June 2019

REFRACTIVE

Presentation Spotlight
Has presbyopia found an “encore”?


by Stefanie Petrou Binder, MD EyeWorld Contributing Writer


EV06 (lipoic acid choline ester) is a prodrug. EV06 penetrates the cornea and is metabolized into choline and lipoic acid, two naturally occurring substances. Enzymes within lens fiber cells chemically reduce lipoic acid to active form dihydrolipoic acid (DHLA). DHLA reduces disulfide bonds between lens proteins and restores lens microfluidics.
Source: Michael Korenfeld, MD

A new topical agent is coming closer than ever to improving the accommodative range for presbyopes. The agent, lipoic acid choline ester (UNR844, Novartis, formerly EV06), is a reducing agent that is purported to reduce the disulfide bonds that form between lens proteins, thus increasing the deformability of the crystalline lens and increasing the accommodative amplitude. According to Michael Korenfeld, MD, who was an investigator in the first human clinical trial using UNR844 in presbyopes, the drug is safe, robust, and persistent, even after the regimen is stopped.
“This chemical was designed to improve the internal rheology of the cytosol within the lens fibers inside the lens capsule,” Dr. Korenfeld said in a presentation at the 36th Congress of the European Society of Cataract and Refractive Surgeons. “It is safe, well-tolerated, and showed statistically significant near visual acuity improvement in clinical trials compared to placebo. The widespread use of this drug stands to radically alter the visual performance of humans within our lifetimes.”

Targeting lens proteins

Presbyopia is not just a matter of lens compliance. It is caused by a few different events, each of which constitutes a potential treatment target: the crystalline lens enlarges over time (ectoderm), the ciliary body undergoes atrophic changes, the vitreous becomes less viscous, and the lens loses its flexibility.
The hypothesis that drove the development of UNR844 addressed lens flexibility or the lack thereof in presbyopia. When lens proteins become oxidized over time, disulfide bonds form, rendering them less able to move relative to one another during the act of accommodation.
“The theory was that if we had a way to chemically reduce these disulfide bonds, the proteins would regain increased degrees of freedom and allow a greater range of deformation of the lens, translating into a greater dynamic range of accommodation. Lipoic acid is a naturally occurring antioxidant and reducing agent,” Dr. Korenfeld said.
To allow the reducing agent to achieve sufficient concentration within the eye, researchers developed a prodrug to improve the compound’s penetration, allowing it to metabolize and convert to its active form (dihydrolipoic acid [DHLA]) once within the lens. DHLA reduces disulfide bonds between lens proteins and restores lens microfluidics.
Proof of concept was confirmed in vitro with human cadaver lenses and in vivo in rabbit eyes, where in both trials the drug produced lens softening and an increase in lens deformability, Dr. Korenfeld said.

Clinical trial

The Phase 1/2 clinical study evaluated safety and efficacy of EV06 ophthalmic solution 1.5% in improving distance corrected near visual acuity (DCNVA) in subjects with presbyopia. The prospective, randomized, double-masked, placebo-controlled study included 75 patients (45–55 years) with hyperopia, myopia, or emmetropia and a diagnosis of presbyopia from four U.S. sites. Patients were randomized 2:1 (EV06=50: placebo=25). The study drug was given for 91 days and patients were monitored during a 7-month follow-up period.
At baseline, the study patients had DCNVA below 20/40 in each eye, best corrected distance visual acuity (BCDVA) of 20/20 or better in each eye, and a difference of ≤0.50 D between manifest refraction spherical equivalent and cycloplegic refraction spherical equivalent.
Visual acuity improvements were most pronounced when subjects employed bilateral vision, with 84% achieving 20/40 bilateral vision or better versus 52% in the placebo group. Fifty-three percent of the study participants achieved a ≥0.2 logMAR change in the bilateral vision versus 22% in placebo.
“EV06 was safe and well-tolerated,” Dr. Korenfeld said. “No subjects discontinued, and there were no sight threatening AEs or changes in IOP. The drug was comfortable upon installation and caused no change in best corrected distance visual acuity, manifest refraction spherical equivalent, cycloplegic refraction, or in pupil diameter.”

Persistent drug effect

An observational follow-up assessment on the long-term effects of bilaterally dosed topical lipoic acid choline ester eye drops demonstrated some interesting results. The drug effects on near visual improvement persisted in the study group long after dosing with EV06 was stopped at day 91. Dr. Korenfeld reported significant effects compared to placebo 241 days after the end of the study period, with only a small amount of treatment degradation.
“Seven months after the end of the 3-month study time, 39% of the subjects treated maintained a ≥0.2 logMAR change in bilateral near vision, compared to only 6% in placebo. More trials using EV06 are being planned for 2019,” he said.
According to Dr. Korenfeld, EV06 was first developed based on the hypothesis that the oxidation of lens proteins was at least partially responsible for lens stiffness in presbyopia and that it might be reversed chemically. “It made sense from a theoretical standpoint. Then it was demonstrated in vitro. Now the hypothesis is being supported by data collected in an active treatment setting, in terms of visual outcomes, significant safety issues, and adverse events. It is plausible that the effect of lipoic acid on ‘softening’ lens proteins could open up further treatment options with the drug. It is conceivable that the early, pre-cataract application of topical EV06 could potentially be used to delay or prevent nuclear sclerotic cataract,” he said.

About the doctor

Michael Korenfeld, MD
Department of Ophthalmology and Visual Sciences
Washington University
St. Louis

Financial interests

Korenfeld: Novartis

Contact information

Korenfeld: michaelskorenfeld@gmail.com

Has presbyopia found an “encore”? Has presbyopia found an “encore”?
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