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NOVEL ADDITION FOR SCRIPT REWRITE IOP REDUCTION Rho kinase inhibitors could shake up medical therapy.

BY JANET B. SERLE, MD

The Rho kinase (ROCK) inhibitors are a new drugs in Rocket 1 among patients who had a baseline IOP class of drugs under investigation for use below 25 mm Hg and in Rocket 4 for patients with a baseline in glaucoma. They are thought to increase IOP below 30 mm Hg. In Rocket 2, IOP reductions with net- aqueous outflow by reversing structural and arsudil were consistent through 12 months of dosing. functional damage at the trabecular mesh- work.1 Additionally, the vasodilatory effect FIXED-COMBINATION THERAPY of some ROCK inhibitors reduces episcleral By reducing the number of daily drop administrations, venous pressure. fixed-combination therapy can enhance patients’ compliance to prescribed medical treatment. A fixed-dose combina- NETARSUDIL tion of netarsudil and (Roclatan 0.02%/0.005%; Netarsudil ophthalmic solution 0.02% (Rhopressa; Aerie Aerie Pharmaceuticals) was compared with the individual Pharmaceuticals) lowers IOP by inhibiting both ROCK components in the clinical studies Mercury 1 (12 months) and the norepinephrine transporter (NET).2-5 The former and Mercury 2 (3 months). Mercury 3 (6 months; Table 2), enhances trabecular outflow and reduces episcleral venous recently begun in Europe, compares netarsudil-latanoprost pressure, while the latter decreases aqueous production. In to a fixed combination of and (Ganfort; contrast, (Glanatec; Kowa), in clinical use only in Allergan; not available in the United States). Japan, is solely a ROCK inhibitor.6 Mercury 18,9 and Mercury 2 demonstrated 1 to 3 mm Hg In phase 1, 2, and 3 clinical trials of netarsudil in more greater IOP lowering (P < .0001) with the fixed combination than 2,000 patients, the 0.02% concentration administered once daily in the evening was the most efficacious and well-tolerated dosing regimen. Clinical trials with netarsudil include a phase 2 comparison with latanoprost7 and four AT A GLANCE phase 3 trials comparing netarsudil to timolol (Table 1). In the phase 2 trial comparing netarsudil and latanoprost, • Rho kinase (ROCK) inhibitors may provide a new way both drugs were administered once daily in the evening for to treat glaucoma. This class of drugs is thought to 28 days. IOP reductions were similar in patients with a base- increase aqueous outflow by reversing structural and line IOP between 22 and 26 mm Hg (-5.8 mm Hg, netarsudil; functional damage at the , and the 5.9 mm Hg, latanoprost). In all enrolled patients (with a vasodilatory effect of some ROCK inhibitors reduces baseline IOP up to 36 mm Hg), netarsudil was 1 mm Hg less episcleral venous pressure. effective than latanoprost (-5.7 vs 6.8 mm Hg) and did not meet the statistical analysis for noninferiority of netarsudil to • Netarsudil ophthalmic solution 0.02% lowers IOP by latanoprost. inhibiting both ROCK and norephinephrine transporter. Rocket 1 (3 months), Rocket 2 (12 months), and Rocket 4 In phase 1, 2, and 3 clinical trials, once-daily dosing in (6 months)—three completed phase 3 clinical trials—com- the evening was efficacious and well tolerated. The new pared netarsudil administered in the evening to timolol drug application for netarsudil was filed during the first 0.5% administered twice daily. Baseline IOP was higher than quarter of 2017. 20 mm Hg and lower than 27 mm Hg in Rocket 1 and 2. • In clinical trials, a fixed-dose combination of netarsudil In Rocket 4, baseline IOP was higher than 20 mm Hg and and latanoprost was more efficacious than the individ- lower than 30 mm Hg. In primary analysis, IOP reductions ual components and well tolerated over 12 months of were similar with netarsudil and timolol in Rocket 2 and 4 dosing. The new drug application filing for the combina- among patients who had a baseline IOP below 25 mm Hg. In tion drug is anticipated in 2018. secondary analysis, IOP reductions were similar with the two

SEPTEMBER/OCTOBER 2017 | GLAUCOMA TODAY 53 TABLE 1. NETARSUDIL 0.02% (RHOPRESSA) ROCK/NET INHIBITOR: PHASE 2 AND 3 CLINICAL TRIALS Study Duration, No. of Description Conclusion Patients Phase 2B7 28 days, 152 QHS vs latanoprost Similar to latanoprost at IOP < 27 mm Hga Rocket 1 3 months, 411 QHS vs timolol BID Similar to timolol at IOP < 25 mm Hga Phase 3 Rocket 2 3 months efficacy, QHS vs timolol BID Similar to timolol at IOP < 25 mm Hg through Phase 3 12 months safety, 755 BID vs timolol BID month 12 Rocket 3 12 months safety, 93 QHS vs timolol BID Ongoing data analysis Phase 3 Rocket 4 3 months efficacy, QHS vs timolol BID Similar to timolol at IOP < 25 mm Hg, SCRIPT REWRITE SCRIPT Phase 3 6 months safety, 708 < 30 mm Hga 90-day results aSecondary endpoint Abbreviations: ROCK, Rho kinase; NET, norepinephrine transporter; QHS, nightly at bedtime; BID, twice daily. TABLE 2. FIXED-DOSE COMBINATION NETARSUDIL 0.02%/LATANOPROST 0.005% (ROCLATAN), ROCK/NET INHIBITOR/PGF2α AGONIST: PHASE 3 CLINICAL TRIALS Study Duration, No. of patients Description Conclusion Mercury 1 3 months efficacy FDC QHS FDC more efficacious than components 1-3 mm Hg Phase 38,9 12 months safety, 718 vs netarsudil QHS at all 9 time points (P <.0001) vs latanoprost QHS Mercury 2 3 months efficacy, 750 FDC QHS FDC more efficacious than components 1-3 mm Hg Phase 3 vs netarsudil QHS at all 9 time points (P <.0001) vs latanoprost QHS Mercury 3 6 months safety and FDC QHS vs Initiating in Europe Phase 3 efficacy FDC bimatoprost/timolol QHS enrollment ongoing

Abbreviations: ROCK, Rho kinase; NET, norepinephrine transporter; FDC, fixed-dose combination; QHS, nightly at bedtime.

of netarsudil and latanoprost than with the individual com- TOLERABILITY ponents at all measurements. In Mercury 1, consistent efficacy In clinical trials, both netarsudil and the fixed combination of the fixed combination was maintained through 12 months. of netarsudil and latanoprost were well tolerated. The most A responder analysis in Mercury 1 demonstrated that sub- frequent side effect was conjunctival hyperemia caused by stantially more patients treated with the fixed combination the vasodilatory effect of the drug. It was observed in 50% achieved greater percentage reductions and lower target IOPs to 60% of patients examined by ophthalmologists. Typically than those treated with the individual components. IOP reduc- graded as mild, hyperemia was sporadic, occurring at every tions of at least 30% were achieved in 65% of patients treated visit in only 10% of patients. with the fixed combination. The same reduction was achieved Other ocular adverse events, which have been reported in only 40% of individual component-treated patients. in 5% to 25% of patients in these trials, included small con- Of the patients treated with the fixed combination of junctival hemorrhages and cornea verticillata, both observed netarsudil and latanoprost, a total of 61% achieved an IOP on slit-lamp examination. The cornea verticillata (microde- of 16 mm Hg or less, and 33% of patients achieved an IOP posits of intracellular phospholipids are observed in almost of 14 mm Hg or less. Among the patients treated with the all patients taking systemic amiodarone)10 were asympto­ individual components, the statistics were 40% or less and matic and did not reduce visual function. The adverse events 15% or less, respectively. In short, the fixed combination was observed during the 12-month trials were consistent with extremely efficacious and in many patients achieved the low those observed during the initial 90-day efficacy period. Few target pressures that glaucoma patients typically require. (Continued on page 66)

54 GLAUCOMA TODAY | SEPTEMBER/OCTOBER 2017 (Continued from page 54) systemic side effects were reported, which can be explained by the systemic absorption of netarsudil, which is below the lower limit of quantification.11

SUMMARY Once-daily dosing of netarsudil and the fixed combination of netarsudil and latanoprost is efficacious, which should enhance patients’ compliance. The efficacy of netarsudil is similar to that of timolol, without the systemic side effects associated with topical ß-blockers. The fixed combination of netarsudil and latanoprost is more efficacious than the individual components, and it was well tolerated over 12 months of dosing. Netarsudil’s mechanisms of action are unique from those SCRIPT REWRITE SCRIPT of drugs currently available for to treat glaucoma. The fixed combination of netarsudil and latanoprost dosed once daily confirms the additivity of these two classes of drugs, with enhanced outflow through both the trabecular pathway from netarsudil and the uveoscleral pathway from latanoprost. The additivity of netarsudil and the fixed combination of netar- sudil and latanoprost to medications in use is anticipated. The new drug application for netarsudil was filed during the first quarter of 2017, and the filing for the fixed combi- nation of netarsudil and latanoprost is anticipated in 2018. When approved for clinical use, these drugs will expand the treatment options for glaucoma patients. n

1. Van de Velde S, De Groef L, Stalmans I, et al. Towards axonal regeneration and neuroprotection in glaucoma: Rho kinase inhibitors as promising therapeutics. Prog Neurobiol. 2015;131:105-119. 2. Wang SK, Chang RT. An emerging treatment option for glaucoma: Rho kinase inhibitors. Clin Ophthalmol. 2014;8:883- 890. 3. Wang RF, Williamson JE, Kopczynski C, Serle JB. Effect of 0.04% AR-13324, a ROCK and norepinephrine transporter inhibitor, on aqueous humor dynamics in normotensive monkey eyes. J Glaucoma. 2015;24(1):51-54. 4. Kiel JW, Kopczynski C. Effect of AR-13324 on episcleral venous pressure in Dutch belted rabbits. J Ocul Pharmacol Ther. 2015;31(3):146-151. 5. Ren R, Guorong L, Le TD, et al. Netarsudil increases outflow facility in human eyes through multiple mechanisms. IOVS. 2016;57(14):6197-6209. 6. Inazaki H, Kobayashi S, Anzai Y, et al. One-year efficacy of adjunctive use of ripasudil, a Rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy [published online ahead of print July 15, 2017]. Graefes Arch Clin Exp Ophthalmol. doi:10.1007/s00417-017-3727-5. 7. Bacharach J, Dubiner HB, Levy B, et al. Double-masked, randomized, dose-response study of AR-13324 versus latanoprost in patients with elevated . Ophthalmology. 2015;122(2):302-307. 8. Asrani S, Kopczynski C, Heah T. A 3-month interim report of a prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, 12-month study assessing the safety and ocular hypotensive efficacy of PG324 ophthal- mic solution. Paper presented at: The 27th Annual AGS Meeting; March 3, 2017; Coronado, CA. 9. Serle JB, Lewis RA, Kopczynski C, Heah T. 3-month interim report of a prospective 12-month safety and efficacy study of topical PG324 (fixed combination of netarsudil 0.02% and latanoprost 0.005%) compared to the individual components in subjects with elevated intraocular pressure. Paper presented at: The ARVO Meeting; May 9, 2017; Baltimore, MD. 10. Raizman, MB, Hamrah P, Holland EJ, et al. Drug-induced corneal epithelial changes. Surv Ophthalmol. 2017;62(3):286- 301. 11. Levy B, Ramirez N, Novack GD, Kopczynski C. Ocular hypotensive safety and systemic absorption of AR-13324 ophthalmic solution in normal volunteers. Am J Ophthalmol. 2015;159(5):980-985.

Janet B. Serle, MD n professor of ophthalmology and glaucoma fellowship director, Icahn School of Medicine at Mount Sinai, New York n [email protected] n financial disclosure: member of the Aerie Pharmaceuticals scien- tific advisory board; consultant to Allergan, Bausch & Lomb, and Pfizer; recipient of research support from Allergan, Inotek, and Ocular Therapeutix; stockholder in Aerie Pharmaceuticals

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