1. Efficacy and safety of Ripasudil in patients with glaucoma insufficiently controlled under multiple medical therapies
● Yoshikuni Arakaki MD, Michiko Yonahara MD,
　　 Yohei Chikaraishi MD, and Hiroshi Sakai MD,
Department of Ophthalmology, Ryukyu University,
School of Medicine, Okinawa, Japan

2. Background
There are many evidence that intraocular pressure (IOP) reduction prevent the onset and progression of glaucomatous optic neuropathy. In clinical practice, numerous drugs such as prostaglandin analogs, β-blockers, carbonic anhydrase inhibitors and α2- agonist to reduce IOP have been used to treat glaucoma. ROCK (Rho-associated coiled coil-containing protein kinase) plays a critical role in regulating the contractile tone of smooth muscle in a calcium-independent manner. ROCK are widely expressed in the human trabecular meshwork, ciliary muscle cells, iris and retina1).

3. ROCK inhibitors are the new class of IOP lowering agents
ROCK inhibitors are the new class of IOP lowering agents. Animal studies and clinical trials have found that inhibition of the ROCK pathway contributes to the lowering the IOP in eyes with glaucoma and ocular hypertension. The exact mechanisms of action to lower the IOP are still unclear, but the modulation of the conventional aqueous outflow pathway is believed to be a mechanism to increase the outflow. Ripasudil is a ROCK inhibitor (K-115) approved and used for ocular hypertension and glaucoma in Japan.
K-115 (Ripasudil hydrochloride hydrate, 4-Fluoro-5-{[(2S)-2-methyl-1, 4-diazpan-1yl]
sulfonyl} isoquinoline monohydrochloride dihydrate )

4. Purpose and Subjects Purpose :
To evaluate the efficacy and safety of ripasudil, a rho- kinase inhibitor, for the patients with glaucoma who had received a single or multiple IOP-lowering drugs.
Subjects :
Subjects included were 1) patients with primary open angle glaucoma and secondary glaucoma who were treated by same IOP-lowering medications longer than 3 months, 2) IOP was thought to be insufficient with current anti-glaucoma medications.

5. Exclusion criteria and the excluded subjects
Reasons of exclusion
Number of the eyes (number of subjects)
Switching IOP-lowering agents
13 (21)
Past intraocular surgery or laser therapy within 3 months
2 (2)
Changing other IOP-lowering agents
12 (14)
Post intraocular surgery or laser therapy within 2 months
8 (8)
Total
35 (45)

6. Backgrounds of Patients
POAG SG P
Gender
eyes (subjects)
Male
22 (16)
7 (6)
0.294*
Female
16 (9)
9 (7)
Age ± S.D (years)
60.4 ± 15.1
66.3 ± 18.5
0.120#　
Status of lens (number; eye)
Phakia 24 6
0.095*
IOL 14 9
Aphakia 1
HFA mean deviation (dB)
-13.2 ± 6.4
-12.5 ± 9.0
0.080#
IOP (mmHg)
16.9 ± 2.8
22.8 ± 6.7
<0.01#
Medication score
3.5 ± 1.0
3.5 ± 1.1
0.685#
（*； Chai-square、#； unpaired t-test）

7. Methods
1. Retrospective, interventional case series study 2. Ripasudil instillation twice daily 3. Ophthalmological examinations including IOP measurement, slit lamp examination, fundus examination were performed before and after addition of ripasudil at 1, 2, 3 and 6 month. 4. Adverse events were also monitored and checked at every time points.

8. Months from treatment start
Result ① Fluctuation of mean intraocular pressure by ripasudil addition in POAG and SG
(mmHg) # # # # # # # * *
Months from treatment start
# : paired t-test
* : unpaired t-test
No. of patients
追加前
追加1M 2M 3M 6M
POAG 38 36 25 37 34 SG 16 8 15 14
・Mean IOPs differences between before and after addition of ripasudil were statistically significant in both POAG and SG.
・There was no statistically significant differences in IOPs between POAG and SG except for baseline and 6 month after addition.

9. Result ② Intraocular pressure reductions of ripasudil from baseline
(mmHg) # * *
　　　　 　　　　 　　 　 6
Months from treatment start
# : paired t-test
No. of patients
追加1M 2M 3M 6M
POAG 36 25 37 34 SG 16 8 15 14
* : unpaired t-test
・There was statistically significant differences in IOPs between 1M and 6M
in POAG.
・Significant difference in IOP reduction at 3 and 6 month in both group.

10. Result ③ Reduction rate of intraocular pressure from baseline
(% )
■POAG　■SG *
　　　　 　　　　 　　 　 6
Months from treatment start
（* : unpaired t-test）
No. of patients
追加1M 2M 3M 6M
POAG 36 25 37 34 SG 16 8 15 14
・There was no statistically significant differences at all points in both group.
・Significant difference in IOP reduction rate was seen at 3 between POAG and SG.

11. Result ④. Adverse Events
ALL
n=54　(%)
POAG
(n=38) SG
(n=16) p
Conjunctival hyphema
12 (22.2) 11 1
Blephalitis
3 (5.6) 3
Itching
1 (1.9)
Ocular pain
Xerophthalmia
Eye irritation
Elevation of IOP
Total
20 (37.0)
17 (44.7)
3 (18.8)
0.120*
（*: Chai-square)
・There was no statistically significant differences between POAG and SG.
・All adverse events were topical not general.

12. Result ⑤ Discontinuation
Case
Age/
Gender
Type
Symptom /
Signs
Timing
(months)
Medication
Score 1
64 / M
POAG
Blephalitis 6 2
81 / F 3
Eye irritation 4
54 / M
Conjunctival hyperemia 5
76 / F SG
74 / M
Ocular pain 7
13 / M
Elevation of IOP
・There was no statistically significant differences between POAG and SG.
・All events resolved once the administration of ripasudil was terminated.

13. Discussion
1. Rho kinase inhibitor (ripasudil) Some reports have suggested that actin-myosin system is related regulatory system on outflow resistance in conventional outflow of aqueous humour3). Rho kinase inhibitors are regarded as one of the cytoskeletal modulating drug 4). These kind of drugs to modulate the actin cytoskeletal are regarded as a novel drug to alter the conventional out-flow of aqueous humor, resulting in significant IOP reduction5). The IOP-lowering effect of K % was statistically significant for 8 weeks by twice daily dosing6). 2. Additive efficacy of ripasudil for glaucoma patients The mechanisms of rho kinase inhibitors are different from the known IOP- lowering mechanisms for other anti-

14. glaucoma medications, so addictive effects of these drugs had been expected.
Tanihara reported additive IOP-lowering effects combined with latanoprost or timolol7). The mean IOP reductions from baseline were -2.9 mmHg and -3.2 mmHg at peak level in ripasudil-timolol study
and in ripasudil-latanoprost study respectively. A difference between ripasudil and placebo were 1.6mmHg (p‹0.001) and 1.4mmHg (p‹0.001) at peak level in ripasudil-timolol study and in ripasudil-latanoprost study, respectively.
3. Long term efficacy and safety of ripasudil8).
Ripasudil showed IOP-lowering effects over 52 weeks in the monotheraphy and additive therapy. 388 cases of open angle glaucoma, ocular hypertension for 52 weeks. The
mean IOP reductions at week 52 were 3.7mmHg in

15. monotherapy, 2. 4mmHg in combination with prostaglandin analogs, 3
monotherapy, 2.4mmHg in combination with prostaglandin analogs, 3.0 mmHg in combination with β-blockers and 1.7mmHg in combination with fixed combination of prostaglandin analogs and β-blockers. Ripasudil showed
IOP- lowering effects for both monotherapy and additive therapy.
Adverse drug reaction were observed in 301 patients (85.0%). The most frequent reactions were events were conjuctival hyperemia (74.6%), blephalitis (20.6%), allergic conjuncitivitis (17.2%) and eye irritation (10.2%). The hyperemia was mild and transient in almost patients % discontinued the study due to blephalitis or allergic conjuncitivitis.
It was also showed that the use of as a Ripasudil was significant risk factor related to the patients that discontinued the drug due to allergic adverse response.

16. The authors have no proprietary interest in this study.
Conclusion
Ripasudil effectively lowered IOP for POAG and PG patients for a long time period. It should be given attention to topical adverse events of additional ripasudil therapy especially in patients who have used more glaucoma medications .
The authors have no proprietary interest in this study.

17. References
Fukiage C et al. Involvement of phosphorylation of myosin phosphatase by ROCK in trabecular meshwork and ciliary muscle contraction. Biochem Biophys Res Commun 2001; 288:
Isobe T et al. Effect of K-115, a Rho-kinase inhibitor, on aqueoues humor dynamics inrabbits. Curr Eye Res 2014; 94:
Rao PV et al. Modulation of aqueous humour outflow facility by Rho kinase-specific inhibitor Y Invest Ophthalmol Vis Sci 2001; 42:
Honjo M et al. Effects of rho-associated protein kinase inhibitor Y on intraocular pressure and outflow facility. Invest Ophthalmol Vis Sci 2001a ; 42:
Kameda T et al. The effects of Rho-associated protein kinase inhibitor on monkey Schlemm’s canal endothelial cells. Invest Ophthalmol Vis Sci 2012; 53:
Tanihara H et al. Phase 2 randomized clinical study of a rho kinase inhibitor, K-115, in primary open-angle glaucoma and ocular hypertensiton. Am J Ophthalmol 2013; 156:
Tanihara H et al. Additive intraocular pressure-lowering effects of the rho kinase inhibitor ripasudil (K-115) combined with timolol or latanoprost. JAMA Ophthalmol 2015; 133:
Tanihara H et al. One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open- angle glaucoma and ocular hypertension. Acta Ophthalmologica 2016; 94: e16-e34.