Calcineurin inhibitors (CNIs) are potent
immunosuppressants that reversibly inhibit T-cell proliferation and prevent the release of pro-inflammatory
cytokines by blocking the activity of
calcineurin, a ubiquitous
enzyme that is found in cell cytoplasm. CNIs can be highly effective in immune-mediated ophthalmic diseases such as
uveitis,
dry eye syndrome and inflammatory
blepharitis, as well as for the prevention of rejection in corneal transplants.
ISA-247/LX-211 is a novel CNI that is in Phase III clinical development for the treatment of various forms of non-infectious
uveitis.
ISA-247/LX-211 is a rationally designed analog of
ciclosporin A that exhibits more predictable pharmacokinetic and pharmacodynamic properties and a 4-fold greater
calcineurin inhibition than its parent compound,
ciclosporin A.
ISA-247/LX-211 has been observed to be effective, well-tolerated, and safe in early clinical trials, exhibiting a much wider therapeutic window compared with classic CNIs, such as
ciclosporin A and
tacrolimus. An alternative approach to widening the therapeutic window for the
therapy of ophthalmic disorders lies in local delivery of CNIs through polymeric implants that release the
drug over long periods of time. The
silicone matrix episcleral implant LX-201 is in Phase III development at present for the prevention of rejection in high-risk
cornea transplantation.