Ripasudil hydrochloride hydrate: targeting Rho kinase in the treatment of glaucoma

Toshihiro Inoue & Hidenobu Tanihara

To cite this article: Toshihiro Inoue & Hidenobu Tanihara (2017): Ripasudil hydrochloride hydrate: targeting Rho kinase in the treatment of glaucoma, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2017.1378344
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EXPERT OPINION ON PHARMACOTHERAPY, 2017

https://doi.org/10.1080/14656566.2017.1378344

DRUG EVALUATION
Ripasudil hydrochloride hydrate: targeting Rho kinase in the treatment of glaucoma
Toshihiro Inoue and Hidenobu Tanihara
Faculty of Life Sciences, Department of Ophthalmology, Kumamoto University, Kumamoto City, Japan

ABSTRACT
Introduction: Among the intraocular pressure (IOP)-lowering drugs used in a clinical setting, Rho kinase (ROCK) inhibitors lower IOP by a unique mechanism, namely the depolymerization of intracellular actin in the conventional outflow tissues: the trabecular meshwork (TM) and Schlemm’s canal (SC). Furthermore, ROCK inhibitors suppress the production of extracellular matrix by TM cells, which represents a potential alternative method of lowering IOP. Considering that conventional outflow is a dominant pathway in humans, IOP-lowering ROCK inhibitors, delivered in conjunction with other drugs, may be able to treat the glaucomatous eye.
Areas covered: Ripasudil hydrochloride hydrate is the first ROCK inhibitor approved for clinical use in Japan (and worldwide) against glaucoma and ocular hypertension. The efficacy of ripasudil, as mono- therapy and as an adjunctive medication to prostaglandin analogs and/or adrenergic β-receptor antagonists, has been confirmed in clinical trials.
Expert opinion: Considering the unique ROCK-inhibiting mechanism by which ripasudil lowers IOP via its actions on TM and SC endothelial cells, it may be an ideal adjunctive medication for treating glaucoma in the clinic.
ARTICLE HISTORY
Received 13 April 2017
Accepted 6 September 2017
KEYWORDS
Glaucoma; ROCK inhibitor; intraocular pressure; ripasudil

⦁ Introduction
Glaucoma is a leading cause of blindness worldwide, and lowering intraocular pressure (IOP) is the only evidence- based therapy currently available [1–3]. IOP depends on the balance between inflow and outflow of aqueous humor. In glaucomatous pathology, an elevation in IOP is caused mainly by increased resistance to aqueous outflow. Among the IOP- lowering drugs used in the clinical setting, Rho kinase (ROCK) inhibitors lower IOP according to a unique mechanism, namely depolymerization of intracellular actin in conventional outflow tissue, which consists of trabecular meshwork (TM) cells and Schlemm’s canal (SC) [4–6]. Furthermore, ROCK inhi- bitors suppress the production of extracellular matrix by TM cells [7,8], which represents a potential alternative method of lowering IOP. Considering that conventional outflow is a dominant pathway in humans, IOP-lowering ROCK inhibitors, delivered in conjunction with other drugs, may be able to treat the glaucomatous eye.

⦁ Overview of available glaucoma-lowering drugs
The first-line drugs used to lower IOP in the glaucomatous eye include prostaglandin analogs and adrenergic β-receptor antagonists [9]. When these are not effective, or not pre- scribed due to concerns about their side effects or contra- indications, second-line drugs such as carbonic anhydrase inhibitors and α2 adrenergic agonists may be given instead. Although numerous IOP-lowering drugs exist, they have only two pharmacological mechanisms of action: reduction of
aqueous inflow and/or increase of uveoscleral outflow [10]. Although cholinergic compounds increase conventional out- flow, they are currently only used in a limited number of cases with angle closure glaucoma due to their side effects, which include myosis and ocular inflammation.

⦁ Introduction to ROCK inhibitors
The ROCK inhibitor Y-27632 is a pyrimidine derivative that was found to reduce IOP in rabbits [4]. Another ROCK inhibitor, Y-39983, was the first to show selective IOP-lowering effects in humans [11]. In another study, isoquinolinesulfonamides exerted a potent inhibitory effect on protein kinase, and fas- udil (HA-1077) inhibited the binding of enzymes to the ade- nosine triphosphate-binding site of protein kinases [12]. Fasudil (HA-1077) is particularly effective in inhibiting ROCK
[13] and has been approved for clinical use in Japan as a cerebral vasospasm therapeutic agent. Of note, fasudil is not a highly specific inhibitor of ROCK: the molecule retains rela- tively weak inhibition activities against PKA, PKB, PKC, PKG, MLCK, and CaMKII. Another ROCK inhibitor, H-1152P, is a modified version of HA-1077 with a superior inhibitory profile [14]. On further examination, the kinase-inhibiting effects of H-1152P were exerted by substituent conversion of either the 2-position of hexahydro-1H-1,4-diazepine or the 4-position of the isoquinoline ring [15].
Ripasudil, a derivative of isoquinolinesulfonamide, affected methylation at the 2-position of hexahydro-1H-1,4-diazepine and fluoridation at the 4-position of isoquinoline, which were

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CONTACT Toshihiro Inoue [email protected] Faculty of Life Sciences, Department of Ophthalmology, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto City, Kumamoto, Japan
© 2017 Informa UK Limited, trading as Taylor & Francis Group

Box 1. Drug summary box.
Drug name Ripasudil hydrochloride hydrate
Phase Launch (Dec 2014)
Indication Glaucoma and ocular hypertension Pharmacology/mechanism of Rho kinase inhibitor/increased aqueous
action humor outflow
Route of administration Topical administration of eye drops Chemical structure C15H18FN3O2S▪HCl▪2H2O
Pivotal trials K-115-05, K-115-06 [25], K-115-08 [25]
these phenomena were reversible [6]. Thus, the IOP-lowering action of ripasudil promotes aqueous outflow via changes in the TM cytoskeleton, thereby reducing outflow resistance and increasing SCE permeability.
On the other hand, nonclinical examinations of rabbits and monkeys did not reveal any ophthalmic or pathological abnormalities, except for conjunctival hyperemia.

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different from the effects of fasudil, characterized by higher potency and specificity [16]. Following further clinical trials, ripasudil was approved, for the first time worldwide, for clin- ical use in Japan as an antiglaucoma agent [Box 1][17].

⦁ Chemistry
Ripasudil hydrochloride hydrate (4-Fluoro-5-{[(2S)-2-methyl- 1,4-diazepan-1-yl]sulfonyl}isoquinoline monohydrochloride dihydrate [C15H18FN3O2S HCl 2H2O]) is the first ROCK inhibitor approved for use in Japan to treat glaucoma and ocular hypertension (OHT) [18]. Ripasudil includes a fluorinated iso- quinoline and methyl-substituted chiral 1,4-diazepane ring [19], which could contribute to its higher potency and selec- tivity relative to other serine/threonine kinases.

⦁ Pharmacodynamics
Ripasudil inhibits human ROCK-1 and ROCK-2 (IC50 0.051 and
0.019 μmol/L, respectively) more potently than does Y-27632 or fasudil. In addition, the IC50s of ripasudil are very low compared to other kinases (PKACα: 2.1, PKC: 27, and CaMKIIα: 0.37 μmol/L), and higher than those of ROCK-1 and ROCK-2 [16]. In rabbits and monkeys with normal IOP, topical instillation of a ripasudil ophthalmic solution exerted a signifi- cant and dose-dependent IOP-lowering effect. Furthermore, the ocular hypotensive effect of ripasudil was immediate, and the maximum IOP-lowering effect was similar to that on episcleral venous pressure [16]. In an investigation of the effect of ripasudil on the aqueous humor dynamics of rabbits, significant increases in outflow facility were observed after the instillation of 0.4% ripasudil ophthalmic solution, with no effect on uveoscleral outflow or the aqueous flow rate [16].
The conventional pathway, through the TM and SC, repre- sents the major route of aqueous humor outflow in primates. The resistance of conventional outflow is mainly generated in the juxtacanalicular region of the TM and the inner wall of SC and is modulated by the Rho-ROCK signaling pathway. ROCK inhibition decreases IOP and increases conventional outflow by altering TM cell morphology and the permeability of Schlemm’s canal endothelial (SCE) cells. Ripasudil induces retraction and rounding of cell bodies, as well as disruption of actin bundles, in monkey TM cells. In a study on the monolayer permeability of SCE cells in monkeys, ripasudil significantly decreased transen- dothelial electrical resistance and increased the transendothelial flux of fluorescein isothiocyanate-labeled dextran. Furthermore, ripasudil disrupted zonula occludens-1 expression in SCE cells;
⦁ Pharmacokinetics
Ripasudil is metabolized into M1, which is the main metabolite of aldehyde oxidase in humans. Although M1 has inhibitory effects on ROCK-1 and ROCK-2, its potency is only one-sixth to one-ninth that of ripasudil [20].
In phase 1 clinical trials, plasma concentrations of ripasudil peaked immediately after instillation (i.e. after 0.080–0.250 h), with rapid release into the systemic circulation. The disappear- ance of ripasudil was also rapid, with a short half-life (0.6–
0.7 h). Plasma concentrations of M1, which has a longer half- life (2.1–2.6 h), were higher than those of ripasudil. The max- imum concentration and area under the curve of M1 were 3- and 22-fold higher, respectively, than those of ripasudil [20].
Ripasudil showed favorable intraocular penetration charac- teristics after instillation into pigmented rabbits, resulting in sufficient concentrations over the IC50 value at its sites of action (the aqueous humor and iris-ciliary body). Following instillation, ripasudil, but not M1, was the major component in ocular tissues. Ripasudil also reached the posterior segment of the eye, where it maintained high concentrations in mela- nin-containing tissues [21].

⦁ Clinical efficacy
Table 1 lists the clinical trials that have been conducted on ripasudil [22–26]. Ripasudil concentrations of up to 0.8% were evaluated in phase 1 studies to evaluate its safety and toler- ability [22]. Concentrations of 0.1%, 0.2%, and 0.4% were evaluated in a phase 2 dose response study, and 0.4% ripasu- dil was identified as the optimal clinical dose with respect to efficacy and safety. The frequency of conjunctival hyperemia tended to be dose-dependent [24]. In a phase 3 study, ripasu- dil monotherapy caused an IOP reduction of approximately 4 mmHg from baseline, which was a statistically significant reduction compared with the placebo [25]. In another phase 3 study, ripasudil demonstrated additional IOP reductions of 3.2 and 2.9 mmHg when administered concomitantly with base treatments of latanoprost and timolol, respectively [25].
In a 52-week clinical trial, ripasudil was administered in conjunction with prostaglandin analogs and β-blockers. Both the ripasudil combination therapy and monotherapy showed a consistent IOP-lowering effect relative to baseline that per- sisted throughout the study period [26].
Ripasudil demonstrated an IOP-lowering effect when admi- nistered both during the day and at night, with peak reduc- tions of 6.4 and 7.3 mmHg, respectively (both at 2 h after administration) [23]. Thus, ripasudil should be prescribed as a twice-daily dosage regimen. Ripasudil expressed its IOP-redu- cing effect after the first administration, with the effect pla- teauing at week 4.

Table 1. Clinical trials of the ripasudil ophthalmic solution.

Trial design Subject Result
Phase Randomization, Placebo, ripasudil OS 0.05%, Healthy volunteer (male: n = 50, Single and repeated ripasudil administration for healthy

1a placebo control, DBT

0.1%, 0.2%, 0.4%, 0.8%
Single administration

10 for each dose)

volunteers showed significant IOP-lowering effect and good torerant.

Phase
Randomization,
(First term) Healthy volunteer (male: n = 50,
Safety information: slight to mild conjunctive hyperemia

1a placebo control, DBT
Placebo, ripasudil OS 0.8%
Single administration (second term)
Placebo, 0.05%, 0.1%, 0.2,
0.4%, 0.8%
One-week administration
10 for each dose)
was founded in more than half of the participants treated with ripasudil

Phase 2b
Randomization, placebo control, crossover trial
Placebo, ripasudil OS 0.2%, 0.4%
One-day administration by each dose
POAG, OH (n = 28) Ripasudil in concentration 0.2% and 0.4% showed
significant IOP-lowering effect.
0.2%: −5.2mmHg, 0.4%: −6.4mmHg, placebo: −2.0mmHg Safety information: conjunctive hyperemia was observed in
0.2% (79%), 0.4% (96%) and placebo (11%)

Phase 2c
Randomization, placebo control, DBT, parallel-group comparison study
Placebo, ripasudil OS 0.1%, 0.2%, 0.4%
Eight-week administration
POAG, OH (n = 210)
[placebo (n = 54), ripasudil 0.1% (n = 53), 0.2% (n = 54),
0.4% (n = 49)]
Ripasudil in concentration 0.1%, 0.2% and 0.4% showed significant IOP-lowering effect. The dose-dependent IOP- lowering effect was demonstrated.
0.1%: −3.7mmHg, 0.2%: −4.2mmHg, 0.4%: −4.5mmHg,
placebo: −2.5mmHg (2 h after administration)
Safety information: conjunctive hyperemia was observed in 0.1% (43.4%), 0.2% (57.4%), 0.4% (65.3%), and placebo
(13.0%).

Phase
Randomization,
Placebo, ripasudil OS 0.4% POAG, OH (n = 107)
Unpublished data.

3 placebo control, DBT, parallel-group comparison study
Eight-week administration
[placebo (n = 54), ripasudil 0.4% (n = 53)]
Ripasudil 0.4% showed significant IOP-lowering effect compared with placebo group

Trial design Subject Result

Phase 3d
Randomization, placebo control, DBT, parallel-group
Placebo, ripasudil OS 0.4% (combined with latanoprost)
POAG, OH (n = 205)
[placebo (n = 103), ripasudil 0.4% (n = 102)]
Ripasudil combined with latanoprost study

comparison study
Eight-week administration The mean IOP reductions from baseline (Trough and Peak): Ripasudil −2.2 and −3.2 mmHg

Phase 3d
Randomization, placebo control, DBT, parallel-group comparison study
Placebo, ripasudil OS 0.4% (combined with timolol) Eight-week administration
POAG, OH (n = 208)
[placebo (n = 104), ripasudil 0.4% (n = 104)]
Placebo −1.8 and −1.8 mmHg

Safety information: conjunctival hyperemia was observed in ripasudil (54.9%), placebo (6.8%). Eye irritation was observed in ripasudil (9.6%), placebo (2.9%).
Ripasudil combined with timolol study
The mean IOP reductions from baseline (Trough and Peak): Ripasudil −2.4 and −2.9 mmHg
Placebo −1.5 and −1.3 mmHg
Safety information: conjunctival hyperemia was observed in ripasudil (65.4%), placebo (5.8%). Eye irritation was observed in ripasudil (5.9%), placebo (7.8%).

Phase 3
Randomization, placebo control, SBT, crossover trial
Placebo, ripasudil OS 0.4% (combined with latanoprost)
Each dose 4-week administration
POAG, OH (n = 33) Unpublished data.

Ripasudil 0.4% showed significant IOP-lowering effect compared with placebo group

Phase 3e
Open trial Ripasudil OS 0.4% (monotherapy and combined with PGA, BB, fixed combination therapy)
Fifty-two-week administration
POAG, exfoliation glaucoma, OH (n = 354)
[monotherapy (n = 173), additive with PGA (n = 62), BB (n = 60), fixed combination therapy (n = 59)]
Ripasudil showed IOP-lowering effects over 52 weeks.
The mean IOP reduction from baseline (Trough and Peak): Monotherapy −2.6 and −3.7 mmHg

Combination with PGA −1.4 and −2.4 mmHg Combination with BB −2.2 and −3.0 mmHg
Combination with fixed combination −1.7 and −1.7 mmHg Safety information: the frequently observed adverse events
were conjunctival hyperemia (74.6%), blephartitis (20.6%), and allergic conjunctivitis (17.2%)

Phase 3
Randomization, placebo control, DBT
Placebo, ripasudil OS 0.4% Healthy volunteer (male: n = 30) (Unpublished data.)
One-week administration Ripasudil 0.4% administration for healthy volunteers showed significant IOP-lowering effect and searched ocular blood flow

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BB, beta-blocker; DBT, double-blind trial; OH: ocular hypertension; OS, ophthalmic solution; Peak, after 2-h administration; POAG, primary open angle glaucoma; PGA, prostaglandin analogue; SBT, single-blind trial,
Trough, before administration.
aJAMA Ophthalmol. 2013 Oct; 131 (10): 1288–95. [22]
bActa Ophthalmol. 2015 Jun; 93 (4): e254–60. [23]
cAm J Ophthalmol. 2013 Oct; 156 (4): 731–6. [24]
dJAMA Ophthalmol. 2015 Jul; 133 (7): 755–61. [25]
eActa Ophthalmol. 2016 Feb; 94 (1): e26–34. [26]

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As shown by the clinical trials described earlier, ripasudil produces a stable reduction in IOP, both when used in com- bination with prostaglandin analogs and β-blockers and as monotherapy. More recently, an approximately 3 mmHg addi- tional reduction of IOP was observed when ripasudil was administered to patients undergoing maximal tolerated med- ical therapies [27,28].

⦁ Safety and tolerability
Most of the previously reported adverse events associated with ripasudil have been eye disorders. The main adverse event is conjunctival hyperemia, which occurs in ~70% of patients administered ripasudil for 8 weeks or longer. Conjunctival hyperemia occurs repeatedly after administra- tion, reaches the peak about 10 min later, and disappears within 2 h. This symptom was unchanged after treatment for 1 year. This event is considered to result from smooth muscle relaxation and subsequent dilatation of the blood vessels.
Blepharitis and conjunctivitis, with or without allergic reac- tions, are also observed in approximately 10% of patients administered a longer course of ripasudil (>8 weeks); however, these events can be resolved with proper treatment. To inves- tigate the cause of allergic reactions, some nonclinical exam- inations were performed. Given the sensitization and ocular toxicity results, these allergic reactions were not caused by ripasudil [29]. Therefore, a more comprehensive clinical study is needed.

⦁ Regulatory affairs
In 2014, ripasudil 0.4% ophthalmic solution was approved for use in Japan to treat glaucoma and OHT.

⦁ Conclusions
Ripasudil hydrochloride hydrate is the first ROCK inhibitor approved for clinical use in Japan (and worldwide) against glaucoma or OHT. The efficacy of ripasudil, as monotherapy or as an adjunctive medication to prostaglandin analogs and/ or adrenergic β-receptor antagonists, has been confirmed in clinical trials.

⦁ Expert opinion
Considering the unique ROCK-inhibiting mechanism by which ripasudil lowers IOP, via its actions on TM and SCE cells, it may be an ideal adjunctive medication for treating glaucoma. Indeed, ripasudil showed significant IOP-lowering effects, without severe side effects, in phase I–III trials and was approved in Japan in 2014. Now, ripasudil has been prescribed in various situations as an anti-glaucoma therapy. Ripasudil reduced IOP significantly, even in patients with glaucoma controlled inadequately with maximum medical therapy [28]. Regardless of the number of medications, ripasudil maintained its IOP-lowering effect and safety even in add-on settings [30]. The unique mechanism, i.e. reducing IOP via the conventional aqueous outflow pathway, which is different from other anti- glaucoma drugs, may contribute to this intriguing effect. In

terms of safety, the most commonly observed adverse effect is conjunctival hyperemia. The severity of conjunctival hypere- mia reached its peak at 5–15 min after the instillation of ripasudil and decreased gradually over 120 min [31]. The transient hyperemia is thought to be caused by the vasodila- tory effects of ripasudil; nonetheless, relatively few patients discontinue ripasudil treatment for this reason.
Commonly prescribed therapies for OHT or primary open- angle glaucoma (POAG) reduce IOP by decreasing aqueous humor production, or by increasing uveoscleral outflow. However, they do not target the main physiological issue: the dysfunctional TM.
Continuously reduced conventional outflow may lead to dysfunction of SCE cells [32]. Thus, IOP-lowering therapy via the conventional pathway, from the early stage of POAG, may be beneficial in maintaining the function of this pathway.
ROCK inhibitors reduce aberrant extracellular matrix deposition [33] and change the cell shape, which is opposite to the reaction observed in OTH or POAG. This effect is expected to prevent the progression of TM impairment or restore the increased resistance. If TM dysfunction is restored by ROCK inhibitors, it may contribute to the maintenance of IOP homeostasis.
Since the IOP-lowering effect of ROCK inhibitors is not as marked as that of first-line drugs, they should be used as second-line drugs when a first-line drug is not effective. If side effects such as hyperemia or blepharitis are not accepta- ble, use of ROCK inhibitors should be avoided.
IOP lowering through ROCK inhibition is a more physiolo- gical and natural approach than any other current therapy, in that preserving aqueous humor flow of the conventional path- way may improve the ability to respond to acute IOP changes. In the near future, it is expected that the potential of ripasudil to reduce IOP will be demonstrated.

Funding
This paper was funded by JSPS Kakenhi (Grant No. 26462664)

Declaration of interest
H Tanihara has received consulting fees from Kowa, and Merck Sharp & Dohme, and board membership fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan. Kowa Pharmaceutical Company has provided drug information to the authors to aid in the preparation of this manuscript. Scientific and Technical Editing services were provided by Textcheck. The authors have no other relevant affilia- tions or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materi- als discussed in the manuscript apart from those disclosed.

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