GLAUCOMA PIPELINE

While ophthalmologists eagerly await the appearance of ROCK (Rho-associated protein kinase)-inhibitors, a potential new class of anti-glaucoma medication, there are still some bumps along the way. One is that a frequent side effect of candidate compounds is hyperaemia.

But early indicators show a substantial range of benefits from ROCK-inhibition make them worthy of pursuit, and one candidate has even made it to a phase-3 clinical trial, according to Megumi Honjo MD, PhD, from the Department of Ophthalmology, Tokyo Metropolitan Geriatric Hospital. At the 5th World Glaucoma Congress she presented an update of research pertaining to ROCK-inhibitors.

ROCK-inhibitors target the trabecular meshwork causing it to undergo some degree of remodelling of tissue architecture to improve aqueous flow. The compounds play a role in regulating the shape and movement of cells by acting on the cytoskeleton.

"The behaviour of cells and extracellular matrix is responsible for the resistance of the outflow. Various drugs (in the ROCK-inhibitor category) acting on the cytoskeleton have also been shown to increase aqueous outflow by acting directly on outflow tissue," she said.

Her group reported IOP-lowering effects of the ROCK inhibitor Y-27632 in 2001, though there are several additional compounds under development by various research groups globally.

At this point approval of the clinical use of ROCK inhibitors is still uncertain, she said. But this category of drug is an exciting direction for new glaucoma treatments. In an earlier animal study, her group applied a topical ROCK-inhibitor in living rabbits and showed a significantly lowered rabbit IOP with a two-fold increase in aqueous outflow.

IOP lowering

In humans, some studies demonstrated a lowering of IOP by 3.0 to 4.0 mmHg within a couple of hours of topical administration. ROCK-inhibitors increase retinal blood flow around the optic disc, can protect neurons against various stresses and promote regeneration of crushed retinal ganglion cell axons. They may even reduce post-surgical scarring, she said.

Overall, several candidate drugs didn’t make it past phase 1 and 2 human clinical trials due to safety and tolerability issues, Dr Honjo said. In one study, of Y-39983, IOP levels decreased following administration in a dose- dependent manner in human volunteers, and normal levels were restored by 24 hours, but conjunctive hyperaemia was observed.

In fact, one study showed conjunctival hyperaemia occurred in 60 per cent of patients – showing this is a recurring problem with these agents. Several agents have been taken out of the race because of side effects.