Treating presbyopia with an eye drop?

July 1, 2016

A topical treatment that breaks apart disulfide bonds between crystalline lens proteins was shown to increase accommodative amplitude and improve near visual acuity in a randomized, placebo-controlled clinical trial.

Reviewed by Richard L. Lindstrom, MD

Topical administration of lipoic acid choline ester 1.5% (EV06, Encore Vision) shows promise as a treatment for restoring accommodation to patients with presbyopia, said Richard L. Lindstrom, MD. Acting via an “anti-crosslinking” mechanism, the treatment increases lens elasticity through reduction of lens protein disulfides, and was associated with impressive improvements in accommodative amplitude and near vision in an initial randomized, double-masked phase I-II clinical trial.

“The changes in near vision associated with topical EV06 were statistically significant compared with placebo and clinically meaningful,” said Dr. Lindstrom, founder, Minnesota Eye Consultants, Bloomington, MN, and adjunct professor emeritus, Department of Ophthalmology, University of Minnesota, Minneapolis. “Furthermore, the EV06 drops were well-tolerated and not associated with any significant adverse events. This is an early, relatively small proof of concept study. Efficacy and safety of EV06 for treating presbyopia need to be demonstrated in larger phase III trials, he noted. "However, this topical treatment is the first agent that has been shown in a clinical trial to restore natural accommodation, and it has exciting potential,” Dr. Lindstrom said. 

EV06 targets the underlying cause of age-related increased lens stiffness-the disulfide bonds that form between the crystallin proteins within lens fiber cells. It is a prodrug that is able to penetrate the cornea. Inside the eye, however, EV06 is broken down into lipoic acid and choline, two naturally occurring substances. Within the lens, the lipoic acid is reduced to the active agent, dihydrolipoic acid, a potent antioxidant that breaks apart the disulfide bonds Initial ex vivo and in vivo animal studies provided proof that topical treatment with lipoic acid choline ester decreased lens protein disulfides and increased lens elasticity.

“I was somewhat skeptical about how the positive results in the preclinical studies would translate into clinical use,” Dr. Lindstrom said. “For that reason, I must admit that I was stunned to see the magnitude of the improvements achieved in accommodation and near vision in the clinical trial.”

About the study

The phase I-II study enrolled 75 participants who were randomly assigned 2:1 to use EV06 or placebo twice daily for 3 months.

Change in distance-corrected near visual acuity (DCNVA) from baseline to day 91 was analyzed as the primary outcome measure, and there was a statistically significant difference favoring EV06 compared with placebo. Mean logMAR DCNVA in the EV06 group improved from 0.397 at baseline to 0.206 at day 91 and from 0.408 at baseline to 0.313 at Day 91 in the controls.

DCNVA was 20/40 or better at baseline in 30% of patients randomized to EV06 and in 28% of controls compared with in 82% of EV06-treated patients and 48% of controls at day 91. At day 91, DCNVA was 20/32 or better in 60% of EV06-treated subjects and 24% of controls, and 20/25 or better in 36% of EV06 patients and only 16% of controls. A benefit of treatment with EV06 was observed at the 2-week follow-up visit, when improvement from baseline DCNVA was already statistically significant compared with the control group.

Furthermore, the proportion of patients gaining 10 or more letters in DCNVA was also significantly greater in the EV06 group compared with controls, 28% versus 0%. At day 91, 36% of EV06 patients and 16% of controls demonstrated a 10-letter or greater gain from baseline DCNVA.

“The efficacy assessments from the serial follow-up visits showed patients were experiencing progressive improvements during the 3-month treatment period,” Dr. Lindstrom said. “Post-treatment follow-up will provide some insight about the durability of the benefit.”

Rating comfort, safety

Study participants were also asked to rate the comfort of the treatment on scale of 0 to 10, where 0 is the best possible score (“very comfortable”). The mean rating for EV06 was 3.0 and comparable to the mean score of 2.7 in the placebo group.

The safety assessment showed no change in best-corrected distance visual acuity occurring with EV06, and no one withdrew from the study because of adverse events or treatment intolerability. Based on the efficacy observed in the phase I-II study, Dr. Lindstrom suggested that a phase III trial might investigate the same concentration and dosing frequency of EV06.

However, he envisioned that it might be designed with longer treatment duration to assess the maximum potential benefit. Further study would also assess whether maintenance of efficacy would require continuous twice-daily dosing or if a reduced schedule or intermittent dosing regimen would be viable. Looking ahead, Dr. Lindstrom also noted the possibility of using topical lipoic acid choline ester as a treatment to retard cataract progression or even reverse cataractous changes in the crystalline lens.

“This might be a reasonable therapeutic target considering that disulfide bond formation also causes nuclear cataract,” he said.

Disclosures:

Richard L. Lindstrom, MD
E: rllindstrom@mneye.com
Dr. Lindstrom is a board member, consultant to, and equity owner in Encore Vision.