Efficacy and Safety of a Preservative-Free Latanoprost Cationic Emulsion in Patients with Open-Angle Glaucoma and Concurrent Ocular Surface Disease: A Randomized Phase 2 Study.

Purpose: To compare intraocular pressure (IOP), ocular surface disease (OSD) parameters, and safety in patients with open-angle glaucoma (OAG)/ocular hypertension (OH) and concurrent OSD treated with preservative-free latanoprost 0.005% cationic emulsion (PF-latanoprost-E) or travoprost-Z 0.004% ophthalmical solution containing a soft preservative system. Methods: Patients with OAG/OH and OSD were randomized to treatment with PF-latanoprost-E or travoprost-Z nightly for 3 months. Outcomes included mean diurnal IOP reduction; OSD endpoints, including symptom improvement, tear break-up time (TBUT), and corneal fluorescein staining (CFS) score; and safety after 1 and 3 months. Results: A total of 105 patients were randomized, 51 to PF-latanoprost-E and 54 to travoprost-Z. IOP reductions (LS mean differences) at 3 months were numerically greater in the PF-latanoprost-E than in the travoprost-Z group at 8AM (7.2 versus 6.0 mmHg), 10AM (6.7 versus 5.9 mmHg), and 4PM (6.0 versus 5.4 mmHg). LS mean changes in IOP from baseline in both groups at 1 and 3 months, however, were comparable. Mean ± SD CFS scores on the Ora scale at month 3 showed significantly greater reductions in the PF-latanoprost-E than in the travoprost-Z group (-1.07 ± 1.863 versus -0.16 ± 2.553 P = 0.0461). The mean TBUT at month 3 showed similar improvements in both groups (1.1 versus 1.0 s, P > 0.05). OSD symptoms improved but did not differ significantly in the two groups. Overall safety was comparable in both groups. Conclusion: PF-latanoprost-E effectively and safely lowered IOP and improved OSD parameters in patients with OAG/OH. These findings provide evidence for the beneficial effects of this new formulation of latanoprost in glaucoma patients with OSD.

[The place of ciclosporin A cationic emulsion 0.1% in the therapy of xerophthalmia]. / Mesto kationnoi emul'sii tsiklosporina A 0,1% v terapii kseroftal'mii.

Dry eye disease (DED) is pathogenetically based on inflammation of the ocular surface. A step-by-step approach to DED treatment involves early initiation of anti-inflammatory therapy, including instillation of cyclosporine A (CsA). However, recommendations for the use of topical CsA in clinical practice are limited. This article presents an expert consensus on practical recommendations for the management of patients with DED, including indications, time of initiation and duration of CsA therapy, comparison of CsA forms currently registered in the Russian Federation, as well as issues of patient education.

Real-world insights and outcomes related to ciclosporin A 0.1% cationic emulsion for the long-term treatment of dry eye disease in Germany: Country-level sub-analysis of the PERSPECTIVE study.

PURPOSE: The PERSPECTIVE study was a real-world European, non-interventional, multicenter, observational study that evaluated the effectiveness, tolerability, and safety of ciclosporin A (CsA) 0.1% cationic emulsion (CE) in routine clinical practice as a treatment for adults with severe keratitis and dry eye disease (DED) that remained insufficiently controlled with artificial tears. This sub-analysis examined data from ophthalmology clinics in Germany to provide more precise insights into treatment patterns, outcomes, and clinical decision-making related to CsA 0.1% CE. METHODS: Study data were collected from adults starting CsA 0.1% CE (one drop in both eyes at bedtime) and followed up at Week 4, 12, and 24, and Month 12. The primary endpoint was mean change from baseline in corneal fluorescein staining (CFS) score (Oxford Grade Scale) at Month 12. Secondary endpoints examined the severity of ocular signs and symptoms, and adverse events (AEs). RESULTS: A total of 236 patients from 20 ophthalmology clinics in Germany participated in the PERSPECTIVE study (69.9% female; mean age 60.8 years). Following treatment with CsA 0.1% CE, patients experienced significant reductions in CFS score from Week 4, which were maintained through to Month 12 (P < 0.0001). From baseline, 81.6% of patients experienced an improvement in CFS score at Month 12. CsA 0.1% CE provided significant reductions in the severity of eyelid and conjunctival erythema at Month 12 compared with baseline (P < 0.001), as well as significant reductions in the severity of subjective ocular symptoms (all P ≤ 0.015). Safety data were consistent with the known safety profile of CsA 0.1% CE. Tolerability was rated as "satisfactory," "good," or "very good" by 97.2% of physicians and 95.7% of patients. CONCLUSION: Outcomes in Germany were similar to those reported for the overall European study population and are indicative of the treatment results that ophthalmologists may expect to see with CsA 0.1% CE treatment in real-life clinical practice. Treatment with CsA 0.1% CE provided long-term improvements over 12 months and was generally well tolerated.

Review of clinical outcomes of a cationic emulsion tear substitute in patients with dry eye disease.

First-line options for the treatment of dry eye disease (DED) rely on artificial tears (ATs), among which cationic emulsion (CE)-based ATs have been developed in order to mimic the healthy tear film for an improved restoration of the ocular surface homeostasis. In this review, we describe the outcomes reported in several studies, assessing the mode of action, ocular tolerance and clinical performance of a CE-based AT. Pilot studies have revealed that CE-based ATs can increase the volume and stability of the tear film while limiting its evaporation rate. Larger studies have demonstrated that CE-based ATs play a significant role in the improvement of both objective and subjective DED parameters, including superior efficacy on DED symptoms compared to several other available AT formulation types. Concomitantly, CE-based ATs have been shown to help patients to prevent or recover from corneal defects associated with refractive surgery. These positive outcomes on ocular surface epithelia are likely due to the combination of unique rheological behaviour and intrinsic anti-inflammatory properties. Based on all clinical findings, CE-based ATs represent a valuable treatment option for patients with various etiologies of DED including evaporative forms and would deserve evaluation of benefits in other surgical intervention types triggering DED.

NOVATIVE: A Phase II/III, Multicenter, Double-masked, Randomized Study of Cyclosporine A 0.05% and 0.1% Ophthalmic Cationic Emulsion Versus Vehicle in Patients with Vernal Keratoconjunctivitis.

PURPOSE: This study evaluates the efficacy and tolerability of cyclosporine A cationic emulsion (CsA-CE) in patients ≥4 years of age with moderate-to-severe vernal keratoconjunctivitis (VKC). METHODS: This Phase II/III, multicenter, double-masked, dose-ranging study had 2 treatment periods: a 4-week, randomized, vehicle-controlled period in which patients received 0.05% CsA-CE, 0.1% CsA-CE, or vehicle eye drops 4 times daily (period 1) and a 3-month period in which patients received 0.05% CsA-CE or 0.1% CsA-CE 2 or 4 times daily (period 2). The primary efficacy end point was rating of subjective symptoms at day 28 in period 1 per the BenEzra scale. FINDINGS: All groups showed improvement in subjective VKC symptoms at day 28, without a statistically significant difference between 0.05% or 0.1% CsA-CE vs vehicle. Both CsA-CE doses produced statistically significant improvements in corneal fluorescein staining scores vs vehicle at day 28; improvements were evident as early as week 1 and continued through month 1. Progressive reduction in subjective itching was evident after week 1 and continued through month 1. Treatment for an additional 3 months further improved subjective symptoms and objective signs of VKC in both CsA-CE groups. Improvement was most notable with 0.1% CsA-CE in patients with severe keratitis. The safety and tolerability profile is favorable. IMPLICATIONS: Although treatment with 0.05% and 0.1% CsA-CE showed clinical efficacy in alleviating keratitis and itching as early as week 1, with sustained benefit through 1 month, the primary efficacy end point was not met. These findings informed the design of the Phase III trial of 0.1% CsA-CE (Vernal Keratoconjunctivitis Study). CLINICALTRIALS: gov identifier: NCT00328653.

Assessment of the efficacy of 0.1% cyclosporine A cationic emulsion in the treatment of dry eye disease during COVID-19 pandemic.

Objective: To assess the efficacy of 0.1% cyclosporine A (CsA) cationic emulsion (CE) in the treatment of dry eye disease (DED) in terms of ocular surface disease index (OSDI). Methods: DED patients with corneal fluorescein staining grade (CFS) ≤ 3 on the Oxford scale and Schirmer test score < 10 mm/ 5 min were enrolled for once-daily CsA use in this observational, prospective, one-center study. Efficacy of CE at 30, 60, and 90-day follow-up visit was evaluated using OSDI questionnaire. Both the overall OSDI score and the outcomes for all subscales - ocular symptoms (OS), vision-related function (VRF) and environmental triggers (ET) were considered. Results: Twelve patients (10 women and 2 men), whose baseline OSDI ranged between 27.08 and 70.03 mm (48.2 ± 11.8), were included. Their achieved mean scores for subscales such OS, VRF and ET were 66.6 ± 16.8, 42.2 ± 12.0 and 42.2 ± 12.5, respectively. Statistically significant results were obtained after 30 days for OSDI (45.5 ± 10.0; p=0.011), whereas after 90 days for both OSDI (35.4 ± 7.4; p=0.003) and OS (47.2 ± 10.9; p=0.005), VRF (30.5 ± 6.1; p=0.003) and ET (33.3 ± 11.2; p=0.008). Conclusions: CsA CE significantly reduced symptoms of patients with DED. Recovery was the most successful after 90 days of treatment and included OSDI, OS, VRF and ET. Abbreviations: CE = cationic emulsion, CFS = corneal fluorescein staining, CsA = cyclosporine A, DED = dry eye disease, ET = environmental triggers, OS = ocular symptoms, OSDI = ocular surface disease index, VRF = vision-related function.

Use of a Cationic Emulsion of Latanoprost to Treat Glaucoma Patients with Ocular Surface Disease: A Preclinical Review.

Prostaglandin analogue topical medications are one of the most effective therapeutic approaches for the chronic management of glaucoma and ocular hypertension, through the reduction of elevated intra ocular pressure (IOP). While many of the first generations of anti-glaucoma eye drops were preserved with benzalkonium chloride, their repeated use may induce chronic ocular surface toxicity that leads to ocular surface disease (OSD) signs and symptoms. As a result, soft-preservatives and preservative-free formulations have been developed with the goal to avoid the long-term iatrogenic toxicity of the preservative agents. In addition, it has been suggested that OSD and its associated inflammation may negatively impact the efficacy of the IOP-lowering medications, including treatment adherence and compliance. Hence, it may be particularly interesting that glaucoma medications can concomitantly protect and "heal" the ocular surface and its environment while lowering elevated IOP, for the greater benefit of glaucoma patients. The objective of the present review is to briefly present the preclinical data of the cationic oil-in-water emulsion of latanoprost (latanoprost-CE) to shed some light on its mechanisms of action. It overall supports the following hypothesis: the restoration of a healthy ocular surface environment and treatment of the OSD signs and symptoms will allow for an improved elevated IOP reduction and glaucoma management. This would be achieved with a once daily dosing regimen to preserve glaucoma patients' vision, ocular surface, and quality-of-life and wellness.

Clinical Outcomes of Topical 0.1% Ciclosporin Cationic Emulsion Used on Label in Children with Vernal Keratoconjunctivitis.

INTRODUCTION: The purpose of this short article is to report the clinical outcomes of topical 0.1% ciclosporin cationic emulsion (CsA-CE) used on label in children with vernal keratoconjunctivitis (VKC). METHODS: In this prospective, non-comparative, observational study children affected by active severe VKC were treated for at least 12 months with topical 0.1% CsA-CE. The drug was instilled in both eyes 4 times daily. Data collected from medical charts for the baseline visit (T0) and 1-year follow-up visit (T1) included symptomatic score (0-15), clinical score (0-15), side effects, rescue therapy (need and total number of courses with 0.1% dexamethasone 4 times daily for 5 days), ocular complications and tolerability (visual analog scale [0-100]). RESULTS: Data from 25 children (20 boys, 5 girls; mean [± standard deviation] age 8.40 ± 2.54 years) were included in the study. Of the 25 patients, 23 (92%) used 0.1% CsA-CE eye drops as per label recommendations, including four patients who had prematurely stopped using topical galenic CsA due to side effects. Symptomatic and clinical scores decreased significantly after treatment, with the mean symptomatic score decreasing from 9.76 ± 1.27 at T0 to 3.80 ± 1.08 at T1, and the mean clinical score decreasing from 9.20 ± 1.32 at T0 to 3.44 ± 1.00 at T1; both P < 0.0001). Five patients (20%) required at least one course of rescue medication (mean 3.4 ± 4.8 courses/year). No patients experienced ocular complications during the study, and treatment tolerability was very high (mean score 89.40 ± 5.46). CONCLUSION: Our findings confirm that topical CsA-CE is an effective on-label option for children with VKC in the real-life setting. In our pediatric patient population, CsA-CE provided good clinical outcomes with a limited need for rescue medication, and it was well tolerated by almost all patients, including those who were intolerant to galenic formulations.

Focusing on the rational application of 0.1% CsA cationic emulsion in ocular surface inflammatory disorder / 中华实验眼科杂志

Ocular surface inflammatory disorder (OSID) is a chronic ocular disease caused by systemic disorders or involving the local immune system.OSID induces persistent inflammatory reaction in the ocular adnexal connective tissues which in turn give rise to tear hypertonicity and ocular surface epithelial damage, leading to dry eye formation or progression.Common immune-related ocular surface diseases include vernal keratoconjunctivitis, Sj?gren syndrome, graft versus host disease, dry eye and immune-related corneal disease, all of which can significantly impact the visual function and quality of life of patients.Current treatments including the use of artificial tears and glucocorticoid eye drops are not always effective and have the risk of adverse events.Cyclosporine A (CsA) is a commonly utilized immunosuppressant that has a strong immunomodulatory effect, but its clinical application is somewhat limited due to the low permeability of its current ophthalmic dosage form.The development of CsA ophthalmic agents has changed the treatment strategy for OSID.The development of 0.1% CsA cationic emulsion has significantly improved the efficacy and safety of topical CsA treatment, which is worth the attention.In order to rationally apply 0.1% CsA cationic emulsion to OSID, ophthalmologists should fully understand the immune-related pathogenesis of each OSID and comprehend the curative effect, indication, application methods and adverse events of topical CsA treatment.

Nonclinical Safety Assessment of Lipid Nanoparticle-and Emulsion-Based Self-Amplifying mRNA Vaccines in Rats.

Vaccines containing mRNA with the capacity to self-amplify represent an alternative to the mRNA vaccines that came to prominence during the COVID-19 pandemic. To gain further insights on the safety profile of self-amplifying mRNA- (SAM-) vaccines, this preclinical toxicology study in rats evaluated the effect of (i) the type of delivery system (lipid nanoparticle [LNP] vs cationic nano-emulsion [CNE]); (ii) antigen-encoding sequence (rabies glycoprotein G vs SARS-CoV-2 Spike); and (iii) RNA amplification. Further analyses also evaluated gene expression in peripheral blood after vaccination, and the biodistribution of vaccine RNA. The SAM vaccines administered as two doses 2-weeks apart had acceptable safety profiles in rats, with respect to clinical signs, blood biochemistry, and macroscopic and microscopic pathology. A transient increase in ALT/AST ratio occurred only in female rats and in the absence of muscle and liver damage was dependent on RNA amplification and appeared related to the greater quantities of vaccine RNA in the muscle and livers of female rats vs male rats. The RNA and delivery-vehicle components, but not the nature of the antigen-coding sequence or the requirement for RNA amplification, affected aspects of the stimulation of innate-immune activity, which was consistent with the transient activation of type I and type II interferon signaling. The delivery vehicle, LNP, differed from CNE as vaccine RNA in CNE compositions appeared independently to stimulate innate-immune activity at 4 hours after vaccination. Our analysis supports further studies to assess whether these differences in innate-immune activity affect safety and efficacy of the SAM vaccine.

Real-World Effectiveness, Tolerability and Safety of Cyclosporine A 0.1% Cationic Emulsion in Severe Keratitis and Dry Eye Treatment.

INTRODUCTION: The PERSPECTIVE study evaluated, in routine clinical practice, the effectiveness, tolerability and safety of cyclosporine A (CsA) 0.1% cationic emulsion (CE) in controlling severe keratitis in adults with dry eye who remained insufficiently controlled despite artificial tear (AT) use. METHODS: A prospective, multicenter, observational study was conducted at 44 ophthalmology clinics across Finland, Germany, Norway, Sweden and the UK. Adults treated with ATs for severe keratitis and dry eye received CsA 0.1% CE therapy (1 drop in both eyes at bedtime) and were followed up at weeks 4, 12 and 24 and at month 12. Primary endpoint was mean [standard deviation (SD)] change from baseline in corneal fluorescein staining (CFS; Oxford Grade Scale) at month 12 following CsA 0.1% CE initiation. Secondary endpoints examined ocular sign and symptom severity and adverse events (AEs). RESULTS: The full analysis set included 472 adults (75.9% female). Mean (SD) age was 61.9 (15.41) years. Mean (SD) CFS score was significantly reduced from baseline [2.56 (1.10)] at month 12 [1.10 (SD 1.13); P < 0.0001]. CFS score reductions were statistically significant from week 4, with further incremental decreases reported at study visits through month 12 (P < 0.0001). Severity of eyelid and conjunctival erythema was significantly reduced from baseline at week 4 and maintained through month 12 (P < 0.001). Tear film breakup time increased significantly from baseline at all study visits through month 12 (P < 0.001). Ocular symptom severity was significantly reduced from baseline at all study visits through month 12 (P < 0.001). Overall, 101 treatment-related AEs were reported. Most were mild/moderate (83.6%) and resolved by month 12 (73.3%). CONCLUSIONS: In routine clinical practice, CsA 0.1% CE provided statistically significant reductions in dry eye signs and symptoms. Improvements were seen at week 4 and maintained over 12 months. Treatment tolerability was good and consistent with previous CsA 0.1% CE clinical studies. TRIAL REGISTRATION: EU PAS register number: EUPAS 22376.

Review of Preclinical Outcomes of a Topical Cationic Emulsion of Cyclosporine A for the Treatment of Ocular Surface Diseases.

BACKGROUND: Cyclosporine A (CsA) has been used as a topical treatment for various ocular surface diseases including dry eye disease (DED). Several CsA formulations are available as solutions or emulsions. PURPOSE: This review describes the development and the preclinical testing of a cationic oil-in-water emulsion of CsA (CE-CsA) in terms of pharmacodynamics, pharmacokinetics, and ocular tolerance. Due to the cationic charge, CE electrostatically interacts with the negatively-charged ocular surface, improving its residence time. Compared to other CsA formulations, CE-CsA and CE itself were found to reduce the signs and symptoms of DED, by restoring tear film stability and properties, and inhibiting the expression and secretion of pro-inflammatory factors. No delay in wound healing nor ocular toxicity were observed using CE formulations. CONCLUSION: these findings indicate that the type of vehicle can significantly affect the performance of eye drops and play an ancillary role in DED treatment. CE appears as a promising strategy to deliver drugs to the ocular surface while maintaining its homeostasis.

Comparative analysis of 0.1% cyclosporin A cationic emulsion and 0.05% cyclosporin A emulsion in murine dry eye cases with different severities.

Dry eye (DE), especially severe DE (SDE), can cause ocular surface defects and reduce the patient's quality of life. Several clinical studies have shown that 0.1% cyclosporin A cationic emulsion (CsA CE) could decrease corneal damage. However, no experimental study has reported the effect of 0.1% CsA CE on SDE. The present study aimed to compare the efficacy of 0.1% CsA CE with that of 0.05% CsA emulsion for ocular surface damage and inflammation in the cases of murine DE with different severities. Following exposure to desiccating stress and subcutaneous injection of scopolamine for 5 days, C57BL/6 female mice were divided into SDE and non-SDE (NSDE) groups based on corneal fluorescein staining scores (CFSs). Mice from both groups were topically treated with 0.05% CsA emulsion or 0.1% CsA CE for 10 days. The results demonstrated that 0.1% CsA CE-treated mice in the SDE and NSDE groups exhibited significant improvements in all the clinical and experimental parameters. Furthermore, the CFS of 0.1% CsA CE-treated mice in the SDE group was lower compared with that of the 0.05% CsA-treated mice. In addition, in the SDE group, 0.1% CsA CE-treated mice had significantly lower levels of nuclear factor-κB activation, inflammatory infiltrations and apoptosis on the ocular surface, and they also exhibited higher conjunctival goblet cell density compared with the 0.05% CsA-treated mice. In summary, these findings indicated that 0.1% CsA CE was more effective than topical 0.05% CsA emulsion at improving corneal epithelial injury and decreasing the levels of inflammatory cytokines and T cells in mice with SDE.

Assessment of a Cationic Emulsion to Control the Tear Film Evaporation Rate.

PURPOSE: To investigate the effect of a single application of cationic emulsion in controlling tear film evaporation and improving tear quality and quantity. MATERIALS A METHODS: Twenty male subjects diagnosed with DE were enrolled in the study with an average age of 45.8 ± 6.37 years. The tear film parameters were observed at several time points post-instillation of the cationic emulsion (10, 20, 30, and 60 min). The tear evaporation rate (TER) was measured with a VapoMeter. Noninvasive tear break-up time and meniscus height were assessed using OCULUS Keratograph. RESULTS: TER decreased by more than 20% at 20, 30, and 60 minutes time points after instillation of single drop of cationic emulsion. Also, a significant improvement in tear film stability was found at all time points following the instillation of cationic emulsion eye drops. The mean tear break-up time increased from 5.55 ± 2.87 to 6.6 ± 4.2 sec at 60 minutes. The maximum increase in tear break-up time occurred at 30 minutes time point. The TMH was also significantly higher post-instillation of oil emulsion eye drops. There was a significant increase in the TMH post-therapy with oil drop at all time points. CONCLUSION: The overall study findings of this study illustrate that the single application of a cationic emulsion effectively controls tear film evaporation in patients with mild to moderate DEs. The cationic emulsion efficiently enhanced both the tear film stability and the tear meniscus volume.

Efficacy of Switching from Cyclosporine A 0.05% Anionic Emulsion to Cyclosporine A 0.1% Cationic Emulsion in Patients with Dry Eye Associated with Sjögren's Syndrome.

Purpose: To evaluate the clinical efficacy of switching from cyclosporine A (CsA) 0.05% anionic emulsion (CsA AE) to CsA 0.1% cationic emulsion (CsA CE) in patients with dry eye (DE) associated with Sjögren's syndrome (SS). Methods: Forty patients with SS-associated DE who were unresponsive to CsA AE for 6 months were enrolled. After baseline measurements, the CsA AE was switched to CsA CE. The ocular surface disease index (OSDI), Sjögren's International Collaborative Clinical Alliance (SICCA), and Schirmer's test scores and tear film breakup time (TBUT) were evaluated at baseline and 1 and 3 months after switching. Results: Two patients dropped out, and 38 were analyzed. OSDI and SICCA ocular staining scores were significantly reduced at 1 and 3 months after switching, compared with the baseline scores (all P < 0.01). Although no significant changes were noted in the corneal staining scores (CSSs), patients with higher baseline CSS (≥4) showed an improvement in the scores at 1 month (P = 0.03) and 3 months (P = 0.01) after switching. There were no significant changes in TBUT and Schirmer's test scores during the follow-up periods. Conclusions: In patients with SS-associated DE, switching from CsA AE to CsA CE was effective in improving ocular symptoms and conjunctival staining. In addition, corneal staining was decreased in patients with severe keratitis.

Ocular surface response of two preservative-free cylcosporine A emulsion eye drops in a mouse model of dry eye.

PURPOSE/AIM: Dry eye (DE) disease is a multifactorial disease in which uncontrolled inflammation can lead to corneal epithelium lesions and symptoms of discomfort. The aim of the present study was to evaluate the efficacy of two cyclosporine emulsions in a mouse model of DE with corneal epithelium lesions. MATERIALS AND METHODS: Six- to 9-week-old female C57BL/6 N mice were housed in a controlled-environment room to induce DE. Following DE development, mice were instilled with: QD 0.1%CsA cationic emulsion (CaEm), BID 0.05%CsA anionic emulsion (AEm), or left untreated. Aqueous tear production and corneal epithelium lesions were assessed throughout the experiment. At the end of the treatment period, left eyes were sampled, fixed, and stained for histology, while the cornea, conjunctiva, and lacrimal gland of right eyes were sampled for transcriptomic analysis. RESULTS: Corneal lesion scores were reduced by 10.4%, 18.4%, and 10.9% at day 6, 10, and 14, respectively, with CaEm (QD), and by 2.6%, 3.0%, and 5.5% at day 6, 10, and 14, respectively, with AEm (BID). Histology demonstrated that 7 out of 10 DE mice presented moderate to severe ocular lesions, while only 2 and 5 out of 10 mice presented slight to moderate ocular lesions when treated with the CaEm (QD) and AEm (BID), respectively. The transcriptomic profile analysis suggests that a different set of inflammatory genes are modulated in the cornea, conjunctiva, and lacrimal gland upon DE development. In addition, the two emulsions distinctively modulate the gene expression profile. CONCLUSIONS: This study demonstrates that both emulsions were effective at reducing corneal lesions, with the CaEm (QD) being slightly better than the AEm (BID). Interestingly, this study suggests that ocular tissues may not respond similarly to a dry environment and that a different set of genes is modulated by the two formulations in the ocular tissues.

Cationic Emulsion-Based Artificial Tears as a Mimic of Functional Healthy Tear Film for Restoration of Ocular Surface Homeostasis in Dry Eye Disease.

Dry eye disease (DED) is a complex multifactorial disease that affects an increasing number of patients worldwide. Close to 30% of the population has experienced dry eye (DE) symptoms and presented with some signs of the disease during their lifetime. The significant heterogeneity in the medical background of patients with DEs and in their sensitivity to symptoms renders a clear understanding of DED complicated. It has become evident over the past few years that DED results from an impairment of the ocular surface homeostasis. Hence, a holistic treatment approach that concomitantly addresses the different mechanisms that result in the destabilization of the tear film (TF) and the ocular surface would be appropriate. The goal of the present review is to compile the different types of scientific evidence (from in silico modeling to clinical trials) that help explain the mechanism of action of cationic emulsion (CE)-based eye drop technology for the treatment of both the signs and the symptoms of DED. These CE-based artificial tear (AT) eye drops designed to mimic, from a functional point of view, a healthy TF contribute to the restoration of a healthy ocular surface environment and TF that leads to a better management of DE patients. The CE-based AT eye drops help restore the ocular surface homeostasis in patients who have unstable TF or no tears.

Persistence of Efficacy of 0.1% Cyclosporin A Cationic Emulsion in Subjects with Severe Keratitis Due to Dry Eye Disease: A Nonrandomized, Open-label Extension of the SANSIKA Study.

PURPOSE: Results from a 6-month double-masked and a 6-month open-label study (SANSIKA) established the efficacy and safety of once-daily 0.1% cyclosporin A cationic emulsion (CsA CE) in severe keratitis due to dry eye disease (DED). This article presents results from the Post-SANSIKA study, a 24-month extension of SANSIKA assessing the sustained efficacy of CsA CE after treatment discontinuation. METHODS: Time to relapse (corneal fluorescein staining [CFS] score ≥4 [modified Oxford scale]) was assessed after treatment discontinuation in patients from the SANSIKA study who had CFS improvement from a score of 4 to ≤2 after 6 or 12 months of treatment with CsA CE. FINDINGS: Of 62 patients who achieved a CFS score ≤2 at the end of the SANSIKA study, 38 did not relapse and 24 (39%) relapsed during the 24-month period after CsA CE discontinuation; the latter (relapse) group comprised 35% of patients initially treated with CsA CE for 12 months in SANSIKA versus 47% of those treated for 6 months only. Patients spent the most time during the extension study at CFS scores of 1 or 2 (median duration of 8.5 weeks and 14.7 weeks per year, respectively), indicating marked improvement, and less time at scores of 3, 4, or 5 (median time, 2.0 weeks, 0 weeks, and 0 weeks per year). Of 23 patients eligible for safety analysis (ie, patients who received the study treatment at least once), 12 (52.2%) reported a total of 26 ocular adverse events (AEs). Among these, 5 ocular AEs, reported in 5 patients (21.7%), were considered related to study treatment: 3 events of mild instillation site pain in 3 patients (13.0%) and eye discharge and foreign body sensation, each reported in 1 patient (4.3%). Only 1 systemic AE (nasal congestion), reported in 1 patient (4.3%), was considered related to study treatment. None of the AEs led to treatment discontinuation. IMPLICATIONS: The majority of patients who discontinued CsA CE after experiencing DED improvement in the SANSIKA study did not experience a relapse in this 24-month follow-up study; these patients spent the most time at CFS scores consistent with marked improvement. CsA CE had a favorable safety/tolerability profile over 2 years. Treatment for up to 12 months with CsA CE provides sustained improvements in patients with severe keratitis due to DED. EudraCT registration no. 2012-002066-12.

Evaluating the novel application of cyclosporine 0.1% in ocular surface disease.

INTRODUCTION: Ocular surface disease (OSD) is a highly prevalent symptomatic condition caused by dry eye disease (DED), intrinsic, environmental, or iatrogenic causes. It affects patient's visual function and quality of life. Its pathophysiology is centered on tear hyperosmolarity, inflammation, and epithelial damage. Current management is suboptimal and includes artificial tear supplementation and short-term use of topical steroids in severe cases. The recent approval of cyclosporine 0.1% has transformed management strategies of severe DED and moderate-to-severe OSD. Areas covered: This review summarizes existing information on the efficacy, safety, and tolerability of the new cyclosporine 0.1% formulation. Expert opinion: Topical cyclosporine A 0.1% represents a promising, novel medication for the management of DED, Meibomian gland dysfunction, and inflammatory OSD. It is primarily beneficial for those patients requiring topical immunomodulatory therapy. This topical formulation also has the potential to meaningfully improve the management of moderate-to-severe glaucoma therapy-related OSD. Currently there is limited published clinical data concerning the efficacy of topical cyclosporine. There are, however, theoretical advantages when comparing this cyclosporine formulation with other established commercial preparations. Future research is needed to delineate the precise role and value of this medication.

Topical ocular 0.1% cyclosporine A cationic emulsion in dry eye disease patients with severe keratitis: experience through the French early-access program.

PURPOSE: The objective of this study was to report the evaluation of efficacy and safety of cyclosporine A cationic emulsion (CsA CE) 0.1% for the treatment of severe keratitis in adults with dry eye disease (DED) in a French early-access program. METHODS: Patients with DED and severe keratitis (corneal fluorescein staining [CFS] score of 3-5 on the Oxford scale and/or the presence of corneal lesions [filaments or ulcers]) were enrolled in a compassionate use program (Authorization for Temporary Use [ATU]) for once-daily CsA CE, which was approved by French health authorities prior to its registration. Efficacy and safety at 1, 3, 6, and 12-month follow-up visits were evaluated. RESULTS: The ATU cohort (n=1,212; mean age =60.5 years; 79.5% female; 98.1% with severe keratitis; 74.5% with corneal lesions) consisted of 601 CsA-naïve patients and 611 patients treated previously with other CsA formulations. The primary DED etiology was Sjögren's syndrome (48.7%). Clinical benefit could be discerned among 548 evaluable patients from months 1 to 12: keratitis improvement, 44.8% at month 1 and 42.1% at month 12; keratitis stabilization, 47.2% and 45.7%, respectively; symptom improvement, 47.2% and 48.6%; and symptom stabilization, 44.8% and 45.0%. Corneal clearing (CFS score =0) increased from 4.8% (month 1) to 11.4% (month 12). No unexpected safety concerns were identified; instillation site pain (10.2%) and eye irritation (7.8%) were the most common adverse events. CONCLUSION: The French ATU cohort provides supportive data on the clinical benefit of CsA CE in improving/stabilizing symptoms and corneal damage in DED patients with severe keratitis in real-world clinical practice.