Advantages and disadvantages of using Rho kinase inhibitors to reduce intraocular pressure

ABSTRACT

Introduction

Rho kinase (ROCK) inhibitors (RKIs) have been available commercially as topical ocular hypotensive agents for approximately a decade. RKIs have promise as their presumed mechanism of action is increased trabecular meshwork (TM) outflow, the presumed primary site of pathology in open-angle glaucoma.

Areas covered

We reviewed recent literature on netarsudil, ripasudil, H-1337, and VVN539 as monotherapy and in combination with other topical ocular hypotensive agents.

Expert opinion

With a unique primary mechanism of increase in trabecular outflow, these agents target the glaucomatous pathology in aqueous humor dynamics. The ocular hypotensive efficacy of netarsudil, once-daily (q.d.), is in the range of non-cardioselective beta-adrenoceptor antagonists. Ripasudil, given twice-daily (b.i.d.), is somewhat less effective. H-1337 and VVN539, at an early development stage, both seem to have efficacy in the range of netarsudil. Conjunctival hyperemia is an adverse event common to all RKIs tested to date. The greater adoption of RKIs in therapy may be limited by financial considerations, at least in the U.S.

Search strategy

We searched PubMed for the keywords netarsudil (AR13324), ripasudil (K-115), H-1337, and VVN539 as of November 2023. We found 349 citations which we reviewed for consideration in this review. Herein we summarize primary research reports, excluding news stories or meeting abstracts. We also searched www.clinicaltrials.gov to find new trials of interest.

KEYWORDS:

• Netarsudil
• ripasudil
• H-1337
• VVN539
• intraocular pressure
• ROCK
• glaucoma

Article highlights

• Rho-kinase inhibitors (RKIs) represent a novel mechanism for the lowering of elevated intraocular pressure (IOP) in patients with ocular hypertension and glaucoma.

• RKIs have been proposed to increase outflow through the trabecular meshwork (TM), the presumed primary site of pathology in open-angle glaucoma. This has been demonstrated in patients with netarsudil, and in animal models with ripasudil.

• Netarsudil 0.02% and Ripasudil 0.4% are topical ocular rho-kinase inhibitors (RKIs) approved for monotherapy in the U.S. and Europe (Rhopressa, Rhokiinsa) and Japan (Glanatec), respectively.

• In pivotal controlled clinical studies, netarsudil 0.02% q.d. had an ocular hypotensive efficacy in the same range as timolol.

• Ripasudil has been shown to reduce IOP relative to vehicle in normotensive subjects, though no clinical trial to date has compared it head-to-head with timolol or latanoprost.

• The most commonly observed adverse event is conjunctival hyperemia, which occurs in roughly half of all patients. Less common adverse events include corneal verticillata, instillation site pain, and corneal endothelial changes. In the studied patient population, the incidence and nature of adverse events is both more frequent and different than latanoprost and timolol.

• A fixed-dose combination (FDC) netarsudil/latanoprost is a more effective ocular hypotensive than either component alone. This agent is approved in both the U.S. and Europe (Rocklatan and Roclanda, respectively.)

• RKIs offer a unique agent that can add to glaucoma regimens. Given the relatively new introductions, equivalence in head-to-head studies to conventional topical therapy, financial barriers, and relatively high adverse event rates, it is not unsurprising that they are not employed as a standard monotherapy to date.

Declaration of interests

GD Novack serves as a consultant to medical device and pharmaceutical companies and in the period of January 2021 to January 2024, GD Novack’s firm has received consulting fees from the following firms: 3E BioAdvisors, 4DMT, Acuta Capital Partners, Aerpio Therapeutics, AimMax Therapeutics, Aldeyra Therapeutics, Almon Therapeutics, American Genomics, AOBiome, Aramis Biosciences, AsclepiX Therapeutics, Astellas Pharma Global Development, Aurion Biotech, Autobahn Therapeutics, Avirmax, Avoro Capital Partners, Axar Laboratories, AxeroVision, Baxis Pharmaceuticals, Beacon Therapeutics, Belite Bio Limited, Bioage Labs, BioTheraVision, Boehringer-Ingelheim, Bridgewest Ventures, BRIM Biotechnology, Broadwing Bio, Calibr (Division of Scripps Research), Calico Life Sciences, Ceramedix Holding, Character Biosciences, Clinical Strategies and Tactics, Cloudbreak Therapeutics, Cognition Therapeutics, D. Western Therapeutics Institute, Daewoong Therapeutics, Design Therapeutics, Dizal Pharmaceutical, dSentz, DTX Pharma, DUB Biologics, Eclipse Life Sciences, Eden Ophthalmic, Eleusis Pharmaceuticals, Emendo Research and Development, Emmetrope Ophthalmics, Empirico Therapeutics, Endogena Therapeutics, Entelexo Biotherapeutics, Exhaura, Eximore, Eyebiotech, EyePoint, Famygen Life Sciences, Feliqs Corporation, Fibrocor Therapeutics, Firecyte Therapeutics, Fortress Biotech, Gelmedix, Gerson Lehman Council, Glia, HanAll Biopharma, Hawkeye Therapeutics, HCR Partners, Hovione, iDrop, Illuminare Biotechnologies, Implicit Bioscience, Inflammx, Innerva Pharmaceuticals, Iolyx Therapeutics, Iota Biosciences, Iuvo Bioscience, Iveric Bio, IVIEW Therapeutics, Janssen, Jenivision, Kallyope, Kedalion Therapeutics, Kriya Therapeutics, LayerBio, Levation, Lexitas Pharma Services, Line 6 Biotechnologies, Mati Therapeutics, MCAL Therapeutics, MediPrint Ophthalmics, Mimetogen Pharmaceuticals, Mobius Scientific, Nanoretinal, Nayan Therapeutics, Neuroptika, Neutrolis, Neuvision Development, New World Medical, Nicox, NovaQuest Capital Management, NVasc, Octant, Ocugenix, Ocular Therapeutix, Oculinea, OcuNexus, Ocuphire, OcuTerra, ONL, Optigo, OrbiMed Advisors, Perceive Biotherapeutics, Peregrine Ophthalmic, Perfuse, Pleyron Therapeutics, PolyActiva, PPD Development, PromiSight, PYC Therapeutics, Qlaris, Rallybio, Regenxbio, Regulatory Professionals, Repoxygen Therapeutics, reVision Therapeutics, Revive Biotechnology, RevOpsis Therapeutics, RHMM, Inc., Ribomic, Seinda Pharmaceutical Guangzhou, Selagine, SIFI, SightStream, Silk Technologies, SiteOne Therapeutics, Skye Bioscience, Smilebiotek Guangzhou, Smilebiotek Zhuhai, Spiral Therapeutics, Spring Discovery, Stealth BioTherapeutics, Sunhawk Vision Biotech, Suzhou Raymon, Sylentis, Tamarix Pharma, Tardimed Sciences, TearClear, Telios Pharma, Telomeye Pharmaceutical, Thea Pharma, Trefoil Therapeutics, Tsubota Lab, University of Illinois, Chicago, Vedere Bio II, VegaVect, Visgenx, Vivavision Biotech, VivusNano Limited, Vyluma, Wells Fargo Securities, Xequel, Yuyu Pharma, Zhaoke Ophthalmology Pharma.

Please note that he owns no stock nor holds any proprietary interest in any firm.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.