One study in 44 eyes with center-involving DME demonstrated a significantly greater improvement of best-corrected visual acuity in patients treated with combination intravitreal Fasudil and bevacizumab compared with bevacizumab alone. That study (NCT01823081), though, was limited by a short follow-up period and no evaluation of side effects on the superficial and deep macular plexus.9

Dr Dedania remains hopeful, however, about the future of Fasudil. “Other studies in animal models have demonstrated the positive effect of ROCK inhibitors in retinal conditions,” she adds. “As more data emerge, ROCK inhibition may prove promising independently or in combination with other intravitreal agents.” 

According to Dr Dedania, the preclinical investigation into AR-13503 (Aerie Pharmaceuticals) (NCT03835884) — may offer patients with wet AMD, diabetic retinopathy, and other related retinal diseases, a potentially new treatment pathway. 

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In its first-in-human clinical study, researchers will evaluate an AR-13503 sustained release implant — a bioerodible polyesteramide polymer implant providing controlled release of AR-13503 — with and without combination aflibercept in patients with neovascular AMD or DME. The trial builds on preclinical results in animal models that found positive therapeutic outcomes in AMD, DME, and proliferative diabetic retinopathy.11,12 Perhaps most importantly, if successful, AR-13503 would require administration via intravitreal injection once every 6 months — a significant reduction from the 4- to-6-week timeframe required with currently available treatment options.10 

Because retinal detachments induce Rho-ROCK pathway activation, ROCK inhibition may reduce the extent of rod synaptic disjunction.13 Preclinical study data of AR-13503 in a porcine model presented at the 2018 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting found that subretinal injection of 0.5 µm of AR-13503 reduced synaptic breakage up to 64% compared with untreated retinal detachments, while intravitreal injections of AR-13503 were associated with a 57.5% decrease in retraction.14 Clinical studies on this particular applicability, though, are not yet underway. 

Fasudil and Y-27632 — a cell-permeable, potent and selective ROCK inhibitor — have also been found to decrease rod axon retraction rates within the first 2 hours following retinal detachment.13

Preventing Structural Damage

For proliferative vitreoretinopathy, the leading cause of failure following retinal detachment surgery, ROCK inhibitors may offer a pharmacologic solution to a problem that currently can only be resolved by additional surgical procedures.15 Research published in Diabetes found that ROCK inhibition “significantly decreased [proliferative vitreoretinopathy] formation” through the suppression of transforming growth factor beta (TGF-β).1,16 Additional in vitro studies suggest that ROCK inhibition might also block the development of traction retinal detachment.15 

Neuroprotective effects may also be a result of ROCK inhibitor use, according to a 2017 review published in in the Journal of Ophthalmology.15 “Microvascular changes underlie [diabetic retinopathy] and AMD, while histological studies have characterized the loss of neurons,” according to that research, which also cites a 2014 report on the oral ROCK inhibitor K115.15-17 

Corneal Applications

Outside of glaucoma and retinal diseases, another future for ROCK inhibitor therapies may lie in managing endothelial dysfunction, according to Colleen P. Halfpenny, MD, an ophthalmologist at Wills Eye Hospital and an assistant professor at the Sidney Kimmel Medical College at Thomas Jefferson University in Philadelphia. 

“I think the main application is going to be for the regeneration of the endothelium,” she explains. Treatment options for patients with Fuchs’ endothelial dystrophy, for example, are currently limited to corneal transplantation.2 

“Right now, corneal transplants have great success rates, but they’re expensive surgeries,” says Dr Halfpenny. “They require patients to be on drops or other topical steroids for long periods, and there’s a limited lifespan to these transplants. They can last an average of 20 to 30 years, but with patients living longer, having to undergo another surgery isn’t ideal. Anything you can do to regenerate endothelial cells is huge.”

For conditions resulting from corneal damage, such as corneal neovascularization and bullous keratopathy, experimental ROCK inhibitors AMA0526 and Y-27632 have demonstrated promising results. In both in vivo and in vitro experimental models, AMA0526 inhibited angiogenesis reduced corneal opacities, and controlled the complete wound healing process in vivo.1,18 Separate in vitro studies of Y-27632 found that the molecule promotes adhesion of corneal endothelial cells, inhibits cell apoptosis, and increases corneal endothelial cell proliferation.1 Topical installation of this ROCK inhibitor, rather than intravitreal injection, was also found to enhance corneal wound healing in an animal model.19 

Are You Ready to ROCK?

Luckily for ophthalmologists, the evidence in favor of therapeutic applications of ROCK inhibitors outside of glaucoma is stacked high. These applications, though, still require rigorous clinical research. 

“There are no FDA-approved ROCK inhibitors for the treatment of retinal conditions at this time,” Dr Dedania explains, underlying the sheer amount of work that still needs to be done before patients can begin benefitting from these advanced treatment modalities. 

For glaucoma, the side effect profile of these drugs is relatively well known and can include hyperemia, epithelial changes, and potential effects on wound healing. Hyperpermeability and angiogenesis resulting from ROCK inhibitor use may be controversial at this time — particularly with regards to the effect of ROCK inhibition on VEGF-induced angiogenesis. 

“The research is still ongoing,” says Dr Halfpenny. But she remains optimistic about the drugs’ potential. “It’s an exciting field,” she says. “I think we’re just going to try and use it everywhere we can and see what happens.” 


  1. Nourinia R, Nakao S, Zandi S, Safi S, Hafezi-Moghadam A, Ahmadieh H. ROCK inhibitors for the treatment of ocular diseases. Br J Ophthalmol. 2018;102:1-5. doi:10.1136/bjophthalmol-2017-310378.
  2. Moshirfar M, Parker L, Birdsong OC, et al. Use of Rho kinase inhibitors in ophthalmology: A review of the literature. Med Hypothesis Discov Innov Ophthalmol. 2018;7(3):101-111.
  3. Centers for Disease Control and Prevention (CCD). Common eye disorders and diseases. Updated June 2, 2020. Accessed March 17, 2021. 
  4. American Academy of Ophthalmology (AAO). US eye disease statistics. Accessed March 17, 2021.
  5. Kim EJ, Lin WV, Rodriguez SM, Chen A, Loya A, Weng CY. Treatment of diabetic macular edema. Curr Diab Rep. 2019;19(9):68. doi:10.1007/s11892-019-1188-4. 
  6. Wang W, Lo ACY. Diabetic retinopathy: Pathophysiology and treatments. Int J Mol Sci. 2018;19(6):1816. doi:10.3390/ijms19061816.
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  8. Nourinia R, Ahmadieh H, Shahheidari M-H, Zandi S, Nakao S, Hafezi-Moghadam A. Intravitreal Fasudil combined with bevacizumab for treatment of refractory diabetic macular edema; a pilot study. J Ophthalmic Vis Res. 2013;8(4):337-340. 
  9. Ahmadieh H, Nourinia R, Hafezi-Moghadam, et al. Intravitreal injection of a Rho-kinase inhibitor (Fasudil) combined with bevacizumab versus bevacizumab monotherapy for diabetic macular oedema: A pilot randomized clinical trial. Br J Ophthalmol. 2019;103(7):922-927. doi:10.1136/bjophthalmol-2019-314702.
  10. Aerie Pharmaceuticals initiates first-in-human clinical trial of AR-13503 sustained release intravitreal implant in patients with neovascular age-related macular degeneration an diabetic macular edema [news release]. Aerie Pharmaceuticals. Published August 20, 2019. Accessed March 17, 2021. 
  11. Lin C-W, Sturdivant JM, deLong MA, Kopcynski C. Effectiveness of AR-13154 monotherapy and combination therapy in animal models of wet age-related macular degeneration and proliferative diabetic retinopathy. Presented at: 2016 ARVO Annual Meeting; May 1-5, 2016; Seattle, WA. 
  12. Ding J, Crews K, Carbajal K, et al. Ocular tissue distribution and duration of release of AR-13503 following administration of AR-13503 sustained release intravitreal implant in rabbits and miniature swine. Presented at: ARVO Annual Meeting; April 28-May 2, 2019; Vancouver, BC. 
  13. Halász E, Townes-Anderson E, Zarbin MA. Improving outcomes in retinal detachment: The potential role of rho-kinase inhibitors. Curr Opin Ophthalmol. 2020;31(3):192-198. doi:10.1097/ICU.0000000000000658.
  14. Halász E, Zarbin MA, Sugino I, Townes-Anderson E. AR-13503, a ROCK inhibitor, reduces rod axon retraction during retinal detachment. Presented at: ARVO Annual Meeting; April 29-May 3; Honolulu, HI. 
  15. Yamaguchi M, Nakao S, Arima M, et al. Rho-kinase/ROCK as a potential drug target for vitreoretinal diseases. J Ophthalmol. 2017;2017:8543592. doi:10.1155/2017/8543592.
  16. Kita T, Hata Y, Kano K, et al. Transforming growth-factor beta-2 and connective tissue growth factor in proliferative vitreoretinal diseases: Possible involvement of hyalocytes and therapeutic potential of Rho kinase inhibitor. Diabetes. 2007;56(1):231-238. doi:10.2337/db06-0581.
  17. Yamamoto K, Maruyama K, Himori N, et al. The novel Rho kinase (ROCK) inhibitor K-115: A new candidate drug for neuroprotective treatment in glaucoma. Invest Ophthalmol Vis Sci. 2014;55(11):7126-7136. doi:10.1167/iovs.13-13842.
  18. Sijnave D, Van Bergen T, Castermans K, et al. Inhibition of Rho-associated kinase prevents pathological wound healing and neovascularization after corneal trauma. Cornea. 2015;34(9):1120-1129. doi:10.1097/ICO.0000000000000493.
  19. Okumura N, Koizumi N, Ueno M, et al. The new therapeutic concept of using a Rho kinase inhibitor for the treatment of corneal endothelial dysfunction. Cornea. 2011;30 Suppl 1:S54-S59. doi:10.1097/ICO.0b013e3182281ee1.