In the Pipeline

A new drug class may advance treatment of patients with glaucoma

Entering late-stage clinical development, ROCK inhibitors represent a new class of IOP-lowering medication.

BY JASON BACHARACH, MD

The primary goal of treating patients who have glaucoma remains the reduction of intraocular pressure (IOP) to prevent or delay damage to the optic nerve. In recent years, innovations in lowering IOP have focused on sustained delivery technologies for available agents that attempt to lower the reliance on patient adherence to drop regimens, and the development of microinvasive glaucoma surgery (MIGS) to improve filtering procedures. Additionally, new combinations of existing drugs have been launched. However, there have been no new classes of IOP-lowering medications with novel mechanisms of action introduced since the prostaglandin analogs first appeared 20 years ago.

A new drug class

This may change as a new group of agents, which share Rho kinase (ROCK) inhibitor activity, enters late-stage clinical development. Like their predecessors, U.S. approval will be based on their demonstrated efficacy, safety, and tolerability, using a comparator and clinical trial design acceptable to the Food & Drug Administration (FDA). Dosing schedule (once-a-day is preferred by the majority of clinicians) and additivity to other agents, particularly prostaglandins, will be important factors in determining the clinical utility of these new classes of drugs.

Conventional glaucoma medications (beta blockers, alpha agonists, or carbonic anhydrase inhibitors) lower IOP primarily by reducing the production of aqueous humor, primarily reduce the production of aqueous humor, whereas prostaglandin analogs decrease IOP by increasing uveoscleral outflow, usually a secondary outflow pathway. There are also products that combine different classes in one bottle.

The ROCK inhibitors attracted the interest of drug developers because of their potential to restore outflow through the eye’s primary drain, the trabecular meshwork. Indeed, the reduced viability of the trabecular meshwork is the underlying cause of disease in most patients with open angle glaucoma.

A closer look

Seven different selective ROCK inhibitors have entered human clinical trials in the United States, Europe, and Japan.¹ Most will not reach the market as a result of modest efficacy, dosing requirements, or tolerability (conjunctival hyperemia is a class effect but varies in severity and duration between agents).

The topical medication ripasudil (K-115, Kowa) has been shown to reduce IOP significantly for at least seven hours with twice-daily dosing.² It was recently approved in Japan as an adjunct to prostaglandin analogs. Amakem Therapeutics recently completed a Phase 2 study of their ROCK inhibitor but these results have not been published.³

The product candidate that has advanced furthest through clinical trials in the United States is the compound AR-13324 (Rhopressa, Aerie Pharmaceuticals), which is in Phase 3 registration trials. Pre-clinical research suggests that this agent is actually a ROCK/NET inhibitor, a distinct class, which increases outflow through the trabecular meshwork through Rho kinase inhibition and decreases fluid production by inhibiting norepinephrine transporter (NET).⁴ In a recently completed study, Rhopressa was also found to reduce episcleral venous pressure (EVP), an important contributor to IOP, particularly at low pressures.⁵

Clinical results

Clinical results suggest that Rhopressa produces consistent IOP-lowering activity regardless of baseline pressure. In a Phase 2b study, administering the drop once-daily at night reduced IOP from 5.2 mmHg to 6.6 mmHg across all time points, about 1 mmHg less than latanoprost.⁶ In a prespecified subgroup of patients with starting pressures below 26 mmHg, the two agents were statistically equivalent. The most frequently reported adverse event associated with Rhopressa in the Phase 2b study was conjunctival hyperemia. This was generally mild and transient, with the frequency of hyperemia observed during the day declining over the length of the study.

Pre-clinical experiments with human tissue have shown that Rhopressa blocks the effect of fibrosis-promoting proteins in trabecular meshwork cells and appears to increase perfusion of the trabecular meshwork with aqueous humor, its only source of nutrients. The data suggest the ROCK inhibitor might increase the health and viability of the trabecular meshwork, a potentially disease-modifying effect in open angle glaucoma. The data have not been published, but were recently presented at the 2015 Association for Ocular Pharmacology and Therapeutics conference.

Rhopressa is now being studied in three Phase 3 FDA registration trials, including a 3-month efficacy study (ROCKET 1), a 1-year safety and efficacy study with a 3-month efficacy read-out (ROCKET 2), and a 1-year safety-only study (ROCKET 3). Top-line results of the first of these studies are expected in the second quarter of this year.

Aerie is also developing a fixed combination of Rhopressa and latanoprost (Roclatan) which, in a Phase 2b study, demonstrated superior IOP-lowering activity at all time points than either agent alone. Aerie is planning to move Roclatan in Phase 3 registration trials in the United States later this year.

The journey continues

The impact of ROCK or ROCK/NET inhibitors on the future of glaucoma therapy remains to be seen. But it is exciting to have novel treatments with new mechanisms of action in development that may eventually provide durable and consistent IOP-lowering with the potential to modify the course of a disease that remains a leading cause of blindness. OP

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