduced clinical signs of inflammation including lid edema, conjunctival hyperemia, and MG plugging compared to vehicle. Quantitative analysis by qPCR demonstrates that both Compound A and dexamethasone reduced IL-17a, INFg, IL-6, IL-1b, and MPO infiltrates relative to vehicle in the mouse eyelid, the target site for MGD associated DED.

Conclusions : By targeting and engaging inflammatory pathways in a murine AED model of DED we show a significant reduction in inflammation and clinical signs of disease. Compound A represents a novel class of Aerie anti-inflammatory compounds that have the potential to be fast-acting, safe and efficacious treatment for ocular inflammatory diseases.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.