Advances in glaucoma

New types of IOP-lowering agents and delivery modes bring hope of more effective medical treatment of glaucoma

Roibeard O’hEineachain

Posted: Sunday, September 1, 2019

Cédric Schweitzer MD
New glaucoma medications with new targets and new mechanisms of actions, and new modes of delivery may extend the range of medical IOP control, reports Cédric Schweitzer MD, Bordeaux University Hospital, France.
“There is a need for additional medical treatment alternatives because current drugs can lead to various systemic or local adverse events in some patients. There are also those patients who do not respond to current medications or do not comply to the treatment recommended by the ophthalmologist,” Dr Schweitzer told the 23rd ESCRS Winter meeting in Athens, Greece.
Some recent developments to that end include the Rho kinase (ROCK) inhibitors, which target the trabecular meshwork. ROCK inhibitors achieve their IOP-lowering effect through a down-regulation of cytoskeleton function that causes disruption of the actin bundles and retraction of cell bodies in the trabecular meshwork, decreasing resistance to outflow.
Peer-reviewed studies indicate that the new ROCK inhibitor ripasudil (Rhopressa, Aerie Pharmaceuticals) reduces IOP by 2.2-to-3.7mmHg. Regarding adverse events, in a monotherapy trial involving 173 patients, conjunctival hyperaemia occurred in 75.7% of patients, but was mild in all but 1.7%, in whom it was moderate. In addition, blepharitis occurred in 25.4% of patients, in 20.2% it was mild and in 5.2% it was moderate.
Another new type of agent in clinical trials are the adenosine receptor agonists. One of the new agents, trabodenoson (Inotek), is a highly selective agonist to the A1 receptors of the trabecular meshwork. It increases the production of matrix metalloproteinase 2 (MMP-2), which results in the increased removal of collagen 4, which, in turn, increases the outflow of aqueous through the trabecular meshwork.
In a phase II randomised controlled trial, trabodenoson lowered IOP by a mean of 4.1mmHg in eyes with ocular hypertension or primary open-angle glaucoma. The main adverse event was conjunctival hyperaemia, which was mild in most cases and occurred in only 17.6%.
Another approach is gene inhibition with small interfering RNA (siRNA). Bamosiran (Sylentis) is a siRNA targeting the beta2-adenoreceptor and is designed to decrease IOP by decreasing the ciliary body’s aqueous humour production. In a phase I clinical trial, it appeared to lower IOP by 20%. The main adverse event was conjunctival hyperaemia, Dr Schweitzer said.
Another new medication is the prostanoid receptor agonist, which has a similar mode of action to prostaglandin analogues. A compound combining an agonist to the F2 alpha prostanoid receptor with nitric oxide latanoprostene bunod (Vyzulta, Bausch + Lomb) is designed to improve both the uveoscleral and trabecular outflow. Phase III randomised controlled trials have shown that it lowers IOP by around 7.0-to-9.0mmHg. Adverse events have included mild-to-moderate hyperaemia.
Several companies are developing sustained-release devices that deliver drug concentrations to ocular target tissues for periods of weeks or months without having to rely on patients’ adherence to their regimen.
Among these new products is the ocular surface sustained-release ring, which is placed beneath the eyelids. In a phase II randomised controlled trial, eyes receiving a ring containing bimatoprost had IOP reductions of 3.2-to-6.4mmHg, compared to reductions of 4.2-to-6.4mmHg with topical timolol. However, conjunctival hyperaemia and punctate keratitis were more frequent with the ring.
There are also new biodegradable implants designed for insertion into the anterior chamber. In a phase II randomised trial the bimatoprost SR implant reduced mean IOP by 8.1-to-9.5 mmHg, which was roughly equivalent to the reduction achieved in eyes receiving topical bimatoprost.
Another strategy entering clinical trials is the use of a subconjunctival injection of medication encapsulated within liposomes. In a phase II trial where patients received a preparation of liposome-encapsulated latanoprost and dorzolamide IOP was reduced by 30% over a period of three months.
Also in clinical trials are new punctum plug sustained-release devices designed to be embedded in the canaliculus. In a feasibility study, a punctum plug containing travoprost produced IOP reductions of 20-to-24% over the 30-day follow-up. The main adverse event was excessive tearing, which occurred in less than 5% of patients.

Cédric Schweitzer: