Effects of Netarsudil and Latanoprost Alone and in Fixed Combination on Corneal Endothelium and Corneal Thickness: Post-Hoc Analysis of MERCURY-2

Abstract

Introduction: To describe the changes in endothelial cell density (ECD), the coefficient of variation (CV), the percentage of hexagonal cells (%HEX), and central corneal thickness (CCT) following 3 months of therapy with netarsudil 0.02%/latanoprost 0.005% fixed combination, and to compare these changes with those seen with netarsudil 0.02% or latanoprost 0.005% in eyes with ocular hypertension or open-angle glaucoma. Methods: A subset of subjects enrolled in a Phase 3 evaluation of the intraocular pressurelowering efficacy and safety of netarsudil 0.02%/latanoprost 0.005% fixed combination once daily (QD) versus each of its individual components underwent corneal endothelial cell imaging by specular microscopy and ultrasound pachymetry at baseline and following 3 months of therapy. Images were evaluated in masked fashion at an independent reading center. Changes from baseline to 3 months in ECD, CV, %HEX, and CCT were compared between treatment groups. Results: Data from 415 subjects obtained at both baseline and Month 3 were included in this post hoc analysis. Changes from baseline to Month 3 in ECD, CV, and %HEX were clinically insignificant in all three groups, and the changes in the netarsudil/latanoprost fixed combination group demonstrated no statistical difference from those seen in the netarsudil and latanoprost groups. Mean CCT decreased more in the fixed combination group (-6.4 lm) than in either the netarsudil group (-3.3 lm, p = 0.0248) or the latanoprost group (-1.2 lm, p \ 0.0001). Conclusions: Netarsudil 0.2%/latanoprost 0.005% fixed combination QD for 3 months in eyes with ocular hypertension or open-angle glaucoma had no clinically significant effects on endothelial cell density or morphology. The significant decrease in CCT in the fixed combination group compared to the two individual component groups may indicate that the potential effects of each drug on CCT are additive, although the magnitude of the observed effects is likely of negligible clinical significance. Clinicaltrials.gov Identifier: NCT02674854.

Netarsudil-associated reticular corneal epithelial edema

“… 19 Wisely et al also described mild morphological CEC changes in humans following three months of therapy with either netarsudil alone or fixed combination netarsudil/latanoprost when compared to latanoprost alone. 16 These changes in CEC density, coefficient of variation, and percentage of hexagonal cells were deemed clinically insignificant and resolved upon discontinuation in most subjects. However, patients who had significant corneal disease were excluded from the study, and therefore the impact of netarsudil on this at-risk patient population has yet to be elucidated.…”

“…Guttata-like endothelial changes with polymegathism and indistinct borders on specular microscopy have also been described, 15 but other studies have not found significant changes in endothelial cell metrics. 16 …”

Corneal endothelial wound healing after Descemet tear with a rho kinase inhibitor

“…Ripasudil has been shown to promote corneal wound healing after Descemet-stripping only surgery surgery for Fuchs dystrophy, whereas netarsudil in a small case series showed worsened vision due to bullous edema in 5 of 6 cases. 3,4,10 Our patient pursued medical management with ripasudil for corneal edema. He achieved similar results with ripasudil as Okumura et al reported with Y-27632.…”

“…Ripasudil has been shown to promote corneal wound healing after Descemet-stripping only surgery surgery for Fuchs dystrophy, whereas netarsudil in a small case series showed worsened vision due to bullous edema in 5 of 6 cases. 3,4,10…”

“Rapid and reversible alteration in corneal contour and power associated with Netarsudil/Latanoprost”

“…During phase 3 clinical trials of the efficacy and safety of netarsudil in lowering IOP in patients with OAG or OHT, conjunctival hyperemia, cornea verticillata, and conjunctival hemorrhage were the most commonly reported adverse effects. 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 Most of these cases were rated as mild, had no impact on visual acuity, and resolved with discontinuation of the drug. 15 , 16 , 19 Cornea verticillata was only detectable via biomicroscopy and had no clinically meaningful impact on vision.…”