Lifitegrast, a Novel Integrin Antagonist for Treatment of Dry Eye Disease

Pérez, Víctor L.; Pflugfelder, Stephen C.; Zhang, Steven; Shojaei, Ali Asghar; Haque, Reza

doi:10.1016/j.jtos.2016.01.001

Cited by 160 publications

(130 citation statements)

References 40 publications

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“…Doxycycline has been found to inhibit MMP-9 activity in human corneal epithelial cells9 and may be used to treat MMP-mediated ocular surface diseases, such as rosacea, recurrent epithelial erosion, and sterile corneal ulceration 45,46. Lifitegrast reduces the overall inflammatory response resulting from T-cell adhesion to endothelial cells before trans-endothelial migration to inflamed tissues as well as at the point of T-cell interaction with antigen-presenting cells 47. These processes should result in decreased levels of pathogenic mediators and less inflammation on the ocular surface 47.…”

Section: Discussionmentioning

confidence: 99%

Presence or absence of ocular surface inflammation directs clinical and therapeutic management of dry eye

Sambursky¹

2016

OPTH

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BackgroundThe presence of clinically significant inflammation has been confirmed in the tears of 40%–65% of patients with symptoms of dry eye. Ocular surface inflammation may lead to tear film instability, epithelial cell irregularities, and permeability, resulting in chronic symptomatic pain and fluctuating vision as well as negative surgical outcomes.Patients and methodsA retrospective single center medical chart review of 100 patients was conducted. All patients were tested with the InflammaDry test to determine if patients exhibited elevated levels of matrix metalloproteinase 9 (MMP-9). InflammaDry-positive patients were started on a combination of cyclosporine 0.05% twice daily, 2,000–4,000 mg oral omega-3 fatty acids, and frequent artificial tear replacement. InflammaDry-negative patients were started on 2,000–4,000 mg of oral omega-3 fatty acids and frequent artificial tear replacement. Each patient was retested at ~90 days. A symptom questionnaire was performed at the initial visit and at 90 days.Results60% of the patients with dry eye symptoms tested positive for elevated MMP-9 at the initial visit. 78% of all patients returned for follow-up at ~90 days including 80% (48/60) of the previously InflammaDry-positive patients and 75% (30/40) of the previously InflammaDry-negative patients. A follow-up symptom questionnaire reported at least 75% symptomatic improvement in 65% (31/48) of the originally InflammaDry-positive patients and in 70% (21/30) of the initially InflammaDry-negative patients. Symptomatic improvement of at least 50% was reported in 85% (41/48) of previously InflammaDry-positive patients and 86% (26/30) of previously InflammaDry-negative patients. Following treatment, 54% (26/48) of previously InflammaDry-positive patients converted to a negative InflammaDry result.ConclusionIdentifying which symptomatic dry eye patients have underlying inflammation may predict patient responses to treatment and influence clinical management strategies.

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Section: Discussionmentioning

confidence: 99%

Presence or absence of ocular surface inflammation directs clinical and therapeutic management of dry eye

Sambursky¹

2016

OPTH

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“…T cell-mediated ocular inflammation has been implicated as a causative factor in DED [2][3][4] . Lifitegrast is a novel small molecule integrin antagonist, currently under development for the treatment of DED 5 . Lifitegrast targets the inflammatory pathways involved in the disease by blocking the binding of intercellular adhesion molecule 1 (ICAM-1) to the integrin lymphocyte function-associated antigen 1 (LFA-1) on the T cell surface 6 , and inhibiting subsequent T cell-mediated inflammation associated with DED.…”

Section: Introductionmentioning

confidence: 99%

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Holland

Whitley

Sall

et al. 2016

Current Medical Research and Opinion

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Objective: Report efficacy findings from three clinical trials (one phase 2 and two phase 3 [OPUS-1, OPUS-2]) of lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease (DED). Research design and methods: Three 84-day, randomized, double-masked, placebo-controlled trials. Adults (!18 years) with DED were randomized (1:1) to lifitegrast 5.0% or matching placebo. Changes from baseline to day 84 in signs and symptoms of DED were analyzed. Main outcome measures: Phase 2, pre-specified endpoint: inferior corneal staining score (ICSS; 0-4); OPUS-1, coprimary endpoints: ICSS and visual-related function subscale (0-4 scale); OPUS-2, coprimary endpoints: ICSS and eye dryness score (EDS, VAS; 0-100). Results: Fifty-eight participants were randomized to lifitegrast 5.0% and 58 to placebo in the phase 2 trial; 293 to lifitegrast and 295 to placebo in OPUS-1; 358 to lifitegrast and 360 to placebo in OPUS-2. In participants with mild-to-moderate baseline DED symptomatology, lifitegrast improved ICSS versus placebo in the phase 2 study (treatment effect, 0.35; 95% CI, 0.05-0.65; p ¼ 0.0209) and OPUS-1 (effect, 0.24; 95% CI, 0.10-0.38; p ¼ 0.0007). Among more symptomatic participants (baseline EDS !40, recent artificial tear use), lifitegrast improved EDS versus placebo in a post hoc analysis of OPUS-1 (effect, 13.34; 95% CI, 2.35-24.33; nominal p ¼ 0.0178) and in OPUS-2 (effect, 12.61; 95% CI, 8.51-16.70; p < 0.0001). Limitations: Trials were conducted over 12 weeks; efficacy beyond this period was not assessed. Conclusions: Across three trials, lifitegrast improved ICSS in participants with mild-to-moderate baseline symptomatology in two studies, and EDS in participants with moderate-to-severe baseline symptomatology in two studies. Based on the overall findings from these trials, lifitegrast shows promise as a new treatment option for signs and symptoms of DED. ARTICLE HISTORY

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“…[6,104–106] Building upon this evidence, current and new investigative therapeutic approaches have been developed to reduce ocular inflammation in order to restore the ocular microenvironment in DED (Table 1). [107–109] …”

Section: Ocular Diseasesmentioning

confidence: 99%

“…[107,125,137] One specific type of immune antagonist that has been analyzed as a potential treatment for DED is the chemokine receptor, CCR2 antagonist. [125] Topical administration of CCR2 antagonist can reduce mRNA expression levels of interleukins, IL-1α, IL-1β, and TNF-α in the cornea and conjunctiva, thereby affecting the pro-inflammatory microenvironment in the ocular tissue.…”

Section: Ocular Diseasesmentioning

confidence: 99%

“…[107] This interaction is essential to a number of T-cell interactions such as T-cell activation by antigen-presenting cells and strong adhesion to the endothelial cells during extravasation. [107,139] Due to the role of LFA-1 in T-cell function, an antagonist of LFA-1 was investigated for the treatment of DED. [139] In a desiccating stress murine model, a reduction of ocular surface inflammation was observed.…”

Section: Ocular Diseasesmentioning

confidence: 99%

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Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

Ratay

Bellotti

Gottardi³

et al. 2017

Adv Healthcare Materials

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Dry eye disease (DED), age-related macular degeneration (AMD), and Uveitis are ocular diseases that significantly affect the quality of life of millions of people each year. In these diseases, the action of chemokines, pro-inflammatory cytokines, and immune cells drives a local inflammatory response that results in ocular tissue damage. Multiple therapeutic strategies have been developed to either address the symptoms or abate the underlying cause of these diseases. Herein, we will review the challenges to deliver drugs to the relevant location in the eye for each of these diseases as well as current and innovative therapeutic approaches that attempt to restore homeostasis within the ocular microenvironment.

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Lifitegrast, a Novel Integrin Antagonist for Treatment of Dry Eye Disease

Cited by 160 publications

References 40 publications

Presence or absence of ocular surface inflammation directs clinical and therapeutic management of dry eye

Presence or absence of ocular surface inflammation directs clinical and therapeutic management of dry eye

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Modern Therapeutic Approaches for Noninfectious Ocular Diseases Involving Inflammation

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