Comparison of safety and efficacy of Netarsudil 0.02% and Bimatoprost 0.01% monotherapy and combination therapy in primary open-angle glaucoma and ocular hypertension

Abstract

Purpose:

To study and compare the efficacy and safety profile of Rho-kinase inhibitor (netarsudil 0.02%) and prostaglandin analog (bimatoprost 0.01%) both as monotherapy and in combination.

Design:

Prospective, randomized, monocentric, open-label clinical trial.

Methods:

Patients ≥20 years of age with primary open-angle glaucoma or ocular hypertension (IOP >21 mmHg) were recruited and randomized to receive either netarsudil 0.02%, netarsudil 0.02% + bimatoprost 0.01%, or bimatoprost 0.01% once daily for a period of 12 weeks. IOP and side effects were documented at 4, 8, and 12 weeks.

Results:

The mean treated IOP ranged 17.51–18.57 mmHg for netarsudil, 15.80–16.46 mmHg for bimatoprost, and 14.00–14.87 mmHg for the combination therapy group. The mean IOP reduction from baseline at 4, 8, and 12 weeks was found to be statistically significant (P < 0.001) in all three groups. The safety profile of netarsudil/bimatoprost combination was consistent with each constituent individually. The only frequently observed ocular adverse event was conjunctival hyperemia, which was seen mostly in netarsudil and netarsudil + bimatoprost groups (P < 0.001).

Conclusion:

The IOP-lowering effect of netarsudil 0.02% once daily is non-inferior to bimatoprost 0.01% in patients with POAG and ocular hypertension with acceptable ocular safety, and the combination therapy achieved a higher IOP-lowering effect. This group of medications can be a useful adjunct in patients on maximal therapy.

Glaucoma is the leading cause of irreversible blindness around the world. There are over 80 million people worldwide living with glaucoma, and this number is expected to increase to nearly 111 million by 2040.[1] It is a multifactorial disorder characterized by optic nerve head changes, progressive visual field loss, and an intraocular pressure (IOP) of 21 mmHg or more on at least a few occasions. The treatment for glaucoma mostly starts with topical medications, which comprise several classes of drugs such as prostaglandin analogs, beta-blockers, alpha agonists, and carbonic anhydrase inhibitors. These medications are generally effective at lowering the IOP, but many patients do not achieve the target IOP with a single medication and thus require a combination of two or more ocular hypotensive medications with frequent and cumbersome dosing schedules. As the number and dose of medications increase, patients often become less compliant with their treatment, which adversely affects the prognosis. Therefore, any drug that effectively lowers the IOP while providing convenient dosing schedule would be much beneficial for glaucoma management.

Rho-kinase inhibitors (ripasudil and netarsudil) are a new class of FDA-approved drugs that act on ROCK and norepinephrine transporter. They have a triple mechanism of IOP reduction by inhibiting the norepinephrine transporter, decreased outflow resistance by reversing the structural and functional damage to the trabecular meshwork, and decreased episcleral venous pressure through their vasodilatory effect.[2] Because ROCK-II plays a pathophysiological role in glaucoma, the inhibitors of ROCK may be beneficial for ameliorating vision loss.[3] These drugs act directly on the neurons in the central visual pathway, interrupting the RGC apoptosis, and thus serve as a novel pharmacological approach for glaucoma neuroprotection. As Rho-kinase inhibitors lower the IOP through different mechanisms of action, they may provide additional IOP-lowering effects when used in combination with other glaucoma medications. We thus set out to study the efficacy and safety profile of Rho-kinase inhibitors in comparison to prostaglandin analogs.

Methods

The study was approved by the institutional ethics committee in accordance with good clinical practice guidelines and tenets of the Declaration of Helsinki. A sample size of 51 in each group was required assuming a one-tailed alpha of 0.05 and medium effect size for a power of 80% to establish non-inferiority of netarsudil to bimatoprost.

This was an open-labeled, parallel-group trial. Eligible patients were >20 years of age with primary open-angle glaucoma or ocular hypertension with an untreated IOP of >21 mmHg and <32 mmHg. Patients on ocular hypotensive medications were allowed to undergo drug-specific washout before entering into the study. Any individual with secondary glaucoma, narrow-angle glaucoma, previous laser or surgical intervention (iridotomy, trabeculoplasty, trabeculectomy), previous ocular surgery (including cataract surgery), history of recent ocular trauma, infection, any other ocular disease or ocular medications (including topical and systemic steroid), or known hypersensitivity to netarsudil or bimatoprost were excluded.

After obtaining informed consent, the patients were randomly assigned to receive netarsudil 0.02% (N), netarsudil 0.02% + bimatoprost 0.01% (NB), and bimatoprost 0.01% (B).

The eye with the higher IOP was selected for statistical analysis. The baseline data were collected, and the mean follow-up IOP was recorded at 4, 8, and 12 weeks between 10 am to 12 pm. Participants were also assessed for any drug-related ocular or systemic side effects at each follow-up visit. Conjunctival hyperemia was assessed and graded from grade 0 (normal) to grade 4 (severe) in every participant based on the Efron scale [Fig. 1].[4] Each study participant was subjected to a set of questions to document the subjective side effects at each follow-up, and adverse effects such as itching, foreign body sensation, erythema of eyelid, instillation site pain or discomfort, diminution of vision, and periocular pigmentation were noted.

Figure 1.

Efron scale [green (0) = white bulbar conjunctiva; light green (1) = mild redness, major vessels engorged; yellow (2) = moderate conjunctival and limbal redness with slight ciliary flush; orange (3) = marked conjunctival and limbal redness with ciliary flush; red (4) = extreme conjunctival and limbal redness with intense ciliary flush]. (Adapted from Efron (2001) Ophthalmic Physiol Opt.)

Data were presented as mean ± SD, range, and percentages. Mean IOP and hyperemia scores were compared using paired t-test and ANOVA with post hoc analysis. Statistical significance was set at 0.05.

Results

A total of 133 patients were recruited as opposed to the 153 required due to low patient turnout during the COVID-19 pandemic. The final random allocation of patients was as follows: 43 in group N, 32 in group NB, and 34 in group B. We lost 24 patients to follow-up.

The baseline demographics are given in Table 1. The baseline IOP was similar among the three groups, ranging from 24 to 27 mmHg (P = 0.06).

Table 1.

Baseline demographics

Patient characteristics		Group N (n=43)	Group NB (n=32)	Group B (n=34)	P
Mean age (years)		44.68 (±10.32)	51.75 (±10.85)	50.07 (±18.75)
Gender	Male	23	17	19
	Female	20	15	15
Mean baseline IOP (mmHg)		26.57 (±4.83)	24.62 (±2.96)	24.57 (±4.58)	0.06
Mean BCVA (LogMAR)		0.07 (±0.12)	0.15 (±0.23)	0.10 (±0.17)	0.27
Severity	Mild	25	19	22
	Moderate	14	11	9
	Severe	4	2	3
Loss to follow-up	Due to adverse events	2	4	0
	Other reasons	4	7	7

The mean change in IOP at 4, 8, and 12 weeks from baseline was statistically significant in all three groups (P < 0.001), with mean IOP ranging 17.51–18.57, 14.00–14.87, and 15.80–16.46 in group N, group NB, and group B, respectively [Fig. 2]. The mean IOP reduction from baseline ranged 8.04–8.74 mmHg in group N, 9.84–11.25 in group NB, and 8.44–9.17 mmHg in group B. On subgroup analysis, the IOP reduction was significantly different at 8 weeks (P = 0.006) and 12 weeks (P = 0.013) [Fig. 3]. The mean percentage IOP reduction was maximum in group NB (44%), whereas in group N (33%) and group B (36%), the change was comparable.

Figure 2.

Mean change in IOP at 4, 8, and 12 weeks, along with confidence intervals

Figure 3.

Raincloud plots for IOP reduction at 4, 8, and 12 weeks

The most frequently reported adverse event was conjunctival hyperemia, which was experienced by nearly 71.4% (25/35) in group N, 83.3% (20/24) in group NB, and 15.3% (4/26) in group B. There was a significant difference in mean hyperemia scores in all three groups (P < 0.001) [Table 2]. On post-hoc analysis, a higher degree of hyperemia was evident in group N and NB as compared to group B, whereas no difference was noted between group N and NB [Fig. 4]. Conjunctival hyperemia led to treatment discontinuation in 2/43 (~5%) eyes in group N, 4/32 (~13%) eyes in group NB, and none in group B. All of the ocular adverse effects that occurred over 12 weeks of follow-up are outlined in Table 3.

Table 2.

Mean conjunctival hyperemia scores

	Mean hyperemia score (±SD)	P
Group (N)	2.45 (±0.91)	<0.001
Group (NB)	2.66 (±0.63)
Group (B)	1.15 (±0.36)

Figure 4.

Raincloud plots showing the difference in hyperemia scores

Table 3.

Observed ocular adverse effects

	Group N (n=43)	Group NB (n=32)	Group B (n=34)
Conjunctival hyperemia	31 (72%)	26 (81%)	6 (18%)
Conjunctival hemorrhage	4 (9%)	6 (19%)	0
Eye pruritus	22 (51%)	16 (50%)	6 (18%)
Erythema of eyelid	4 (9%)	2 (6%)	0
Increased Lacrimation	12 (28%)	6 (19%)	2 (5%)
Foreign body sensation	6 (14%)	4 (12%)	2 (5%)
Pain on instillation	17 (39%)	4 (12%)	0
Periocular pigmentation	0	0	4 (11%)

Discussion

Rho-kinase inhibitors are a new class of antiglaucoma medications that act on ROCK and norepinephrine transporter. They have a novel triple mechanism of IOP reduction by inhibiting the norepinephrine transporter, decreased outflow resistance by reversing the structural and functional damage to the trabecular meshwork, and decreased the episcleral venous pressure through their vasodilatory effect.[5] As Rho-kinase inhibitors lower the IOP through different mechanisms of action, they may provide additional IOP-lowering effects when used in combination with other glaucoma medications.[5] Therefore, we set forth to explore the efficacy and safety profile of Rho-kinase inhibitors in comparison to prostaglandin analogs.

In this study, netarsudil 0.02%, bimatoprost 0.01%, and particularly, their combination achieved clinically relevant and statistically significant reductions in mean IOP from baseline at all follow-up visits. The maximum IOP reduction was observed with combination therapy (44%). The difference in mean IOP reduction among the three groups reached significant levels at 8 and 12 weeks. In addition, no serious systemic or ocular adverse events were recorded, and only six patients discontinued the treatment because of adverse events. Conjunctival hyperemia was the most common ocular adverse event among netarsudil and netarsudil/bimatoprost combination-treated patients. Conjunctival hyperemia is possibly the extension of the pharmacological effect of ROCK inhibition, which causes dilatation of blood vessels due to the relaxation of vascular smooth muscles. Prostaglandin analog-related side effects such as periocular or iris pigmentation and hypertrichosis were not observed with netarsudil.

Similar to us, Asrani et al. (2019)[5] in an RCT on 625 patients reported a statistically significant reduction in mean IOP across all nine study time points (P < 0.001) in netarsudil, latanoprost, and netarsudil/latanoprost fixed drug combination (FDC), with the maximum reduction noted for FDC. Conjunctival hyperemia was reported as mild in netarsudil and netarsudil/latanoprost-treated patients. They also reported cornea verticillata in netarsudil groups. Unlike our study, Gonzalez et al. (2021)[6] in a literature review that evaluated seven eligible studies found netarsudil to be inferior to latanoprost and non-inferior to timolol. They, however, have suggested further clinical trials comparing Netarsudil and other medications, and also its role as primary therapy.

In the ROCKET 1 study conducted by Serle et al. (2018),[2] mean IOP decreased to 17.2–19.8 and 17.4–18.5 mmHg in netarsudil and timolol groups, respectively, over 12 weeks. They also reported conjunctival hyperemia of mild grade, which was transient and self-resolving in the netarsudil group. Kahook et al. (2019),[7] in the ROCKET 2 study, also concluded that netarsudil 0.02% once daily as well as twice daily is non-inferior to timolol 0.5%, and netarsudil produced similar reductions in IOP across all three follow up visits at 2 weeks, 6 weeks, and 3 months. Like our study, Khouri et al. (2019)[8] in the ROCKET 4 study on 708 patients found a statistically significant reduction in mean IOP relative to baseline in both netarsudil and timolol groups (P < 0.001). In addition, netarsudil met the criteria for non-inferiority to timolol. They also noted that most adverse events with netarsudil were mild and manageable.

Zaman et al. (2021),[9] in their study of 260 patients with OAG and ocular hypertension who were prescribed netarsudil 0.02% as monotherapy or added with concomitant therapy, reported a statistically significant reduction in IOP in both subgroups at 6 and 12 weeks. In a randomized study by Araie et al. (2021)[10] on 207 patients, the IOP-lowering effect of three concentrations (0.01%, 0.02%, and 0.03%) of netarsudil ophthalmic solution was compared to placebo over 4 weeks in POAG and ocular hypertension patients. The study showed a superior mean reduction in diurnal IOP from baseline as compared to placebo (P < 0.001) in all concentrations of netarsudil. They also reported that adverse events occurred in a concentration-dependent manner in patients instilling netarsudil.

Villegas et al. (2021),[11] conducted a retrospective chart review of 45 patients who were on ≥3 ocular hypotensive medications and needed adjunctive ocular hypotensive therapy. They concluded that adding netarsudil 0.02% once daily to patients with inadequate IOP control on otherwise maximally tolerated medical therapy resulted in significant IOP reduction, thus deferring the need for glaucoma laser or incisional surgery. In a study by Fridman et al. (2021),[12] the efficacy and safety of netarsudil were evaluated by a retrospective chart review on 130 patients with severe glaucoma. They obtained an IOP reduction rate of 16.5%–17.5%, equivalent to 3.01–3.21 mmHg. Conjunctival hyperemia was the most frequent adverse event observed, reported by 54 patients (42%). Futakuchi et al. (2020)[13] conducted a retrospective cohort study on 332 eyes with secondary glaucoma at 18 centers in Japan, including 109 uveitic, 181 exfoliation, and 42 steroid-induced glaucoma cases. Their findings were strongly suggestive of satisfactory IOP-lowering effects of another Rho-kinase inhibitor, ripasudil, in patients with secondary glaucoma.

With the currently available data, the use of Rho-kinase inhibitors should be reserved as add-on therapy, particularly in patients on maximal medical therapy. Their use as the primary treatment modality should be discouraged, keeping in mind the adverse effects.

A reduced sample size is a major limitation of our study as a large sample could further validate its efficacy and safety. In addition, their utility in other types of glaucoma, that is, congenital and secondary, should be explored.

Conclusion

In our study, we found meaningful IOP reduction with netarsudil monotherapy and combination therapy as compared to prostaglandin analogs. Therefore, we conclude that the IOP-lowering effect of netarsudil 0.02% is non-inferior to bimatoprost 0.01% in patients with POAG and ocular hypertension. Netarsudil, a Rho-kinase inhibitor, is a new ocular hypotensive drug that effectively lowers IOP with convenient once-daily dosing and can be used both as monotherapy and combination therapy. In addition, it can be a useful adjunct in patients who are on maximal glaucoma therapy. Although conjunctival hyperemia was reported with a higher frequency and severity, it should not be a deterrent to its routine use in glaucoma management.

Financial support and sponsorship:

Nil.

Conflicts of interest:

There are no conflicts of interest.