Phase 2, Randomized, Open-Label Parallel-Group Study of Two Dosing Regimens of Netarsudil for the Treatment of Corneal Edema Due to Fuchs Corneal Dystrophy

Richard L Lindstrom, Amber E Lewis, Edward J Holland, John D Sheppard, John A Hovanesian, Michelle Senchyna, David A Hollander, Richard L Lindstrom, Amber E Lewis, Edward J Holland, John D Sheppard, John A Hovanesian, Michelle Senchyna, David A Hollander

Abstract

Background: This phase 2 study evaluated the therapeutic potential of netarsudil to reduce corneal edema and to improve vision in patients with Fuchs corneal dystrophy (FCD). Methods: Patients (N = 40) with baseline central corneal thickness (CCT) of ≥600 μm and best-corrected visual acuity (BCVA) of 70-20 letters (20/40-20/400 Snellen equivalent) were randomized 1:1 to receive netarsudil once a day (QD) or twice a day (BID) for 8 weeks. Primary endpoint was mean CCT change from baseline at week 4. Results: Netarsudil QD and BID significantly reduced CCT at week 4 [mean change (standard error of mean), 28.4 (7.99) μm, P = 0.0021; and 20.1 (8.75) μm, P = 0.0335, respectively]. Five (12.5%) patients achieved complete resolution of corneal edema at week 4. BCVA improved by 3.2 (2.76) letters with QD and 1.5 (2.84) letters with BID, and 10 (25%) patients [5 with QD (P = 0.0078) and 5 with BID (P = 0.0096)] gained ≥10 letters at week 4. Improvements in CCT and vision were observed at week 2 and persisted at week 8, without significant differences between the 2 doses at any time point. Netarsudil QD significantly improved visual acuity and glare factor scores on the Visual Function and Corneal Health Status (V-FUCHS) questionnaire at weeks 4 and 8 (mean change, -0.4 to -0.3; P ≤ 0.0200). Netarsudil was well tolerated. Reticular edema developed in one (2.5%) patient with BID, which resolved with treatment discontinuation. Conclusions: Netarsudil QD led to significant reductions in corneal edema as well as improvements in vision and patient-reported symptoms of glare and visual impairment in patients with FCD. Clinical Trial Registration Number: NCT04498169.

Keywords: Fuchs corneal dystrophy; Rho kinase inhibitor; V-FUCHS questionnaire; central corneal thickness; corneal edema; netarsudil.

Conflict of interest statement

E.J.H., J.A.H., R.L.L., and J.D.S.: consultants to Aerie Pharmaceuticals. M.S.: employee of Aerie Pharmaceuticals. D.A.H. and A.E.L.: former employees of Aerie Pharmaceuticals.

Figures

FIG. 1.
FIG. 1.
Patient disposition. BID; twice a day; QD, once a day.
FIG. 2.
FIG. 2.
Mean change from baseline CCT in the study eye. *Statistically significant at 5% level. P values based on one-sample t-test for within-group comparisons to baseline. CCT, central corneal thickness; SEM, standard error of mean.
FIG. 3.
FIG. 3.
Percentage of patients with complete resolution of corneal edema in the study eye. *Statistically significant at 5% level. Responder analyses: P values are based on a logistic regression model fitted with binary outcome variable (Y/N) and baseline mean CCT as a covariate and treatment group as a main effect.
FIG. 4.
FIG. 4.
Mean change from baseline BCVA in ETDRS letter score in the study eye. *Statistically significant at 5% level. P value based on one-sample t-test for within-group comparison to baseline. BCVA, best-corrected visual acuity; ETDRS, Early Treatment of Diabetic Retinopathy Study.
FIG. 5.
FIG. 5.
Proportion of study eyes with ≥10-letter (2-line) gain from baseline in BCVA. *Statistically significant at 5% level. Responder analyses: P values are based on a logistic regression model fitted with binary outcome variable (Y/N) and baseline BCVA letter score as a covariate and treatment group as a main effect.

References

    1. McLaren JW, Bachman LA, Kane KM, et al. . Objective assessment of the corneal endothelium in Fuchs' endothelial dystrophy. Invest Ophthalmol Vis Sci 2014;55(2):1184–1190; doi: 10.1167/iovs.13-13041
    1. Okumura N, Hayashi R, Koizumi N. Perspective of future potent therapies for fuchs endothelial corneal dystrophy. Open Ophthalmol J 2018;12:154–163; doi: 10.2174/1874364101812010154
    1. Moshirfar M, Somani AN, Vaidyanathan U, et al. . Fuchs Endothelial Dystrophy. StatPearls Publishing: Treasure Island:FL; 2021.
    1. Gain P, Jullienne R, He Z, et al. . Global Survey of Corneal Transplantation and Eye Banking. JAMA Ophthalmol 2016;134(2):167–173; doi: 10.1001/jamaophthalmol.2015.4776
    1. Garcerant D, Hirnschall N, Toalster N, et al. . Descemet's stripping without endothelial keratoplasty. Curr Opin Ophthalmol 2019;30(4):275–285; doi: 10.1097/ICU.0000000000000579
    1. Koizumi N, Okumura N, Ueno M, et al. . New therapeutic modality for corneal endothelial disease using Rho-associated kinase inhibitor eye drops. Cornea 2014;33(Suppl 11):S25–S31; doi: 10.1097/ICO.0000000000000240
    1. Okumura N, Ueno M, Koizumi N, et al. . Enhancement on primate corneal endothelial cell survival in vitro by a ROCK inhibitor. Invest Ophthalmol Vis Sci 2009;50(8):3680–3687; doi: 10.1167/iovs.08-2634
    1. Okumura N, Kinoshita S, Koizumi N. Application of Rho kinase inhibitors for the treatment of corneal endothelial diseases. J Ophthalmol 2017;2017:2646904; doi: 10.1155/2017/2646904
    1. Schlötzer-Schrehardt U, Zenkel M, Strunz M, et al. . Potential functional restoration of corneal endothelial cells in fuchs endothelial corneal dystrophy by ROCK Inhibitor (Ripasudil). Am J Ophthalmol 2021;224:185–199; doi: 10.1016/j.ajo.2020.12.006
    1. Okumura N, Koizumi N, Kay EP, et al. . The ROCK inhibitor eye drop accelerates corneal endothelium wound healing. Invest Ophthalmol Vis Sci 2013;54(4):2493–2502; doi: 10.1167/iovs.12-11320
    1. Koizumi N, Okumura N, Ueno M, et al. . Rho-associated kinase inhibitor eye drop treatment as a possible medical treatment for Fuchs corneal dystrophy. Cornea 2013;32(8):1167–1170; doi: 10.1097/ICO.0b013e318285475d
    1. Syed ZA, Rapuano CJ. Rho kinase (ROCK) inhibitors in the management of corneal endothelial disease. Curr Opin Ophthalmol 2021;32(3):268–274; doi: 10.1097/ICU.0000000000000748
    1. Fujimoto H, Kiryu J.. Efficacy of the Rho-kinase Inhibitor Ripasudil for Fuchs' endothelial corneal dystrophy. J Opthalmol Res 2021;4:231–243.
    1. Kinoshita S, Colby KA, Kruse FE. A close look at the clinical efficacy of Rho-associated protein kinase inhibitor eye drops for Fuchs endothelial corneal dystrophy. Cornea 2021;40(10):1225–1228; doi: 10.1097/ICO.0000000000002642
    1. RHOPRESSA® (netarsudil ophthalmic solution) 0.02%, for topical ophthalmic use. December 2017. Aerie Pharmaceuticals, Inc.: Irvine, CA, USA.
    1. Price MO, Price FW Jr. Randomized, double-masked, pilot study of netarsudil 0.02% ophthalmic solution for treatment of corneal edema in Fuchs dystrophy. Am J Ophthalmol 2021;227:100–105; doi: 10.1016/j.ajo.2021.03.006
    1. Fernandez MM. Reticular Epithelial edema in edematous corneas treated with netarsudil. Ophthalmology 2018;125(11):1709; doi: 10.1016/j.ophtha.2018.08.004
    1. Liu KC, Gupta D. Netarsudil-associated reticular corneal epithelial edema with raised intraocular pressure. Ophthalmol Glaucoma 2019;2(3):166; doi: 10.1016/j.ogla.2019.01.001
    1. Moumneh K, Sheybani A, Fellman RL, et al. . Reticular corneal edema or corneal honeycombing in eyes treated with netarsudil: A case series. J Glaucoma 2020;29(7):607–610; doi: 10.1097/IJG.0000000000001516
    1. Wisely CE, Liu KC, Gupta D, et al. . Reticular bullous epithelial edema in corneas treated with netarsudil: A case series. Am J Ophthalmol 2020;217:20–26; doi: 10.1016/j.ajo.2020.04.002
    1. Wacker K, Baratz KH, Bourne WM, et al. . Patient-reported visual disability in Fuchs' endothelial corneal dystrophy measured by the visual function and corneal health status instrument. Ophthalmology 2018;125(12):1854–1861; doi: 10.1016/j.ophtha.2018.06.018
    1. Srinivas SP. Cell signaling in regulation of the barrier integrity of the corneal endothelium. Exp Eye Res 2012;95(1):8–15; doi: 10.1016/j.exer.2011.09.009
    1. Beckers CML, Knezevic N, Valent ET, et al. . ROCK2 primes the endothelium for vascular hyperpermeability responses by raising baseline junctional tension. Vascul Pharmacol 2015;70:45–54; doi: 10.1016/j.vph.2015.03.017
    1. Ploysangam P, Patel SP. A case report illustrating the postoperative course of descemetorhexis without endothelial keratoplasty with topical netarsudil therapy. Case Rep Ophthalmol Med 2019;2019:6139026; doi: 10.1155/2019/6139026
    1. Hirabayashi KE, Mark D, Lau J, et al. . Descemet stripping only for a chronic descemet detachment after cataract surgery. Cornea 2020;39(3):379–381; doi: 10.1097/ICO.0000000000002195
    1. Davies E, Jurkunas U, Pineda R 2nd. Pilot study of corneal clearance with the use of a Rho-kinase inhibitor after descemetorhexis without endothelial keratoplasty for Fuchs endothelial corneal dystrophy. Cornea 2021;40(7):899–902; doi: 10.1097/ICO.0000000000002691
    1. Davies E. Case Series: Novel utilization of Rho-kinase inhibitor for the treatment of corneal edema. Cornea 2021;40(1):116–120; doi: 10.1097/ICO.0000000000002421

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