Slow progress sees unmet

Medical management of glaucoma: the future

There remains an unmet need for effective alternatives with longer duration of action that address issues of adherence. Dermot McGrath reports

Although topical prostaglandins remain the first-line medical treatment of choice for glaucoma with proven safety and efficacy over many years, there remains a compelling unmet need for effective alternatives that have a longer duration of action and address issues of adherence, according to Paul Rafuse MD, PhD.

“In the near future we are going to have to start with new routes of administration of known compounds which do not rely on patient adherence and which have longer durations of action,” he said at the World Ophthalmology Congress 2020 Virtual.

In a wide-ranging talk on the future of the medical management of glaucoma, Dr Rafuse, Associate Professor at the Department of Ophthalmology & Visual Sciences at Dalhousie University, Halifax, Canada, said that although there have been improvements in formulations and fixed combination therapies over recent years, no novel class of drugs for the treatment of glaucoma has been approved since latanoprost in 1996. The progress has been evolutionary rather than revolutionary, he said.

“We have seen the introduction of some other prostaglandin analogues such as bimatoprost and travoprost, as well as combinations of existing hypotensive lipids with beta blockers such as timolol. We have also seen an increase in benzalkonium chloride (BAC) avoidance strategies because of the known negative impact of preservatives on the ocular surface,” he said.

In the past two years, two promising drugs that represent entirely new classes of glaucoma medication have also come on the market, said Dr Rafuse: Vyzulta (latanoprostene bunod ophthalmic solution 0.024%, Bausch & Lomb) and Rhopressa (netarsudil ophthalmic solution 0.02%, Aerie Pharmaceuticals).

Both of these drugs have mechanisms of action different from previous glaucoma medications.

“Vyzulta is a monotherapy consisting of two active moieties: latanoprost acid, a prostaglandin analogue, works primarily

One of the concerns with this drug, however, is that corneal deposits may form in some patients Paul Rafuse MD, PhD

within the uveoscleral pathway and butanediol mononitrate releases nitric oxide, which is thought to relax the trabecular meshwork. Some initial studies suggest that it is more efficacious than timolol and perhaps even more effective than latanoprost,” he said.

The rho kinase (ROCK) inhibitor Rhopressa lowers IOP by enhancing trabecular meshwork outflow and seems to work well combined with latanoprost, said Dr Rafuse.

“One of the concerns with this drug, however, is that corneal deposits may form in some patients. If the deposits are centrally located they can blur vision. Some patients have developed red eye problems and even conjunctival haemorrhage in certain cases, so we need more safety data on this going forward,” he said.

There are many known issues with topical drugs for glaucoma that limit their potential usefulness, noted Dr Rafuse. This includes problems of adherence, local and systemic side-effects, cost and the question of whether they really do slow visual field progression.

“Getting the drop in the eye for an elderly patient with arthritis can be a major obstacle and we have seen many devices and approaches to this over the years to try to address the problem. Local side-effects include redness, foreign body sensation, itch, burning, tearing and blurred vision. Eye drops also make a subsequent trabeculectomy more difficult,” he said.

Systemic side-effects of beta-blockers are also problematic and renders them contraindicated in patients with pulmonary disease and some cardiac conditions, he added.

The prohibitive cost of some glaucoma medications is another formidable barrier to their widespread adoption, noted Dr Rafuse. He cited a study by Zhao et al. in 2018 that looked at median annual household income (MA-HHI) and how much of it was used up by medications compared to laser trabeculoplasty, and trabeculectomy surgery.

“It was a cross-sectional observational study with the prices of drugs, laser and surgery obtained for 38 countries, 17 developed and 21 developing. There was a threshold where if a drug cost less than 2.5% of MA-HHI it was deemed affordable,” he said.

The authors found that timolol was the most affordable medication in all countries studied and was 2.5% or more of MA-HHI in only two countries (5%). The annual cost of latanoprost, however, was 2.5% or more of MA-HHI in 15 countries (41%) (15 developing countries [75%] and no developed countries). In 18 countries (53%), laser trabeculoplasty cost less than a three-year latanoprost supply.

There is strong evidence from the scientific literature that less than half of patients actually take their glaucoma medication.

“The most vexing aspect is that we don’t know which half is non-compliant,” said Dr Rafuse.

Despite the obstacles, topical medications are effective when used properly, he said, citing Garway-Heath’s study in 2015 that showed that topical latanoprost is effective at slowing the rate of visual field progression in open-angle glaucoma.

“This is why we need sustained release strategies in the future, which may come in the form of contact lenses, scleral plugs, punctal plugs, cul-de-sac rings or slowrelease reservoirs that can be implanted. We need to circumvent the ocular surface so that the drug gets to the site of action inside the eye,” he concluded. Paul Rafuse: prafuse@dal.ca

Consider zonules before surgery

Surgeons should assess zonules and warn patients of associated risks. Dermot McGrath reports

Surgeons can expect to find higher rates of zonulopathy in patients with various forms of angle closure pathologies and should plan lens extraction surgery with this possibility in mind, according to Paul Harasymowcyz MD.

“We looked at this in a recent study and found that the rates of zonulopathy in primary angle-closure suspect (PACS), primary angle closure (PAC) and primary angle-closure glaucoma (PACG) patients undergoing lens extraction was significantly higher than reported in the general population. Secondary pigment dispersion is also associated with a higher rate of zonulopathy. Ophthalmologists should be aware of the risks and be prepared to manage the zonulopathy intraoperatively,” he said at the World Ophthalmology Congress 2020 Virtual.

“Our hypothesis was that because angle closure glaucoma is in part caused by weak or loose or absent zonules that the rate of vitreous loss or zonulopathy would be much higher in the PACS, PAC or PACG population. A secondary hypothesis was that the rate of secondary pigment dispersion and rubbing of the lens and iris pigment epithelium would also be more frequent in this population,” said Dr Harasymowcyz, University of Montreal, Canada.

Dr Harasymowcyz’s retrospective cohort study included 1,013 consecutive eyes that underwent lens extraction by a single surgeon (PACS 266, PAC 366, PACG 381). The primary outcome was the rate of intraoperative zonulopathy as indicated by floppy capsule, phacodenesis, capsular tension ring use, anterior vitrectomy, or lens particles in the anterior vitreous. Secondary outcome was the presence of secondary pigment dispersion. Patients with a history of trauma, exfoliation syndrome or hereditary diseases were excluded.

“We found a 3.5% incidence of zonulopathy versus 0.5% in the general population. Three-quarters of patients (75%) required CTRs and the rate of secondary pigment dispersion was 15.3%. We feel that it is probably underestimated as a cause of angle closure glaucoma. Ophthalmologists should be aware of the intraoperative risks of cataract surgery in patients with angle closure, discuss this with their patients prior to surgery and prepare accordingly,” he said.

In the future, ophthalmologists will be able to draw on advances in imaging technologies such as ultrasound biomicroscopy (UBM) in order to better assess the condition of the zonules prior to surgery in patients with angle closure.

“There is definitely an unmet need for direct imaging of the zonules We found as many of the signs we currently use to detect a 3.5% zonulopathy are indirect incidence of ones. With UBM, we can show the presence zonulopathy or absence of zonules, but we need improved modalities in the future to versus 0.5% in the general determine the length and strength of the zonules,” population he concluded. Paul Harasymowcyz MD

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