Pooled results from two pivotal randomized controlled clinical trials: ESSENCE-1 and ESSENCE-2 to assess efficacy and safety of a water-free ciclosporin 0.1% formulation for the treatment of dry eye disease

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Abstract
Purpose This pooled analysis of two pivotal studies (ESSENCE-1 and ESSENCE-2) evaluated treatment effects of a water-free ciclosporin 0.1% solution in dry eye disease (DED) patients in the overall population and in subgroups according to sex, age, and baseline severity of disease. Methods In these randomized, multicenter, double-masked, vehicle-controlled studies patients received ciclosporin 0.1% or vehicle (1:1 ratio) in both eyes twice daily for 85 and 29 days, respectively. Total and central corneal fluorescein staining (tCFS; cCFS; NEI scale, 0–15) were assessed at Day 15 and 29. Other endpoints included conjunctival staining and blurred vision scores. Safety and tolerability parameters comprised adverse events, ophthalmic examinations and drop comfort assessments. Results In total 1162 patients were included in the analysis (585 ciclosporin 0.1%; 577 vehicle). Patients age (mean [SD]: 58.3 [15.23] years) and gender distribution (73% females) are consistent with DED epidemiology. Change from baseline (LS mean [SE]) in tCFS significantly improved compared to vehicle, both at Day 15 (ciclosporin: -3.24 [0.112]; vehicle -2.71 [0.113]; Δ= -0.52 [0.144], p=0.0003) and Day 29 (ciclosporin: ‑3.83 [0.115]; vehicle:‑3.30 [0.116]; Δ: ‑0.53 [0.147], p=0.0003). 56.8% and 66.4% of patients responded to ciclosporin 0.1% with a tCFS improvement of ≥ 3 scores on Day 15 and 29, respectively. A consistent effect on tCFS favoring ciclosporin over vehicle was observed in all subgroups. Improvements favoring ciclosporin were seen in cCFS and conjunctival staining in the overall population and in blurred vision score in patients with significant corneal staining. Incidence of ocular adverse events was 13.2% in both treatment groups. Mild instillation site reactions were reported by 7.9% patients in the ciclosporin group. Discontinuation rates were low with 2.6% and 2.1% in ciclosporin and vehicle groups. Ciclosporin 0.1% was rated comfortable upon instillation by 84.7% of patients. Conclusion The pooled analysis confirmed that the water-free ciclosporin 0.1% solution is effective in improving ocular surface staining after 2 weeks of treatment to a clinically relevant extent in more than 50% of patients in the overall population and subgroups. With an early onset and good tolerability, the product has the potential to address an unmet medical need in DED. ClinicalTrials.gov identifier NCT03292809 on 21-July-2017; NCT04523129 on 20-August-2020 Key messages What Was Known: Ciclosporin eye drops are a standard of care in dry eye disease (DED) therapy not controlled by artificial tears. A novel water-free ciclosporin 0.1% ophthalmic solution with improved efficacy has recently been commercialized in the United States and approved in the European Union. What This Paper Adds: The water-free cyclosporine 0.1% solution showed consistent and early improvement of ocular surface damage in patients with moderate and severe dry eye disease as well as in subgroups according to age and sex. Responder analysis showed the clinical relevance of these improvements in more than 50 % of treated patients after 2 weeks of treatments. This eye drop formulation was well tolerated and no new safety signals were detected.

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