Is Presbyopia Reversible with a Drop?

Presbyopia is a nearly universal age-related visual disorder, typically driven by progressive stiffening of the crystalline lens. According to Aadithreya Varman, this process results from biochemical changes, particularly cross-linking and the formation of disulphide bonds.

“The progressive stiffening leads to a lack of accommodation with near vision difficulties,” he said. “Preventing these disulphide bonds from occurring may prevent the progressive stiffening and return the lens to its more elastic nature.”

Now, lipoic acid-based therapies are the leading candidates in the pharmacological lens softening concept, Dr Varman explained. The goal is to reduce the disulphide cross-linking naturally occurring in an ageing eye by using lipoic acid to function as a redox-active antioxidant.

This treatment approach demonstrated encouraging results during preclinical phase one trials but did not meet statistical relevance in phase two trials. Phase three data, on the other hand, provided more advances in a multi-approach strategy that considered a topical delivery system.

In the preclinical phase, eight-month-old mice with biologically aged lenses were incubated with lipoic acid. The results showed a promising dose-dependent reduction in protein disulphide levels, with a corresponding increase in lens elasticity.¹ The challenge is getting the lipoic acid to adequately penetrate further. For this reason, additional research was conducted to develop a prodrug that can be released into the aqueous humour. This led to the formulation of lipoic acid choline ester, which Dr Varman said can penetrate the cornea and release the drug into the aqueous humour.

Topical eye drops were eventually assessed in aged mice, showing a significant increase in elasticity in comparison to untreated eyes—providing the first real proof that age-related stiffening is reversible in vivo, Dr Varman said.

The following randomised, double-masked, placebo-controlled phase one/two study showed a greater improvement in distance-corrected near visual acuity (DCNVA) than placebo. In this study, 53% of treated patients gained more than 10 letters compared to the 21.7% of the placebo group. The promising part, Dr Varman said, is these effects lasted five to seven months after treatment, suggesting some true disease modification.² The phase two study, however, failed to show statistical improvement over placebo on a larger group at the three-month endpoint in the thrice-a-day application protocol. Despite the high tolerability, the clinical programme was discontinued, he reported.

Dr Varman believes there is some rationale to suggest the strategy can really work. Evidence of an elasticity increase was demonstrated in previous studies, with patients gaining more DCNVA. The challenge is permeability, he pointed out, observing how formulation issues could have been the cause for failure in the phase two study.

Renewed interest led to the development of CLX-162, a new compound combining lipoic acid and pilocarpine to the formulation for an immediate meiotic effect. This new solution already showed promising results in preclinical studies.³

“The first-generation challenges were not a failure,” he emphasised. “The next steps of this compound would be to separate the symptomatic effect from true disease modifications. This requires a thoughtful decalibration and not a total abandonment of the therapy.”

The FDA has approved three prescription eye drops for presbyopia treatment: Vuity (Allergan) and Qlosi (Orasis Pharmaceuticals) use pilocarpine (1.25% and 0.40%, respectively) and VIZZ (LENZ Therapeutics) uses aceclidine hydrochloride 1.44%.

There are currently no FDA-approved eye drops to prevent or treat cataracts. Experimental agents under evaluation include lanosterol, C-KAD (Livionex), ethylenediaminetetraacetic acid, and methylsulfonylmethane.

Dr Varman spoke at the 2026 ESCRS Winter Meeting in Helsinki.

Aadithreya Varman MS, FWCRS, FAICO(Cataract/Phaco) is a cataract and refractive surgeon at the Uma Eye Clinic in Chennai, India. aadithreyavarman@gmail.com

1. Garner WH, Garner MH. Invest Ophthalmol Vis Sci, 2016; 57(6): 2851–2863. doi:10.1167/iovs.15-18413

2. Korenfeld MS, et al. Eye (Lond), 2021; 35(12): 3292–3301. doi:10.1038/s41433-020-01391-z

3. Robb E, et al. Transl Vis Sci Technol, 2025; 14(11): 17. doi:10.1167/tvst.14.11.17