Water-Free Cyclosporine Solution Achieves Modest Improvement in Dry Eye

More than 70% of patients with chronic dry eye disease (DED) had rapid and clinically meaningful symptomatic improvement with an investigational water-free cyclosporine ophthalmic solution (CyclASol), a large randomized, vehicle-controlled trial showed.

After a month of treatment, 71.6% of patients randomized to the cyclosporine ophthalmic solution, 0.1%, had at least a 3-grade improvement in total corneal fluorescein staining (tCFS) versus 59.7% of patients randomized to vehicle control. Responding patients had significantly greater improvement in dryness and blurred visions compared with patients who did not respond. Adverse events occurred in a small number of patients in both treatment arms.

The findings provided confirmation for a prior randomized study that demonstrated the safety and efficacy of the cyclosporine solution and preliminary evidence of efficacy, reported Esen K. Akpek, MD, of Johns Hopkins Wilmer Eye Institute in Baltimore, and co-authors, in JAMA Ophthalmology.

"Rapidity and the magnitude of improvements on the corneal epithelial damage are potential differentiators to existing therapies," the researchers concluded. "More data from clinical practice would be beneficial in understanding the potential of this treatment."

Despite the favorable results, the clinical significance of the findings remains unclear, according to the authors of an accompanying editorial. The overall lack of association between signs and symptoms is a well-recognized phenomenon of DED, and the trial showed a significant impact on symptoms only in patients who met response criteria.

The high cost of medical treatment for DED cannot be overlooked, continued Jennifer Rose-Nussbaumer, MD, and co-authors, all of the Byers Eye Institute at Stanford University in California. The water-free cyclosporine solution may represent a marginal improvement over cyclosporine ophthalmic emulsion (Restasis), which has a lower concentration of active ingredient, reduced efficacy, and burning and stinging on application, along with a high cost.

"As acknowledged by the authors, a longer-term study comparing water-freer cyclosporine, 0.1%, to other established dry eye therapies ... is warranted," the editorialists continued. "One wonders what the cost of this new eye drop will be when the main improvement appears to be a superior vehicle?"

Currently, no standard criteria exist for clinical management of DED. The American Academy of Ophthalmology recommends staged management based on the severity of physician-measured findings. When nonprescription medication, eyelid hygiene measures, and environmental manipulation fail to improve the condition, several types of prescription eye drops, cyclosporine, lifitegrast, and short-term corticosteroids are the next step in clinical management, Rose-Nussbaumer and co-authors said.

The FDA approved cyclosporine 0.05% ophthalmic emulsion in 2002, but Akpek and colleagues noted that the cyclosporine is less soluble in the product's vehicle. In contrast, the water-free ophthalmic solution has a higher cyclosporine concentration (0.1%) and a preservative-free vehicle designed to improve bioavailability and efficacy.

In a phase II dose-finding study, the water-free ophthalmic solution achieved a larger reduction in corneal staining as compared with vehicle and the 0.05% emulsion. The phase III ESSENCE-1 trial confirmed the beneficial effects of the water-free cyclosporine ophthalmic solution observed in the phase II trial, providing the basis for the phase III ESSENCE-2 trial comparing the efficacy, safety, and tolerability of cyclosporine 0.1% solution versus its water-free vehicle in DED.

Investigators at 27 sites randomized 834 patients with chronic DED, associated with a tCFS score ≥10, dryness score ≥50, and a total conjunctival staining ≥2, and presence of ocular symptoms. For each study participant, the eye with the highest tCFS score was designated as the study eye. If the tCFS score was the same in both eyes, the right eye was designated as the study eye.

The primary efficacy endpoints were the mean change from baseline to day 29 in tCFS score and dryness score. If statistical superiority was achieved for both endpoints, quantitative secondary analyses were performed.

The primary analysis showed a change of -4.0 tCFS grades versus -3.6 in the patients randomized to vehicle (95% CI -0.8 to 0, P=0.03). Hierarchical testing of the second primary endpoint of dryness score showed mean improvement that favored the control group (-13.6 vs -12.2 points from baseline, P=0.38).

The investigators defined response as ≥3-grade improvement in tCFS. That analysis showed that the cyclosporine group had 293 responders compared with 236 in the control group, translating to an absolute 12.6% difference (95% CI 6.0-19.3, P<0.001). Irrespective of treatment group, responding patients had greater improvement in a variety of symptoms.

The proportion of patients with at least one treatment-emergent adverse event (TEAE) or ocular TEAE was similar between groups:

• TEAE: 16.8% for cyclosporine vs 17.8% for vehicle
• Ocular TEAE: 13.5% vs 15.1%

The most common ocular TEAE in both groups were instillation-site reaction (10.2% vs 8.8%, respectively), all mild other than one moderate case in each group.

Study limitations, the researchers said, included the inclusion of patients with predominantly aqueous-deficient DED, which might mean that the observed outcomes may not be generalizable to all patients with DED; and the short duration of the treatment.

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