Pilocarpine Promising as Presbyopia Treatment

Laird Harrison

November 18, 2020

A new formulation of pilocarpine eyedrops, Allergan's AGN-190584, could take the place of reading glasses for many people with presbyopia, researchers say.

A significant proportion of patients gained three lines of uncorrected near visual acuity in two phase 3 trials, Gemini 1 and 2, said Michael Robinson of Allergan.

"Given once a day, it works through dynamic pupil modulation," he told Medscape Medical News. "It can contract the pupil size to have a greater range of near to intermediate vision."

Allergan announced the phase 3 results in a press release and reported phase 2b results at the virtual American Academy of Ophthalmology (AAO) 2020 Annual Meeting.

The drops are likely to appeal to people who have enjoyed good distance vision and are frustrated that they have to wear glasses for the first time in their lives, according to John Hovanesian, MD, a spokesperson for the American Academy of Ophthalmology, who is an ophthalmologist at Harvard Eye Associates in Orange County, California.

They could increase the demand for refractive procedures such as LASIK, because the combination would allow people with myopia to stop using glasses as well. "It's a huge market," he told Medscape Medical News.

At least a half dozen companies are working to develop similar eyedrops, he said. "Allergan, to my knowledge, is furthest ahead. There are other companies that are a short way behind."

Ophthalmologists have long known that miotics can improve near vision by contracting the iris sphincter, which reduces the pupil size and creates a pinhole camera effect. Some drugs, including pilocarpine, may also increase accommodation through mild contraction of the ciliary muscle.

But, combined with preservatives, these eyedrops often cause side effects, including headaches, brow aches, and loss of mesopic vision. Pilocarpine, most commonly used to treat glaucoma, has largely been superseded by other glaucoma medications, partly because of these side effects.

"All pilocarpines are in an acidic environment in order to preserve stability," Robinson said. "It stings a lot when you put it in and causes vision blur. We optimized it in a vehicle to reduce this issue." Headaches and brow aches may diminish as patients become accustomed to the contraction of their ciliary muscles caused by the medication, he said.

After trying various concentrations of pilocarpine in phase 2 trials, Allergan settled on 1.25% for AGN-190584.

For the two phase 3 trials described in the press release, the investigators recruited a total of 750 people with presbyopia and randomly assigned them to receive either AGN-190584 or the vehicle as a placebo.

The patients took the drops in both eyes once a day for 30 days. The researchers tested the participants at day 30, hour 3 to see how many had gained three ETDRS lines or more in mesopic, high-contrast, binocular distance-corrected near visual acuity, a standard of success set by the US Food and Drug Administration (FDA).

In both trials, more people in the AGN-19058 group than in the placebo group met this standard, and the difference was statistically significant, the researchers say. In GEMINI 2, those who took AGN-19058 met this standard without loss of greater than five letters in corrected distance visual acuity with the same refraction.

The researchers also indicated that a significant proportion of patients reported improvement in vision-related reading ability on questionnaires. The patients also indicated that presbyopia as well as the use of "coping behaviors" to manage presbyopia had less of an impact on daily life.

No serious adverse events were associated with the use of AGN-190584. More than 3% of those who took the drug suffered headache, conjunctival hyperemia, blurred vision, or eye pain.

Allergan declined to provide further details of these trials, pending presentations at meetings next year, but the phase 2b trials give some idea of the magnitude of the effects. In a trial of 157 patients divided into subgroups that received different concentrations of pilocarpine, the average change in near visual acuity from baseline over the course of 2 days with 1.0% pilocarpine was about five letters. With this concentration, 2% of the patients reported headache.

At day 28 in a second phase 2 trial of 151 patients, 30% of those who received 1.0% pilocarpine met the three-line improvement standard 8 hours after taking the eyedrops.

In one of the phase 2 trials, the number of patients who experienced adverse events such as headache and pain at instillation did not exceed 9%.

In the phase 2 trials, the researchers tested various concentrations of oxymetazoline in an effort to reduce the incidence of headache, but without success.

Allergan will file a new drug application with the FDA in the first half of 2021, Robbins said.

"I think it's really promising that Allergan has had the results they have, and it's really promising that they're not alone in this area," Hovanesian said. "If one fails, we'll have others."

Novartis, Presbyopia Therapies, Orasis, Visus, and Eyenovia are working to develop new drugs for this indication, some using pilocarpine and some using other molecules. Some, like the Allergan product, may be administered in both eyes, whereas others are administered in only one to preserve vision in dim light. OSRX Pharmaceuticals, a compounding pharmacy, is working on a combination of existing drugs that might be sold without an application to the FDA.

It's possible that one product will work well for one group of patients and another for another group, said Hovanesian.

"I have done extensive studies with pilocarpine," said Herbert E. Kaufman, MD, from Louisiana State University School of Medicine, New Orleans, Louisiana. "In my patients, it was not effective enough in improving near vision and did not last long enough," he told Medscape Medical News in an email. Kaufman's competing presbyopia treatment, a combination of carbachol and brimonidine tartrate, is being developed by Visus.

American Academy of Ophthalmology (AAO) 2020 Annual Meeting: Session PA039.01. Presented November 13, 2020.

Laird Harrison writes about science, health and culture. His work has appeared in magazines, newspapers , and online publications. He is at work on a novel about alternate realities in physics. Harrison has taught writing at San Francisco State University, UC Berkeley Extension and the Writers Grotto. Visit him at lairdharrison.comor follow him on Twitter: @LairdH .

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