Dry eye disease is a common condition in which insufficient tears are present to keep the eye healthy and lubricated, or the quality of those tears is low. The dry eye condition with the highest incidence is keratoconjunctivitis sicca, where the inner water layer of tears is inadequate. The result can be that eyes feel scratchy, gritty or even have a burning sensation, and they may be watery and have blurred vision.
In advanced cases, the eye can be damaged as a result, permanently impairing vision. It represents a significant unmet medical need.
A new drug has been developed by Shire to counteract this. Lifitegrast is a small molecule integrin inhibitor which binds to the integrin LFA-1, or lymphocyte function-associated antigen-1, preventing this integrin from interacting with its cognate ligand ICAM-1, or intercellular adhesion molecule-1.1 ICAM-1 is overexpressed in the tissue of the cornea and conjunctiva in dry eye disease, and the interaction between the ligand and its receptor contributes to the formation of immunological synapses. This results in the activation of T-cells, and their migration to target tissues.
Several clinical trials have been carried out to support its recent submission to the FDA for approval. In a Phase II trial, a total of 230 patients with dry eye, who were selected via the use of a controlled adverse environment, were given 0.1, 1.0 or 5.0% lifitegrast eye drops or placebo twice a day for 12 weeks.2 The main criteria for eligibility were an exacerbation in corneal staining and ocular symptoms in that adverse environment, and an absence of lid margin disease. Ocular symptoms and signs were assessed after 14, 42 and 84 days, and no additional artificial tears were permitted.
A significant improvement in corneal staining score and visual related function were seen for those given the drug compared with the placebo group, and improvements in tear production and symptoms were seen after the first couple of weeks. There were no serious ocular adverse events, and those that did occur were both mild and transient.
The highest strength dose was investigated in a Phase III trial. In the prospective, randomised, double masked, placebo-controlled, parallel arm study, 588 patients with dry eye disease were given 5% lifitegrast eye drops or placebo twice a day for 12 weeks, after a 14-day open label placebo run-in period.3
Subjects were again evaluated after 14, 42 and 84 days. Corneal fluorescein staining and conjunctival lissamine staining were both significantly reduced in those given the active agent compared with placebo after 14 days, and the improvements were maintained through to the end of the trial. Significant improvements were also seen after 12 weeks in ocular discomfort and eye dryness, which were the most severe and common symptoms the subjects had reported at the start of the trial.
The most common ocular adverse events were irritation and discomfort at the instillation site when the first dose of lifitegrast was administered, but this was transient.
References
1. M. Zhong et al. ACS Med. Chem. Lett. 2012, 3, 203
2. C.P. Semba et al. J. Ocul. Pharmacol. Ther. 2012, 153, 1050
3. J.D. Sheppard et al. Ophthalmol. 2014, 121, 475