Presbyopia Eye Drops: The Next Frontier in Vision Correction

Presbyopia is a common vision disorder characterized by the progressive inability to focus on objects at near. It is attributed to the increase in lens hardening and decrease in ciliary muscle flexibility that occurs around 40 years of age. There are estimated to be more than 1.8 billion people with presbyopia worldwide; 111 million of them reside in the US alone.¹

Up until now, the only options available for presbyopes were reading glasses, multifocal contact lenses, corrective laser surgery, or clear lens implants. Many of these options are limiting to the patient and interfere with their quality of life. However, in the next few months, pharmaceutical companies may change the game in how we treat presbyopia. Soon to be released are “presbyopia-correcting” eye drops. There are two types of presbyopia drops coming to market: miotic-based eye drop and lens restoration drops.

This article will discuss the pros and cons of current presbyopic treatment options as well as provide a thorough overview of the presbyopia drops currently in clinical trials.

Current treatment options

Spectacles

Spectacles are generally the most accessible intervention for correcting the symptoms of presbyopia. However, currently no spectacle lens can fully restore the dynamic range of accommodation in the aging eye.

Single near-vision spectacles correct sight at one distance only and are required to be removed or replaced with a distance pair when looking far away. They are usually the cheapest option and provide a wide range of view.

PALS/trifocals/bifocals are advantageous in that only one lens is needed for all viewing distances. However, the intermediate zone tends to be narrow, there is peripheral blur, and they are expensive.

Contact lenses

Multifocal contact lenses allow the patient to view distance, intermediate and near without the use of spectacles. However, the optics are never as clear as glasses and the intermediate vision tends to be limited.

Monovision and enhanced monovision involves correcting one eye for distance and one eye for reading or multifocal. Although less expensive than multifocal lenses, monovision can reduce stereopsis and contrast sensitivity.

Surgical options

Refractive lens exchange (RLE)

Refractive lens exchange involves exchanging the natural lens for an intraocular lens (IOL). RLE can reduce the need for glasses by using monovision, multifocal, extended depth of focus, or accommodating intraocular implants. Monovision lenses should only be implanted if the patient has tried monovision contact lenses and adapted well. Multifocal implants can sometimes provide moderate distance and near, but neither is crystal clear. Accommodating IOLs respond to ciliary body contraction and induce accommodation. However, they only have a limited accommodative ability.

Diffractive RLE

A recent development in refractive lens exchange is the light adjustable lens. This allows post-operative titrations in the IOL power after the eye has healed, facilitating customization and optimization of the lens to achieve the desired prescription. A retrospective study review of 29 patients implanted with a diffractive multifocal IOL were spectacle-free at their 6-month check.² Furthermore, in a 2015 study, it was reported that 3 months after undergoing RLE with a zonal refractive IOL, over 90% of 220 patients found the procedure to improve their lives.³

Corneal inlays

Corneal inlays consisted of minimally invasive surgical implantation of an inlay into the corneal stroma of one eye. It has high satisfaction and spectacle independence for near vision. However, it can possibly compromise night vision and distance vision, and there is the potential for corneal haze development.

A new inlay called KARMA is an FDA-approved, small-aperture inlay that has shown a higher safety and efficacy profile. However, since it restricts light entering the eye, patients have reported reduced contrast sensitivity and night vision.⁴

LASIK/PRK

Nowadays, LASIK/PRK can correct more than just distance vision. Multifocal LASIK and PRK aim to correct both distance and near vision by changing the refractive power of the cornea. This is done by either increasing the depth of focus through ablation of the peripheral cornea or creating a bifocal cornea. A more common procedure is monovision laser vision correction in which one eye is corrected for distance and one for near. However, this procedure can result in reduced binocular visual acuity and stereopsis.

Miotic eye drops

Miotic drops work by constricting the pupil and thereby creating a pinhole effect that increases the patient’s depth of field and improves near vision. These new drops are promised to be fast-acting with sustained results, no substantial decrease in distance vision and an excellent safety profile. They show minimal amounts of miotic problems such as headaches, reduced contrast sensitivity, and decreased night vision.

Vuity (Allergan)

Allergan (an AbbVie Company) recently introduced Vuity, an FDA-approved pilocarpine HCL ophthalmic solution 1.25%. This drop is instilled daily in both eyes and works in as little as 15 minutes, lasting up to 6 hours. Furthermore, it improves near and intermediate vision without impacting distance vision. You may be thinking “Well it is just another rebranding of pilocarpine which is not safe for use.”

However, this drop is an enhanced formulation of pilocarpine delivered with pHast technology. This pHast technology allows pilocarpine HCL ophthalmic solution 1.25% to rapidly adjust to the pH of the tear film.

The Vuity eye drop has completed two phase 3 trials, GEMINI 1 and GEMINI 2. In these studies, 750 subjects were tested, ages 40 to 55 years old, with presbyopia. There were two groups: the treatment group (Vuity) and the control group (placebo). The participants were asked to either instill one drop of VUITY or placebo in each eye daily. As you can see on the graph below, both studies showed there was a statistically significant higher number of participants in the VUITY group compared to the control group who gained an additional three lines or more on the near vision chart after 30 days.⁵

There were no serious side effects reported in participants treated with Vuity. The most common side effects were headaches and red eyes which only occurred at a low frequency (5%). Some other side effects included accommodative spasms and night driving difficulty.⁵

CSF-1 (Orasis Pharmaceuticals)

CSF-1 is also a parasympathomimetic agent combined with an NSAID in an oil-based vehicle that adds to the comfort of the drop. The oil-based vehicle helps to reduce discomfort caused by ciliary spasms and also reduces the risk of uveitis. The active ingredient is not yet known, however, it is a low-dose pupillary miotic. The company recently reported a successful phase 2 study which showed participants gained three-line of near vision acuity with no significant reduction in distance vision in both bright and dim lighting conditions. It is advancing to phase 3 development in 20216.

MicroLine (Eyenovia)

The MicroLine drop is a 2% pilocarpine formulation that utilizes a novel microdosing spray technology known as microdose array print (MAP) via the company’s Optejet delivery dispenser. Essentially, this dispenser allows for a smaller amount of solution to be dosed compared to traditional eye droppers, which prevents excessive overdosing. The VISION-1 Phase 3 study showed a higher number of participants in the treatment group gained three lines or more in near vision under normal lighting conditions after 2 hours compared to the placebo.

Effects on vision lasted at least 3 hours. Ocular adverse events including headache and brow ache were trace-to-mild in severity. The company is now starting phase 3 trial VISION-2.⁷

EyeFocus (OSRX Pharmaceuticals)

EyeFocus is a presbyopia-correcting drop that includes a combination of pilocarpine, phenylephrine, pheniramine, and ketorolac. The company will be releasing two different strengths of this drop called EyeFocus and EyeFocus+ near the end of 2020. EyeFocus is composed of 0.302% pilocarpine HCL and EyeFocus+ is 0.604% pilocarpine HCL. Since compounded medications are not subject to FDA approval the drops may be released sooner than some of the other presbyopia drops still being tested.

The mechanism of this drop involves a delicate balance of pilocarpine and phenylephrine. Pilocarpine works by constricting the pupil and acting on the ciliary body, thereby improving accommodation (focusing at near). Phenylephrine, nepafenac and pheniramine works to inhibit excess pupil constriction and counteract ciliary muscle spasms, vascular congestion and hyperemia induced by pilocarpine. Naphazoline works synergistically with pilocarpine to relax the pupillary dilator muscle. All these molecules work together to improve near vision, maintain distance vision, and keep side effects such as hyperemia and headaches to a minimum.

A small study was performed that looked at the safety and efficacy of this drop. Nine presbyopic patients received one drop of EyeFocus in each eye after 1 hour and then another after 5 hours. In these patients, near vision improved by an average of three lines. After the first hour, 66% of patients could read 20/40 or better. At 3-5 hours, reading vision was 20/40 in 89% of patients and 20/30 in 66% of patients. After 8 hours, 75% of the patients were still able to read 20/40 or better.⁸

Nyxol + LDP (Ocuphire Pharma Inc)

The Nyxol drop consists of preservative-free phentolamine 0.75% and 0.4% low-dose pilocarpine (LDP). The former is a nonselective alpha-adrenergic antagonist that inhibits the contraction of the smooth muscle in the iris. The goal is to use both the iris dilator and the iris sphincter muscles moderately to improve near vision without any side effects with the use of pilocarpine.

In the phase 2 trial (VEGA-1), it was revealed that 61% of Nyxol + LDP subjects gained 15 letters or more (>/= 3 lines) in near vision after 1 hour compared to 28% of participants that were assigned the placebo. The drops were effective 30 minutes after installation and worked for at least 6 hours. The company reported mild conjunctival hyperemia in <5% of subjects. Nyxol will be dosed at night/bedtime, and pilocarpine in the morning. Phase 3 trials are in effect.⁹

Brimochol (Visus Therapeutics)

This drop contains carbachol, a cholinergic agent, and brimonidine, an alpha-2 agonist. Together, these two molecules decrease the pupil’s size, creating a sustained pinhole effect. Brimonidine tartrate also potentially lessens miotic-induced side effects and prolongs carbachol’s duration of action. Onset of effect usually occurs within 30 minutes of installation and lasts 8 hours with once-a-day dosing.

Phase 2 clinical trial was started March 2021 to assess safety and efficacy of two formulations of Brimochol in patients who have emmetropic phakic and pseudophakic presbyopia. Trial results are expected second half of 2021.¹⁰

PRX-10 (Presbyopia Therapies/ LENS Therapeutics)

Similar to Allergan compounds,PRX-100 (Presbyopia Therapies) is a miotic drug that results in pupillary constriction and therefore improved near vision. The drop’s active ingredient is aceclidine. It is a parasympathomimetic miotic agent, meaning it works on the parasympathetic system, to constrict the pupil. Aceclidine is currently used to treat narrow-angle glaucoma.

According to the company’s statements, PRX-100 will have a 30-minute onset of action and will last approximately 4 hours. It is meant to be used binocularly. Interestingly, it has little impact on accommodation, only miosis, since aceclidine has been shown to have only a minimal effect on the ciliary muscle which controls accommodation.

Phase 2b trials, completed in 2018, demonstrated that 53% of patients who received this drop once a day achieved at least 3 lines in near VA at 30 minutes post-treatment. Additionally, 81% gained at least two lines of near vision, and 50% of these patients noted this improvement lasting for up to 7 hours. This formulation was well-tolerated, with no significant loss in distance vision, and no serious adverse events. The company is now gearing up for phase 3 studies.¹¹

Lens restoration drops

This second category of presbyopic eye drops are lens restoration drops that work to reactivate the elasticity of the patient’s aging crystalline lens. There is only one product currently being developed in this category.

UNR844-CL (Novartis)

This presbyopia drop from Novartis uses lipoic acid choline ester 1.5% (an antioxidant) to break apart the disulfide bonds that form between proteins within the lens, and by doing so, increasing the lens flexibility and elasticity. What is unique about this drop is that it may have the potential to restore natural accommodation instead of just creating a pinhole effect like the miotic drops.

In phase 1 and 2 studies, UNR844 demonstrated good initial results. All patients showed a substantial improvement in near acuity by day 15. At the end of three months, 82% of patients had 20/40 or better near vision and 36% had 20/25 or better. Therefore, the drop will likely be used twice a day for 90 days to achieve maximal effects. After discontinuing the drop after 90 days, the drug’s effects lasted up to 7 months without further dosing. The company expects to market the drug by the end of 2021.¹²

Future of presbyopia

Spectacles, contact lenses, and corrective surgery will always serve as viable options for presbyopia correction. Although the drops show promise, they may still need to be used in conjunction with other refractive devices or surgeries in order to be effective enough to improve the patient’s quality of life.

Numerous companies are planning to release their presbyopia drops to the market in the near future. These drops will likely be geared towards pre-cataract-age patients with presbyopia who have enjoyed great distance vision throughout their lives and/or those who have had previous refractive surgeries.

Pupillary miotics are likely to be the first pharmaceutical treatments for the presbyopia market (such as VUITY) and optometrists need to understand how they work, and the side effects and contraindications associated. Many of the drops appear to have a high safety profile but we must be careful to monitor patients closely in the initial few months of treatment.

Lastly, since these drops can only be prescribed by eye doctors at this stage, this new surge of presbyopia eye drops will potentially drive more patients into our offices in hopes of improving their near vision. This will help with patient retention and satisfaction. Remember, it is up to us to provide the most innovative yet safe solutions to our patients that help improve their quality of life.

References

Fricke TR, Tahhan N, Resnikoff S, Papas E, et al. Global prevalence of presbyopia and vision impairment from uncorrected presbyopia. Ophthalmology. 2018;125(10):1-8
Chang JS, Ng JC, Lau SY. Visual outcomes and patient satisfaction after presbyopic lens exchange with a diffractive multifocal intraocular lens. J Refractive Surg. 2012;28(7):468–474. doi:10.3928/1081597X-20120612-01
Venter JA, Pelouskova M, Bull CE, Schallhorn SC, Hannan SJ. Visual outcomes and patient satisfaction with a rotational asym- metric refractive intraocular lens for emmetropic presbyopia. J Cataract Refract Surg. 2015;41(3):585–593. doi:10.1016/j. jcrs.2014.06.035
Vukich JA, Durrie DS, Pepose JS, Thompson V, van de Pol C, Lin L. Evaluation of the small-aperture intracorneal inlay: three-year results from the cohort of the US Food and Drug Administration clinical trial. J Cataract Refract Surg. 2018;44 (5):541–556. doi:10.1016/j.jcrs.2018.02.023
Phase 3 Efficacy Study of AGN-190584 in Participants with Presbyopia. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03804268. Updated November 2, 2020
Safety, tolerability, and efficacy of PresbiDrops (CSF-1), a topical ophthalmic drug for presbyopia. Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT02745223. Updated July 2021
Safety & Efficacy of Pilocarpine Eye Solutions for Temporary Improvement of Near Vision in Presbyopic Adults (VISION-1) Clinicaltrais.gov. https://clinicaltrials.gov/ct2/show/NCT04657172. Updated August 9, 2021
EyefocusFormulations. https://www.osrxpharmaceuticals.com/sites/default/files/resource-files/OMNI_EyeFocus_Brochure_v3_0.pdf . Accessed May 1, 2021.
Safety and Efficacy of Nyxol With Pilocarpine Eye Drops in Subjects With Presbyopia. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT04675151. Updated June 25, 2021
Safety and Efficacy Study of BRIMOCHOL™, BRIMOCHOL™ F, and Carbachol in Subjects With Emmetropic Phakic and Pseudophakic Presbyopia. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT04774237. Updated November 8, 2021
Presbyopia Therapies announces primary safety and efficacy endpoints met in a Phase IIb study of its topical PRX ophthalmic solution for the treatment of presbyopia. https://tinyurl.com/4au4nh8u . Updated July 2018.
A study of safety and efficacy of UNR844 chloride (UNR8440Cl) eye drops in subjects with presbyopia. Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT03809611. Updated April 15, 2020.