NEW GLAUCOMA DRUGS

A new class of drugs that targets trabecular outflow appears to provide IOP-lowering effects in clinical trials, reported Hidenobu Tanihara MD, PhD at the World Ophthalmology Congress in Tokyo.

The new class of drugs, known as Rho kinase (ROCK) inhibitors, represents a different pharmacological approach to the treatment of glaucoma. Several drugs in this class are now in clinical trials. Dr Tanihara, professor and chairman, Dept of Ophthalmology, Facult of Life Sciences, Kumamoto University, Kyushu, Japan, reviewed the latest findings. He presented his own recent work with one agent, K-115 (Ripasudil), which has completed Phase III studies. He reported that the drug produced significant, dose-dependent reductions in IOP in eyes with glaucoma and ocular hypertension. The effects were additive when combined with current prostaglandin agent or β–blocker.

A randomised, placebo controlled Phase I study confirmed the safety of a selective ROCK inhibitor, K-115, in healthy male adult volunteers. The investigators noted IOP reductions after each instillation in dose concentrations ranging from 0.05 per cent, 0.1 per cent, 0.2 per cent, 0.4 per cent and 0.8 per cent.

In a subsequent Phase II study, 210 patients with primary open-angle glaucoma or ocular hypertension were divided into four groups and given one of three doses (0.1 per cent, 0.2 per cent or 0.4 per cent) of K-115 or placebo twice daily for eight weeks. The study showed statistically significant, lasting dose-dependent reductions in mean IOP. IOP dropped 4.5 mmHg two hours after instillation, with the effect lasting at least 12 hours. Based on that study, Phase III clinical studies were conducted using a K-115 dose of 0.4 per cent and revealed the additive IOP-lowering effects of 0.4 per cent K-115 to 0.005 per cent latanoprost or 0.5 per cent timolol in patients with primary open-angle glaucoma or ocular hypertension.

The new drug produced tolerable side effects mostly limited to transient hyperaemia. However, this event has been seen in up to 70 per cent of patients. The drug is under review by the administrative authority (PMDA) in Japan, noted Dr Tanihara.

“This is one of the new classes of drugs to target the trabecular meshwork directly. ROCK inhibitors appear to enhance aqueous drainage by acting on the actin cytoskeleton and cellular motility in the trabecular meshwork, Schlemm’s canal and in ciliary muscle. These drugs may lower IOP by decreasing resistance to aqueous outflow by cellular relaxation in the trabecular meshwork,” he explained.

The mechanism of action of ROCK inhibitors suggests there may be benefits beyond IOP lowering. Studies indicate that drugs in this class increase retinal blood flow by relaxing vascular smooth muscle cells. This could provide a neuroprotective effect. A better understanding of how these drugs work will also provide new insights into the pathology of glaucoma. In addition to K-115 (Kowa), several other drugs in this class are at or near the clinical trial stage. These include AM0076 (Amakem) now in Phase II and Roclatan (Aerie Pharmaceuticals) also in Phase II, which combines a ROCK inhibitor with latanoprost.

Hidenobu Tanihara: tanihara@pearl.ocn.ne.jp