Table 1.
Summary of Phase 2 and 3 Clinical Trials of Rho Kinase Inhibitors
| Study | Study Design | Duration of Treatment | Diagnosis and Baseline IOP Inclusion Range (mmHg) | Drugs (number of subjects) | Baseline IOP mmHg (SD) | Efficacy mmHg (SD) | Frequent Adverse Events | Comments | |||
|---|---|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||||
| SNJ-1656 Phase 2 Inoue et al (2015)100 |
Multicenter RCT Double-masked Placebo control |
7 days | POAG (37%) OHT (63%) |
~22.5 | Change from baseline at trough | Change from baseline at peak | CH | ||||
|
|
|
|
|||||||||
| Placebo | −2.2 (1.9) | −1.5 (2.2) | Not reported | ||||||||
| 22≤ IOP ≤ 31 | SNJ-1656 0.03% (16) | −3.8 (2.7) | −5.0 (2.4) | 60% | |||||||
| SNJ-1656 0.05% (15) | −4.3 (2.3) | −4.4 (2.7) | 100% | ||||||||
| SNJ-1656 0.1% (18) | −4.0 (2.5) | −4.5 (1.9) | 83% | ||||||||
|
| |||||||||||
| AR-12286 Phase 2 Williams et al (2011)101 |
Multicenter RCT Double-masked Vehicle control |
3 consecutive 7-day dosing periods: QD AM QD PM BID |
OAG (58%) OHT (42%) |
Mean diurnal | Mean diurnal IOP reduction from baseline | CH | |||||
| QD AM Group | BID Group | ||||||||||
|
|
|
|
|
||||||||
| 24≤ IOP ≤ 36 | Vehicle (22) | 26.3 (2.47) | −1.9 | −2.4 | 9.1% | ||||||
| AR-12286 0.05% (22) | 26.0 (2.17) | −4.0 | −4.1 | 27.3% | |||||||
| AR-12286 0.1% (23) | 27.3 (3.18) | −5.0 | −4.4 | 39.1% | |||||||
| AR-12286 0.25% (22) | 26.9 (2.03) | −4.8 | −6.0 | 59.1% | |||||||
|
| |||||||||||
| Ripasudil Phase 2 Tanihara et al (2013)l105 |
Multicenter RCT Double-masked Placebo control |
8 weeks | POAG (41%) OHT (59%) |
9 AM | Change from baseline at trough | Change from baseline at peak | CH | ||||
|
|
|
|
|
||||||||
| Placebo (54) | 23.0 (2.1) | −2.2 | −2.5 | 13% | |||||||
| 21< IOP < 35 | Ripasudil 0.1% (53) | 23.3 (2.4) | −3.4 | −3.7 | 43% | ||||||
| Ripasudil 0.2% (54) | 23.2 (2.0) | −3.2 | −4.2 | 57% | |||||||
| Ripasudil 0.4% (49) | 23.2 (1.9) | −3.5 | −4.5 | 65% | |||||||
|
| |||||||||||
| Ripasudil Phase 3 Tanihara et al (2016)108 |
Multicenter Non-randomized open-label clinical trial |
1 year | POAG (65%) OHT (31%) XFG (4%) |
9 AM | Change from baseline at trough | Change from baseline at peak | All Treatments: CH
(75%) Blepharitis (21%) Allergic conjunctivitis (17%) |
||||
|
|
|
|
|||||||||
| Ripasudil 0.4% BID (173) | 19.3 (2.7) | −2.6 | −3.7 | ||||||||
| 15< IOP ≤ 35 | Ripasudil 0.4% BID + PGA (62) | 17.6 (2.0) | −1.4 | −2.4 | |||||||
| Ripasudil 0.4% BID + BB (60) | 18.2 (2.3) | −2.2 | −2.0 | ||||||||
| Ripasudil 0.4% BID + FC PGA and BB (59) | 17.6 (2.0) | −1.7 | −1.7 | ||||||||
|
| |||||||||||
| Additive effect of ripasudil with
timolol Phase 3 Tanihara et al (2015)107 |
Multicenter RCT Double-masked Placebo control |
8 weeks | POAG (47%) OHT (53%) IOP ≥ 18 on timolol |
On timolol 9 AM | Change from baseline at trough | Change from baseline at peak | CH | ||||
|
|
|
|
|
||||||||
| Placebo (104) | 19.7 (1.7) | −1.5 | −1.3 | 5.8% | |||||||
| Ripasudil 0.4% BID (104) | 19.9 (1.9) | −2.4 | −2.9 | 65.4% | |||||||
|
| |||||||||||
| Additive effect of ripasudil with
latanoprost Phase 3 Tanihara et al (2015)107 |
Multicenter RCT; Double-masked Placebo control |
8 weeks | POAG (61%) OHT (39%) IOP ≥ 18 on latanoprost |
On latanoprost 9 AM | Change from baseline at trough | Change from baseline at peak | CH | ||||
|
|
|
|
|
||||||||
| Placebo (103) | 19.6 (1.9) | −1.8 | −1.8 | 8.7% | |||||||
| Ripasudil 0.4% BID (102) | 20.1 (1.9) | −2.2 | −3.2 | 55.9% | |||||||
|
| |||||||||||
| Netarsudil Phase 3 Bacharach (2015)109 |
Multicenter RCT Double-masked |
28 days | POAG (60%) OHT (40%) |
Mean diurnal IOP | Change at trough | Change in mean diurnal IOP | CH | Netarsudil did not meet pre-determined criteria for non-inferiority to latanoprost. Eyes with baseline IOP ≤ 26 mm Hg did meet those criteria | |||
|
|
|
|
|
||||||||
| netarsudil 0.01% QD (74) | 25.8 | −5.4 | −5.5 | 52% | |||||||
| 24 ≤ IOP ≤ 36 | netarsudil 0.02% QD (72) | 25.6 | −5.9 | −5.7 | 57% | ||||||
| latanoprost 0.005% QD (77) | 25.5 | −7.6 | −6.8 | 16% increased lacrimation (5–7%) and CH (5–6%) also observed with netarsudil |
|||||||
|
| |||||||||||
| ROCKET-1 Netarsudil Phase 3 Serle et al (2017)112 |
Multicenter RCT Double-masked |
3 months | POAG (66%) OHT (34%) |
Mean diurnal IOP | Change from baseline (diurnal range) | CH | HEM | VER | Netarsudil did not meet the non-inferiority criteria. | ||
|
|
|
|
|||||||||
| 20<IOP < 27 at 8 AM and | netarsudil 0.02% QD (202) | 22.5 | −3.3 to −5.0 | 53% | 13% | 5% | |||||
| 17< IOP < 27 at 10 AM & 4 PM | timolol 0.5% BID (209) | 22.3 | −3.7 to −5.1 | 7% | 0.5% | 0% | |||||
|
| |||||||||||
| ROCKET-2 Netarsudil Phase3 Serle et al (2017)112 |
Multicenter RCT Double-masked |
3-month Interim data reported for the 12-month trial |
POAG (66%) OHT (34%) |
Mean diurnal IOP* | Change from baseline (diurnal
range)* *Primary efficacy population (maximum baseline IOP < 25 mmHg) |
CH | HEM | VER | Netarsudil QD & BID met non-inferiority criteria in the primary efficacy population | ||
|
|
|
|
|||||||||
| 20< IOP < 27* at 8 AM and | netarsudil 0.02% QD (251) | 21.4 | −3.3 to −4.6 | 50% | 15% | 9% | |||||
| 17< IOP < 27* at 10 AM and 4 PM | netarsudil 0.02% BID (254) | 21.5 | −4.1 to −5.4 | 59% | 17% | 15% | |||||
| timolol 0.5% BID (251) | 21.5 | −3.7 to −5.1 | 10% | 0% | 0.4% | ||||||
|
| |||||||||||
| Fixed Combination netarsudil and
latanoprost (PG324) Phase 2 Lewis et al (2016) 111 |
Multicenter RCT Double-masked |
28 days | POAG (56%) OHT (44%) |
Mean diurnal IOP | Mean diurnal IOP | CH | Fixed combination formulations superior to latanoprost and netarsudil | ||||
|
|
|
|
|||||||||
| 24≤ IOP < 36 at 8 AM and | latanoprost – netarsudil 0.01% QD (74) | 25.1 (2.3) | 17.3 (2.8) | 41% | |||||||
| IOP ≥ 21 at 10 AM and 4 PM | latanoprost – netarsudil 0.02% QD (73) | 25.1 (2.4) | 16.5 (2.6) | 40% | |||||||
| latanoprost QD (73) | 26.0 (2.8) | 18.4 (2.6) | 14% | ||||||||
| netarsudil 0.02% (78) | 25.4 (2.7) | 19.1 (3.2) | 40% | ||||||||
Abbreviations: IOP = intraocular pressure; SD = standard deviation; RCT = randomized clinical trial; POAG = primary open-angle glaucoma; OHT = ocular hypertension; QD = once daily; BID = twice daily; OAG = open-angle glaucoma; XFG = exfoliation glaucoma; PGA = prostaglandin analog; BB = beta-blocker; FC = fixed combination; CH = conjunctival hyperemia; HEM = conjunctival hemorrhage; VER = cornea verticillata