Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye.
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ABSTRACT:
SUBMITTER: Zhong M
PROVIDER: S-EPMC4025648 | biostudies-literature | 2012 Mar
REPOSITORIES: biostudies-literature
Publications
Discovery and Development of Potent LFA-1/ICAM-1 Antagonist SAR 1118 as an Ophthalmic Solution for Treating Dry Eye.
Zhong Min M Gadek Thomas R TR Bui Minna M Shen Wang W Burnier John J Barr Kenneth J KJ Hanan Emily J EJ Oslob Johan D JD Yu Chul H CH Zhu Jiang J Arkin Michelle R MR Evanchik Marc J MJ Flanagan W Mike WM Hoch Ute U Hyde Jennifer J Prabhu Saileta S Silverman Jeffrey A JA Wright Jasmin J
ACS medicinal chemistry letters 20120131 3
LFA-1/ICAM-1 interaction is essential in support of inflammatory and specific T-cell regulated immune responses by mediating cell adhesion, leukocyte extravasation, migration, antigen presentation, formation of immunological synapse, and augmentation of T-cell receptor signaling. The increase of ICAM-1 expression levels in conjunctival epithelial cells and acinar cells was observed in animal models and patients diagnosed with dry eye. Therefore, it has been hypothesized that small molecule LFA-1 ...[more]
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Project description:Dry eye disease (DED) is a common ocular disorder associated with inflammation of the lacrimal gland and ocular surface. The interaction of the integrin lymphocyte function-associated antigen-1 (LFA-1) with its cognate ligand intercellular adhesion molecule-1 (ICAM-1) is known to have important roles in the interaction of a variety of cells involved in immune responses and inflammation, including those prominent in ocular surface inflammation. Lifitegrast, an LFA-1 antagonist that blocks binding of ICAM-1 to LFA-1, has recently been approved in the United States for the treatment of signs and symptoms of DED. In this review, we evaluate research findings to explore the potential role of LFA-1/ICAM-1 interaction in the pathophysiology of DED, and the evidence supporting LFA-1/ICAM-1 interaction as a rational therapeutic target in DED. The results of our review suggest that LFA-1/ICAM-1 interaction may play important roles in the cell-mediated immune response and inflammation associated with DED, including facilitating the homing of dendritic cells to the lymph nodes, interaction of dendritic cells with T cells and subsequent T cell activation/differentiation, migration of activated CD4+ T cells from the lymph nodes to the ocular surface, reactivation of T cells by resident antigen-presenting cells at the ocular surface, and recruitment and retention of LFA-1-expressing T cells in the conjunctival epithelium. Based on the available evidence, inhibition of LFA-1/ICAM-1 interaction represents a rational targeted approach in treating DED. Notably, inhibition of LFA-1/ICAM-1 binding with lifitegrast offers a novel approach to reducing ocular surface inflammation in this condition.
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Project description:Aimto assess the effectiveness of a new combination of topical solution with Hyaluronic Acid 0.2% and arnica extract 0.1% in reducing dry eye symptoms in a population of pediatric patients.Methods52 pediatric patients (aged 9 to 14 years) with signs and symptoms of dry eyes and allergic conjunctivitis were included in the study. Twenty-six patients were assigned to the Hyaluronic Acid 0.2%/ Arnica extract 0.1% group (Study Group) while 26 patients to the Hyaluronic Acid 0.2% group (Control Group). Clinical signs and symptoms were assessed at baseline and at week 4. The assessment plan included: slit-lamp examination, tear film break up time (TBUT), Schirmer's test and conjunctival hyperemia score. Ocular surface disease index (OSDI) score was used to evaluate subjective symptoms of dry eye disease.ResultsBoth treatment groups showed improvements in the estimated clinical parameters after treatment. OSDI score was significantly lower in both treatment groups (Study group p = 0.02; Control group p = 0.04) at the end of the follow up period. Improvements in TBUT, Schirmer's test results and conjunctival hyperemia were statistically significant only in the Study group (p = 0.021; p = 0.03; p < 0.01 respectively).ConclusionsPreliminary findings suggest that combined topical Hyaluronic Acid 0.2% and arnica extract 0.1% can be effective in reducing symptoms and signs of dry eye disease in children.
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Project description:Rebamipide ophthalmic solution is a mucin secretagogue which is an important therapeutic agent in the treatment of dry eye. It has been noted that dry eye in office workers is associated with a decrease in secretory mucin. This study aimed to evaluate the effects of 2% rebamipide ophthalmic solution in mice subjected to environmental dry eye stress (EDES), which mimics the conditions of office workers. Thirty eyes from thirty BALB/c mice (eight-week-old males) were divided into three treatment groups: artificial tear (vehicle), 2% rebamipide ophthalmic solution, and 0.1% hyaluronic acid (HA) ophthalmic solution. After four days of pretreatment, mice were exposed to EDES for three days. The corneal subbasal nerve and inflammatory cells were then examined using in vivo confocal microscopy. Following EDES exposure, the lissamine green staining score was significantly lower and corneal sensitivity was more preserved in the 2% rebamipide group than in the HA group. In addition, the subbasal nerve fiber density was significantly higher and the DC density was significantly lower in the 2% rebamipide group than in the HA group. Overall, the topical rebamipide ophthalmic solution showed more favorable therapeutic effects when compared to the HA ophthalmic solution in a mouse model of EDES, likely owing to its anti-inflammatory and neuroprotective effects.
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Project description:PurposeCharacterize the safety and tolerability of lifitegrast ophthalmic solution 5.0% for the treatment of dry eye disease.MethodsPooled data from five randomized controlled trials were analyzed. Key inclusion criteria were adults with dry eye disease (Schirmer tear test score ⩾1 and ⩽10 mm, eye dryness score ⩾40 (visual analog scale 0-100), corneal staining score ⩾2.0 (0-4 scale)). Participants were randomized to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 or 360 days. Treatment-emergent adverse events and drop comfort scores were assessed.ResultsOverall, 2464 participants (lifitegrast, n = 1287; placebo, n = 1177) were included. Ocular treatment-emergent adverse events occurring in >5% in either group were instillation site irritation (lifitegrast, 15.2%; placebo, 2.8%), instillation site reaction (lifitegrast, 12.3%; placebo, 2.3%), and instillation site pain (lifitegrast, 9.8%; placebo, 2.1%); the most common (> 5%) nonocular treatment-emergent adverse event was dysgeusia (lifitegrast, 14.5%; placebo, 0.3%). The majority of treatment-emergent adverse events were mild to moderate in severity. Discontinuation due to treatment-emergent adverse events occurred in 7.0% (lifitegrast) versus 2.6% (placebo) of participants (ocular: 5.5% vs 1.5%; nonocular: 1.9% vs 1.1%). Drop comfort scores with lifitegrast improved within 3 min of instillation and the score at 3 min improved across visits (12-week trials (both eyes, day 84 vs 0): 2.0 vs 3.3; SONATA (day 360 vs 0): right eye, 1.2 vs 1.7; left eye, 1.2 vs 1.8).ConclusionLifitegrast ophthalmic solution 5.0% appeared to be safe and well tolerated for the treatment of dry eye disease. Drop comfort with lifitegrast improved within 3 min of instillation.
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Project description:PurposeTo evaluate the 1-year safety of lifitegrast ophthalmic solution 5.0% in patients with dry eye disease compared with placebo.MethodsSONATA (Safety Of a 5.0% coNcentrATion of lifitegrAst ophthalmic solution) was a multicenter, randomized, prospective, double-masked, placebo-controlled phase 3 study (NCT01636206). Adults (≥18 years) with dry eye disease (Schirmer test score ≥1 and ≤10 mm; corneal staining score ≥2.0) were randomized 2:1 to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 360 days. The primary objective was percentage and severity of treatment-emergent adverse events (TEAEs). Secondary objectives were ocular safety measures: corneal fluorescein staining, drop comfort, best-corrected visual acuity, slit-lamp biomicroscopy, and intraocular pressure over 7 visits. Exploratory objectives included concentration of lifitegrast in plasma.ResultsThe safety population comprised 331 participants (220 lifitegrast; 111 placebo). There were no serious ocular TEAEs. Overall, 53.6% of participants receiving lifitegrast experienced ≥1 ocular TEAE versus 34.2% in the placebo group; most TEAEs were mild to moderate in severity. Rates of discontinuation because of TEAEs were 12.3% (lifitegrast) versus 9.0% (placebo). The most common (>5%) TEAEs occurring in either treatment group were instillation site irritation (burning), instillation site reaction, visual acuity reduced, dry eye, and dysgeusia (change in taste). Ocular safety parameters for lifitegrast were similar to placebo. The mean plasma lifitegrast concentration at 360 days (n = 43) was below the limit of detection. There was no indication of systemic toxicity or localized infectious complications secondary to chronic immunosuppression.ConclusionsLifitegrast ophthalmic solution 5.0% seemed safe and well tolerated in this study, with no unexpected adverse events.
| S-EPMC4859202 | biostudies-literature
Project description:IntroductionTo evaluate the effects of a new lubricating, antioxidant solution (VisuEvo®) on dry eye disease (DED) in patients undergoing cataract surgery.MethodsPatients requiring cataract surgery with either healthy ocular surface or mild DED (tear break-up time, TBUT > 7, Schirmer I test > 15 mm/5 min) were enrolled in this multicenter, open-label, randomized, prospective study. Scheduled visits were 2 weeks before surgery (screening), day of surgery (V0), week 1 (V1), and 2 (V2) after surgery. VisuEvo® was self-administered three times daily for the whole study duration (group A); the control group (group B) had no tear substitute administration. The primary endpoint was the change in TBUT over time; the secondary endpoints were changes in Ocular Surface Disease Index (OSDI), ocular surface staining, the Schirmer I test, and osmometry.ResultsA total of 45 patients were included (group A, 23; group B, 22; age 74 ± 8 years). At the screening, TBUT was similar between the groups (group A, 8.5 ± 1.8 s; group B, 7.8 ± 0.7, p = 0.11). At the scheduled visits, TBUT increase vs screening visit was significantly higher in group A: +1.2 s at V0, +1.4 s at V1, and +1.9 s at V2 (p < 0.01). Also, OSDI was significantly lower in group A at V0, V1, and V2 (p < 0.027). After surgery, corneal staining was absent in 65-78% of group A compared with 54-59% in group B. The two groups did not show any significant differences of osmometry and the Schirmer I test.ConclusionsThe ocular surface was more protected and quickly restored from surgery when VisuEvo® was used from 2 weeks preoperatively to 2 weeks postoperatively.Trial registrationClinicalTrials.gov identifier, NCT03833908.
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Project description:The purpose of this study was to investigate the efficacy and safety of the administration of retinol palmitate (VApal) ophthalmic solution (500 IU/mL) for the treatment of patients with dry eye.This study included 66 patients with dry eye. After a 2-week washout period, patients were randomized (1:1) into either a VApal ophthalmic solution or a placebo group, and a single drop of either solution was administered six times daily for 4 weeks. Efficacy measures were 12 subjective symptoms, rose bengal (RB) and fluorescein staining scores, tear film breakup time, and tear secretion. Safety measures included clinical blood and urine analyses and adverse event recordings.In comparisons of the two groups, the mean change in RB staining score from baseline was significantly lower in the VApal group at 2 and 4 weeks (P<0.05 and P<0.01, respectively). Furthermore, the fluorescein clearance rate (fluorescein staining score) was significantly higher in the VApal group at 4 weeks (P<0.05). The VApal group showed a significant improvement in blurred vision at 1 and 2 weeks (P<0.01 and P<0.05, respectively), and the mean change in the total score for subjective symptoms from baseline was significantly lower in the VApal group at 1 week (P<0.05). In before- and after-intervention comparisons, the fluorescein and RB staining scores showed improvement in both groups. Improvement was noted for 11 subjective symptoms in the VApal group and for seven symptoms in the placebo group. No significant differences in adverse events and reactions were found between the groups.VApal ophthalmic solution (500 IU/mL) is safe and effective for the treatment of patients with dry eye.
| S-EPMC5491700 | biostudies-other
Project description:AimThe aim of this study is to evaluate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status in patients with dry eyes.Materials and methodsA prospective study was carried out on forty eyes of patients having signs and symptoms of dry eye. Two percent rebamipide ophthalmic solution was applied four times a day for a period of 4 weeks. Patients were evaluated on the basis of dry eye-related symptom score, tear film break-up time (TFBUT), tear meniscus height, fluorescein ocular surface staining score (FOSS), and the Schirmer's test at the end of 2, 4, 6, and 12 weeks and their values were compared with the baseline.ResultsSignificant improvement was noted in the mean dry eye-related symptom score, TBUT, and the FOSS values from the baseline at the end of 2, 4, 8, and 12 weeks. The values of tear meniscus height and Schirmer's test were improved at the end of 8 weeks but were not statistically significant.ConclusionNearly 2% rebamipide ophthalmic solution provided relief in the symptoms of patients having dry eyes. It also prevented further ocular surface damage and aided in stabilizing the tear film.
| S-EPMC6219330 | biostudies-literature
Project description:ObjectiveDry eye disease (DED) is a worldwide source of ocular discomfort. This first-in-human phase 2 clinical study determined the efficacy of treating signs and symptoms of DED using an ophthalmic solution of synthesized mimetic of human collagen (ST-100).DesignThis double-masked, randomized, study compared high (60 μg/mL) and low (22 μg/mL) dose ST-100 to vehicle utilizing the Ora, Inc. Controlled Adverse Environment (CAE) during a 28-day period.ParticipantsParticipants included males and females ≥ 18 years of age with signs and symptoms of DED for ≥ 6 months that worsened during CAE exposure who were not taking any topical prescription therapeutic.InterventionParticipants applied ST-100 or vehicle placebo topically to both corneas (1 drop) twice daily via a blow-fill-sealed preservative-free container.Main outcome measuresThe prespecified primary efficacy sign end point was mean change from baseline (CFB) in total corneal fluorescein staining, and the primary symptom end point was mean CFB in ocular discomfort. A secondary prespecified efficacy end point was CFB in unanesthetized Schirmer's test for tear film production.ResultsOf 160 subjects in the intent-to-treat population (112 female, 48 male, median age 64), 146 completed the study. Total corneal fluorescein staining CFB improved for high-dose ST-100, with superiority over vehicle when both eyes were considered together (2-sample t test: P = 0.0394). High-dose ST-100 was superior to vehicle in Schirmer's CFB for the study eye (least squares mean difference [confidence interval] = 2.3 [0.6, 4.0], P = 0.0094). For study eyes, the proportion of Schirmer's test responders (CFB ≥ 10 mm, Schirmer's responder rate) was 12.2% for high-dose ST-100 versus 0.0% for vehicle (P = 0.0266). The CFB for ocular discomfort score improved in study eyes for high- and low-dose ST-100 (paired t test, P = 0.0133, P = 0.0151, respectively) but without superiority over vehicle (ANCOVA: P = 0.5696, P = 0.8968, respectively). ST-100 Schirmer's responders also demonstrated total elimination of worsening of corneal fluorescein stain during the stress of CAE sessions.ConclusionsST-100 significantly improved tear production and related outcomes in DED and was well-tolerated in reducing symptoms.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
| S-EPMC10838901 | biostudies-literature
Project description:ImportanceAn investigation of the treatment effect of lifitegrast ophthalmic solution, 5.0%, in different subgroups by severity of dry eye disease (DED) seems warranted.ObjectiveTo explore the heterogeneity across different subgroups of DED and identify which participants were most likely to achieve clinically meaningful benefit with lifitegrast treatment.Design, setting, and participantsThis post hoc responder analysis was performed using the data from the phase 3 OPUS-2 and OPUS-3 studies, which were 12-week, prospective, double-masked, multicenter, placebo-controlled, randomized, parallel-arm clinical trials that previously demonstrated the efficacy of lifitegrast in DED. Pooled data were stratified into 4 subgroups based on severity of inferior corneal staining score (ICSS; ≤1.5 vs >1.5) and eye dryness score (EDS; <60 or ≥60) at baseline. Data were collected from December 7, 2012, to October 5, 2015, and post hoc analysis was performed from April 14, 2020, to July 30, 2021.InterventionsLifitegrast or placebo twice daily for 84 days.Main outcomes and measuresProportion of participants with (1) a clinically meaningful improvement in signs (ICSS or total corneal staining score [TCSS]) and symptoms (EDS or global visual analog scale [VAS]) and (2) a composite response for a given sign and symptom end point pair at day 84 were measured. Clinically meaningful improvement was defined as at least 30% improvement in symptoms (EDS or global VAS) and either at least a 1-point improvement in ICSS or at least a 3-point improvement in TCSS. For the composite responder analysis, the end point pairs were defined as at least a 30% reduction in EDS and at least a 1-point improvement in ICSS; at least a 30% reduction in EDS and at least a 3-point improvement in TCSS; at least a 30% improvement in global VAS and at least a 1-point improvement in ICSS; and at least a 30% improvement in global VAS and at least a 3-point improvement in TCSS.ResultsIn total, 1429 participants (716 in the placebo group and 713 in the lifitegrast group) were analyzed (1087 women [76.1%]; mean [SD] age, 58.7 [14.3] years). For the overall pooled population, responder and composite responder rates favored lifitegrast vs placebo (odds ratio range, 1.29 [95% CI, 1.05-1.59] to 2.10 [95% CI, 1.68-2.61]; P ≤ .02). In the composite analysis, the subgroup with ICSS of greater than 1.5 and EDS of at least 60 at baseline (ie, moderate to severe DED) demonstrated a 1.70- to 2.11-fold higher odds of achieving clinically meaningful improvement with lifitegrast across all sign and symptom end point pairs (P ≤ .001).Conclusions and relevanceThese post hoc findings suggest that lifitegrast ophthalmic solution, 5.0%, treatment may be associated with a response in participants with moderate to severe signs and symptoms of DED.Trial registrationClinicalTrials.gov Identifier: NCT02284516.
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