sar-1118 and Dry-Eye-Syndromes

Dry eye disease (DED) is a multifactorial disease of the ocular surface characterized by loss of homeostasis of the tear film and accompanied by symptoms such as ocular discomfort and visual disturbance. DED is one of the most common reasons for seeking medical care in the United States and across the world. Despite this, there are a limited number of pharmacologic therapies for the treatment of DED in the United States and Europe. This review examines the different pivotal trials for DED medications and the impact the vehicle in each trial.In recent clinical trials, the vehicle of the active formulation of the medication is often used as the active comparator. A literature review of published dry eye clinical trials was performed to identify the pivotal clinical trials of DED medications and to compare treatment effect and further understand the impact of the vehicle on clinical trial outcomes.The pivotal clinical trials for the currently approved treatments for dry eye have widely varying study designs. The variations include differences in inclusion criteria, outcome measures and efficacy endpoints, and whether or not the use of concomitant artificial tears is allowed. These differences make it difficult for accurate comparisons to be made between DED medications. Each trial demonstrated that the vehicle alone has some beneficial effect on signs and symptoms of dry eye disease.This review discusses the varying trial designs and vehicles used in the pivotal studies for the four approved dry eye medications in the United States and Europe, as well as novel vehicles under development and clinical trial recommendations.

Topics: Administration, Ophthalmic; Clinical Trials as Topic; Cyclosporine; Dry Eye Syndromes; Emulsions; Humans; Ophthalmic Solutions; Pharmaceutical Vehicles; Phenylalanine; Sulfones

Homeostasis of the lacrimal functional unit is needed to ensure a well-regulated ocular immune response comprising innate and adaptive phases. When the ocular immune system is excessively stimulated and/or immunoregulatory mechanisms are disrupted, the balance between innate and adaptive phases is dysregulated and chronic ocular surface inflammation can result, leading to chronic dry eye disease (DED). According to the Tear Film and Ocular Surface Society Dry Eye Workshop II definition, DED is a multifactorial disorder of the ocular surface characterized by impairment and loss of tear homeostasis (hyperosmolarity), ocular discomfort or pain, and neurosensory abnormalities. Dysregulated ocular immune responses result in ocular surface damage, which is a further contributing factor to DED pathology. Several therapeutics are available to break the vicious circle of DED and prevent chronic disease and progression, including immunosuppressive agents (steroids) and immunomodulators (cyclosporine and lifitegrast). Given the chronic inflammatory nature of DED, each of these agents is commonly used in clinical practice. In this study, we review the immunopathology of DED and the molecular and cellular actions of current topical DED therapeutics to inform clinical decision making.

Topics: Administration, Topical; Clinical Decision-Making; Cyclosporine; Dry Eye Syndromes; Goblet Cells; Homeostasis; Humans; Immunologic Factors; Immunosuppressive Agents; Inflammation; Integrins; Intercellular Adhesion Molecule-1; Lacrimal Apparatus; Lymphocyte Function-Associated Antigen-1; Phenylalanine; Steroids; Sulfones; T-Lymphocytes; Tears

Topics: Academies and Institutes; Cyclosporine; Diagnostic Techniques, Ophthalmological; Dry Eye Syndromes; Humans; Immunosuppressive Agents; Ophthalmic Solutions; Ophthalmology; Phenylalanine; Physical Examination; Practice Patterns, Physicians'; Sulfones; United States

Dry eye disease (DED) is a common inflammatory disorder of the ocular surface. Millions of people are affected by DED worldwide. Lifitegrast is a novel drug designed to inhibit DED-associated ocular inflammation. Four clinical trials have shown that lifitegrast is well tolerated and effective in improving symptoms and signs of DED over 12 weeks. A fifth trial showed long-term safety over 1 year. Lifitegrast has been in clinical use for more than one year in the United States and was recently approved in Canada (in December 2017). In this review, we discuss lifitegrast's novel mechanism of action and provide an overview of its clinical trial program.

Topics: Animals; Clinical Trials as Topic; Dry Eye Syndromes; Humans; Ophthalmic Solutions; Phenylalanine; Sulfones; Treatment Outcome

Sjogren's syndrome (SS) is an autoimmune disease affecting the lacrimal glands resulting in dry eye disease (DED). Ophthalmologists may be the first line of detection of Sjogren's syndrome given the frequency of DED in SS and that dry eye is often the presenting symptom. Numerous symptom questionnaires and tests have been developed to help diagnose DED, but as of yet, there is no "gold standard." Minimally invasive objective metrics are needed for a reliable diagnosis of DED. Currently there is no single test to diagnose SS-associated DED. Although there are several approaches to treatment, none are specific for DED in SS, and, generally, several methods need to be tried to find what works best for a specific patient. Treatment for DED continues to be an unmet medical need, especially given that DED in SS is typically on the severe end of the spectrum.

Topics: Administration, Ophthalmic; Cyclosporine; Dry Eye Syndromes; Fatty Acids, Omega-3; Glucocorticoids; Humans; Immunosuppressive Agents; Lubricant Eye Drops; Muscarinic Agonists; Ophthalmology; Phenylalanine; Pilocarpine; Punctal Plugs; Quinuclidines; Sjogren's Syndrome; Sulfones; Thiophenes

Dry eye disease (DED) is a common ocular disorder that can have a substantial burden on quality of life and daily activities. Lifitegrast ophthalmic solution 5.0% is the first medication approved in the US for the treatment of the signs and symptoms of DED. The aim of this article is to summarize the preclinical and clinical data on lifitegrast and discuss how lifitegrast may fit into the current treatment landscape for DED. Areas covered: A literature search of published preclinical and clinical data was conducted to review the chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy/safety of lifitegrast. The impact that lifitegrast may have on DED treatment practices is also discussed. Expert opinion: The introduction of lifitegrast provides a potentially important additional option for eye care professionals treating DED. In clinical trials conducted in adults with DED, lifitegrast ophthalmic solution 5.0% improved both signs and symptoms of DED. Of note, in 2 phase 3 trials, symptom improvements were observed as early as 2 weeks, which may be explained by lifitegrast's unique mechanism of action of blocking a specific signaling pathway in inflammation. Future research should include evaluation of whether lifitegrast can be used in combination with other DED treatments.

Topics: Adult; Clinical Trials as Topic; Dry Eye Syndromes; Humans; Lymphocyte Function-Associated Antigen-1; Ophthalmic Solutions; Phenylalanine; Quality of Life; Sulfones; Treatment Outcome

Lifitegrast is a novel small molecule integrin antagonist that blocks the binding of intercellular adhesion molecule 1 (ICAM-1) to lymphocyte function-associated antigen 1 (LFA-1). Lifitegrast ophthalmic solution 5% (Xiidra™) was recently approved in the USA for the treatment of dry eye disease. The efficacy of lifitegrast ophthalmic solution 5% was compared with vehicle in a 12-week phase 2 study and three 12-week phase 3 studies (OPUS-1, OPUS-2 and OPUS-3) in patients with dry eye disease. Taken as a whole, results of these trials support the treatment effect of lifitegrast ophthalmic solution 5% in improving a symptom of dry eye disease (i.e. the change from baseline to day 84 in the eye dryness visual analogue scale score) and a sign of dry eye disease (i.e. the change from baseline to day 84 in the inferior corneal fluorescein staining score). Lifitegrast ophthalmic solution 5% was generally well tolerated. In conclusion, lifitegrast ophthalmic solution 5% provides a new option for the treatment of dry eye disease.

Topics: Dry Eye Syndromes; Humans; Ophthalmic Solutions; Phenylalanine; Sulfones

The etiology of dry eye disease (DED) is complex and not yet fully understood, but the disease is now recognized as being associated with ocular surface inflammation. The latest advances in the understanding of the pathophysiology of DED have directed the focus of recent drug development to target the inflammatory pathways involved in the disease. Lifitegrast is a novel small molecule integrin antagonist that inhibits T cell-mediated inflammation by blocking the binding of two important cell surface proteins (lymphocyte function-associated antigen 1 and intercellular adhesion molecule 1), thus lessening overall inflammatory responses. This review highlights the role of T cells and integrins in the inflammatory process involved in the pathophysiology of DED and outlines the scientific rationale for the role of lifitegrast. In addition, the preclinical development, pharmacological properties, clinical efficacy, and safety of lifitegrast are described.

Topics: Cell Adhesion; Dry Eye Syndromes; Humans; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Phenylalanine; Sulfones

Topics: Data Collection; Dry Eye Syndromes; Humans; Nasal Sprays; Ophthalmic Solutions; Treatment Outcome; Varenicline

Topics: Cyclosporine; Dry Eye Syndromes; Humans; Nasal Sprays; Ophthalmic Solutions; Treatment Outcome; Varenicline

Characterize the safety and tolerability of lifitegrast ophthalmic solution 5.0% for the treatment of dry eye disease.. Pooled 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.. Overall, 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).. Lifitegrast 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.

Topics: Aged; Aged, 80 and over; Double-Blind Method; Drug-Related Side Effects and Adverse Reactions; Dry Eye Syndromes; Female; Humans; Male; Middle Aged; Ophthalmic Solutions; Phenylalanine; Prospective Studies; Sulfones; Treatment Outcome; Visual Analog Scale

Lifitegrast is a lymphocyte function-associated antigen-1 antagonist developed to reduce inflammation in dry eye disease (DED). We report the results of OPUS-3 (NCT02284516), a phase III study evaluating the efficacy and safety of lifitegrast versus placebo in participants with DED.. Twelve-week, phase III, randomized, double-masked, multicenter, placebo-controlled study.. Adults aged ≥18 years with Schirmer tear test (without anesthesia) ≥1 and ≤10 mm, corneal fluorescein staining score ≥2.0 (0-4 scale), eye dryness score (EDS) ≥40 (0-100 visual analogue scale [VAS]), and history of artificial tear use within 30 days of study entry.. After a 14-day placebo run-in, participants were randomized 1:1 to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 days.. The primary efficacy end point was change from baseline to day 84 in EDS. Key secondary efficacy end points were change from baseline to days 42 and 14 in EDS. Other secondary efficacy end points included additional VAS items (burning/stinging, itching, foreign body sensation, eye discomfort, photophobia, pain), ocular discomfort score (ODS), and safety/tolerability of lifitegrast versus placebo.. In the study, 711 participants were randomized: placebo, 356; lifitegrast, 355 (intention-to-treat [ITT] population). At day 84, lifitegrast-treated participants experienced significantly greater improvement from baseline in EDS versus those receiving placebo (treatment effect [TE], 7.16; 95% confidence interval [CI], 3.04-11.28; P = 0.0007). Mean changes from baseline in EDS also significantly favored lifitegrast on days 42 (TE, 9.32; 95% CI, 5.44-13.20; P < 0.0001) and 14 (TE, 7.85; 95% CI, 4.33-11.37; P < 0.0001). No statistically significant differences were observed in ODS between treatment groups at days 84, 42, or 14. A greater improvement was observed in lifitegrast-treated participants at day 42 in itching (nominal P = 0.0318), foreign body sensation (nominal P = 0.0418), and eye discomfort (P = 0.0048) versus participants receiving placebo. Most treatment-emergent adverse events were mild to moderate in severity; no serious ocular adverse events were reported.. Lifitegrast significantly improved symptoms of eye dryness, as measured by EDS, versus placebo in participants with DED. Improvement in EDS was observed as early as day 14. Lifitegrast appeared well tolerated.

Topics: Adult; Aged; Double-Blind Method; Dry Eye Syndromes; Eye Pain; Female; Humans; Lymphocyte Function-Associated Antigen-1; Male; Middle Aged; Ophthalmic Solutions; Phenylalanine; Sulfones; Visual Acuity

To evaluate the 1-year safety of lifitegrast ophthalmic solution 5.0% in patients with dry eye disease compared with placebo.. SONATA (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.. The 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.. Lifitegrast ophthalmic solution 5.0% seemed safe and well tolerated in this study, with no unexpected adverse events.

Topics: Adult; Aged; Aged, 80 and over; Double-Blind Method; Dry Eye Syndromes; Female; Fluorophotometry; Humans; Intraocular Pressure; Lymphocyte Function-Associated Antigen-1; Male; Middle Aged; Ophthalmic Solutions; Phenylalanine; Prospective Studies; Sulfones; Visual Acuity; Young Adult

Lifitegrast is an integrin antagonist that decreases T-cell-mediated inflammation associated with dry eye disease (DED). We report the results of OPUS-2, a phase III study evaluating the efficacy and safety of lifitegrast compared with placebo for the treatment of DED.. A 12-week, multicenter, randomized, prospective, double-masked, placebo-controlled clinical trial.. Adults aged ≥18 years with use of artificial tears within 30 days, inferior corneal staining score ≥0.5 (0-4 scale), Schirmer tear test (without anesthesia) ≥1 and ≤10 mm, and eye dryness score ≥40 (0-100 visual analogue scale [VAS]).. Subjects were randomized 1:1 after 14-day placebo run-in to lifitegrast ophthalmic solution 5.0% or placebo twice daily for 84 days.. Co-primary efficacy end points were change, from baseline to day 84, in eye dryness score (VAS, both eyes) and inferior corneal fluorescein staining score in the designated study eye. Secondary end points were change, from baseline to day 84, in ocular discomfort score (0-4 scale) in study eye, eye discomfort score (VAS), total corneal staining score in the study eye, and nasal conjunctival lissamine green staining score (0-4 scale) in the study eye. Treatment-emergent adverse events (TEAEs) were recorded.. A total of 718 subjects were randomized: placebo, n = 360; lifitegrast, n = 358 (intent-to-treat population). Lifitegrast-treated subjects experienced greater improvement in eye dryness than placebo-treated subjects (treatment effect, 12.61; 95% confidence interval [CI], 8.51-16.70; P < 0.0001). There was no between-group difference in inferior corneal staining (treatment effect, 0.03; 95% CI, -0.10 to 0.17; P = 0.6186). There was nominally significant improvement of secondary symptom end points among lifitegrast-treated subjects: ocular discomfort (nominal P = 0.0005) and eye discomfort (nominal, P < 0.0001). There were no between-group differences on secondary signs: total corneal staining and nasal lissamine staining. More lifitegrast-treated subjects (33.7%) than placebo-treated subjects (16.4%) experienced ocular TEAEs; no ocular TEAEs were serious.. Lifitegrast met the co-primary symptom end point (eye dryness) but not the co-primary sign end point (inferior corneal staining). Secondary end point findings were consistent with this pattern. Most ocular TEAEs were mild to moderate; there were no unexpected TEAEs. Lifitegrast warrants further consideration as a treatment for DED.

Topics: Adult; Aged; Aged, 80 and over; Cornea; Double-Blind Method; Dry Eye Syndromes; Female; Humans; Lymphocyte Function-Associated Antigen-1; Male; Middle Aged; Ophthalmic Solutions; Phenylalanine; Prospective Studies; Sulfones; Tears; Treatment Outcome; Visual Acuity; Visual Analog Scale; Young Adult

To assess the efficacy and safety of lifitegrast ophthalmic solution 5.0% compared with placebo in subjects with dry eye disease.. Prospective, randomized, double-masked, placebo-controlled, parallel arm, multicenter clinical trial.. A total of 588 adult subjects with dry eye disease.. Eligible subjects were randomized 1:1 to receive topically administered lifitegrast (5.0%) or placebo (vehicle) twice daily for 84 days after a 14-day open-label placebo run-in period. After enrollment (day 0), subjects were evaluated at days 14, 42, and 84. Key objective (fluorescein and lissamine staining scores [Ora scales]) and subjective (Ocular Surface Disease Index [OSDI], 7-item visual analog scale, and ocular discomfort score [Ora scale]) measures were assessed at all visits.. The primary objective efficacy measure (sign) was mean change from baseline 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.. The study met the primary objective efficacy ICSS end point in demonstrating superiority of lifitegrast compared with placebo (P = 0.0007). Lifitegrast significantly reduced corneal fluorescein staining (superior, P = 0.0392; total cornea, P = 0.0148) and conjunctival lissamine staining (nasal, P = 0.0039; total conjunctiva, P = 0.0086) at day 84 versus placebo. Significant (P < 0.05) improvements in nasal and total lissamine scores were observed at day 14 and maintained through day 84. 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 (AEs). The most frequent reported ocular AEs were transient intermittent instillation site symptoms (irritation, discomfort) primarily on the initial lifitegrast dose at day 0.. Lifitegrast ophthalmic solution 5.0% significantly reduced corneal fluorescein and conjunctival lissamine staining and improved symptoms of ocular discomfort and eye dryness compared with placebo when administered twice daily over 84 days.

Topics: Administration, Topical; Adult; Aged; Aged, 80 and over; Conjunctiva; Cornea; Double-Blind Method; Dry Eye Syndromes; Female; Fluorescein; Fluorometry; Humans; Lissamine Green Dyes; Lymphocyte Function-Associated Antigen-1; Male; Middle Aged; Ophthalmic Solutions; Phenylalanine; Prospective Studies; Staining and Labeling; Sulfones; Treatment Outcome; Young Adult

The aim of the study was to examine subjective responses to cyclosporine A (CsA) 0.05% versus lifitegrast 5% in individuals with dry eye disease.. This study was a retrospective review of individuals with clinically diagnosed dry eye disease treated with both CsA 0.05% and lifitegrast 5% over the course of their disease. Information collected included demographics, comorbidities, and dry eye disease signs. Treatment preferences were noted as mild or strong for a particular medication, no preference, or unable to tolerate either medication. The primary outcome measure was patient-reported medication preference. The secondary outcome measure was an examination of individual and eye factors that related to medication preference.. Sixty-four individuals (mean age 66.73 ± 13.17 years; 82.8% male, 71.9% White, 29.7% Hispanic) used both CsA and lifitegrast over the course of their disease. Of those, 33 preferred CsA (12.5% mildly and 39.1% strongly), 14 preferred lifitegrast (3.1% mildly and 18.8% strongly), 12 had no preference (18.8%), and 5 could not tolerate either medication (7.8%) due to side effects. No demographic characteristics, comorbidities, or ocular surface findings correlated with medication preference.. In individuals who used both CsA 0.05% and lifitegrast 5% over the course of their disease, a higher frequency of individuals preferred CsA. No clinical factors correlated with medication preference.

Topics: Aged; Cyclosporine; Dry Eye Syndromes; Female; Humans; Male; Middle Aged; Ophthalmic Solutions; Sulfones

Dry eye disease (DED) is a disorder characterized by loss of tear film homeostasis that causes ocular surface inflammation and damage. The incidence of DED increases with age. Cyclosporine ophthalmic solution 0.09% (CEQUA. This real-world, retrospective, longitudinal cohort study utilized Symphony Health Integrated Dataverse claims from July 2019 to June 2021. The dataset included all patients with OTX-101 claims and patients with CsA or LFT claims randomly selected 2:1 to OTX-101. Patients were sorted into 3 cohorts based on index treatment. Index date was that of first treatment claim, and follow-up period was from index date to end of clinical activity or data availability. Time to treatment discontinuation (TTD), probability of discontinuation, and treatment persistence were assessed for OTX-101 vs. CsA, then OTX-101 vs. LFT. Subgroup analysis was performed based on age and prior DED treatment. Kaplan-Meier analysis and log-rank test were used to examine TTD. A logistic model evaluated association between index treatment and discontinuation. Unadjusted and adjusted odds ratios, 95% confidence intervals, and P-values were reported, with statistically significant associations based on P-values < 0.05.. Overall, 7102 patients (OTX-101 n = 1846; CsA n = 2248; LFT n = 3008) were eligible. Median TTD was 354 days for patients receiving OTX-101 vs. 241 days for CsA and 269 days for LFT. Log-rank test indicated TTD was significantly longer for patients on OTX-101 vs. CsA (P = 0.033). Patients on CsA were 35% more likely to discontinue treatment than patients on OTX-101; OTX-101 and LFT groups had similar discontinuation rates. After 360 days, 49.8% of patients receiving OTX-101 remained on treatment vs. 39.4% of patients on CsA (P = 0.036) and 44.0% of patients on LFT (P = 0.854).. Patients receiving OTX-101 remained on treatment significantly longer and were significantly less likely to discontinue treatment than patients on CsA. Older patients remained on OTX-101 significantly longer than CsA. These findings highlight treatment pattern differences in patients with DED receiving these anti-inflammatory agents.

Topics: Anti-Inflammatory Agents; Cyclosporine; Dry Eye Syndromes; Emulsions; Humans; Longitudinal Studies; Ophthalmic Solutions; Retrospective Studies

An investigation of the treatment effect of lifitegrast ophthalmic solution, 5.0%, in different subgroups by severity of dry eye disease (DED) seems warranted.. To explore the heterogeneity across different subgroups of DED and identify which participants were most likely to achieve clinically meaningful benefit with lifitegrast treatment.. This 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.. Lifitegrast or placebo twice daily for 84 days.. Proportion 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.. In 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).. These 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.. ClinicalTrials.gov Identifier: NCT02284516.

Topics: Double-Blind Method; Dry Eye Syndromes; Female; Humans; Male; Middle Aged; Ophthalmic Solutions; Phenylalanine; Prospective Studies; Randomized Controlled Trials as Topic; Sulfones; Treatment Outcome

The etiology of meibomian gland dysfunction (MGD) is incompletely understood, despite being a common ophthalmic condition and an area of unmet medical need. It is characterized by an insufficiency in glandular provision of specialized lipids (meibum) to the tear film and is a major cause of dry eye. Work in the allergic eye disease (AED) mouse model has revealed an immunopathogenic role in MGD causation, now raising interest in the applicability of immunomodulatory therapies. As such, we herein ask whether inhibition of lymphocyte function associated antigen (LFA)-1/intracellular adhesion molecules (ICAM)-1 signaling via topical lifitegrast administration has a therapeutic effect on MGD in AED mice.. Mice were induced with AED by i.p. injection of ovalbumin (OVA) mixed with alum and pertussis toxin, followed 2 weeks later by once daily topical OVA challenges for 7 days. Mice were treated topically with 5% lifitegrast ophthalmic solution or vehicle (PBS) 30 min prior to challenge. We developed a clinical ranking method to assess MGD severity, and also scored clinical allergy. Conjunctivae and draining lymph nodes were collected for flow cytometry.. Topical lifitegrast significantly inhibited clinical MGD severity, which was associated with diminished pathogenic T. In AED mice, lifitegrast inhibited MGD severity marked by a reduction in select immune populations in the conjunctiva. Our findings warrant future examination of lifitegrast in the treatment of patients with forms of MGD.

Topics: Animals; Dry Eye Syndromes; Eyelid Diseases; Humans; Hypersensitivity; Immunity; Lymphocyte Function-Associated Antigen-1; Meibomian Gland Dysfunction; Meibomian Glands; Mice; Phenylalanine; Sulfones; Tears

Graft-versus-host disease (GVHD) is a common complication in patients undergoing allogeneic stem cell transplantation for acute myeloblastic leukemia that could be very difficult to treat. Lifitegrast 5% (Xiidra@, Novartis), a new immunosuppressive eye drop, was recently approved by the FDA for the treatment of severe dry eye and is currently under review by the European Medicines Agency. In France, lifitegrast has been approved by the French authorities for temporary use in refractory dry eye syndrome resistant to tear substitutes and topical cyclosporine. To date, serious complications have been reported only exceptionally. In this article, we report the case of a 65-year-old patient with a medical history of acute myeloid leukemia (AML) diagnosed in 2015 who received a first matched related donor transplant. In 2019, this patient developed chronic GVH involving the skin, oral mucosa and eye. Despite taking topical and systemic medications for 3 months, the patient did not report relief of ocular symptoms. Therefore, lifitegrast was prescribed. To our knowledge, we report the first case of corneal perforation in which evisceration was required following treatment with topical lifitegrast for chronic GVH. In the case presented here, it can be assumed that the underlying mechanisms leading to corneal perforation are multifactorial. Using drug accountability criteria, lifitegrast appears to be strongly associated with the development of bacterial keratitis and corneal perforation.

Topics: Aged; Amputation, Surgical; Dry Eye Syndromes; Graft vs Host Disease; Humans; Phenylalanine; Sulfones

To evaluate the clinical characteristics, outcomes, and adverse reactions after the use of lifitegrast 5% ophthalmic solution for the treatment of patients with dry eye disease (DED).. Retrospective chart review was performed in 121 patients seen at the Duke Eye Center with DED who were prescribed lifitegrast 5% and seen for follow-up after treatment initiation. Charts were reviewed for meibomian gland dysfunction (MGD) grading, conjunctival and corneal staining scores, and tear breakup time (TBUT), as well as matrix metalloproteinase-9 (MMP-9) levels. Ocular Surface Disease Index (OSDI) questionnaire scores and self-reported adverse reactions were also assessed.. The average patient age was 60.5 years (range, 22-88 years); 87.6% were female, and 20.7% had a previous autoimmune disease diagnosis. Of the 54 eyes with an initial positive MMP-9, 21 eyes (38.9%) normalized after treatment. The ocular symptoms OSDI subscore demonstrated an improvement of -2.43±6.85 (P=0.011) after treatment. Corneal staining scores showed an average change of -0.15 (P=0.007). The average change in TBUT was 1.9 sec (P<0.001). Self-reported adverse reactions were noted in 31.4% of patients. There was no statistically significant change in MGD grading. Patients with moderate-severe DED showed statistically significant improvements in conjunctival and corneal staining scores and TBUT (-0.17±0.66, P=0.0442; -0.54±0.65, P<0.001; +2.02±2.63, P=0.004, respectively).. Lifitegrast 5% is a useful therapeutic option for DED with a moderate proportion of self-reported adverse reactions, all of which were related to ocular discomfort. Treatment with lifitegrast was associated with statistically significant improvements in MMP-9 levels, ocular symptoms, corneal staining, and TBUT.

Topics: Adult; Aged; Aged, 80 and over; Conjunctiva; Cornea; Dose-Response Relationship, Drug; Dry Eye Syndromes; Female; Follow-Up Studies; Humans; Lymphocyte Function-Associated Antigen-1; Male; Matrix Metalloproteinase 9; Middle Aged; Ophthalmic Solutions; Phenylalanine; Retrospective Studies; Sulfones; Tears; Treatment Outcome; Young Adult

Increased interferon gamma (IFN-γ) expression in dry eye causes ocular surface epithelial disease termed keratoconjunctivitis sicca (KCS). The purpose of this study was to investigated the effects of the LFA-1 antagonist, lifitegrast, in a mouse desiccating stress (DS) dry eye model that develops KCS similar to Sjögren syndrome.. Mice were treated with vehicle or lifitegrast twice daily for 5 days and expression of Th1 family genes (IFN-γ, CXCL9, and CXCL11) was evaluated by real-time polymerase chain reaction. Cornea barrier function was assessed by Oregon Green dextran staining and goblet cell number and area were measured.. Compared to the vehicle-treated group, the lifitegrast-treated group had significantly lower expression of Th1 family genes, less corneal barrier disruption, and greater conjunctival goblet cell density/area.. These findings indicate that lifitegrast inhibits DS-induced IFN-γ expression and KCS. This suggests that ICAM-LFA-1 signaling is involved with generation of Th1 inflammation in KCS.

Topics: Animals; Chemokine CXCL11; Chemokine CXCL9; Dry Eye Syndromes; Female; Inflammation; Interferon-gamma; Keratoconjunctivitis Sicca; Mice; Mice, Inbred C57BL; Ophthalmic Solutions; Phenylalanine; Sulfones; Th1 Cells

This study evaluated the clinical activity of RGN-259 (thymosin β4) in comparison with cyclosporine A (CsA), diquafosol (DQS), and lifitegrast (LFA) in a murine model of dry eye. The model was NOD.B10-H2

Topics: Animals; Conjunctiva; Cornea; Cyclosporine; Disease Models, Animal; Dry Eye Syndromes; Female; Goblet Cells; Humans; Inflammation Mediators; Lacrimal Apparatus; Male; Mice; Mice, Inbred NOD; Mucins; Ophthalmic Solutions; Phenylalanine; Polyphosphates; Prescription Drugs; Scopolamine; Sulfones; Tears; Thymosin; Treatment Outcome; Uracil Nucleotides

Five new drugs marketed within the last year that are used for medical problems often experienced by the elderly have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs include two antidiabetic agents, an agent for gout, an antipsychotic agent, and a drug for dry eye disease.

Topics: Anti-Inflammatory Agents; Antipsychotic Agents; Drugs, Investigational; Dry Eye Syndromes; Gout Suppressants; Humans; Hypoglycemic Agents; Insulin, Long-Acting; Peptides; Phenylalanine; Piperidines; Sulfones; Thioglycolates; Triazoles; Urea

Topics: Administration, Ophthalmic; Anti-Inflammatory Agents; Drug Administration Schedule; Dry Eye Syndromes; Humans; Lymphocyte Function-Associated Antigen-1; Ophthalmic Solutions; Phenylalanine; Sulfones; Treatment Outcome

Dry eye disease is an extremely common condition affecting millions worldwide. The underlying pathophysiological mechanism is thought to be localized inflammation of the ocular surface resulting in the localization of T cells at this surface followed by their activation and subsequent liberation of cytokines. This effect on T cells results from the binding of lymphocyte function-associated antigen-1 (LFA-1) located on T cells to intercellular adhesion molecule 1 (ICAM-1) expressed on inflamed epithelium and endothelium, and on T cells. Lifitegrast is a T-cell integrin antagonist designed to mimic ICAM-1, thus blocking the interaction of LFA-1 and ICAM-1. Lifitegrast enters the systemic circulation to a limited extent thus reducing the likelihood of unwanted systemic reactions. Clinical trials in over 2,500 subjects with dry eye disease have shown that 5.0% lifitegrast given by ocular instillation causes a significant reduction in objective and subjective signs and symptoms of the disease. These beneficial effects are associated with a relatively low incidence of unwanted effects, almost all local in nature. In light of these findings, lifitegrast was approved by the Food and Drug Administration (FDA) in 2016 for the treatment of dry eye disease, the first drug with this mechanism of action to be so approved.

Topics: Anti-Inflammatory Agents; Clinical Studies as Topic; Drug Evaluation, Preclinical; Dry Eye Syndromes; Humans; Inflammation; Intercellular Adhesion Molecule-1; Lymphocyte Function-Associated Antigen-1; Ophthalmic Solutions; Phenylalanine; Sulfones; T-Lymphocytes