Presbyopia Drops in the Pipeline for 2023

Topical eye drops are used to treat myriad ocular surface conditions in optometry, but their use as means of managing presbyopia is a novel concept. Michael Dittman, OD,  discusses some of the potential advantages of using pilocarpine drops for presbyopia management and the potential benefits of some topical treatments that have yet to receive US FDA approval.

Until recently, clinicians have relied on spectacles and contact lenses to manage presbyopia, a condition affecting approximately 83% to 85% of all adults aged 45 years or older.¹ For a patient with emerging presbyopia, changes to their vision and the new need for corrective devices can be concerning. Both spectacle and contact lenses can correct near visual acuity, but they require care and maintenance. Some individuals may be reluctant to wear reading glasses for fear that they symbolize aging.   

Recently, pharmaceutical manufacturers have attempted to provide some relief for patients with presbyopia by developing drops that address their needs. Although only 1 US Food and Drug Administration (FDA)-approved topical treatment currently exists, at least 5 additional eye drops are in the pipeline and may eventually prove efficacious for managing presbyopia. Since many of these clinical trials have been completed within the past year, results have not been published in the scientific literature and can only be substantiated by the manufacturer’s claims.   

Pharmacological Options Available Now

In late 2021, the US FDA approved the use of Vuity^® (Allergan), a pilocarpine HCl ophthalmic solution 1.25% for presbyopia management. According to the GEMINI-1 (ClinicalTrials.gov Identifier: NCT03804268) and GEMINI-2 (ClinicalTrials.gov Identifier: NCT03857542) trials, participants with presbyopia gained 3 or more lines of near visual acuity in mesopic conditions without losing more than 5 letters of corrected distance visual acuity. No serious adverse events were reported in either clinical trial. The most common adverse events were headaches and eye redness, which were reported by less than 5% of patients treated.  

Vuity utilizes pHast™ technology, a proprietary vehicle which allows the pilocarpine to remain in the bottle at an acidic pH (3.5-5.5) until instillation.² Once it comes in contact with the ocular surface, it adjusts rapidly to the pH of the tear film. This treatment aims to improve comfort and decrease vision blur, making it more tolerable than other methods of pilocarpine delivery.²

CSF-1 

CSF-1 (Orasis) is a preservative-free formulation with a lower concentration of pilocarpine than Vuity (0.4% vs 1.25%) that is being investigated for use twice per day. Researchers completed phase 3 studies, NEAR-1 (ClinicalTrials.gov Identifier: NCT04599933) and NEAR-2 (ClinicalTrials.gov Identifier: NCT04599972), in April 2022.³  In both studies, CSF-1 met primary and key secondary endpoints on day 8, achieving a statistically significant 3-line or more gain in distance-corrected near visual acuity (DCNVA) without the loss of 1 or more lines in distance visual acuity, according to a press release from the manufacturer.³ Overall, CSF-1 was well tolerated among participants and the most commonly reported adverse effects were headache and instillation site pain, which occurred in 6.8% and 5.8% of participants, respectively.³ 

Nyxol

Nyxol^® (Occuphire) is also preservative-free and contains 0.75% phentolamine, a nonselective alpha adrenergic antagonist that inhibits the contraction of smooth muscles of the iris. It presents little risk for retinal detachment since it neither affects the iris dilator muscle nor inhibits the ciliary muscle. Phase 1 and 2 of the VEGA-1 study (ClinicalTrials.gov Identifier: NCT04675151) investigated nightly bedtime dosing in conjunction with 0.4% pilocarpine administered every morning. The combination of Nyxol and low dose pilocarpine met the primary study endpoint at 1 hour with 61% of participants gaining 15 or more letters (3 lines) in near vision, according to claims made by the manufacturer.⁴ No serious adverse events were noted and the most commonly reported issue was mild, transient conjunctival hyperemia (<5% of participants).⁴

LNZ100 and LNZ101

LNZ100 and LNZ101 (Lenz Therapeutics) are drops that contain aceclidine, a parasympathetic miotic agent used to treat glaucoma in stronger doses. It works by targeting the iris sphincter and avoiding the ciliary muscle. This helps to prevent myopic shifts that may be brought about by pilocarpine use, the manufacturer claims.⁵ Both LNZ100 and LNZ101 contain 1.75% aceclidine, but LNZ101 also contains brimonidine, which may allow for a longer treatment duration and increased eye whitening.⁵ According to research from the phase 2 INSIGHT study (ClinicalTrials.gov Identifier: NCT05294328), both LNZ100 and LNZ101 achieved the primary endpoint of a 3-line or greater improvement in near visual acuity, without losing 1 line in distance visual acuity at 1-hour ( 71% and 56% respectively), according to the manufacturer’s claims.⁶

Brimochol

Brimochol^® (Visus) contains 2.75% carbachol, a cholinergic agent, and 0.1% brimonidine tartrate, an alpha-2 agonist. Although carbachol is a potent miotic, adding brimonidine tartrate may inhibit ciliary muscle contractions, potentially mitigating the side effects commonly associated with miotics. Brimonidine may also help with bioavailability by prolonging the medication’s effects.⁷ In a phase 2 investigation (VIVID; ClinicalTrials.gov Identifier:  NCT04774237), a preservative-free formulation of Brimochol reached an endpoint of a 3-line gain in binocular near visual acuity without losing 1 line of distance vision in 83% of participants, according to the manufacturer.⁸  

Microline

Microline^® (Eyenovia) contains 2.0% pilocarpine. Instead of being applied as an eye drop, the drug is sprayed onto the ocular surface. This likely results in using less medication — one-fifth the amount of a traditional eye drop, according to the manufacturer.⁹ In a phase 3 investigation (VISION-2; ClinicalTrials.gov Identifier: NCT05114486), a significant number of individuals treated with the spray demonstrated a 15-letter or more improvement in DCNVA with less than a 5-letter loss in distance acuity compared with individuals treated with a placebo in low light conditions at 2 hours post-treatment.¹⁰

Dioptin 

Dioptin^® (Novartis) was different from other topical presbyopia treatments in that it sought to increase lenticular elasticity instead of adjusting the pupil size. However, a poor showing in phase 2b trials convinced the manufacturer to  abandon development of this medication.¹¹

Clinicians must frequently communicate undesirable findings and results to their patients. And while presbyopia may not be a systemic disease with life-threatening repercussions, it may still be a life-altering experience for patients who are trying to process the fact that they are aging. Although patient preferences will vary, a less cumbersome treatment method that does not involve wearing a visible sign of aging is a good presbyopia management tool for any optometrist to have at their disposal.