Rho-kinase inhibitors highly effective in lowering intraocular pressure

Rho-kinase (ROCK) inhibitors are highly effective in lowering intraocular pressure (IOP), and are acceptably tolerated locally and well-tolerated systemically, Jason Bacharach MD told Glaucoma Day at the 2016 ASCRS•ASOA Symposium & Congress in New Orleans, USA.

Following successful clinical trials, ROCK inhibitors are likely to become the first new IOP-lowering drug class approved by the US Food and Drug Administration (FDA) in two decades, with a market approval filing expected later this year.

Because ROCK inhibitors involve mechanisms of action that complement existing therapies, and are especially effective in patients with lower baseline IOP, they are also likely to be the first drug class offered in combination with prostaglandins in the USA, said Dr Bacharach, of the California Pacific Medical Centre, San Francisco, USA.

ROCK inhibitors are thought to lower IOP in three ways, Dr Bacharach said. Firstly, ROCK inhibition relaxes trabecular meshwork cells, and reduces actin stress fibres and local adhesions, increasing aqueous outflow (Wang, Clin Ophthalmol 2104), Dr Bacharach observed.

Secondly, at least some ROCK inhibitors, such as netarsudil (Aerie Pharmaceuticals), also inhibit norepinephrine transport, reducing aqueous production (deLong, Invest Ophthalmol Vis Sci 2012). This effect has been validated in a monkey model (Wang, J Glaucoma 2015), said Dr Bacharach, who is an investigator for Aerie. Thirdly, netarsudil may reduce episcleral venous pressure (EVP), reducing the IOP needed to achieve aqueous outflow, Dr Bacharach said. In rabbit eyes, the compound reduced IOP 39 per cent and EVP 35 per cent three hours after administration.

While netarsudil is statistically equal to timolol and latanoprost in reducing mean IOP among patients with baselines less than 25mmHg, registration trial data show that netarsudil is more effective at lower baseline pressure. For every 1.0mmHg baseline reduction, netarsudil loses just 0.1mmHg efficacy compared with about 0.5mmHg for timolol and latanoprost. “That’s probably because they don’t affect EVP,” Dr Bacharach noted.

In clinical trials, a fixed combination of netarsudil with latanoprost lowered IOP more than either alone (Lewis, BJO 2015), and patients previously treated with prostaglandins responded more to netarsudil alone than prostaglandin-naïve patients. Mean IOP in netarsudil patients also rose less at 12 months than with timolol. Safety was good for netarsudil, with no serious adverse events in 12 months. The most common side effect, conjunctival hyperaemia, was mild and sporadic in most cases, Dr Bacharach reported.

Jason Bacharach: jbacharach@northbayeye.com

Disclaimer: The views and opinions expressed in the article are those of Dr Bacharach and do not represent or reflect the official policy or position of Aerie Pharmaceuticals. No authorised representative of Aerie Pharmaceuticals was consulted during the preparation of the above article