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A novel topical integrin antagonist (lifitegrast) for the treatment of dry eye: results of a multicenter, randomized, prospective, double-masked, placebo-controlled study

Session Details

Session Title: Cornea Medical

Session Date/Time: Monday 07/10/2013 | 08:00-10:00

Paper Time: 08:12

Venue: Elicium 1 (First Floor)

First Author: : J.Sheppard USA

Co Author(s): :    C. Semba              

Abstract Details

Purpose:

Dry eye disease can become perpetual and debilitating, causing significant damage to the ocular surface and a negative impact upon quality of life. Chronic inflammation is widely accepted as responsible for the cycle that causes many types of dry eye disease. The chronic inflammatory process in dry eye disease is mediated by CD4+ lymphocytes (T-cells) in response to desiccating stress. Lifitegrast is an investigational small molecule integrin antagonist that inhibits lymphocyte function antigen-1 (LFA-1; CD11a/CD18; ?L?2) and prevents binding of LFA-1 to intercellular adhesion molecule-1 (ICAM-1; CD54). LFA-1/ICAM-1 binding mediates T-cell trafficking/signaling and forms the basis of the immunological synapse between antigen presenting cells (APCs) and T-cells. Lifitegrast acts as an ICAM-1 decoy and blocks T-cell activation, proliferation, adhesion, migration, and cytokine release. The goal of intervention with lifitegrast is to inhibit the chronic cycle of T-cell activation/mobilization and improve signs and symptoms of dry eye disease. A Phase 3 pivotal study was conducted to assess the efficacy and safety of lifitegrast ophthalmic solution (LIF) 5.0% compared to placebo in subjects with dry eye disease.

Setting:

Multicenter, prospective, randomized, double-masked, placebo-controlled study.

Methods:

Subjects were randomized 1:1 to receive lifitegrast ophthalmic solution 5.0% or placebo eye drops twice daily (BID) for 84 days. Eligibility criteria included demonstration of exacerbation in corneal staining and ocular symptoms when challenged in a desiccating chamber, no active lid margin disease, and a Schirmer Tear Test (unanesthetized, mm/5 min) of ? 1 and ? 10 mm. A two-week pre-enrollment run-in period using placebo drops was conducted in each group. After enrollment (Day 0), subjects were evaluated at Days 14, 42 and 84. Objective measures included fluorescein and lissamine staining scores (Ora scales). Subjective assessments included the Ocular Surface Disease Index (OSDI), a 7-item visual analog scale evaluating dry eye symptoms, and an ocular discomfort score (Ora scale). The primary objective efficacy measure (sign) was mean change from baseline in inferior corneal staining score (ICSS) at Day 84. The co-primary subjective efficacy measure (symptom) was the mean change from baseline in the visual-related function subscale score of the Ocular Surface Disease Index (VR-OSDI). Supportive measures included corneal fluorescein scores (superior, central, total region) and conjunctival lissamine scores (nasal, temporal, total region) and symptom scores at Day 84.

Results:

A total of 588 subjects were analyzed (293 LIF, 295 placebo). The study met the primary objective efficacy ICSS endpoint in demonstrating superiority of lifitegrast compared to placebo (P=0.0007). Lifitegrast also significantly reduced corneal fluorescein staining (superior, P=0.0392; total cornea, P=0.0148) at Day 84 versus placebo. Significant improvements in the mean change from baseline in nasal and total lissamine scores were observed as early as Day 14 (nasal, P=0.0032; total conjunctiva, P=0.0149) and maintained through Day 84 (nasal, P=0.0039; total conjunctiva, P=0.0086). The study did not meet the co-primary subjective VR-OSDI measure (P=0.7894). However, significant improvements were observed at Day 84 in ocular discomfort (P=0.0273) and eye dryness (P=0.0291), the most common and severe symptoms reported at baseline in both groups. There were no unanticipated or serious ocular adverse events. The most frequent ocular adverse events were transient instillation site complaints (irritation, discomfort) primarily upon the initial lifitegrast dose immediately following 90 minutes in the dessicating chamber on Day 0.

Conclusions:

Lifitegrast ophthalmic solution 5.0% is a novel small molecule integrin antagonist that acts as an ICAM-1 decoy, blocking a key step in the chronic dry eye inflammatory cycle which is central to T-cell activation. When administered twice-daily for 84 days, lifitegrast significantly reduced corneal fluorescein and conjunctival lissamine staining, hallmarks of damage to the ocular surface caused by dry eye disease. These results were seen as early as two weeks after initiation of therapy. Lifitegrast also significantly improved the most common symptoms reported by subjects in the study - ocular discomfort and eye dryness. Lifitegrast appeared safe and well-tolerated. Adverse events were primarily instillation site complaints on Day 0.

Financial Interest:

... has significant investment interest in a company producing, developing or supplying product or procedure presented, ... travel has been funded, fully or partially, by a company producing, developing or supplying the product or procedure presented, ... research is funded, fully or partially, by a competing company, ... research is funded, fully or partially, by a company producing, developing or supplying the product or procedure presented, ... receives consulting fees, retainer, or contract payments from a competing company, ... receives consulting fees, retainer, or contract payments from a company producing, developing or supplying the product or procedure presented, ... is employed by a for-monetary company with an interest in the subject of the presentation