December 2019

IN FOCUS

Examining presbyopia treatments
Getting the drop on presbyopia


by Chiles Samaniego EyeWorld Contributing Writer

Presbyopes, in general, represent “an enormous market, and a very motivated one,” John Hovanesian, MD, said. “You see these people now who have presbyopia, people in their late 40s, 50s, into their 60s. These are people who are at the maximum earning potential of their lives and so they can afford surgery. They’re really bothered by needing reading glasses, on the whole.”
Nonsurgical options for presbyopes have, to date, been limited to bifocal spectacles and contact lenses, but eye drops are just on the horizon.
“There are several companies developing eye drops for the treatment of presbyopia,” Michael Korenfeld, MD, wrote in correspondence with EyeWorld.
EyeWorld spoke with Dr. Hovanesian and corresponded with Michael Korenfeld, MD, Jorge Alió, MD, PhD, (writing with Veronica Vargas, MD), and Felipe Vejarano, MD, to get the drop on pharmacological approaches to treating presbyopia before they hit the market.

Small aperture pupils

Most drops in development “are based upon the principle of delivering a miotic drug in sufficient amount to trigger pupillary miosis but less or no ciliary muscle contraction,” Dr. Korenfeld said. “By making the pupil smaller, the depth of focus is improved and so is the ability to resolve things that are in the intermediate and near range.” Essentially, pupils are turned into small aperture optics.
This is the case with the drops being developed by Allergan (AGN-199201 and AGN-190584), Orasis Pharmaceuticals (CSF-1), and Presbyopia Therapies (PRX-100), Dr. Hovanesian said. Allergan’s presbyopia eye drops, he added, may end up being the first to enter the U.S. market, which may see the first drops sometime in the next 2 years.
Dr. Vejarano noted that most of these agents induce what he called a spasmodic—as opposed to dynamic—accommodation, resulting in a myopic shift to improve near vision. The presbyopia-treating eye drop in these cases is used in the nondominant eye to create pharmacological monovision.
According to Dr. Vejarano, these drops subscribe to the standard theory of presbyopia—that the crystalline lens gets stiffer with age, preventing accommodation—and so induce a ciliary muscle spasm to bypass the factor of the crystalline lens’s inflexibility. In contrast, Dr. Vejarano believes that the major cause of decreasing near vision in advancing age is a decrease in the force from the ciliary muscle—hence the sudden onset of the inability to focus, which he does not believe can be explained by the loss of crystalline lens elasticity.

Dynamic accommodation

Based on this theory, Dr. Vejarano developed FOV Tears as “a mix of many components,” including a parasympathetic substance to generate accommodation and alpha agonists to counteract ciliary muscle spasm in a precise concentration to keep the pupil dynamic, that is more responsive to changes in light , avoiding a fixed miosis and resulting in variable accommodation—thus, more physiological.
Dr. Alió and Dr. Vargas, explaining how FOV Tears work, wrote that while “pilocarpine stimulates accommodation and pupillary miosis, phenylephrine, nepafenac, and pheniramine stop excess pupil constriction and counteract ciliary muscle spasm, vascular congestion, and hyperemia induced by pilocarpine. Naphazoline intensifies the relaxing effect of pilocarpine on dilator pupillae. The synergistic effect improves near vision, preserves distance vision, and reduces side effects such as hyperemia and headaches.”
Dr. Alió, Dr. Vargas, and Dr. Vejarano conducted a pilot study using FOV Tears, published earlier this year in Ophthalmology and Therapy.1 Using FOV Tears in 117 presbyopic patients, they looked at binocular uncorrected near visual acuity, ocular scatter index (OSI), and pupil size under photopic and mesopic conditions evaluated 2 hours after binocular instillation.
They found that FOV Tears “improved near vision by one or more lines (mean improvement 0.18 lines) in 92.3% of the patients at 2 [hours] following the instillation of the eye drops.” They also found no statistically significant change in OSI, while there was significant change in pupil size between photopic and scotopic conditions.
In terms of safety, Dr. Alió and Dr. Vargas also evaluated endothelial cell count and the ocular surface 1 month after instillation of FOV Tears and found no changes nor evidence of tachyphylaxis. “The only side effect was headache, which was reported in 10% of the patients,” they wrote.
Dr. Vejarano himself wrote that he has been taking the drops daily for 10 years. “Until now, I don’t have any secondary effect that cause any risk for the normal health of the eye or put in jeopardy the visual capacity,” he wrote. “I see 20/20 for far and near, and I am 52.”

Revitalizing the crystalline lens

In contrast, working with the standard theory of presbyopia as described by Dr. Vejarano, Novartis has been developing UNR844. Derived from EV06, a lipoic acid choline ester, Dr. Hovanesian said the drop is intended to increase the flexibility of the aging crystalline lens.
A principal investigator for Novartis, Dr. Korenfeld wrote that UNR844 “is designed to reduce the disulfide bonds that form between proteins within the crystalline lens. Crosslinking of these proteins constrains their movement, one relative to the other, and this results in reduced deformability of the lens when it is acted upon by the forces produced by ciliary muscle tone variations, and conveyed to the lens via the zonules. This pharmacologic approach does not go away in less than a day, and in studies done so far, the effect after 90 days of dosing can last up to 7 months later without additional dosing.”
Given that the mechanism of action of UNR844 is on the crystalline lens itself, essentially reversing the aging process of which cataract formation is a part, could these drops delay or even prevent cataract formation? UNR844, Dr. Korenfeld said, “has that potential, but it has not been studied yet.”

In practice

These drops will most likely play a role in the younger, phakic, pre-cataract group of presbyopes. This group includes emmetropes who’ve had great vision their whole life or those with previous LASIK, and who, in either case, became frustrated needing reading glasses. “It’s interesting that we don’t really have a good surgical option for the emmetropic presbyope,” Dr. Hovanesian said. The drops may fill that niche—at least until the patient develops a cataract and needs surgery anyway.
Certainly, Dr. Vejarano sees these drops as occupying a space in practice entirely their own.
Ultimately, Dr. Hovanesian sees these drops as working synergistically with other treatment modalities. He expects that people who develop the need for reading glasses “will gravitate toward these drops as they become available, as a way to sort of test the waters.”
“I think a fairly large number of people are going to enjoy the benefits of the drops, but probably not like either the side effects of the drops or just their need to continue taking them, and then they’ll probably gravitate towards surgery,” he said.
Furthermore, the drops can also be used in preparation for other interventions, such as monovision. Rather than using a contact lens to test a patient’s receptivity to monovision, instead they could try pharmacological monovision.
In that sense, Dr. Hovanesian said, the drops will “propel surgery forward.”
“In my practice, we want to be identified as a presbyopia-treating practice—we already are for lens implants, but we want people who are younger than cataract age to come to us,” Dr. Hovanesian said. “Think about it from the strategic standpoint. You want patients in their pre-cataract years to come to you for visual solutions so that they stay with you when they need cataract surgery.”
Dr. Alió and Dr. Vargas continue to see a role for the drops even in patients who have already had cataract surgery. “They are a good option for young presbyopes, patients with previous PresbyLASIK or monovision who are not satisfied with their near vision, or they can also be used in patients who had already been implanted with a monofocal IOL and wish to improve their near vision,” they wrote. “The drops have the advantage of being noninvasive, reversible, and with few side effects, distance vision remains stable after their use, which is an advantage over PresbyLASIK and LASIK monovision, and there is no need for neuroadaptation unlike multifocal IOL implantation.”
In any case, Dr. Hovanesian said, “we should be open to these. Let’s be open to these kind of treatments and see how they work.”

At a glance

• Drops for presbyopia correction typically work by inducing miosis to extend the range of focus and can be used as pharmacological monovision.
• Some drops in development work based on opposing theories of presbyopia in an attempt to restore or retain the eye’s ability to accommodate.
• Some doctors think drops will have their own niche role in a presbyopia-treating practice, potentially even driving surgery forward by allowing patients to “test the waters” of presbyopia treatment.

About the doctors

Jorge Alió, MD, PhD
University Miguel Hernandez, Vissum Instituto Oftalmologico
Alicante, Spain

John Hovanesian, MD
Harvard Eye Associates
Laguna Hills, California

Michael Korenfeld, MD
Comprehensive Eye Care Ltd.
Washington, Missouri

Veronica Vargas, MD
University Miguel Hernandez, Vissum Instituto Oftalmologico
Alicante, Spain

Felipe Vejarano, MD
Fundación Oftalmológica Vejarano
Popayán, Colombia

Reference

1. Vargas V, et al. Near vision improvement with the use of a new topical compound for presbyopia correction: A prospective, consecutive interventional non-comparative clinical study. Ophthalmol Ther. 2019 March;8(1):31–39.

Relevant financial interests

Alió
: None
Hovanesian: Refocus Group, Novartis, Allergan
Korenfeld: Encore Vision, Novartis, Allergan, Orasis
Vargas: None
Vejarano: None

Contact information

Alió: jlalio@vissum.com
Hovanesian: jhovanesian@harvardeye.com
Korenfeld: michaelskorenfeld@gmail.com
Vargas: draverovargasfragoso@gmail.com
Vejarano: felipev@fov.com.com

Getting the drop on presbyopia Getting the drop on presbyopia
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