SCY-641 - A Water-Soluble Cyclophilin Inhibitor for the Treatment of Dry Eye Disease

Abstract

Purpose: : To identify a water soluble cyclosporine derivative with good immunomodulatory properties and ocular distribution profile consistent with treating dry eye disease.

Methods: : New semi-synthetic derivatives of cyclosporine A were prepared and tested for immunosuppressive potential (inhibition of IL-2 from stimulated Jurkat T-cells) and anti-cytokine activity (inhibition of TNF, IL-1 from corneal epithelial cells). The solubility of new compounds in water, and water/excipient mixtures, was measured by shake-flask methods with HPLC analysis. The ocular distribution of lead compounds was determined by topical administration to rabbits followed by measurement of corneal and conjunctival tissue concentrations.

Results: : SCY-641 was identified as a potent inhibitor of cytokine production by stimulated corneal epithelial cells (TNF, IL-1 IC₅₀ 0.6, 11 uM) and T-cells (IL-2 IC₅₀ 0.04 uM), and to be immunosuppressive in a mixed lymphocyte proliferation assay (EC₅₀ 0.2 uM) . The solubility of SCY-641 in water, PEG/water and carboxymethylcellulose/water (0.17, 0.24, and 0.3 mg/mL) was 10-30 fold higher than corresponding values for cyclosporine A. A clear solution of SCY-641 (0.3 mg/mL, 0.03%) in a CMC/water vehicle, autoclaved to achieve sterility, was found to be stable over several months. Topical administration of a 0.03% SCY-641 solution (0.05 mL, q15minX4) to rabbit eyes was well tolerated (slit lamp microscopy, Shaddock-McDonald scoring) and resulted in corneal and conjunctival concentrations (2000 and 2100 ng/g tissue respectively) above the anticipated therapeutic range.

Conclusions: : SCY-641 is a new cyclosporine derivative with good immunosuppressive, and anti-cytokine, activity and notably improved aqueous solubility. SCY-641 is readily taken into rabbit corneal and conjunctival tissue following topical application and warrents further evaluation as an alternative treatment for Dry Eye disease.

Keywords: cyclosporine • cornea: tears/tear film/dry eye • aqueous