Dataset Information

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies.

ABSTRACT:

Background

Keratoconjunctivitis sicca affects 5% to 33% of the population and is often accompanied by symptoms such as burning and dryness. This pooled analysis evaluated total and central corneal fluorescein staining (CFS) in patients receiving OTX-101 0.09% or vehicle in phase 2b/3 and 3 studies and whether improvements in corneal staining correlated with improved visual acuity.

Methods

In these randomized, vehicle-controlled studies, patients received 1 drop of OTX-101 or vehicle in both eyes twice daily. Corneal staining was performed at baseline and days 28, 56, and 84. CFS was evaluated in each zone (0-to-4 scale); total corneal staining (0-to-20 scale per eye) was averaged over both eyes. Pooled safety assessments included adverse event monitoring.

Results

Mean baseline CFS total scores (SD) were 4.2 (2.5) and 4.3 (2.6) for the OTX-101 (n = 523) and vehicle (n = 525) groups, respectively. For total corneal staining, least squares mean changes from baseline (standard error) were -0.9 (0.08) versus -0.5 (0.08) for OTX-101 and vehicle, respectively (P = 0.0008), on day 28 and -1.4 (0.09) versus -0.9 (0.09) on day 84 (P = 0.0002). There was a significantly high correlation (P = 0.0117) between reduced central corneal staining and improved visual acuity on day 84. Treatment-related adverse events were mostly mild, with instillation site pain reported by 21.8% and 4.0% of patients receiving OTX-101 and vehicle, respectively.

Conclusions

Treatment with OTX-101 led to greater improvements versus vehicle in corneal surface staining as early as 4 weeks, and further improvements were seen up to 12 weeks. OTX-101 was well tolerated in patients with keratoconjunctivitis sicca.

SUBMITTER: Malhotra R

PROVIDER: S-EPMC6749965 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Publications

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies.

Malhotra Ranjan R Devries Douglas K DK Luchs Jodi J Kabat Alan A Schechter Barry A BA Shen Lee Bridgitte B Shettle Lee L Smyth-Medina Robert R Ogundele Abayomi A Darby Charles C Bacharach Jason J Karpecki Paul P

Cornea 20191001 10

<h4>Background</h4>Keratoconjunctivitis sicca affects 5% to 33% of the population and is often accompanied by symptoms such as burning and dryness. This pooled analysis evaluated total and central corneal fluorescein staining (CFS) in patients receiving OTX-101 0.09% or vehicle in phase 2b/3 and 3 studies and whether improvements in corneal staining correlated with improved visual acuity.<h4>Methods</h4>In these randomized, vehicle-controlled studies, patients received 1 drop of OTX-101 or vehic ...[more]

PMID: 31306284

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Project description:Sjögren syndrome (SS) is an autoimmune condition that targets the salivary and lacrimal glands, with cardinal clinical signs of dry eye (keratoconjunctivitis sicca, KCS) and dry mouth. The conjunctiva of SS patients is often infiltrated by immune cells that participate in the induction and maintenance of local inflammation. The purpose of this study was to investigate immune-related molecular pathways activated in the conjunctiva of SS patients. Female SS patients (n=7) and controls (n=19) completed a series of oral, ocular surface exams. Symptom severity scores were evaluated using validated questionnaires (OSDI and SANDE). All patients fulfilled the ACR/EULAR criteria for SS and the criteria for KCS. Fluorescein and lissamine green dye staining evaluated tear-break-up time (TBUT), corneal and conjunctival disease, respectively. Impression cytology of the temporal bulbar conjunctiva was performed to collect cells lysed and subjected to gene expression analysis using the NanoString Immunology Panel. 53/594 differentially expressed genes (DEGs) were observed between SS and healthy controls; 49 DEGs were upregulated, and 4 were downregulated (TRAF5, TGFBI, KLRAP1, and CMKLRI). The top 10 DEGs in descending order were BST2, IFITM1, LAMP3, CXCL1, IL19, CFB, LY96, MX1, IL4R, CDKN1A. Twenty pathways had a global significance score greater or equal to 2. Spearman correlations showed that 29/49 upregulated DEGs correlated with either TBUT (inverse) or OSDI or conjunctival staining score (positive correlations). Venn diagrams identified that 26/29 DEGs correlated with TBUT, 5/26 DEGs correlated with OSDI, and 16/26 correlated with conjunctival staining scores. Five upregulated DEGs (CFB, CFI, IL1R1, IL2RG, IL4R) were uniquely negatively correlated with TBUT. These data indicate that the conjunctiva of SS patients exhibits a phenotype of immune activation, although some genes could be inhibitory. Some of the DEGs and pathways overlap with previous DEGs in salivary gland biopsies, but new DEGs were identified, and some of these correlated with symptoms and signs of dry eye. Our results indicate that gene analysis of conjunctiva imprints is a powerful tool to understand the pathogenesis of SS and develop new therapeutic targets.

Project description:BackgroundDry 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®; OTX-101), cyclosporine ophthalmic emulsion 0.05% (Restasis®; CsA), and lifitegrast ophthalmic solution 5% (Xiidra®; LFT) are anti-inflammatory agents indicated for DED. This analysis compared treatment patterns in patients with DED receiving OTX-101, CsA, or LFT.MethodsThis 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.ResultsOverall, 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).ConclusionsPatients 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.

Dataset Information

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies.

Background

Methods

Results

Conclusions

Publications

Effect of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, on Corneal Staining in Patients With Keratoconjunctivitis Sicca: A Pooled Analysis of Phase 2b/3 and Phase 3 Studies.

Similar Datasets

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