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 Table of Contents  
NEW DRUG UPDATE
Year : 2021  |  Volume : 59  |  Issue : 1  |  Page : 56-60

Rho-kinase inhibitors in ophthalmology


Department of Glaucoma, Glaucoma Services, Aravind Eye Hospital, Puducherry, India

Date of Submission30-Sep-2020
Date of Decision26-Dec-2020
Date of Acceptance07-Jan-2021
Date of Web Publication27-Mar-2021

Correspondence Address:
Dr. Srinivasan Kavitha
Glaucoma Services, Aravind Eye Hospital, Puducherry
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/tjosr.tjosr_146_20

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  Abstract 


Rho-kinase (ROCK) inhibitor is the newer drug available for glaucoma in the Indian market. It seems to target the actual area of disease pathology which has not been the case with the available medications. With the ever-evolving potential of these drugs in various diseases in ophthalmology, it would be wise to know about them. This review article aims to provide information regarding the role of ROCK and its inhibitors in glaucoma, corneal diseases, and retinal pathologies. A thorough search of several databases was conducted with ROCK inhibitors being one of the main keywords.

Keywords: Corneal endothelial disease, glaucoma, rho-kinase, rho-kinase inhibitors


How to cite this article:
Gopalakrishna M, Kavitha S. Rho-kinase inhibitors in ophthalmology. TNOA J Ophthalmic Sci Res 2021;59:56-60

How to cite this URL:
Gopalakrishna M, Kavitha S. Rho-kinase inhibitors in ophthalmology. TNOA J Ophthalmic Sci Res [serial online] 2021 [cited 2021 Oct 20];59:56-60. Available from: https://www.tnoajosr.com/text.asp?2021/59/1/56/312294




  Introduction Top


Glaucoma is the second-leading cause of blindness worldwide.[1] The global burden of glaucoma is only going to increase further and estimated to be 110 million by 2040.[2] Intraocular pressure (IOP) is still the only modifiable risk factor in preventing progression of glaucoma. Most of the treatment modalities still circle around decreasing the IOP. The available drugs decrease IOP mainly by decreasing aqueous production or increasing uveoscleral outflow. There are no medications which address the actual disease pathology, which is the resistance to conventional pathway of aqueous outflow. Although alternative treatment modalities in terms of neuroprotection are being extensively researched, an effective therapy is yet to be known. There have been no new drugs for glaucoma management since the mid-1990s, and a new drug in the market was long awaited. The wait is now over, and the Rho-kinase (ROCK) inhibitors are the newer drugs available in the market. This review article will throw light on the role of ROCK inhibitors in ophthalmology, based on the available evidence.


  Methods Top


A thorough search of several databases was conducted including PubMed, Google Scholar, and Medical Subject Headings (MeSH). The search was conducted with the keywords Rho-kinase inhibitors, Rock inhibitors, antiglaucoma medication, ripasudil, netarsudil and additional words such as corneal endothelium protection and diabetic retinopathy (DR) was used along with above. The search was conducted with the keywords Rho-Kinase Inhibitors, Rock Inhibitors, antiglaucoma medication, Ripasudil and Netarsudil.

Rho-kinase

Rho is a family of small GTPases which are signaling G proteins. They have three isoforms RhoA, RhoB, and RhoC. They become active on binding to guanosine triphosphate (GTP) and inactive in guanosine diphosphate form. ROCK is a serine/threonine protein kinase which is the downstream effector of Rho GTPases and involved in the complex cellular processes through a variety of transduction pathways. ROCK has two isomer types ROCK1 and ROCK2. ROCK1 and ROCK2 are both ubiquitously expressed in various tissues all over the body. In the GTP-bound active form, the Rho GTPase reacts with downstream effector proteins like ROCK. This active form regulates actin skeleton, smooth cell contraction, cell migration, gene transcription, cell proliferation, microtubule dynamics, and a number of enzymatic activities.[3] ROCK acts on cellular contraction in smooth muscle by facilitating myosin light-chain (MLC) phosphatase in phosphorylation of various substrates.

Rho-kinase inhibitors

The multiple roles of ROCK have made way for ROCK inhibitors to be used in diseases like cerebral vasospasm. Fasudil is one such drug being used and was approved in Japan in 1995. In the recent times, ROCK inhibitors have found their way in treating ophthalmological conditions as well. In the eye, they act by inhibiting the ROCK isoforms mainly in the trabecular meshwork (TM). Both ROCK1 and ROCK2 have been found in the human aqueous outflow pathway. By 2001, investigations began on the effect of ROCK inhibitors on IOP and as a treatment option for glaucoma. By 2010, studies highlighting their role in corneal and retinal diseases came forward.

Role of rho-kinase inhibitors in glaucoma

Rho signaling pathway plays an important role in the cellular contractility and morphology in the conventional aqueous humor outflow pathway. These drugs not only decrease IOP but also seem to have neuroprotection which is an added benefit in a patient with glaucoma. It also has antifibrotic activity which adds to its usefulness on post-trabeculectomy patients [Table 1].
Table 1: Mechanism of action of Rho-kinase inhibitors in glaucoma

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Ocular hypotensive effect

Topical ROCK inhibitors reduce IOP by inhibiting the ROCK in the TM and decrease the aqueous humor resistance most likely by acting on the actin in the cytoskeleton of TM. The TM properties change over age and also in diseases like primary open-angle glaucoma (POAG).[4] These drugs would be good for such glaucomas where the TM resistance is the main mechanism.[5]

Neuroprotection

ROCK inhibitors have been known to relax vascular smooth muscle so have a role in increasing ocular and retinal blood flow.[6] Abnormal ocular blood flow is involved in the pathogenesis of certain forms of glaucoma like normal-tension glaucoma (NTG).[7] ROCK inhibitors can hence provide additional therapeutic benefit in these types of glaucoma. There is increasing evidence demonstrating the protective effects of ROCK inhibition on retinal ganglion cells (RGCs). The ischemia/reperfusion-induced apoptosis of retinal cells is inhibited.[8] They are known to promote regeneration of crushed axons of retinal ganglion cells.[9] These play a role in neuroprotection of the optic nerve head in various forms of glaucoma, especially in NTG.

Antifibrotic activity

Trabeculectomy is the most widely done filtration surgery to manage glaucoma. However, its failure is mainly due to fibroblastic activity leading to scarring of the filtering bleb. Reports suggest that transforming growth factor-β (TGF-β) myofibroblast transdifferentiation of human Tenon's fibroblasts is blocked by ROCK inhibitors.[10] They have shown promising results in inhibiting cell migration and adhesion, thus playing a role in wound healing and preventing subconjunctival scar formation.[11] Unlike other antiglaucoma medications, these drugs can prevent the failure of glaucoma filtration surgery.

Drugs

  • Ripasudil 0.4% (available in India)
  • Netarsudil 0.02% (Available in India)
  • SNJ-1656 and AR-12286 (under trial)
  • Fixed-dose combination (FDC) of netarsudil with latanoprost


Ripasudil (K 115)

Ripasudil is a fluorinated analog of fasudil but more selective ROCK inhibitory activity. It was the first ROCK inhibitor to get approval in Japan in 2014 (K-115; Glanatec®; Kowa Company, Ltd., Nagoya, Aichi, Japan).[12]

Mechanism of action

  • Increase aqueous humor outflow by conventional pathway
  • Neuroprotection
  • Decrease scar formation, post-trabeculectomy.


Dosage

0.4% formulation to be applied twice daily.

Indications

It has been approved for POAG and ocular hypertension (OHT).

Adverse effect

One of the common adverse effects is conjunctival hyperemia which is dose dependent and usually transient.[13] This may be attributed to the vasodilatory property of the drug. Allergic conjunctivitis and blepharitis have also been reported.[13],[14]

Available literature

A dose-dependent reduction in IOP was found in Phase II clinical trials with up to 3.1 mmHg at 0.4% concentration at 8 h after instillation.[13] A Phase III trial studying the long-term profile for up to 1 year showed IOP reductions at trough and peak of −2.6 and −3.7 mmHg respectively.[14]

Trials were conducted to evaluate the additive effect of ripasudil with timolol maleate 0.5% and latanoprost 0.005% in POAG and OHT patients. With timolol, an additive effect was 0.9 mmHg at trough and 1.6 mmHg at peak was found. However, with latanoprost, IOP reduction of 1.4 mmHg was found only at the peak and no statistical difference at trough.[15] In another study by Inoue et al., Ripasudil was added to POAG or OHT patients on maximum medical therapy of average 3.8 medications. A significant additional IOP lowering was seen at 1 and 3 months.[16] In the 3-month interim analysis of ROCK J trial of 3058 patients, ripasudil was found to decrease IOP significantly in all glaucomas such as POAG, OHT, primary angle-closure glaucoma (PACG), exfoliation glaucoma, uveitic glaucoma, and steroid-induced glaucoma except in neovascular glaucoma.[17] Adverse effects were seen in only 244 (8%) of the participants. Interestingly, although TM resistance is not the primary area of pathology in PACG, these drugs seem to decrease IOP significantly in PACG as well, though long-term results are awaited. Due to vasodilatory properties, theoretically we might expect an increased inflammation in uveitic glaucoma. However, a retrospective study suggests that it is safe to use in secondary raised IOP in patients with uveitis.[18]

Netarsudil (AR-13324)

Netarsudil (Rhopressa, Aerie Pharmaceuticals), approved in the United States in 2017, is not only a ROCK inhibitor but also norepinephrine transporter inhibitor leading to additional benefits in glaucoma.[19]

Mechanism of action

  • Increase aqueous humor outflow by conventional pathway
  • Decrease aqueous production
  • Decrease episcleral venous pressure[20]
  • Decrease scar formation in post-trabeculectomy blebs.


Dosage

0.02% to be applied once daily.

Indication

It has been approved for open-angle glaucoma and OHT.

Adverse effect

  • Conjunctival hyperemia
  • Subconjunctival microhemorrhages
  • Cornea verticillata
  • Instillation-site pain
  • Erythema of the eyelid
  • Blurred vision
  • Increased lacrimation.


Available literature

A randomized dose–response study compared netarsudil (0.01% and 0.02%) with latanoprost in POAG and OHT patients, with IOP between 24 and 36 mmHg. On day 28, neither concentrations of the drug were found to be as effective as latanoprost. However, in patients with IOP <26 mmHg, netarsudil was found to be noninferior to latanoprost.[21] The double-masked randomized ROCKET 1 trial compared netarsudil 0.02% once daily (QD) with timolol 0.5% twice daily. In ROCKET 2, netarsudil once daily, timolol twice daily, and netarsudil twice daily were compared. In both the trials, netarsudil was found to be noninferior to timolol in only patients with baseline IOP of <25 mmHg.[22] About 10%–12% in the netarsudil QD group and 30% in the BID group dropped out due to adverse effects. About 50%–53% of the QD group and 59% of the BD group reported conjunctival hyperemia. The hyperemia resolved within 13 weeks after the cessation of drug.

Fixed combination

The FDC of latanoprost 0.005% with netarsudil 0.02% has been approved by the United States Food and Drug Administration in 2019 as Rocklatan™ (PG324) (Aerie Pharmaceuticals).

Mechanism of action

  • Increase aqueous humor outflow by conventional pathway
  • Decrease aqueous production
  • Decrease episcleral venous pressure
  • Decrease scar formation in post-trabeculectomy blebs
  • Increase uveoscleral outflow.


Dosage

Once daily in the evening.

Indication

It has been approved for open-angle glaucoma and OHT.

Adverse effect

  • Conjunctival hyperemia
  • Subconjunctival microhemorrhages
  • Cornea verticillata.


Available literature

In comparison with each of the drug individually, statistically significant IOP lowering was achieved in the FDC in POAG and OHT as reported by 28 days, Phase II trial.[23] MERCURY trials were conducted which were double-masked randomized multicenter trials comparing the efficacy of the FDC, each of the individual drugs. MERCURY I[24] trial was conducted in the United States of America (USA) for 12 months and MERCURY II[25] in the USA and Canada for 3 months. These trials both individually and as a pooled analysis showed that FDC lowered IOP significantly more than either of the individual components, with an acceptable safety profile.[26] Conjunctival hyperemia was again the most common adverse effect and was graded as mild in 86.9% of the patients with the hyperemia. With this combination acting on almost all mechanisms, it might be the drug of choice in resistant glaucomas.

Role of rho-kinase inhibitors in corneal endothelial diseases

Corneal endothelial cells are frozen in cell cycle and do not proliferate. Hence, endothelial cell loss due to trauma or dystrophy or surgeries leads to only enlargement of the remaining cells, and the dysfunction of cells is usually irreversible. Surgical intervention in the form of lamellar keratoplasty is usually the only option left. However, they come with their own set of complications such as graft rejection, graft failure, and loss of cell density. ROCK inhibitors have been found to improve corneal endothelial cell proliferation and adhesion. They prevent cell apoptosis and said to promote healing.[27] In vivo, in vitro, animal models and pilot studies in humans all have shown promising results,[28] thus suggesting a role in corneal endothelial diseases such as Fuchs' dystrophy[29] and post-cataract surgery corneal decompensation. ROCK inhibitors have been tried in the form of topical eye drops and intracameral injections along with cultured endothelial cells.[30]

Role of rho-kinase inhibitors in vitreoretinal diseases

Intravitreal anti-vascular endothelial growth factor is the main stay of treatment for macular diseases such as wet age-related macular degeneration[31] and macular edema due to various causes. However, it needs repeated administrations and has local and systemic adverse effects. Retinal surgeons are therefore on the lookout for novel treatment options. ROCK inhibitors have shown to reduce fibrosis in choroidal neovascular membranes in animal models.[32]

Leukocyte stasis plays a role in the microvascular complications in DR.[33] ROCK pathway has been reported to regulate certain adhesion molecules in vascular endothelial cells.[34] ROCK inhibitors can be beneficial for patients with symptoms of DR, by reducing the adhesion of leukocytes and increasing nitric oxide levels. They also prevent RGC apoptosis.[35] ROCK inhibitors might represent a new treatment strategy in early stages of DR which usually is only observed with no ophthalmic therapeutic intervention. Intravitreal implants to deliver these ROCK inhibitors are also being studied. In the later stages of DR, retinal neovascularization and epiretinal fibrovascular membranes are formed, the contraction of which can cause tractional retinal detachment. ROCK inhibition has effectively prevented contraction of these membranes in animal model.[36] ROCK inhibitors have also been studied as therapeutic agents for diabetic macular edema[37] and retinal ischemia.

Administration of ROCK inhibitors in retinal vein occlusion in murine models has shown to decrease retinal edema, size of nonperfusion areas, and improved retinal blood flow.[38]

Newer agents under trial

SNJ-1656 (Previously Known as Y-39983) (Senju Pharmaceuticals, Osaka, Japan):

Phase I and II clinical trials of the drug in comparison to placebo showed good IOP reduction and still under study.[39]

AR-12286 (Aerie Pharmaceuticals, Bedminster Township, NJ, USA):

Phase II trials in OHT/POAG patients have shown IOP reduction of about 4.5 mmHg as compared to placebo.[40] However, it is no longer in development as they did not meet their clinical end points.

PHP-201 (AMA-0076) (Amakem Therapeutics, Limburg, Belgium) and ATS-907 (Altheos, Inc., San Francisco, CA, USA) are some of the newer drugs under study.


  Conclusion Top


ROCK inhibitors seem to be a promising new drug with a different mechanism of action. They can be considered as second line of treatment or as adjuvants. Along with the IOP lowering action, it increases ocular blood flow and prevents RGC death. ROCK inhibitor can hence possibly be considered as first line of treatment in NTG. It is valuable in patients in whom IOP is not under control with maximum medical therapy, which is a common scenario in developing countries like ours. Ripasudil can be considered as the initial drug while restarting antiglaucoma medications in post-trabeculectomy patients due to its antifibroblastic activity. ROCK inhibitors have shown promising results in secondary glaucomas as well. Its additional uses such as corneal endothelial protection and role in DR and macular edema are helpful in patients with glaucoma with these diseases. Conjunctival hyperemia being reported in a significant number of patients might limit its use. Reassuring the patient prior to starting the drug regarding this possible side effect might go a long way in improving compliance. The ROCK inhibitor with its novel mechanism of action is a useful tool in an ophthalmologist's armamentarium.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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