A Prospective Study to Assess the Hypotensive Efficacy of Rho-Kinase Inhibitor AR-12286 Ophthalmic Solution 0.5% and 0.7% in Patients With Uncontrolled Advanced Glaucoma With Prior Failed Trabeculectomy or Tube Shunt

A. To evaluate the ocular hypotensive efficacy of the rho-kinase Inhibitor (AR-12286 0.5% and 0.7%) ophthalmic solutions in glaucoma patients with failed prior glaucoma filtering surgery and uncontrolled IOP who are facing further surgical intervention. Patients will be treated for 6 months in this initial trial.
B. To evaluate the efficacy of AR-12286 in enabling treated patients to delay or avoid the necessity of further surgical intervention.

Start Date01 Jun 2014

Sponsor / Collaborator

New York Glaucoma Research Institute

NCT02152774 / Unknown statusPhase 2IIT

A Prospective Study to Assess the Hypotensive Efficacy of Rho-Kinase Inhibitor AR-12286 Ophthalmic Solution 0.5% and 0.7% in Patients With Chronic Angle-closure Glaucoma

To evaluate the ocular hypotensive efficacy of Rho kinase Inhibitor (AR-12286 0.5% and 0.7%) ophthalmic solutions in patients diagnosed with chronic angle-closure glaucoma treated for 6 months.
Secondary Outcome
Secondary objectives are:
To evaluate the early effect of Rho kinase Inhibitor (AR-12286) in reducing intraocular pressure (IOP).
To evaluate the long term effect of the drug on IOP.
To determine if AR-12286 can be used as directed therapy for CACG, reducing or eliminating the structural blockage of the trabecular meshwork that leads to development of elevated IOP.

Start Date01 May 2014

Sponsor / Collaborator

New York Glaucoma Research Institute

100 Clinical Results associated with Verosudil

100 Translational Medicine associated with Verosudil

100 Patents (Medical) associated with Verosudil

Literatures (Medical) associated with Verosudil

03 Feb 2023·Investigative Opthalmology & Visual Science

Rho Kinase Inhibitor AR-12286 Reverses Steroid-Induced Changes in Intraocular Pressure, Effective Filtration Areas, and Morphology in Mouse Eyes

Article

Author: Ren, Ruiyi ; Kopczynski, Casey ; Gong, Haiyan ; Humphrey, Anne A.

PurposeWe investigated mechanisms of reduction of intraocular pressure (IOP) by Rho kinase inhibitor AR-12286 in steroid-induced ocular hypertension (SIOH).MethodsC57BL/6 mice (N = 56) were randomly divided into Saline, dexamethasone (DEX), DEX + AR-12286, and DEX-discontinuation (DEX-DC) groups. IOP was measured weekly during the first four weeks in all groups. Beginning at week 5, the DEX-DC group was followed without treatment until IOP returned to normal, and the other groups were treated as assigned with IOP measured every other day for another week. Fluorescent tracer was injected into the anterior chamber to visualize the outflow pattern in the trabecular meshwork (TM) and TM effective filtration area (EFA) was determined. Radial sections from both high- and low-tracer regions were processed for electron microscopy.ResultsAR-12286 reduced IOP in SIOH mouse eyes in one day (P < 0.01). At the end of week 5, mean IOP in the DEX + AR-12286 group was ∼4 mm Hg lower than DEX group (P < 0.001) and ∼2 mm Hg lower than DEX-DC group (P < 0.05). After one-week AR-12286 treatment (P < 0.05) or five-week DC of DEX (P < 0.01), DEX-induced reduction of EFA was rescued and DEX-induced morphological changes in the TM were partially reversed.ConclusionsAR-12286 reversed steroid-induced morphological changes in the TM and reduced EFA, which correlated with reduced IOP in SIOH eyes. AR-12286 reduced IOP elevation in SIOH eyes more effectively than discontinuing DEX treatment even when accompanied by continuous DEX treatment. Therefore Rho kinase inhibitors may lower SIOH in patients who rely on steroid treatment.

01 Sep 2016·Journal of GlaucomaQ3 · MEDICINE

Efficacy of Topically Administered Rho-Kinase Inhibitor AR-12286 in Patients With Exfoliation Syndrome and Ocular Hypertension or Glaucoma

Q3 · MEDICINE

Article

Author: Ritch, Robert ; Skaat, Alon ; Jasien, Jessica V.

Purpose:To evaluate the efficacy of rho-associated protein kinase inhibitor, AR-12286 topical solution, for its effect in eyes with exfoliation syndrome (XFS) and ocular hypertension (OHT) or exfoliative glaucoma (XFG) and examine any lasting effect on intraocular pressure (IOP) after discontinuation.Methods:Prospective, double-masked, randomized, interventional study. Patients with XFS and OHT or XFG were enrolled. The study eyes were treated once daily with AR-12286, randomized to 0.5% or 0.7% for 24 weeks. Visits included baseline, 1, 4, and 12 weeks after drug initiation; at 12 weeks AR-12286 was discontinued for 1 week and was resumed at week 13. At the week 24 visit, AR-12286 was discontinued, and a final reexamination was performed at week 25.Results:Ten patients were treated. Mean baseline IOP was 25±2.4 mm Hg, mean IOP was reduced to 19.1±2.3 mm Hg at 1 week (P<0.001), 17.5±3.6 mm Hg at 4 weeks (P<0.001), and 17.4±3.6 mm Hg at 12 weeks (P<0.001), yielding an average IOP reduction of 23.6%, 30%, and 30.4%, respectively. At the week 13 visit, 1 week after the drug was discontinued, mean IOP increased to 21.6±5.4 mm Hg (P=0.06 compared with baseline visit). At week 24, the mean IOP was 21.8±7.8 mm Hg (P=0.2, and AR-12286 was discontinued). At week 25, the mean IOP was 21.3±5.3 mm Hg (P=0.06).Conclusions:AR-12286 was well tolerated and provided statistically significant reduction in IOP in patients with XFS and OHT or XFG. This drug may represent an additional therapeutic paradigm for the treatment of XFG.

01 Mar 2014·Journal of Ocular Pharmacology and Therapeutics

Emerging Trabecular Outflow Drugs

Author: Epstein, David L. ; Kopczynski, Casey C.

Glaucoma is a progressive optic neuropathy that is a leading cause of irreversible blindness worldwide.1 Elevated intraocular pressure (IOP) is commonly associated with glaucoma, and multiple longitudinal studies have demonstrated that lowering IOP in patients can slow optic nerve degeneration and preserve vision.2 Although medications are available to reduce elevated IOP, the most commonly prescribed drugs do not address the underlying cause of elevated IOP in glaucoma, the deteriorating function of the trabecular outflow pathway. The trabecular outflow pathway is the primary draining tissue for the aqueous humor in the eye. It consists of 3 structures, the trabecular meshwork (TM), juxtacanalicular tissue, and Schlemm's canal. In a healthy eye, IOP is maintained within a narrow range through dynamic regulation of trabecular outflow resistance. In a glaucomatous eye, elevated IOP is due to an abnormally high resistance to outflow in the trabecular outflow pathway.3 The causes of increased outflow resistance are not fully understood, but it has been hypothesized to involve an increase in the contractile tone and stiffness of the TM and changes in extracellular matrix composition and/or a change in the conductance of Schlemm's canal.4 There is a significant need for glaucoma drugs that specifically target the physiologic cause of elevated IOP and thereby enhance trabecular outflow. The tissues of the trabecular outflow pathway are avascular and rely on the aqueous humor to supply nutrients, growth factors, and antioxidants. The most widely prescribed glaucoma drugs, the prostaglandin analogues (PGAs), lower IOP by increasing the aqueous drainage through the unconventional uveoscleral outflow pathway.5 The older, non-PGA drug classes, the beta blockers, alpha agonists, and carbonic anhydrase inhibitors, lower IOP by decreasing the production of aqueous humor.5 By shunting the aqueous humor through the uveoscleral pathway or decreasing the aqueous production, the commonly used glaucoma medications actually decrease the outflow of aqueous humor through the diseased TM. Thus, while protecting the optic nerve from damage by lowering IOP, current medications may be allowing further degradation of the trabecular outflow pathway. PGAs have become the initial therapy of choice for most physicians because they are generally more effective at lowering IOP and better tolerated than non-PGA drugs, and they offer a once-daily dosing regimen. Although PGAs often provide adequate efficacy as an initial therapy, nearly half of all patients started on PGA monotherapy ultimately require 1 or more non-PGA drugs to be added to their treatment regimen. This is the primary reason why half of all prescriptions are still written for non-PGA products.6 It does not appear that PGAs become less effective at promoting the uveoscleral outflow over time. IOPs continue to rise over time because the function of the trabecular outflow pathway continues to deteriorate over time. Fortunately, several new drug classes that target the trabecular outflow pathway have entered clinical development (Table 1). The drug class with the longest history in the clinic is the class of selective Rho kinase inhibitors. Rho kinase is a serine/threonine kinase whose activity increases actomyosin contraction in smooth muscle cells, including the smooth muscle-like cells of the TM. The therapeutic potential of Rho kinase inhibitors was initially demonstrated in preclinical studies using the Rho kinase inhibitor Y-27632, which was shown to relax precontracted TM tissue ex vivo,7 increase trabecular outflow in perfused enucleated porcine eyes,8 and lower IOP in live rabbits upon topical ocular application.9 Table 1. Recent Clinical Development of Trabecular Outflow Drugs According to clinical trial registries in the U.S., Europe, and Japan, 7 different selective Rho kinase inhibitors have been tested in human clinical trials.10 The most studied compound of this class is Aerie Pharmaceuticals' AR-12286. Although Aerie has replaced AR-12286 with the Rho kinase/norepinephrine transporter (ROCK/NET) inhibitor AR-13324 as its lead trabecular outflow drug (see below), much was learned about the potential clinical utility of selective Rho kinase inhibitors from AR-12286 clinical studies. For example, transient hyperemia is a class effect of Rho kinase inhibitors that results from relaxation of the smooth muscle cells of conjunctival blood vessels. A 28-day study of AR-12286 in patients with elevated IOP showed that transient hyperemia associated with Rho kinase inhibition could be effectively managed by dosing the drug once-daily in the evening to allow the hyperemia to resolve overnight.11 Specifically, once-daily P.M. dosing of 0.5% AR-12286 achieved IOP reductions of 2.9 to 6.1 mmHg, similar to twice-daily dosing of 0.25% AR-12286. However, the hyperemia incidence with the once-daily P.M. dosing regimen was only 11% compared with 46% for the twice-daily dosing regimen. Another AR-12286 clinical study demonstrated that Rho kinase inhibition can be used successfully in combination with PGAs to achieve a greater IOP lowering than PGA therapy alone.12 In patients with elevated IOP, a fixed-dose combination of 0.5% AR-12286 and 0.004% travoprost achieved IOP reductions of 9 to 12 mmHg when dosed once-daily in the evening and produced a reduction in diurnal IOP that was 2 mmHg greater than travoprost alone. The incidence and severity of hyperemia for the fixed-dose combination was similar to travoprost monotherapy. Given that physicians often need to prescribe non-PGA drugs as add-on therapy to PGAs, it is important that the Rho kinase mechanism of action is compatible with the PGA mechanism of action. Phase 2 clinical study results have recently been published for another selective Rho kinase inhibitor, K-115, from Kowa.13 In patients with elevated IOP, twice-daily dosing of 0.4% K-115 achieved IOP reductions of 3.1 to 4.5 mmHg. A 65% incidence of transient, mild hyperemia was reported for this concentration. The 0.4% concentration of K-115 has been advanced to Phase 3 studies in Japan. Adenosine A1 receptor agonists represent another new drug class that targets the trabecular outflow pathway. Adenosine A1 agonists are thought to increase the trabecular outflow by reducing the cell volume and increasing the expression of matrix metalloproteinases.14 The clinical study results from a 28-day Phase 2 trial have recently been presented for the adenosine A1 agonist trabodenoson (INO-8875).15 In patients with elevated IOP, twice-daily dosing of 500 μg trabodenoson produced IOP reductions of 4.9 to 6.5 mmHg. A transient, mild hyperemia was observed, although the incidence of hyperemia was not reported. The newest class of trabecular outflow drugs is the dual-action ROCK/NET class. ROCK/NET inhibitors are single molecules that act through a dual mechanism of action, simultaneously inhibiting Rho Kinase to increase trabecular outflow and inhibiting the NET to reduce the production of aqueous humor.16,17 Aerie Pharmaceuticals' AR-13324 is the first compound of this class to be tested in the clinic and has replaced AR-12286 as Aerie's lead trabecular outflow drug. In a 7-day clinical trial in patients with elevated IOP, once-daily A.M. dosing of AR-13324 (0.01%, 0.02%, or 0.04%) produced IOP reductions ranging from 5.6 to 7.2 mmHg.18 The morning dosing regimen produced transient, mild to moderate hyperemia with an incidence of 29% for the 0.02% concentration (the top of the dose–response curve) on day 7. The 0.01% and 0.02% concentrations of AR-13324 have been advanced to a 28-day Phase 2b study to evaluate the efficacy and tolerability of AR-13324 when dosed once-daily in the evening. In addition, clinical development has begun for PG324, a fixed-dose combination product that combines AR-13324 with latanoprost. Physicians have long desired a drug that could effectively treat the source of elevated IOP in glaucoma, the diseased trabecular outflow pathway. Once available, it will be possible to address potential benefits that may be unique to a trabecular outflow drug. Does improving the flow of nutrients and growth factors to the trabecular outflow pathway stop or even reverse its degeneration? Is it important that trabecular outflow drugs be used early in the course of treatment, before the outflow pathway is damaged beyond repair? Does improving trabecular outflow restore the normal ability of the TM to dampen spikes in IOP and thereby provide greater protection to the optic nerve? Fortunately, significant progress is being made toward bringing an effective and well-tolerated trabecular outflow drug to the practice of glaucoma medicine.

100 Deals associated with Verosudil

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Glaucoma, Open-Angle	Phase 3	US	Aerie Pharmaceuticals, Inc.	01 May 2011
Ocular Hypotension	Phase 3	US	Aerie Pharmaceuticals, Inc.	01 May 2009
Ocular Hypertension	Phase 3	-	Aerie Pharmaceuticals, Inc.	-

Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01936389 (Pubmed \| J Glaucoma) Manual	Phase 2	Ocular Hypertension \| Exfoliation Syndrome \| Glaucoma	10	AR-12286	(ygsqinmhyh) = ujjroncxum khncsiyxuq (qmftgwutoj ) View more	Positive	01 Sep 2016
NCT01936389 (ROCK, CTgov)	Phase 2	Glaucoma, Open-Angle \| Exfoliation Syndrome	10	AR-12286 (0.5%)	bhmzrjkhpb(bnuniwzzpv) = mcvzwoldyt mivmepmgha (naedewxyfr, ikchzwmhpm - khpcxmgakh) View more	-	24 Apr 2015
				AR-12286 (0.7%)	bhmzrjkhpb(bnuniwzzpv) = hwtrharomm mivmepmgha (naedewxyfr, xqgblldfns - ezprcyzvdb) View more
ARVO2013	Not Applicable	Ocular Hypotension	93	AR-12286 0.25%	(zqfmdtquah) = The most frequently reported events were mild to moderate conjunctival hyperemia, 32% (10/31), 59% (17/29) and 42% (14/33) in the PG286-0.25%, PG286-0.5% and travoprost groups, respectively. The incidence of conjunctival hyperemia of grade 2 or greater at Day 7 was 0%, 12% and 12%, respectively. huradiuyss (vifxbthzpd )	Positive	01 Jun 2013
				AR-12286 0.5%
NCT00902200 (Pubmed \| Am J Ophthalmol)	Phase 2	Ocular Hypertension \| Glaucoma	89	0.05% AR-12286 Ophthalmic Solution	(mwquyzxuft) = jiyqpvqoer mdnebzexqr (lfabuiswsu ) View more	Positive	01 Nov 2011
				0.1% AR-12286 Ophthalmic Solution	(mwquyzxuft) = xytnrfstzc mdnebzexqr (lfabuiswsu ) View more
PO105 (AAO2011)	Not Applicable	-	18	0.5% AR-12286 Ophthalmic Solution	(qljotgczvq) = trace to moderate transient conjunctival hyperemia nevovuvfql (biaakqvshj )	Positive	23 Oct 2011
NCT01250197 (ARVO2011)	Phase 1	-	18	0.5% AR-12286 Ophthalmic Solution	(afkrwocded) = trace to moderate conjunctival hyperemia that gradually returned to baseline by 8 hrs after dosing pzujzpsmjx (lgxgyurpyw )	Positive	01 Apr 2011
NCT00902200 (ARVO2010)	Phase 3	Ocular Hypotension	89	0.05% AR-12286 Ophthalmic Solution	(kyblvlbjpp) = hckrwhgkky dugodsdrnk (qzhgvaengf ) View more	Positive	01 Apr 2010
				0.1% AR-12286 Ophthalmic Solution	(kyblvlbjpp) = utsrapejgo dugodsdrnk (qzhgvaengf ) View more

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