PRESBYOPIA IS AN EVENTUALITY for all human beings and is estimated to affect more than 1.8 billion people worldwide, more than 120 million in the United States alone.¹ With shifting demographic patterns, it is predicted that these numbers will only increase. Presbyopia, although a normal aging process of the eye, has a significant, negative impact on our patients’ perceived quality of life.² Traditional methods for the management of presbyopia include the use of spectacles (single vision near or multifocals) and contact lenses (monovision or multifocals). For presbyopic people who have undergone laser vision correction, near vision is addressed with reading glasses or monovision laser treatment. For patients undergoing cataract surgery, management of near vision postsurgically includes reading glasses, monovision powered intraocular lenses (IOLs), or multifocal IOLs. More recently, pharmaceutical approaches to presbyopia management have been explored to expand patient options.

Mechanism of Action

The primary mechanism of action of pharmaceutical agents used to address presbyopia is constriction of the pupil, which results in the extension of depth of focus. These miotic agents fall into the class of drugs called cholinergics. Their influence on stimulation of the pupil sphincter muscle will induce miosis, and through what is commonly called the pinhole effect, near vision is improved. Cholinergic miotics can be considered either nonselective miotics or selective miotics.

Nonselective cholinergic miotics that are currently used for the management of presbyopia include various concentrations of either pilocarpine or carbachol. Nonselective cholinergic miotics not only induce miosis but also significantly stimulate the ciliary muscle and induce crystalline lens thickening and anterior-lens displacement. Negative effects of the nonselective nature of these agents can potentially result in accommodative spasm/myopic shift, posterior synechiae formation, and anterior displacement of the crystalline lens and the vitreous, with the potential for tractional retinal tears and detachment. These adverse side effects are typically concentration dependent, however, and so is the miotic effect. As the concentration is increased, miosis is improved, but the influence on the ciliary muscle, along with the potential for the above undesirable side effects, also increases. The difficulty of treating presbyopia with a nonselective cholinergic miotic is a balancing act among pupil miosis, distance vision, and side effects, which may result in an inability to manage and treat presbyopia.

A selective miotic would disassociate miosis from ciliary stimulation, enabling the agent to target an ideal pupil size unbound by the constraints of a nonselective cholinergic. Research data, in vivo data, and data that have influenced the design of recently approved small-aperture IOLs indicate that a pupil size of 2 mm or less is needed to achieve a clinically impactful improvement in near vision, as seen in Figures 1 and 2.^3,4

Aceclidine

Aceclidine is a selective cholinergic miotic agent that has been used in the treatment of glaucoma in Europe since the 1970s but has never previously received approval for use in the United States. Aceclidine targets the pupil sphincter muscle with relatively minimal effect on the ciliary muscle. Compared to nonselective miotics, such as pilocarpine and carbachol, aceclidine’s relative stimulation of the ciliary muscle is significantly less and, as such, induces far less miotic myopic shift, lens thickening, and lens anterior displacement (see Figures 3 and 4).^5,6

Aceclidine is under clinical development by LENZ Therapeutics for the management of presbyopia and currently is in phase 3 clinical trials. Results have been reported from the phase 2 INSIGHT clinical trial of 2 preservative-free investigational formulations of aceclidine to treat presbyopia. The study design was double masked, randomized, and crossover placebo controlled with evaluation over a 10-hour duration. The study population included subjects aged 46 to 73 years old with a refractive range from -3.25D to +1.50D spherical equivalent and included post-LASIK presbyopic and pseudophakic subjects. The results indicated that both LNZ100 (preservative-free aceclidine 1.75%) and LNZ101 (preservative-free aceclidine 1.75% + brimonidine) achieved the primary endpoint of a 3-line or greater improvement in near visual acuity, without losing 1 line or more in distance visual acuity at 1 hour. Seventy-one percent of patients treated with LNZ100 and 56% of patients treated with LNZ101 met this endpoint compared with 6% of patients treated with vehicle. Additionally, 37% of patients treated with LNZ100 and 48% of patients treated with LNZ101 maintained a 3-line or greater improvement compared with vehicle for all time points, including the last measurement at 10 hours. Both formulations maintained an average pupil size of 1.5 mm to 2 mm for 10 hours, which, as mentioned previously, is a biomarker for near vision improvement. LNZ100 and LNZ101 were well tolerated with no serious drug-related adverse events reported in the phase 2 study. Current Phase 3 trials will help LENZ to determine the ultimate superiority of LNZ100 vs LNZ101.

Managing presbyopia with miotic agents to extend the depth of focus and thus improve near vision may be optimized with a drop that can achieve a pupil size of less than 2 mm for an extended period without inducing significant stimulation of the ciliary muscle, which has numerous potential side effects. This proprietary, preservative-free formulation of aceclidine, based on its selective miotic properties and duration of action, holds promise to meet the requirements needed to properly and successfully address the pharmacological management of presbyopia. Outcomes from the LENZ Therapeutics phase 2 clinical trials support this promise. ■

References

1. Fricke TR, Tahhan N, Resnikoff S, et al. Global prevalence of presbyopia and vision impairment from uncorrected presbyopia: systemic review, meta-analysis, and modelling. Ophthalmology. 2018;125(10):1492-1499.
2. Goertz AD, Stewart WC, Burns WR, Stewart JA, Nelson LA. Review of the impact of presbyopia on quality of life in the developing and developed world. Acta Ophthalmol. 2014;92(6):497-500.
3. Charman WN. Pinholes and presbyopia: solution or sideshow? Ophthalmic Physiol Opt. 2019;39(1):1-10.
4. Xu R, Thibos L, Bradley A. Effect of target luminance on optimum pupil diameter for presbyopic eyes. Optom Vis Sci. 2016;93(11):1409-1419.
5. Ishikawa H, DeSantis L, Patil PN. Selectivity of muscarinic agonists including (+/-)-aceclidine and antimuscarinics on the human intraocular muscles. J Ocul Pharmacol Ther. 1998;14(4):363-373.
6. François J, Goes F. Ultrasonographic study of the effect of different miotics on the eye components. Ophthalmologica. 1977;175(6):328-338.

Dr. Eiden is medical director of North Suburban Vision Consultants, a multispecialty group practice. He is CEO and cofounder of the International Keratoconus Academy of Eye Care Professionals. Dr. Eiden is also senior advisor for professional relations for LENZ Therapeutics, Inc., as well as cofounder and president of EyeVis Eye and Vision Research Institute. He is an assistant clinical professor at the University of Illinois at Chicago Medical Center and an adjunct faculty member of the Indiana, Illinois, Midwestern, Salus, SUNY, and UMSL Colleges of Optometry.

Dr. Odrich has been in both private and academic practice and is currently associate professor of ophthalmology at the University of Virginia, where he practices clinical ophthalmology, specializing in refractive surgery and ocular surface disease. He has had pivotal roles in the development and commercialization of the excimer laser and the femtolaser as former medical director for Visx, Inc., and he currently consults for multiple companies in the areas of corneal and refractive surgery, presbyopia correction, and dry eye disease. He is also chief medical officer for LENZ Therapeutics.