Safety and efficacy of ripasudil in Japanese patients with glaucoma or ocular hypertension: 12-month interim analysis of ROCK-J, a post-marketing surveillance study

Glaucoma is the leading cause of irreversible blindness in the world [1]. According to estimates published in 2014, between 64 and 70 million people globally are affected by glaucoma [1, 2], but as this is a condition associated with aging, the prevalence of glaucoma is estimated to increase to 76 million in 2020 and to more than 111 million by 2040 [2]. In Japan, the estimated prevalence of glaucoma is 5.0% in people ≥40 years of age [3].

Currently, the main goals of glaucoma treatment are to slow disease progression and maintain quality of life, and the only proven treatment approach is to reduce intraocular pressure (IOP) [1, 4]. International guidelines, including the Japan Glaucoma Society Guidelines for Glaucoma (fourth edition) [4], the American Academy of Ophthalmology Preferred Practice Patterns guideline [5], and guidelines from the National Institute of Health and Care Excellence in the UK [6], recommend prostaglandins as the initial medical therapy for primary open-angle glaucoma (POAG) and ocular hypertension (OH). In the Japanese guidelines, β-blockers may also be used in first-line treatment, but should be selected with due attention to contraindications and risk of adverse drug reactions (ADRs); the recommended second-line treatments are carbonic anhydrase inhibitors, α2 agonists, Rho-associated protein kinase (ROCK) inhibitors, α1 blockers, ion-channel openers, nonselective nerve stimulants, or parasympathetic nerve stimulants [4].

ROCK inhibitors reduce IOP by a different mechanism from other IOP-lowering medications; these agents increase aqueous humor outflow by reducing resistance in the trabecular meshwork [7‐11]. The ROCK inhibitor ripasudil (Glanatec® ophthalmic solution 0.4%; Kowa Co. Ltd., Tokyo, Japan) was approved in Japan in September 2014 for the treatment of glaucoma and OH when other drugs are not effective or cannot be administered [11, 12]. In clinical trials, ripasudil has demonstrated IOP-lowering effects when used as monotherapy or in combination with prostaglandin analogs or β-blockers [13‐17]. Ripasudil had an acceptable safety profile in these studies, with the most common ADRs being conjunctival hyperemia, blepharitis and allergic conjunctivitis [13‐17]. However, there was a potential safety signal for an increased risk of allergy and/or inflammation-related ADRs with long-term treatment [15].

A long-term, large-scale post-marketing surveillance (PMS) study is being conducted in Japan to evaluate the safety and efficacy profile of ripasudil in the real-word clinical setting. Three-month interim results have been reported previously, and showed the safety and efficacy of ripasudil in reducing IOP in patients with various subtypes of glaucoma [18]. Because of the potential risk of allergy during long-term treatment with ripasudil, it is important to establish whether the short-term results seen in the 3-month analysis of the PMS study were maintained during long-term therapy. Here we report the 12-month interim results from the large-scale PMS study of ripasudil in Japan.

The current 12-month interim analysis provides long-term data on the safety and efficacy of ripasudil in a large group of patients (> 3000) receiving treatment in a real-world clinical practice setting. Our results confirm the earlier results from the 3-month interim analysis of this PMS study [18], showing that ripasudil is effective in lowering IOP across a range of patients, and that the lack of safety issues seen during short-term treatment is also true during treatment for 12 months. While no major safety issues were found in this study with ripasudil for 12 months, ongoing data collection is important, as is continued monitoring of potential safety issues in patients on ripasudil.

In this PMS study, approximately 30.1% of patients withdrew from the study – a reasonable proportion considering the real-world nature of this study. This percentage is lower than in a previous Japanese study, which reported that 39.1% of patients who start topical therapy with antiglaucoma medication discontinue such treatment within 12 months [19]. The most common reasons for discontinuation in our study were development of an AE (13.4%), the patient stopped visiting the hospital or transferred (7.3%), and insufficient efficacy (5.5%). It should be noted that discontinuation due to AEs is not only based on the judgment of the physician but also on the judgment of the patient; therefore, it may include discontinuation due to cataract surgery (which is not necessarily causally related to ripasudil). The reasons why patients stopped visiting the hospital or transferred are not known, as this information is not recorded during routine clinical practice. For patients with glaucoma, lack of knowledge and/or skepticism can negatively impact adherence, which is an important risk factor for progression of the disease [20].

The incidence of ADRs over 12 months of treatment was 18.6% and the incidence of allergy- and/or inflammation-related ADRs was 11.6%. The most common ADRs were blepharitis (including allergic blepharitis), which developed in 5.6% of patients, and conjunctivitis (including allergic forms), which developed in 4.2%. The incidence of ADRs in the current PMS study was low compared with data from our previous long-term uncontrolled clinical trials with ripasudil, which reported blepharitis in 17.8% of patients and allergic conjunctivitis in 15.3% [15].

In the phase III long-term study, there was no consistent trend in the time from the start of ripasudil administration to the onset of blepharitis and allergic conjunctivitis, and there was no relationship between the time to onset of these ADRs and their severity [15]. Similarly, in the current study, no consistent trend was found in the timing of onset of allergy- and/or inflammation-related ADRs during long-term administration.

There may be a number of reasons for the low incidence of ADRs seen in the current study compared with previous research. First, controlled clinical trials that proactively follow up patients on a regular protocol-defined schedule tend to identify more ADRs than studies with less active surveillance (such as our study in patients who were seen in routine clinical practice) [21]. Second, clinically minor AEs may be overlooked by patients. Research suggests that only about 50% of patients who develop an AE in routine clinical practice report the event to their physician, and only ~ 20% of AEs are documented by physicians in the medical records [22]. Third, patients were informed before the study that ripasudil can cause conjunctival hyperemia, so they may not have reported this event as an ADR. Furthermore, it is possible that the conjunctival hyperemia was transient and disappeared in the time between application and examination [23]. Therefore, while the incidence of ADRs may have been underestimated in this study, the reported incidence likely reflects those ADRs that are bothersome enough to patients that they prompt a report to their physicians. In this regard, fewer patients than we had anticipated reported bothersome ADRs or discontinued treatment because of AEs.

Corneal disorders were rare in the current study. The recent phase III ROCKET-1 and -2 studies with the ROCK inhibitor netarsudil reported corneal verticillata in 8.8% of patients receiving netarsudil alone and in 14.6% of patients receiving netarsudil in combination with timolol [24]. Moreover, in ROCKET-2, approximately 25% of patients who used netarsudil once or twice daily for 12 months developed corneal verticillata [25]. In animal models and in vitro studies, ripasudil induced transient morphological changes in corneal endothelial cells, but these changes favored corneal wound healing [26]. Consistent with this, none of the patients receiving ripasudil in the current study developed corneal verticillata, and there were no ADRs suggestive of corneal endothelial dysfunction (e.g. corneal opacification, corneal edema or bullous keratopathy) in patients who received ripasudil for 12 months.

This study also found that ripasudil significantly reduced IOP, with the change apparent at the 3-month assessment and maintained over 12 months of treatment. The significant reduction in IOP was seen in almost all subgroups when patients were stratified by treatment initiation pattern, glaucoma subtype, baseline IOP and number of concomitant active ingredients. Subgroups in which no significant change in IOP between baseline and 12 months was detected (i.e. those with neovascular glaucoma and those receiving ≥5 concomitant medications at baseline) contained fewer than 15 patients, and were therefore probably underpowered to detect a significant treatment difference. As noted in the 3-month study results, there was an absence of significant IOP reduction in patients with neovascular glaucoma, an effect thought to be a result of the pathogenesis of the disease [18]. This phenomenon may be explained by the fact that, in the pathogenesis of neovascular glaucoma, the trabecular meshwork is seriously damaged by the proliferation of neovascular tissue [27]. It is interesting to note that adding ripasudil to treatment with up to four other glaucoma active ingredients still resulted in a significant decrease in IOP between baseline and 12 months. The most common concomitant medications were prostaglandin analogs, β-blockers, carbonic anhydrase inhibitors and α2 stimulants. These data suggest that a ROCK inhibitor may provide a valuable add-on treatment option to any glaucoma medication combination because it has a distinct mechanism of action.

This study has a number of limitations. First, as an observational study, there is a potential for selection bias (and/or regression to the mean) and there was no control group comparator. Similarly, as an observational study, all treatment decisions, including when and how to initiate treatment, choice of combination therapies, discontinuation or switching, were at the treating physician’s discretion, which complicates analysis of efficacy and safety. Second, as the study is ongoing, it is possible that the findings may differ at the 24-month assessment as a result of further data retrieval and analysis.

The current study demonstrates the safety and efficacy of ripasudil over 12 months in patients with glaucoma or ocular hypertension receiving this agent during routine clinical care. No new safety signals or major safety concerns were identified, and significant reductions in IOP that were apparent at 3 months were maintained over 12 months of treatment. This 12-month interim analysis of a PMS study suggests that ripasudil is a promising agent for the treatment of glaucoma when used in various dosage forms or in combination with other glaucoma therapies.