Lens-Softening Drug May Offer Presbyopia “Cure”

Phase 2 trials underway for eyedrops intended to restore some accommodation. Howard Larkin reports

Most approved or nearly approved presbyopia drugs work by inducing miosis to extend depth of focus. But the effects last a few hours at most and may interfere with night driving and low-light vision.

By contrast, the experimental compound UNR844 (lipoic acid/ choline ester 1.5% solution, Novartis) works not by affecting pupil size but by increasing the flexibility of the crystalline lens, theoretically restoring some accommodation. The resulting 0 near add is pupil size-independent so it does not reduce incoming light—and the effect may last for months after a few weeks of treatment.

This is why John A Hovanesian MD sees UNR844, currently in phase 2b clinical trials, as a potential breakthrough in presbyopia treatment.

“We want something safe, tolerable, and has long-term benefit, and that’s where this drug is unique,” he said. DISSOLVING BONDS The choline component of UNR844 is designed to help penetrate the cornea so the active ingredient, lipoic acid, can reach the aqueous humour and crystalline lens fibres. There, lipoic acid is hydrolysed and reduced into dihydrolipoic acid, which dissolves disulfide bonds thought to be a major contributor to lens stiffening. This also is thought to allow cytosol to again flow freely and may free bound proteins that stiffen the lens.

Theoretically, this restores lens flexibility, allowing it to change shape and accommodate. In a mouse model, lipoic acid significantly increased lens viscoelasticity, Dr Hovanesian noted.i

More to the point, the drug appears to work in humans. In a phase 2a study of UNR844 involving 72 patients, 52% of UNR844 patients gained 10 or more letters of distance corrected visual acuity (DCNVA) after 90 days of twice-daily installation compared with 20% of placebo patients. From baseline to day 91, UNR844-treated subjects demonstrated an improved mean DCNVA change of logMAR -0.159 compared with -0.079 (0.116) for the placebo group (p=0.007).

Moreover, UNR844 patients maintained most of their near vision gains 150 and 210 days after they stopped treatment, demonstrating the durability of the drug’s effect.ii

The phase 2b study currently underway involves 600 patients. The primary endpoints are the percentage of patients gaining 10 or more letters of DCNVA and change in bilateral DCNVA from baseline.

A novel compound, UNR844 has the potential to work on patients with early cataract. While it is unlikely to reduce the need for eventual cataract surgery, it may be a semi-permanent solution, he said.

“This is a drug that might actually cure presbyopia. So, it is a pretty exciting prospect for treating this common condition,” Dr Hovanesian concluded.

UNR844: Day 150 and 210 DCNVA Impact

EV-C-002

0.25 (final treatment day) Placebo (n=18) 0.2 UNR844 (n=34) 0.15 0.1 0.05

n=18 n=34 n=17 n=33 n=18 n=33 Day 91 Day 150 post-treatment* Day 210 post-treatment*

*Days 150 and 210 post-treatment refer to 241 and 301 days from baseline (Day 1), respectively. logMAR = logarithmic of the minimum angle of resolution; Obs = observational. Lindstrom, RL. Presented at: ASCRS 2017;May 5-9, 2017; Los Angeles, CA. Hovanesian

Change in Mean Bilateral DCNVA (logMAR) From Baseline EV-C-003 observational period

“We want something safe, tolerable, and has long-term benefit, and that’s where this drug is unique.”

Dr Hovanesian presented his findings at the American Society of Cataract and Refractive Surgery 2022 Annual Meeting in Washington, DC, US.

i Investigative Ophthalmology & Visual Science. 2016; 57(6): 2851–63. ii Lindstrom RL. ASCRS 2017; Korenfeld MS. Eye, 2021; 35: 3292–3301.

John A Hovanesian MD is in private practice at Harvard Eye Associates in Laguna Hills, California, US, and is a clinical instructor at Jules Stein Eye Institute, University of California–Los Angeles, US. drhovanesian@harvardeye.com