Rock'n roll with glaucoma

ROCK’n Role
In Glaucoma Treatment
Mohamed Awwad
Glaucoma Fellow, King’s College Hospital
London 2020

Many Glaucoma patients with severe damage or low baseline
IOP require very low target Pressure to stabilise their disease
process. (1)
(1)Tanna AP and Johnson M.Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension .Ophthalmology Volume 125, Number 11, November 2018

Most existing glaucoma eyedrops, which
either work to decrease aqueous humour
production or target the eye’s secondary
drainage system (eg, uveoscleral
pathway).
Earlier attempts to develop drugs
targeting the TM had to be abandoned
decades ago due to adverse side effects.
(1) (2)
(1)Tagart M. Success at Last! Two New Glaucoma Drugs Reach the Market. Bright Focus Foundation. Science news.
(2)Sampaolesi R, Sampaolesi JR and Zarate J. Structure and Function of the Tissues That Are in Contact with the Aqueous Humour. The Glaucomas pp 39-70

ROCK is a protein kinase
involved in the regulation and modulation of a wide spectrum of fundamental
Cellular events (1)
(1) Moshirfar M, Parker L, Birdsong O, Ronquillo Y, Hofstedt D, Shah T, Gomez A and Hoopes P. Use of Rho kinase inhibitors in ophthalmology. A review of literature.Med Hypothesis Discov Innov Ophthalmol. 2018; 7(3)

ROCK signalling is involved in
variety of diseases, including (1) (2)
(1)Okumura N, Kinoshita S and Koizumi N.Application of Rho Kinase Inhibitors for the Treatment of Corneal Endothelial Diseases . Hindi Journal of OphthalmologyVolume 2017, Article ID 2646904, 8 pages
(2) Moshirfar M, Parker L, Birdsong O, Ronquillo Y, Hofstedt D, Shah T, Gomez A and Hoopes P. Use of Rho kinase inhibitors in ophthalmology. A review of literature.Med Hypothesis Discov Innov Ophthalmol. 2018; 7

(1)Moshirfar M, Parker L, Birdsong O, Ronquillo Y, Hofstedt D, Shah T, Gomez A and Hoopes P. Use of Rho kinase inhibitors in ophthalmology. A review of literature.Med Hypothesis Discov Innov Ophthalmol. 2018; 7(3)
(2)Hall A. Rho GTPases and the actin cytoskeleton. Science. 1998 Jan 23;279(5350):509-14.
In 2001, studies began at both the University of
Tokyo in Japan and Duke University in North
Carolina to investigate the effects of ROCK
inhibitors on lowering of IOP (1) (2)
In 1998, Alan Hall showed that the Rho kinase pathway was an
important regulator of the actin cytoskeleton and that various
reactions within the pathway, coordinated with many cellular
responses and changed different characteristics, such as shape
and adhesion. (2)

Research on ROCK began in the late 1990’s. (1)
They were able to show that cytoskeletally active agents such as H7 (a protein
kinase inhibitor that affects ROCK) significantly decreased aqueous
humour outflow resistance.
These studies marked the beginning of a focus on the role of cell mechanics in
the aqueous humour outflow pathways and the role of ROCK in this
process. (2)
In 1993, Dr. David Epstein organised the second Trabecular Meshwork Study Club
and invited experts on aqueous outflow. They began a collaboration examining the role
of cells in regulating aqueous humour outflow resistance.

The Rho family (RhoA, RhoB, RhoC) are small G-proteins that are active
when bound to GTP and inactive when bound to GDP.
They are activated by a number of secreted cytokines, including endothelin-1
(ET-1), thrombin, angiotensin II, lysophosphatidic acid, and transforming growth
factor (TGF)-b, or via integrin activation. (1)
They
regulate
cell

The effectors of the Rho family are the Rho kinases
(ROCK)
ROCK1 and ROCK2 (2 serine/threonine kinase isoforms)
are Rho GTP binding proteins.
ROCK phosphorylates a number of downstream target proteins (1)

A hydrodynamic interaction between pores in the inner wall of
Schlemm’s canal and the ECM in the JCT makes inner wall pore
density an important determinant of outflow resistance.

(1)Ren R, Li G, Duong Lr T, Kopczynski C, Stater WD and Gong H.Netarsudil Increases Outflow Facility in Human Eyes Through Multiple Mechanisms . IOVS j November 2016 j Vol. 57 j No. 14 j 6198

•Developed by Senju pharmaceutical (Osaka, Japan).
•First ROCK inhibitor studied in a clinical trial to lower IOP
•In animal studies, topical administration of SNJ-1656 resulted in large
reduction in outflow resistance and IOP
•Peak IOP reduction was achieved at 4 hours after instillation, 3.0 +/- 1.2 mmHg
with the highest concentration tested (0.1%) (1) (2)
•Side effects:
• Conjunctival Hyperaemia (60% of subjects)
•One subject experienced hepatic dysfunction that resolved after discontinuation of
treatment.(1)Tanna AP and Johnson M.Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension .Ophthalmology Volume 125, Number 11, November 2018

• Developed by Aerie pharmaceutical (North Carolina, USA).
• Phase 1 Study in normal subjects: significant IOP reduction of average 7 mmHg
• Phase 2 trials in POAG, OHT: maximum average pressure reduction of approximately
4.5 mmHg
• AR-12286 was abandoned by Aerie Pharmaceuticals, Inc, for use in glaucoma because
netarsudil, also developed by the same company, was judged to have longer duration of
action. (1) (2)
•Side effects:
• Conjunctival Hyperaemia, ocular irritation, increased lacrimation & blurred vision

•Approved in Japan for the treatment of glaucoma and OHT in September 2014
• Phase 1 & Phase 2 trials (Ripasudil 0.4% BID): lowered IOP on average by 2 - 4.4
mmHg 2 hours after instillation
• Phase 3 trials to evaluate the additive IOP-lowering efficacy of Ripasudil 0.4% BID
with timolol 0.5% BID (additive effect was 0.9-1.6 mmHg)or latanoprost 0.005% QD
(additive effect of 1.4 mmHg) (1) (2)

•Two retrospective studies evaluated adjunctive treatment with Ripasudil in Japanese
patients already on maximum medical therapy: IOP reductions ranging from 2.6 - 3.1
mmHg or approximately 15% to 16% from baseline.
•Two retrospective studies suggest it is safe to use Ripasudil to lower IOP in ocular
hypertensive eyes with uveitis. (1) (2)
•Side effects:
• Conjunctival Hyperaemia

•ROCK inhibitor & norepinephrine transporter inhibitor, developed by Aerie
Pharmaceuticals (1) (2)
•It was approved for use in the US to treat glaucoma in late 2017
•It is different from other ROCK inhibitors in that:
1. Not only lowering IOP by decreasing outflow resistance
2. But also decreases aqueous production
3. And decreases episcleral venous pressure

•A 28-day double-masked randomised clinical trial on patients with POAG or OHT after
washout with baseline IOP (24-36 mmHg) compared efficacy of
Lowering IOP
effect on day
14 was similar
to day 28
Neither concentration of netarsudil was as
effective as latanoprost (1) (2)

•In the subgroup of patients with baseline IOP 26 mmHg, however, the ocular
hypotensive efficacy of Netarsudil 0.02% was statistically non inferior to latanoprost.
•Therefore, Netarsudil was thought to be relatively more effective in patients with lower
baseline IOP, possibly because of its ability to lower episcleral venous pressure.
•Side effects: 1. Conjunctival hyperaemia (52-57%)
2. Cornea verticillata (9-15%)
3. Increased lacrimation (6%)
4. Subconjunctival haemorrhage (5%)
Visual acuity was not affected by any of these adverse events, and resolution
occurred after cessation of netarsudil. (1) (2)

•To evaluate Netarsudil as an adjunctive agent in combination with latanoprost, a 28-day
randomized, controlled clinical trial evaluated the fixed combination of Netarsudil (at
concentrations of 0.01% and 0.02%) and latanoprost 0.005% dosed QD.
•The mean diurnal efficacy of the fixed combination formulated with a concentration of
netarsudil 0.02% was statistically superior to each of its components alone by a margin
of 2.6 mmHg versus netarsudil and 1.9 mmHg vs Latanoprost (each agent dosed QD) (1) (2)
The fixed combination of 0.02% netarsudil and 0.005% latanoprost is
known as Rocklatan (Aerie Pharmaceuticals)
The types of adverse events that occurred and their frequencies are similar to those
observed in previous studies with netarsudil

•The incidence of discontinuation due to adverse events was approximately 6% to 7% in
the fixed combination and netarsudil groups by month 3 and approximately 20% by
month 12 compared with approximately 2% in the latanoprost group at both time points.
(1) (2)

•Fasudil 0.5% and 1.2% were examined in 4 eyes of 4 patients with POAG and no light
perception in the study eyes. Baseline IOP was 53.5 +/- 3.4 mmHg, and the IOP
reductions at 2 to 4 hours were 8-9 mmHg (1)
•No results have been published as yet in peer-reviewed literature.
Conjunctival hyperaemia was found in 1 patient with 1.2%
Fasudil.
(1)Parkavan M, Beni AN, Ghahari E, Varshochian R, Yazdani S, Esfandiari H and Ahmadieh H. The Ocular Hypotensive Efficacy of Topical Fasudil, a Rho-Associated Protein Kinase Inhibitor,
in Patients With End-Stage Glaucoma. Am J Ther. 2017 Nov/Dec;24(6):e676-e680.

None of the Rho kinase inhibitors tested in these clinical trials proved
themselves superior to commonly used first line agents for lowering IOP
These new agents are likely to have their greatest utility is as adjunctive
agents because their mechanism of action is thought primarily to be one of
lowering of aqueous humour outflow resistance, and thus should be
somewhat additive to the actions of other agents in clinical use that act on
aqueous inflow or unconventional outflow. (1)
While pressures above 24 mm Hg demonstrated
slightly better control with timolol, Rhopressa
consistently had a better response in patients with
pressure below 24 mm Hg. (2)

Ripasudil’s additional IOP-lowering efficacy when added to Timolol is similar
to the additive IOP lowering observed with Brimonidine or Dorzolamide;
however, the incidence of conjunctival hyperaemia was substantially higher
than Ripasudil.
Netarsudil lowers IOP approximately an additional 2 mmHg when added to a
Prostaglandin. This is in the same range as has been observed with other
agents that are commonly used adjectively with PGAs; however, the incidence
of adverse events is higher with Netarsudil.

ROCK inhibitors induce relaxation of vascular smooth muscle, explaining the
high incidence of conjunctival hyperaemia and possibly subconjunctival
haemorrhage in these studies.
It is notable that a large proportion of patients withdrew from clinical trials
because of adverse events, raising some questions about the ease with which
these agents can be used in clinical practice.
Despite that concern, there are no known contraindications to the use of
Ripasudil or Netarsudil nor are there any known interactions with other
medications.

•In some patients with glaucoma, worsening of the disease continues
despite seemingly adequate IOP reduction, suggesting IOP-
independent mechanisms may play a major role in the disease process.
For this reason, there is much interest in the development of neuro-
protective strategies for glaucoma treatment.

•ROCK singling is critical in axonal development, maintenance and regeneration.
•Its rule is exerted in part through its regulation of many elements of axonal
cytoskeleton, including actin, microtubules and intermediate filaments as well
as regulation of inflammation mediated by activation of nuclear factor KB.
•CNS axons are limited in their ability to regenerate
when injured due in part to the presence of growth
inhibitors in their extracellular milieu.
•Because microglia use ROCK signalling to regulate
axonogenesis, it is not surprising that ROCK
inhibition results in enhanced axonal regeneration.

(1)Hu J and Selzer M.RhoA as a target to promote neuronal survival and axon regeneration. Neural Regeneration Research. 2017;12(4):525-528.
•Ripasudil has been shown to have neuro-protective
activity in rodent optic nerve crush injury models.
•In one of these studies, topical Netarsudil enhanced
retinal ganglion cell survival and axonal
regeneration. Reduced phosphorylation of cofilin and
LIM kinase, 2 downstream targets in the Rho kinase
signaling pathway, was observed in retinal ganglion
cells and optic nerve glial cells. (1)

•Neuro-protective activity of ROCK inhibitors has been demonstrated in the
eye. Treatment with the Fasudil at the time of iatrogenic RD in a pig model
was associated with reduced photoreceptor degeneration and relative
preservation of the rod-bipolar synapse.
•Significantly elevated levels of RhoA have been found in the optic nerve head
of glaucomatous eyes compared with age-matched controls supporting a
possible role for Rho in Glaucoma optic neuropathy.
•Further investigation, particularly human clinical trials, will be required to
determine if these agents are therapeutically effective in neuro-protection in
glaucoma beyond their IOP-lowering effect.

(1)Kohomoto R, Sugiyama T, Kojima S, Ueki M and Ikeda T.Optic Nerve Head Blood Flow Changes Induced by Ripasudil Added to Prostaglandin Analogues in Primary Open Angle Glaucoma. EC Ophthalmology 4.6 (2017): 640-647.
•Large, population-based studies suggest that lower
ocular blood flow and perfusion pressure are
associated with glaucoma prevalence and are risk
factors for the incident development of glaucoma
and progression of the disease.
•Both the optic nerve head and the retinal
circulation are subject to autoregulation, and some
investigators have reported evidence of abnormal
autoregulation in patients with POAG,
particularly those with lower baseline IOP levels. (1)

(1)Ohta Y, Takaseki S and Yoshitomi T. Effects of ripasudil hydrochloride hydrate (K-115), a Rho-kinase inhibitor, on ocular blood flow and ciliary artery smooth muscle contraction in rabbits.Japanese Journal of Ophthalmology volume 61,423–432(2017)
In Rabbits (1)

(1)Kohomoto R, Sugiyama T, Kojima S, Ueki M and Ikeda T.Optic Nerve Head Blood Flow Changes Induced by Ripasudil Added to Prostaglandin Analogues in Primary Open Angle Glaucoma. EC Ophthalmology 4.6 (2017): 640-647.
•As yet no reports have reported on the effect of ROCK inhibitors on ocular blood flow in
humans, and the results described suggest such studies may be warranted.
•However, recent studies have shown that extreme dips in nocturnal
blood pressure are associated with glaucoma and thus, even if ROCK
inhibitors can effectively improve human ocular blood flow, it is
unclear if this effect would be sufficient to overcome the
deleterious effects of these extreme dips in blood pressure. (1)

•The most common cause of surgical failure is formation of excessive subconjunctival
fibrosis, which prevents or limits the egress of aqueous humour. (1)
•TGF-Beta is an important cytokine involved in the regulation of post-surgical wound
healing and scar formation in the setting of glaucoma surgery.
•In vitro studies showed inhibitory effect of Ripasudil on TGF-Beta mediated activation of
fibroblasts in human conjunctiva. (2)
•During the course of observation of patients after
trabeculectomy surgery, clinicians can often detect a
pattern of gradual fibrosis and contraction of the
filtering bleb. Intervention with a ROCK inhibitor could
potentially serve a dual purpose in such patients in that
the drug could be used to lower IOP and to slow or
prevent further scar formation.
(1)Schlunk G, Meyet-Ter-Vehn T and Grehn F. Conjunctival fibrosis following filtering glaucoma surgery. Experimental eye research 2016

1. ROCK inhibitors primary mechanism of action is different from conventional ocular
hypotensive medications (decrease outflow resistance).
2. Although these agents have been shown to be effective in lowering IOP, both as mono-
therapy and adjunctively with beta-blockers and prostaglandin analogs, their side
effect profile raises serious concerns about the likelihood of their acceptance by
patients.The laboratory evidence suggesting ROCK inhibitors may have neuro-
protective activity and might improve ocular blood flow is tantalising.
3. The first-generation ROCK inhibitors, despite their limitations, are therapeutically
effective. It would be beneficial to develop next-generation ROCK inhibitors that are
targeted to the cells of the outflow pathway or to the retina so that local adverse
effects can be minimised while maximising their therapeutic effects. (1) (2)

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