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Retinal Physician

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Rho Kinase Inhibitors for Diabetic Macular Edema

A sustained-release implant has promise for both DME and Wet AMD.

By: Michael A. Singer, MD, Jennifer Gallagher, MD
Retinal Physician September 1, 2020 Vol 17, Issue September 2020 Page(s): 24-26

Read all articles in this “new pathways” special section:

In the age of intravitreal pharmacotherapy, there is a continuous yearning for new treatment modalities that both provide significant visual gains as well as longevity with subsequent reduction in treatment burden for patients. Vascular permeability, angiogenesis, and inflammation play an important role in both neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR), and vascular endothelial growth factor (VEGF) has been the main target of treatment to date. However, an in vitro study showed that upregulation of the Rho/Rho kinase (ROCK) pathway in diabetes promotes leukocyte adhesion to the microvasculature by affecting the expression of these molecules, and this has been identified as a key factor in angiogenesis, as in nAMD and DR, as well as microscopic vasculopathy seen in DR.1,2 The ROCK pathway regulates actin reorganization during cell adhesion, migration, contraction, and proliferation, and its activation depends on RhoA-GTP, which is transformed to RhoA-GDP (Figure 1) and is formed in response to proangiogenic stimuli by endothelial cells.3 Targeting of the ROCK pathway could be an alternative therapy for diseases of angiogenesis or could be used as an adjunct to already available therapies.

Figure 1. Activation of Rho kinase by RhoA-GTP in endothelial cells.
Figure 1. Activation of Rho kinase by RhoA-GTP in endothelial cells.

AR-13503 monotosylate (Figure 2) is a novel ROCK and protein kinase C (PKC) inhibitor currently being developed by Aerie Pharmaceuticals. It is the pharmacologically active esterase metabolite of netarsudil, which is the active ingredient in the Aerie Pharmaceuticals’ glaucoma medicine Rhopressa (netarsudil ophthalmic solution) as well as a component of Rocklatan (netarsudil 0.02%, latanaprost 0.005%). It has the potential to inhibit angiogenesis, preserve the blood–retinal barrier, and reduce retinal fibrosis in retinal diseases such as nAMD and diabetic macular edema (DME).4-10 By targeting multiple disease processes that underlie disease progression rather than a single factor such as VEGF, ROCK and PKC inhibitors may prove useful as alternative or additive therapy to currently available. In addition, the intravitreal delivery in a controlled fashion via a controlled delivery platform may provide prolonged drug delivery as well as a different mechanism of action for patients who are refractory to current treatment.

Figure 2. Structure of AR-15303 monotosylate.
Figure 2. Structure of AR-15303 monotosylate.

The AR-13503 sustained-release implant is a fully biodegradable PEA-III-X25 polymer matrix that undergoes hydrolysis and/or enzymatic degradation to provide delivery of AR-13503 over a target period of 4 months to 6 months. The target dose of each implant is 10.6 μg, and it is delivered using a single-use applicator with a 27-gauge needle.

PHARMACOKINETICS AND TOXICITIES

Animal studies performed to evaluate systemic (plasma) exposure potential were performed in-house at Aerie Pharmaceuticals. The results demonstrated that the concentration of AR-13503 reached therapeutic levels (>150 ng/g) in the retina and retina pigment epithelium/choroid and maintained these levels for 5 months to 6 months. The concentration of AR-13503 in surrounding ocular tissues never exceeded 20% of that of the retina and retina pigment epithelium/choroid, and plasma levels in miniature swine revealed negligible systemic exposure.

AR-13503 implants were associate with a transient dose-independent lens capsule or cortical opacities. In animal studies, this was seen more often in those who had also received repeated bevacizumab injections. There was also a slight reduction in intraocular pressure early on, but intraocular pressure relative to prestudy levels were similar across all study groups.

CURRENT EVIDENCE AND ONGOING TRIALS

Ahmadieh et al performed a randomized clinical trial of 44 eyes with center-involving DME who received monthly injections of either bevacizumab alone or in combination with intravitreal fasudil (HA-1077 a Rho kinase inhibitor available in Japan from Stemcell Technologies) injections for 3 months.1 Their study demonstrated a statistically significant improvement in best-corrected visual acuity at 3 months and 6 months in the combined group compared to the bevacizumab group as well as a statistically significant improvement in central macular thickness. Although the follow-up was short in this study, the increased sustainability of the treatment effects of the combination therapy proves promising for the future of intravitreal therapies in combating resistant disease. Currently, a phase 1 trial is under way in the United States evaluating this implant in patients with wet AMD and DME who are refractory to treatment.

CONCLUSION

The AR-13503 implant is a promising adjunct to the retina specialists’ arsenal in treating neovascular disease. The novel mechanism of action of this implant, combining inhibition of ROCK and PKC, may in the future offer physicians and patients an additional therapeutic option in the treatment algorithm for retinal diseases, especially in eyes refractory to current therapies. RP

Michael Singer, MD, is a vitreoretinal specialist and the director of clinical research at Medical Center Ophthalmology Associates in San Antonio, Texas. He reports consultancy to Aerie Pharmaceuticals, Allegro Ophthalmics, Allergan, Genentech, Kodiak Sciences, Novartis, Regeneron, Santen, and Eyepoint Pharmaceuticals; speaker’s fees from Allergan, Genentech, Mallinckrodt Pharmaceuticals, Novartis, Regeneron, and Spark Therapeutics; and research for Aerie Pharmaceuticals, Allegro Ophthalmics, Allergan, DRCR Retina Network, Genentech, Iconic Therapeutics, Ionis Pharmaceuticals, Kalvista, Kodiak Sciences, Novartis, Opthea, Optos, Regeneron, Santen, Senju Pharmaceutical Company, and Sydnexis. Jennifer Gallagher, MD, is a vitreoretinal fellow at UT Health in San Antonio, Texas. She reports no related disclosures. Reach Dr. Singer at msinger11@me.com.

REFERENCES

  1. Ahmadieh H, Nourinia R, Hafezi-Moghadam A, et al. Intravitreal injection of a Rho-kinase inhibitor (fasudil) combined with bevacizumab versus bevacizumab monotherapy for diabetic macular oedema: a pilot randomised clinical trial. Br J Ophthalmol. 2019;103(7):922-927.
  2. Liu J, Wada Y, Katsura M, et al. Rho-associated coiled-coil kinase (ROCK) in molecular regulation of angiogenesis. Theranostics. 2018;8(21):6053-6069.
  3. Arita R, Hata Y, Ishibashi T. ROCK as a therapeutic target of diabetic retinopathy. J Ophthalmol. 2010;2010:175163.
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  8. Nourinia R, Ahmadieh H, Shahheidari MH, 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. Yamaguchi M, Nakao S, Arima M, et al. Rho-kinase/ROCK as a potential drug target for vitreoretinal diseases. J Ophthalmol. 2017;2017:8543592.
  10. Yamaguchi M, Nakao S, Arita R, et al. Vascular normalization by ROCK inhibitor: therapeutic potential of ripasudil (K-115) eye drop in retinal angiogenesis and hypoxia. Invest Ophthalmol Vis Sci. 2016;57(4):2264-2276.

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