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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.

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.

Purpose/Aim: Inflammation is recognized as playing an etiological role in dry eye disease. This study aimed to assess the efficacy of various topical cyclosporine A (CsA) formulations on cornea inflammatory markers in a mouse model of dry eye., Material and Methods: Six- to 7-week-old mice treated with scopolamine were housed in a controlled environment room to induce dry eye. Following dry eye confirmation by corneal fluorescein staining (CFS), the mice were treated three times a day with: 0.05%CsA (Restasis, Allergan), 0.1%CsA (Ikervis, Santen), 1%CsA oil solution, and 0.5% loteprednol etabonate (LE, Lotemax, Baush+Lomb), or left untreated. Aqueous tear production and CFS scores were assessed during the treatment period, and corneas were collected to measure the expression profile of a selection of inflammatory genes., Results: After 7 days of treatment, the CFS scores were reduced by 21%, 31%, and 44% with 0.05%CsA, 0.1%CsA, and 1%CsA eye drops, respectively. By contrast, 0.5% LE did not decrease corneal fluorescein staining at day 10. A statistically significant dose-dependent CFS reduction was observed only between the 0.05% and 1%CsA formulations. The gene expression profiles indicated that 12, 18, 17 genes were downregulated by 0.05%CsA, 0.1%CsA, 1%CsA, respectively. Among them, the genes significantly downregulated were: IL1A, IL1R1, and TLR4 with 0.05%CsA; H2-Eb1, IL1A, IL1B, IL1RN, IL6, TGFB2, TGFB3, TLR2, TLR3, and TLR4 with 0.1%CsA; IL1B, IL6, TGFB3, and TLR4 with 1%CsA. TGFB1 and TGFBR1 were the only genes upregulated in all groups, but only TGFB1 upregulation reached significance. IL6RA was significantly upregulated by 0.05%CsA., Conclusions: This study indicates that the three CsA formulations effectively modulated TLR4, TGFβ1, IL1, and IL6 pathways to reduce corneal epithelium lesions in a mouse model of severe dry eye. The study also suggests that the different anti-inflammatory eye drops modulated inflammatory genes in a slightly different manner.

Background/aim: To assess the treatment effect of 0.1% ciclosporin A cationic emulsion (CsA CE) versus vehicle on signs/symptoms of dry eye disease (DED) in various subgroups (moderate-to-severe DED/severe DED/Sjögren's syndrome (SS)/SS with severe DED)., Methods: Pooled data were analysed from two similar phase III studies: SICCANOVE (moderate-to-severe DED) and SANSIKA (severe DED with severe keratitis). In both studies, patients aged ≥18 years received CsA CE 0.1% (n=395) or vehicle (n=339) once daily for 6 months. A composite responder efficacy endpoint (corneal fluorescein staining-Ocular Surface Disease Index (CFS-OSDI) at month 6) was used to evaluate the efficacy of CsA CE in alleviating signs/symptoms of DED (response defined as improvement of ≥2 grades in CFS and ≥30% in OSDI (baseline to month 6)). Human leucocyte antigen-DR (HLA-DR) conjunctival expression was used as a biomarker of ocular surface inflammation., Results: CsA CE-treated patients were significantly more likely to be CFS-OSDI responders than vehicle-treated patients in the overall (OR 1.66, 95% CI 1.11 to 2.50; P=0.015), severe DED (1.80, 1.04 to 3.19; P=0.038) and SS with severe DED (3.37, 1.20 to 11.19; P=0.030) populations. The difference was not significant for CsA CE versus vehicle for the overall Sjögren's population (OR 1.77, CI 0.89 to 3.66; P=0.109). CsA CE also significantly reduced median HLA-DR expression versus vehicle at 6 months (P=0.002)., Conclusion: Pooled phase III data indicate CsA CE produced significant improvement in signs/symptoms versus vehicle in patients with moderate-to-severe DED (especially in those with severe keratitis), including patients with SS with severe DED., Competing Interests: Competing interests: AL is a consultant for, or has received a research grant from, Allergan, Alcon, MediVis, Santen, SIFI and Théa and was an investigator in the SICCANOVE and SANSIKA studies. EMM is a consultant for, or has received speaker honoraria from, Alcon Pharma GmbH, Dompé, Pharm-Allergan GmbH, Santen GmbH, Shire, Théa Pharma GmbH, TRB Chemedica AG, Ursapharm and VISUfarma and was an investigator in the SICCANOVE study. ML is a consultant for, or has received a research grant from, Alcon, Allergan, Bausch & Lomb, Dompé, Santen and Théa and was an investigator in the SICCANOVE and SANSIKA studies. MA is an employee of Santen SAS. J-SG is an employee of Santen SAS. DI is an employee of Santen SAS. MS-d-l-M is a consultant for Santen and was an investigator in the SICCANOVE and SANSIKA studies. FCF is a consultant for, or has received a research grant from, Allergan, Théa and Santen and was an investigator in the SICCANOVE and SANSIKA studies. CB is a consultant for, or has received a research grant from, Alcon, Allergan, Santen and Théa and was a clinical investigator in the SICCANOVE and SANSIKA studies., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: The SANSIKA study evaluated the efficacy/safety of 0.1% (1 mg/mL) cyclosporine A cationic emulsion (CsA CE) for treating dry eye disease (DED) with severe keratitis. The double-masked phase demonstrated that CsA CE was effective in reducing corneal damage and ocular surface inflammation, and was well-tolerated over 6 months. Here we report efficacy and safety findings of SANSIKA's open-label extension (OLE)., Methods: In this multicenter, double-masked, phase III study, patients with severe DED (corneal fluorescein staining [CFS] grade 4, modified Oxford scale) were randomized to once-daily CsA CE (Ikervis ® ) or its vehicle for 6 months, followed by 6-month open-label, once-daily CsA CE (CsA CE/CsA CE and vehicle/CsA CE groups)., Results: A total of 177 patients completed the OLE. Efficacy results reiterated the double-masked phase: CsA CE reduced CFS score and human leukocyte antigen-antigen D related expression, improved corneal clearing, and produced continuous improvements in global symptom scores (ocular surface disease index [OSDI], visual analogue scale). The CFS-OSDI response rates (≥2 CFS points, ≥30% OSDI improvement vs baseline) at 12 vs 6 months were 39.1% vs 28.6%, respectively, for CsA CE/CsA CE and 38.0% vs 23.1% for vehicle/CsA CE. Cyclosporine A CE's safety profile was similar to the initial 6 months. The most common treatment-related treatment-emergent adverse event was instillation site pain (7.8%, CsA CE/CsA CE group; 19.0%, vehicle/CsA CE group). No unexpected safety signals were observed; systemic CsA levels were undetectable/negligible in all patients except 2 previously treated with systemic CsA., Conclusions: In this 12-month study, once-daily CsA CE was well-tolerated and showed reductions in ocular surface inflammation and improvements in signs/symptoms in DED patients with severe keratitis.

Purpose: The SICCANOVE study aimed to compare the efficacy and safety of 0.1% cyclosporine A cationic emulsion (CsA CE) versus vehicle in patients with moderate to severe dry eye disease (DED)., Methods: In this multicenter, double-masked, parallel-group, controlled study, patients were randomized (1:1) to receive CsA CE (Ikervis®) or vehicle for 6 months. The co-primary efficacy endpoints at month 6 were mean change from baseline in corneal fluorescein staining (CFS; modified Oxford scale) and in global ocular discomfort (visual analogue scale [VAS])., Results: The mean change in CFS from baseline to month 6 (CsA CE: n = 241; vehicle: n = 248) was significantly greater with CsA CE than with vehicle (-1.05 ± 0.98 and -0.82 ± 0.94, respectively; p = 0.009). Ocular discomfort improved similarly in both groups; however, the percentage of patients with ≥25% improvement in VAS was significantly higher with CsA CE (50.2%) than with vehicle (41.9%; p = 0.048). In a post hoc analysis of patients with severe ocular surface damage (CFS score 4) at baseline (CsA CE: n = 43; vehicle: n = 42), the percentage of patients with improvements of ≥2 grades in CFS score and ≥30% in Ocular Surface Disease Index score was significantly greater with CsA CE (p = 0.003). Treatment compliance and ocular tolerability were satisfactory and as expected for CsA use., Conclusion: Cyclosporine A CE was well-tolerated and effectively improved signs and symptoms in patients with moderate to severe DED over 6 months, especially in patients with severe disease, who are at risk of irreversible corneal damage.

Local ocular delivery of cyclosporine A (CsA) is the preferred method for CsA delivery as a treatment for ocular inflammatory diseases such as uveitis, corneal healing, vernal keratoconjunctivitis and dry eye disease. However, due to the large molecular weight and hydrophobic nature of CsA and the natural protective mechanisms of the eye, achieving therapeutic levels of CsA in ocular tissues can be difficult. This review gives a comprehensive overview of the current products available to clinicians as well as emerging drug delivery solutions that have been developed at both the academic and industry levels., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: To assess medical practices surrounding the use of topical ocular cyclosporine A across European Union nations., Methods: Key stakeholders (ophthalmologists, hospital pharmacists, regulatory health authorities) from European Union member states were interviewed by telephone using a semi-structured, open-ended questionnaire. Ophthalmologists responded to questions about practice patterns of cyclosporine A use (prescription frequency, indication, dosage), pharmacists about cyclosporine A formulations (composition, manufacturing process, quality control, distribution), and the regulatory authorities about market authorization and pharmacovigilance for various cyclosporine A products., Results: Over the years, cyclosporine A use for ophthalmic indications has increased across all European Union nations. Prevalence of cyclosporine A use was heterogeneous, with Belgium, France, Germany, Italy, Portugal, Spain and the United Kingdom reporting the highest frequency. Compounded cyclosporine A formulations and other cyclosporine A products were prescribed through temporary authorization on a compassionate use or named-patient basis. Cyclosporine A was prescribed for dry eye disease, atopic and vernal keratoconjunctivitis, corneal graft rejection, and other autoimmune and inflammatory diseases. Concentrations of prescribed topical cyclosporine A ranged between 0.05-2% and formulations were instilled 1-6 times daily. Interviewed stakeholders expressed concern regarding, (1) paucity of product information, (2) lack of standardized manufacturing processes and quality control of cyclosporine A formulations, and (3) poor regulation and pharmacovigilance of ocular cyclosporine A-based products., Conclusions: Medical practice surrounding ocular cyclosporine A use in European Union nations differs based on variations in concentration, dosage, prescription indication, formulation, availability and distribution, manufacturing, quality, and regulatory monitoring., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Dry eye disease (DED) is a complex, multifactorial pathology characterized by corneal epithelium lesions and inflammation. The aim of the present study was to evaluate the efficacy of a cationic emulsion of cyclosporine A (CsA) in a mouse model that mimics severe dry eye. Eight to 12-week-old female C57BL/6N mice with tail patches of scopolamine were housed in controlled environment chambers to induce dry eye. At day three, following dry eye confirmation by corneal fluorescein staining (CFS, score 0-15) and phenol red thread (PRT) lacrimation test, the mice (n = 10/gp) were either treated 3 times a day in both eyes with drug-free cationic emulsion, a 0.1% CsA cationic emulsion, or 1% methylprednisolone (positive control), or non-treated. Aqueous tear production and CFS scores were evaluated at baseline and throughout the treatment period. The lacrimation test confirmed the scopolamine-induced decrease in aqueous production by the lacrimal gland. A reduction of 59% in induced-CFS was observed following topical treatment with 0.1% CsA. The beneficial effect of the cationic emulsion vehicle itself on keratitis was also clearly evidenced by its better performance over 1% methylprednisolone, -36%, vs. -28% on the CFS scores, respectively. This study indicates that the cationic emulsion of CsA (0.1%) was a very effective formulation for the management of corneal epithelium lesions in a severe DED mouse model. In addition, it performed better than a potent glucocorticosteroid (1% methylprednisolone). This cationic emulsion of CsA (0.1%), combining CsA and a tear film oriented therapy (TFOT), i.e. with vehicle properties that mechanically stabilize the tear film, represents a promising new treatment strategy for the management of the signs of dry eye., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The SANSIKA study was conducted to assess the treatment effect of 0.1% cyclosporine A cationic emulsion (CsA CE) eye drops on signs and symptoms of patients with severe dry eye disease (DED)., Methods: This was a multicenter, randomized, double-masked, 2-parallel-arm, 6-month phase III study with a 6-month open-label treatment safety follow-up. Patients with severe DED with corneal fluorescein staining (CFS) grade 4 on the modified Oxford scale were randomized to receive once-daily CsA CE (Ikervis®) or its vehicle., Results: A total of 246 patients were randomized. The proportion of patients achieving ≥2 grades improvement in CFS and a 30% improvement in symptoms (Ocular Surface Disease Index [OSDI]) by month 6 was 28.6% with CsA CE vs 23.1% with vehicle (p = 0.326) (primary endpoint). Assessment of corneal damage showed greater improvement with CsA CE over vehicle in mean adjusted CFS change from baseline to month 6 (-1.764 vs -1.418, p = 0.037). There was a reduction in ocular surface inflammation assessed by human leukocyte antigen DR expression in favor of CsA CE at month 6 (p = 0.021). The mean OSDI change from baseline was -13.6 with CsA CE and -14.1 with vehicle at month 6 (p = 0.858). The main adverse event was instillation site pain (29.2% vs 8.9% in the CsA CE and vehicle groups, respectively), and it was mostly mild., Conclusions: CsA CE was well-tolerated and effective in improving corneal damage and ocular surface inflammation and confirmed the positive benefit-risk ratio of this new formulation of CsA for the treatment of severe keratitis in DED.

Purpose: The aim of this study was to compare the ocular and systemic distribution of cyclosporine A (CsA) in rabbits after the instillation of preservative-free CsA cationic and anionic emulsions., Methods: For the single-dose pharmacokinetic (PK) study, rabbits were instilled with 50 μL of the test material. For the multiple-dose PK study, rabbits were instilled twice daily with Restasis or once daily with NOVA22007 for 10 days. At each time point, the cornea, conjunctiva, and whole blood were harvested for CsA quantification. Ocular and systemic distribution were determined after 4 times daily instillations with 50 μL of 3H-CsA cationic and anionic emulsions for 7 days. Restasis was used as a reference in all studies., Results: Single-dose PK data demonstrated that NOVA22007 0.1% and 0.05% delivered higher CsA concentrations to the cornea than Restasis [concentration maximum (C max): 2692, 1372, and 748 ng/g, respectively] and have a better exposition (area under the curve). Conjunctival Cmax values were 1914, 696, and 849 ng/g and area under the curve values were 3984, 2796, and 2515 ng/g · h, for either dose of the cationic emulsions and Restasis, respectively. The multiple-dose PK and the 3H-CsA distribution data demonstrated that the systemic distribution after repeated instillations was low and comparable for all emulsions., Conclusions: These data demonstrate that the CsA cationic emulsions were more effective than Restasis at delivering CsA to target tissues, thus confirming the potential advantage of cationic emulsions over anionic emulsions as vehicle for ocular drug delivery for the treatment of ocular surface diseases.

Purpose: Topical preparations of cyclosporine (CsA) are common therapeutics for the treatment of dry eye. However, they are not devoid of side effects, such as allergy and irritation. The present study aimed at evaluating the safety profile of a new CsA formulation in cationic emulsion (CEm) in vitro with a dynamic corneal wound healing assay using human corneal epithelial (HCE) cells, and in vivo in a rabbit acute toxicity model., Methods: Three different csa formulations were tested: 1) 0.05%CsA-CEm, 2) commercial 0.05%CsA-Anionic emulsion (CsA-AEm, Restasis®), and 3) 0.05%CsA-Oil solution. Phosphate buffered saline (PBS) was used as negative control and 0.02% benzalkonium chloride (BAK) as the toxic control. In vitro, a wound was created by scratching through a confluent HCE cell layer and exposed 30 min to 1/10 dilutions of the different formulations. Cytotoxicity, cell migration, and proliferation were performed to analyze the recovery at days 1, 2, and 3. In vivo, the eye drops were applied to rabbit eyes 15 times at 5-min intervals. The ocular surface structures were examined with a slit-lamp and by corneal in vivo confocal microscopy (IVCM) for detailed examination of corneal epithelium, stroma, limbus, and conjunctiva-associated lymphoid tissue (CALT) structures., Results: The in vitro study confirmed that a 0.02% BAK solution delayed the corneal healing process (-57%) by severely damaging the remaining HCE cells. The other formulations maintained a normal healing rate with a similar behavior for CsA-CEm, CsA-AEm, and PBS with no significant differences (at D3, 66%-74% closure). In the rabbit, 0.02%BAK showed the highest toxicity, inducing redness, chemosis with damaged corneal epithelium, and inflammatory cell infiltrations. CsA-AEm and CsA-Oil induced moderate infiltrations of inflammatory cells around the CALT. CsA-CEm presented the lowest toxicity with patterns similar to PBS., Conclusions: The combination of these in vitro and in vivo models evaluated the tolerance/cytotoxicity and the dynamic wound healing potential of CsA in different formulations. While CsA-AEm, CsA-CEm, and CsA-Oil are generally well tolerated, only CsA-CEm appeared to maintain the HCE cells' normal healing rate in vitro and low levels of inflammation in vivo.