Glaucoma Treatment Under Pressure

Current therapies for the management of open-angle glaucoma specifically aim at controlling IOP to avoid optic nerve damage. Topical treatments are still first-line but come with a plethora of side effects. Even newcomers like rho-kinase inhibitors may not keep the initial spark of enthusiasm.

On the other hand, the interventional approach has shown good outcomes through the years, with trabeculectomy still widely used and SLT and MIGS candidates for first-line IOP management in the early stages of the disease. However, minimally invasive procedures are still far from being perfect, with a narrow margin for IOP control, high costs, and some postoperative complications.

Glaucoma is still a manageable but not curable condition, said Luis Abegão Pinto MD, PhD. Despite the many different treatment options available, it all boils down to a single goal: lowering IOP to the value ophthalmologists think will stop meaningful progression.

“Even if we are far less conservative than 10 years ago, with far more options on our hands, we are basically still monitoring intraocular pressure,” he said.

There are a lot of good treatments that can prevent damage caused by glaucoma. As Anthony Khawaja MD, PhD pointed out, there are situations like lens extraction for primary angle-closure glaucoma where the problem can be fixed enough to consider the patient “truly treated.” However, time is of the essence.

“Because the damage is irreparable, we want to treat this condition before the damage to the optic nerve gets substantial,” he said. “We cannot regenerate the optic nerve.”

Things are moving slowly and steadily, with the threshold for surgical procedures becoming lower as the technology advances, Dr Pinto said. From medical glaucoma, the industry is moving more into the interventional approach, as new devices—and procedures such as SLT and DSLT—are becoming easier and faster, “but not more effective,” he warned. Some of these are still far from fully tested and might not prove capable of bringing some added value or even standing the test of time.

So how should glaucoma treatment be improved in the near term? Proactively perfecting prevention and early treatment can indeed be one of the most effective strategies, but it comes with a catch. Dr Khawaja noted it could be tricky to rely on people to realise there is something wrong with their intraocular pressure, go to the eye doctor for a check-up, and eventually get treated. Glaucoma is asymptomatic. Screening could be a valuable solution, he said, but unfortunately, glaucoma is not prevalent enough to justify screening on a wide scale.

AI and genomics

However, recent developments in genetics and artificial intelligence could be a game-changer. “Genetics and genomics can help us identify the subset of the population at high risk, and AI can help refine the test to be more affordable and accurate,” Dr Khawaja said. “With these, we are in a new position to really screen to prevent late presentation.” Working with the European Glaucoma Society, Dr Khawaja established a task force for screening in the UK.

Yet genetic testing also comes with a downside, Dr Pinto observed. It is not a viable option in continental Europe due to strict regulations preventing the downsides of early genetic testing. First, Dr Pinto outlined one problem not dissimilar to what the 1997 dystopian film Gattaca predicted—access to services and insurance. Imagine a patient will have a disease in 40 years, with no control over what happens: Would they be able to obtain a loan, a mortgage, or insurance if they have the genetics saying they surely will develop a health issue in the future? And what about countries with insurance-based healthcare? Would patients pay a premium just because they have a bad gene?

On the other hand, AI comes with fewer downsides in ophthalmology. Glaucoma specialists could really benefit from risk assessment algorithms, as AI could help the doctor decide, facilitate patient flow into the clinic, get broader access to information, and set a visiting routine for the patient. “It can redesign the circuits by using the same number of doctors and devices, but much more efficiently,” Dr Pinto said.

“As an esteemed senior and retired colleague once said, ‘In my whole career, I haven’t seen one full natural history of glaucoma,’” Dr Khawaja reported. Glaucoma works in the long term, so “how could I predict an outcome?” he asked. Data collection and AI could help accomplish that, giving the possibility to take advantage of automated processes and constant information on how a treatment could work for a specific patient, using real-world data that is far more realistic than the literature.

Dr Khawaja added the near future will not see some substantial change on the market but will be a great time for experimentation. He further remarked glaucoma needs surgery, and a good trabeculectomy can make the disease stable for a long time, but not without some risks. “Now we have less invasive surgeries—less risky but also less effective. We still have this drive for an effective and safe procedure, but we are not there yet.”

From his point of view, gene therapy and gene editing will not be a viable option within the next decade for glaucoma treatment, despite it being a disease caused in some cases by a mutation in the sole myocilin gene. “This is not going to be a thing in 2030, but it could be an exciting idea.”

That said, neuroprotection is paving the way for a promising future. Four clinical trials, still in the preclinical phase, are investigating nicotinamide and results are expected soon. Dr Khawaja noted it would be fascinating to have a well-tolerated tablet that could effectively help patients—despite not being a valuable replacement for IOP management.

Giving a supplement capable of helping the mitochondria of retinal neurons to scavenge out oxidants would not restore a patient’s vision at a youth level, Dr Pinto said, but at the end of the day, if the patient can see and maintain vision, it would be a win.

According to Dr Pinto, the future path for the management of glaucoma treatment should look at the reduction of daily eye drops for the patient. He pointed out a drug-free patient is free from the troubles of compliance and drop burden, but could feel anxious and unprotected, requiring close monitoring and home monitoring—something to address in the future because there is no available technology to make home monitoring practical and accessible.

The costs of innovation

What’s more, future innovations will have to deal with a conservative and cautious market. The current gold standards in both the medical and surgical fields are sufficiently effective and very low priced, making it difficult for brand new ideas to become immediately competitive.

“The barrier to innovation is that our current standard of care in terms of surgery (trabeculectomy) or medication (prostaglandin analogue) is already good enough to make sure whatever comes next needs to be better or cheaper,” Dr Pinto said. “The problem with all novelties is you do not have long-term data to evaluate them properly.”

“To borrow a definition from Professor Sir Peng Tee Khaw, we will have to reach the 10-10-10 target,” Dr Khawaja suggested. “A surgical procedure that lasts 10 minutes and gets the pressure down to 10 millimetres of mercury for 10 years. Having a cheap and effective procedure that developing countries can also easily afford, in a cataract-like fashion, can make all the other approaches feel unnecessary. I think that what will be the real future game changer—a highly effective, easy, and safe procedure. I think we will achieve that one day.”

Anthony Khawaja MD, PhD is Professor of Ophthalmology and Honorary Consultant Ophthalmic Surgeon at the UCL Institute of Ophthalmology and Moorfields Eye Hospital, London, UK. anthony.khawaja@ucl.ac.uk

Luis Abegão Pinto MD, PhD, FEBOS-G is Head of the Glaucoma Clinic of the Department of Ophthalmology at the Centro Hospitalar Lisboa Norte, Portugal. abegao.pinto@ulssm.min-saude.pt