The FDA approved Xiidra (lifitegrast ophthalmic solution 5%, Shire Pharmaceuticals) for the treatment of signs and symptoms of dry eye disease (DED) in mid-July 2016. It is the first medication in a new class of drugs called lymphocyte function-associated antigen-1 (LFA-1) antagonists.
The pivotal FDA study for Xiidra was one of the largest dry eye trials on record, involving more than 1,200 patients on 5% lifitegrast alone. However, the most impressive study outcome actually resulted during the Phase III OPUS-3 efficacy and safety trial, which included 355 patients on lifitegrast and 356 control subjects. At the study’s conclusion, OPUS-3 researchers noted that patients using lifitegrast reported a statistically significant improvement in dry eye symptoms when compared with placebo at days 14, 42 and 84 following therapy initiation.
Following Xiidra’s approval, we’ve continued to see such positive results in hundreds of thousands of patients in the United States. In my experience, patients report an improvement in dry eye symptoms within two to four weeks following therapy initiation.
With respect to safety data and adverse events, the most common ocular findings associated with Xiidra use were instillation site burning and blurred vision (both >5%). The most common nonocular finding was dysgeusia (>5%). Most adverse events were reported as being mild to moderate in severity. Nonetheless, I make certain to inform all patients that they may experience stinging and transient blur persisting for a few hours, days or even weeks, as well note that they could experience an unpleasant following drop instillation.
The Mechanism of Action
Knowing the mechanism of action for any topical, systemic or injectable drug helps us better understand the agent, as well as its therapeutic effect. Numerous studies have associated dry eye disease (DED) with inflammation involving the conjunctiva and lacrimal glands.1,2
When the tear film can no longer maintain homeostasis and develops hyperosmolarity, the ocular surface over-expresses a ligand known as intercellular adhesion molecule-1 (ICAM-1).3 These fingerlike projections on the epithelium have binding sites for T-lymphocytes. The specific binding occurs via an LFA-1 antagonist on the migrating T-lymphocyte, which then binds to ICAM-1.
The interaction of LFA-1 and ICAM-1 results in activation and migration of the T-cell into tissue. It then binds to an antigen-presenting cell via the same mechanism, yielding cytokine release.4-7 The cascade of inflammation advances, as these cytokines precipitate further ICAM-1 expression.8
Lifitegrast is a small molecule integrin antagonist that blocks binding of ICAM-1 to LFA-1 on the T-cell surface, consequently inhibiting T-cell recruitment and activation associated with DED-based inflammation.9-11
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10. Sun Y, Zhang R, Gadek TR, et al. (2013). Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocular Pharmacol. 2013;29:395-402.
11. Zhong, M., Gadek, T.R., Bui, M. et al. (2012). Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye. ACS medicinal chemistry letters 3, 203-6.