Dataset Information

Once-Daily Cyclosporine-A-MiDROPS for Treatment of Dry Eye Disease.

ABSTRACT: Purpose:To determine if a Microemulsion Drug Ocular Penetration System (MiDROPS) formulation of cyclosporine A (CsA) delivers more drug and is more efficacious for treatment of dry eye disease (DED) than the current clinical formulation. Methods:Tissue distribution of CsA was quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). To assess tolerability, CsA-MiDROPS (0.1%) was applied to the eyes of rabbits twice per day for 14 days and assessed using ophthalmoscopic examinations. Mice were exposed to desiccating stress for 10 days and received daily topical instillation of the vehicle or test agent. Cornea staining was done to quantify corneal permeability. Histologic quantification of goblet cell (GC) density and CD4+ T-cell infiltration in the conjunctiva was performed. Results:Ophthalmic distribution studies indicate significantly increased drug concentration with CsA-MiDROPS compared with Restasis. CsA-MiDROPS is well tolerated with little toxicity in a 2-week tolerability study. In the DED model, both 0.05% and 0.1% CsA-MiDROPS conferred a significant effect and were more effective than Restasis for treating experimental DED when dosed twice per day. As compared with Restasis dosed twice per day, 0.1% CsA-MiDROPS dosed once per day demonstrated superiority. Conclusions:CsA-MiDROPS showed superior drug delivery and efficacy compared with other clinical formulations. As this product is simple to produce and needs to be only applied once daily, the clinical development of CsA-MiDROPS will help to reduce societal and patient burdens by lowering drug costs and accelerating/improving the activity of CsA. Translational Relevance:MiDROPS has broad application concerning the ophthalmic development of lipophilic small molecule therapeutics.

SUBMITTER: Coursey TG

PROVIDER: S-EPMC6181191 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Once-Daily Cyclosporine-A-MiDROPS for Treatment of Dry Eye Disease.

Coursey Terry G TG Wassel Ronald A RA Quiambao Alexander B AB Farjo Rafal A RA

Translational vision science & technology 20180901 5

<h4>Purpose</h4>To determine if a Microemulsion Drug Ocular Penetration System (MiDROPS) formulation of cyclosporine A (CsA) delivers more drug and is more efficacious for treatment of dry eye disease (DED) than the current clinical formulation.<h4>Methods</h4>Tissue distribution of CsA was quantified by liquid chromatography with tandem mass spectrometry (LC-MS/MS). To assess tolerability, CsA-MiDROPS (0.1%) was applied to the eyes of rabbits twice per day for 14 days and assessed using ophthal ...[more]

PMID: 30323997

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Project description:PurposeTo compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1% and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED). An open-label Restasis (Allergan, Irvine, CA) arm was included to allow a direct comparison with an approved therapy.DesignAn exploratory phase II, multicenter, randomized, vehicle-controlled clinical trial, double-masked between CyclASol and vehicle with an open-label comparator.ParticipantsTwo hundred and seven eligible patients with a history of dry eye disease were randomized 1:1:1:1 to 1 of 4 treatment arms (CyclASol 0.05%, n = 51; CyclASol 0.1%, n = 51; vehicle, n = 52, and Restasis, n = 53).MethodsAfter a 2-week run-in period with twice-daily dosing of Systane Balance (Alcon, Fort Worth, TX), patients were randomized to the respective treatment arm and dosed twice daily for 16 weeks.Main outcome measuresThe study was set up to explore efficacy on a number of sign and symptom end points including total and subregion corneal fluorescein staining, conjunctival staining, visual analog scale (VAS) for dry eye symptoms VAS severity, and Ocular Surface Disease Index (OSDI) questionnaire.ResultsCyclASol showed a consistent reduction in corneal and conjunctival staining compared with both vehicle and Restasis over the 16-week treatment period, with an early onset of effect (at day 14). A mixed-effects model-based approach demonstrated that the CyclASol drug effect was statistically significant over vehicle (total corneal staining P < 0.1, central corneal staining P < 0.001, conjunctival staining P < 0.01). This model-based analysis suggests a significant CyclASol effect for OSDI as symptom parameter (P < 0.01). The numbers of ocular adverse events were low in all treatment groups.ConclusionsCyclASol showed efficacy, safety, and tolerability at 2 concentrations in moderate-to-severe DED. In a direct head-to-head against open-label Restasis, CyclASol was found to have an earlier onset of action, as early as after 2 weeks of treatment, in relieving the signs of DED, as measured by corneal and conjunctival staining. The central region of the cornea, an important area for visual function in dry eye sufferers, was shown to have the most benefit from treatment. Excellent safety, tolerability, and comfort profile supports this new CsA formulation as having a positive benefit-to-risk ratio.

Project description:IntroductionThe 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.MethodsA 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).ResultsThe 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%).ConclusionsIn 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 registrationEU PAS register number: EUPAS 22376.

Project description:Background: The purpose is to perform a cost effectiveness analysis amniotic membrane vs. topical medications in the use of treating dry eye disease. A cost effectiveness analysis comparing amniotic membrane?+?other topical medications to topical cyclosporine A?+?other topical medications was evaluated using accepted decision tree modeling software.Methods: TreeAge Pro 2019 software was used to evaluate the base case costs over a one year timeframe. Sensitivity analysis was performed on those variables which had the greatest effect on choosing one therapy versus the other based on cost. Monte Carlo simulation was run 1,000 times to determine the most effective, least costly alternative. Costs were evaluated from a societal level (direct?+?indirect). Quality of life utility scores were evaluated using known time tradeoffs from prior studies (scale 0-1; with 1 being perfect vision).Results: Over a one year timeframe, the base case demonstrated that amniotic membrane?+?topical medications was the less expensive alternative and provided for incremental utilities versus topical cyclosporine?+?other medications (Cost/utility: $18,275/0.78 vs. $20,740/0.74). If examining direct costs only, topical cyclosporine was the least expensive option over a one year timeframe: $4,112 vs. $10,300. Sensitivity analysis demonstrated that in order for topical cyclosporine to be the less expensive alternative the following variables would need to be:?<?68 days productivity lost;?<?$161 productivity lost/day;?>?79% of amniotic membrane implants would need to be re-implanted at month 4 (for whatever reason);?>?$2677 per amniotic membrane implant procedure (Medicare reimbursement rate);?>?96% positive response to topical cyclosporine A at month 4;?>?58% positive response to topical cyclosporine A at month 6 and;?<?54% probability clinical improvement with amniotic membrane. Monte Carlo simulation demonstrated that amniotic membrane was the less costly, most effective alternative 91.5% of the time.Conclusion: Based on improved outcomes using amniotic membrane, patient productivity was improved resulting in lower societal costs (less days lost from work). When considering the untoward effects of dry eye disease on societal costs, an improvement of the dry eye disease condition was accomplished most often with amniotic membrane.

Dataset Information

Once-Daily Cyclosporine-A-MiDROPS for Treatment of Dry Eye Disease.

Publications

Once-Daily Cyclosporine-A-MiDROPS for Treatment of Dry Eye Disease.

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