Efficacy and Safety of a Water-Free Topical Cyclosporine, 0.1%, Solution for the Treatment of Moderate to Severe Dry Eye Disease

Abstract

ImportanceDry eye disease (DED) is a common public health problem with significant impact on vision-related quality of life and well-being of patients. Medications with rapid onset of action and a good tolerability profile remain an unmet need.ObjectiveTo assess efficacy, safety, and tolerability of a water-free cyclosporine ophthalmic solution, 0.1% (CyclASol [Novaliq GmbH]), applied twice daily in DED compared with vehicle.Design, Setting, and ParticipantsCyclASol for the Treatment of Signs and Symptoms of Dry Eye Disease (ESSENCE-2) was a phase 3, multicenter, randomized, double-masked, vehicle-controlled clinical study conducted from December 5, 2020, to October 8, 2021. Following a 14-day run-in period with an artificial tear administered 2 times per day, eligible participants were randomly assigned 1:1 to the treatment groups. Patients with moderate to severe DED were included in the study.InterventionsCyclosporine solution vs vehicle administered 2 times per day for 29 days.Main Outcomes and MeasuresThe primary end points were changes from baseline in total corneal fluorescein staining (tCFS; 0-15 National Eye Institute scale) and in dryness score (0-100 visual analog scale) at day 29. Conjunctival staining, central corneal fluorescein staining, and tCFS responders were also assessed.ResultsA total of 834 study participants were randomly assigned to cyclosporine (423 [50.7%]) or vehicle (411 [49.3%]) groups at 27 sites. Participants had a mean (SD) age of 57.1 (15.8) years, and 609 (73.0%) were female individuals. The majority of participants self-identified in the following race categories: 79 Asian (9.5 %), 108 Black (12.9%), and 635 White (76.1%). Participants treated with cyclosporine solution had greater improvement in tCFS (−4.0 grades) than the vehicle group (−3.6 grades) at day 29 (change [∆] = −0.4; 95% CI, −0.8 to 0; P = .03). The dryness score showed treatment benefits from baseline in both groups: −12.2 points for cyclosporine and −13.6 points for vehicle (∆ = 1.4; 95% CI, −1.8 to 4.6; P = .38). In the cyclosporine group, 293 participants (71.6%) achieved clinically meaningful reductions of 3 grades or higher in tCFS vs 236 (59.7%) in the vehicle group (∆ = 12.6%; 95% CI, 6.0%-19.3%; P < .001). These responders showed greater improvement in symptoms at day 29 including dryness (∆ = −4.6; 95% CI, −8.0 to −1.2; P = .007) and blurred vision (Δ = −3.5; 95% CI, −6.6 to −4.0; P = .03) compared with nonresponders.Conclusions and RelevanceThe ESSENCE-2 trial confirmed that treatment with a water-free cyclosporine solution, 0.1%, results in early therapeutic effects on the ocular surface compared with vehicle. The responder analyses suggest that the effect is clinically meaningful in 71.6% of participants in the cyclosporine group.Trial RegistrationClinicalTrials.gov Identifier: NCT04523129

Comparison of Water-Free Commercially Available Cyclosporine Ophthalmic Preparations—Different, but the Same

“…Best practice would be to define only 1 primary outcome or to split the P value between the 2 primary outcomes, resulting in an α of .025 for each. Neither of the 2 primary outcomes in the study by Akpek et al 1 would have been statistically significant if they had split the P value. They did use hierarchical testing to preserve their α for the 2 primary outcomes but did not give specifics about whether this was a prespecified approach or their exact methodology.…”

“…In this JAMA Ophthalmology edition, Akpek et al 1 present a randomized, double-masked, vehicle-controlled trial to evaluate the efficacy, safety, and tolerability of a water-free cyclosporine, 0.1%, ophthalmic solution (CyclASol [Novaliq]) compared with its vehicle for moderate to severe dry eye. We must congratulate Akpek et al 1 for their nicely designed trial, promising findings, and enduring attempt to find alternative treatments for this widespread problem.…”

Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics

“…Topical diclofenac mitigates primary afferent neuronal hypersensitivity which is responsible for its antiallodynic and antihyperalgesic effects (Kalangara et al., 2016; Yamada et al., 2002). Lifitegrast is another available anti‐inflammatory that inhibits the interplay between lymphocyte function‐associated antigen 1 and intercellular adhesion molecule‐1, interrupting migration of dendritic cells, thus mitigating ocular surface inflammation (Akpek et al., 2023; Perez et al., 2016). However, the effect of lifitegrast on peripheral nerve anatomy/function still needs to be specifically studied.…”

Water-Free Cyclosporine Ophthalmic Solution vs Vehicle for Dry Eye Disease

“…SHR8028 (CyclASol [Novaliq]), 0.1%, is a water-free cyclosporine ophthalmic formulation using a novel EyeSol (Novaliq) ocular drug delivery technology based on perfluorobutylpentane (F4H5). 11 The product obtained US Food and Drug Administration approval under the trade name Vevye (Novaliq) in May 2023 in the US. The vehicle F4H5 is a colorless liquid free of oils, surfactants, and preservatives, with a high vapor pressure and a low surface tension.…”

“…12 Later, a phase 3 pivotal study, CyclASol for the Treatment of Signs and Symptoms of Dry Eye Disease (ESSENCE-2), was conducted in the US to further validate the superiority of water-free cyclosporine, 0.1%, over vehicle in participants with moderate to severe DED. 11 This study was designed in parallel to the ESSENCE-2 trial as a bridging study to compare the efficacy and safety of water-free cyclosporine vs vehicle in China.…”