Presbyopia Eye Drops are in Sight

The future looks bright for topical presbyopia treatment.

By Brian Chou, OD

Release Date:
February 23, 2018

Expiration Date:
February 23, 2021

Goal Statement:
Major headway has been made in the development of topical treatments for presbyopia. Currently, two domestic efforts—Liquid Vision (Presbyopia Therapies) and UNR844 (Novartis)—and several international efforts show promise. With a strong working knowledge of upcoming options for topical presbyopia care, ODs should be able to confidently and efficiently incorporate these treatments into their practices. This article reviews the options in this new treatment category, as well as the implications for ODs and their clinical practices.

Faculty/Editorial Board:
Brian Chou, OD

Credit Statement:
This course is COPE approved for 1 hour of continuing education credit. Course ID is 56822-GO. Check with your state licensing board to see if this counts toward your CE requirements for relicensure.

Joint-Sponsorship Statement:
This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.

Disclosure Statement:
Authors: Dr. Chou has no financial relationships to disclose.

Editorial staff: Jack Persico, Rebecca Hepp, William Kekevian, Michael Iannucci and Francesca Crozier-Fitzgerald all have no relationships to disclose.

At a glance, it might seem like a fake news headline shared on social media: "Eye drops get rid of reading glasses." However, the prospect of topical treatment for presbyopia is real and on the horizon. Two domestic efforts are in the pipeline—Liquid Vision (Presbyopia Therapies) and UNR844 (Novartis)—and several efforts from abroad are in the wings. This article reviews the latest in this emerging treatment category, along with the implications for patients and our profession.

Fig. 1. Eye drops for presbyopia could reach commercialization in the not-too-distant future.

A New Option
Presbyopia affects nearly 1.7 billion people worldwide today, and that figure is expected to reach 2.1 billion by 2020, according to one industry estimate.1 While eyeglasses, contact lenses and surgery each play a role in treating presbyopia, the global need for improved treatment is still large and growing. Pharmacologic topical therapy is an emerging class of treatment with presbyopia in its crosshairs.

The etiology of presbyopia is still under debate, and the relative contributions of lenticular sclerosis, reduced capsular elasticity, increasing lenticular circumferential diameter, reduced zonular tension and loss of ciliary body movement are not clear. Most eye drops proposed for presbyopia are a mixture of two or more drugs that stimulate pupillary constriction and accommodation for a few hours.2

Pinhole Effect
With Liquid Vision, Presbyopia Therapies set out to commercialize a binocularly instilled drop that, unlike pilocarpine, produces a pinhole effect without inducing significant ciliary body spasm, thereby avoiding brow ache and any myopic shift that would disturb distance vision. 

According to company CEO Jim McCollum, the drops were created by combining the miotic agent aceclidine and the cycloplegic agent tropicamide, with the intent of producing strong miosis with negligible accommodation, improving both distance and near vision (Figures 2 and 3). In other words, the dosage of tropicamide is calibrated to counteract the accommodation and ciliary body contraction stimulated by aceclidine, while the miosis from aceclidine helps moderate the dilatory effect of tropicamide. The key is in the ratio and balance of the drugs working together. 

Onset of action for the drops is approximately 30 minutes, creating a stable pupil below 2mm in diameter, and their effect is estimated to last at least four hours.3 Mr. McCollum says the fast onset will also allow practitioners to sample the drops therapeutically during routine visits, and that a second dosing could allow for a full day of vision correction.

Another major benefit of Liquid Vision, according to McCollum, is that it is a complement to existing presbyopia treatments such as glasses and contact lenses rather than a permanent replacement. In one preliminary trial for this eye drop, patients ranging in age from 46 to 63 reportedly experienced improved near visual acuity from three to seven lines on the Jaeger scale without compromising distance vision.3 Some patients reported a dimming effect, but it resolved after the first few days.

According to Mr. McCollum, the FDA conducted a Phase IIa proof of concept trial for dosing, safety and efficacy in 2016, and results showed improvement in uncorrected near visual acuity compared with placebo at multiple near distances and time points following a single dose. Additionally, the drug was well tolerated, with no serious adverse events. Mr. McCollum says an FDA Phase IIb trial is underway to evaluate a potentially more powerful formulation with enhanced protocol; data should be available at the end of 2018's second quarter. He hopes the drug will be commercialized by 2022.

Business Impact
To appreciate the potential business opportunity here, suppose that an elective prescriptive therapy for presbyopia costs $83.33 per month for ongoing use, the equivalent of $1,000 per year. If just one million users out of the more than 110 million presbyopes in the United States (less than 1% market penetration) elected to start up with the therapy, it would stand to generate $1 billion in annual revenue.1

One presbyopia study looked at use of 3% carbachol combined with 0.2% brimonidine in the non-dominant eye.4 Carbachol stimulates the parasympathetic innervation, the muscarinic and nicotinic receptors on the iris sphincter muscle, leading to miosis and increased depth of focus. Brimonidine, meanwhile, binds to alpha-2 receptors on the presynaptic nerve endings of the dilator muscle, inhibiting release of neurotransmitters and reducing activity of the dilator muscle to facilitate miosis. 

In one prospective, randomized clinical trial of 10 naturally emmetropic and presbyopic subjects between ages 42 and 58, the combined drop treatment showed statistically significant improvement in mean near visual acuity in all subjects compared with those who received separate forms of carbochol or brimonidine alone.4 This was also accomplished without any change to binocular distance acuity. However, the study does not indicate what happened to the visual acuity of the treated eye. Interestingly, none of the subjects reported symptoms of reduced depth perception from the difference in retinal illuminance (i.e., the Pulfrich effect).4

Dynamic Pseudoaccommodation
Colombian ophthalmologist Luis Felipe Vejarano, MD, has developed a combination eye drop for binocular twice-daily use called FOV Tears. According to Dr. Vejarano, the onset of action is five to 10 minutes for 70% of users by the third month of use, and the duration of effect is approximately four to five hours initially but extends to approximately eight hours with continued use. The drops contain pilocarpine 0.247%, phenylephrine 0.78%, polyetheleneglycol 0.09%, nepafenac 0.023%, pheniramine 0.034% and naphazoline 0.003%. The rationale behind this formulation, Dr. Vejarano says, is to allow for what he calls "dynamic pseudoaccommodation," in which the predominant improvement in near vision comes from real accommodation rather than the pinhole effect. The benefit is that the maintenance of physiological pupil diameter variation prevents indoor vision dimming. The pilocarpine provides both miosis and accommodation. Meanwhile, the phenylephrine, nepafenac, pheniramine and naphazoline counteract ciliary muscle spasm, vascular congestion and hyperemia induced by the pilocarpine, and help to avoid excessive pupillary constriction. Finally, polyetheleneglycol is a lubricant that improves drop tolerance upon instillation.

In a pilot study published in 2016, researchers describe the results of 14 presbyopic subjects aged 41 to 55 using the FOV Tears formulation.5 The results showed a mean improvement in uncorrected near visual acuity about two to three lines in each eye and binocularly from a baseline mean of about J3.5 to about J1.5 with an improvement ≥3 lines until four hours for seven patients (50% of the subjects). None of the patients experienced a loss in unaided distance visual acuity, either monocularly or binocularly, and there were no adverse events reported.

According to Dr. Vejarano, results will soon be published from a study of FOV Tears on more than 300 presbyopes in two groups, one of natural emmetropes and the other of emmetropes following LASIK. Additionally, he says a trial involving 60 patients in Europe will begin soon. Currently, FOV Tears is only available in Colombia.

Prolonged Effect 
Claes Feinbaum, MSc, PhD, a professor emeritus of optometry at Ben Gurion University of Negev in Israel uses a combination oil-based eye drop for bilateral therapy with an undisclosed parasympathomimetic to stimulate miosis and accommodation, along with a nonsteroidal anti-inflammatory drug (NSAID) to prolong the effect of the parasympathomimetic. Dr. Feinbaum reports the duration of effect is up to 12 to 14 hours.

Favorable results of the combination were initially presented at the 2013 European Society of Cataract & Refractive Surgeons meeting in Amsterdam when the formulation was referred to as Presbyeyedrops, a name that has since become PresbiDrops (CSF-1, Orasis Pharmaceuticals).6

In another study of the combination drops, this one featuring 81 patients, one to two drops of the PresbiDrops formulation in both eyes caused mean pupil diameter to decrease significantly from 3.77mm to 2.63mm.7 Additionally, patients experienced significant improvements in mean unaided distance visual acuity, from 0.932 (20/21 Snellen chart equivalent) to 1.141 (20/17), and unaided near visual acuity from 0.356 (20/56) to 0.649 (20/31). Three-fourths of the patients experienced no adverse reaction, while four patients experienced nausea immediately after instillation that quickly resolved, and another four patients developed headaches that gradually disappeared over 10 to 15 minutes. There were also two cases of dryness or burning, four cases of stinging and four cases of blurry distance vision, all of which dissipated over five minutes. 

PresbiDrops is currently in the process of completing FDA regulatory approval, where it will soon start Phase IIb.8

Fig. 2. Pilocarpine, a traditional miotic drug, does not provide a pinhole effect, according to Presbyopia Therapies. Image: Presbyopia Therapies
Figs. 2 and 3. Above, pilocarpine, a traditional miotic drug, does not provide a pinhole effect, according to Presbyopia Therapies. Below, Liquid Vision drops use aceclidine to create a strong pinhole effect, while tropicamide regulates accommodation. The combination and ratio of drugs aids both near and distance vision. Images: Presbyopia Therapies
Fig. 3. Liquid Vision drops use aceclidine to create a strong pinhole effect, while tropicamide regulates accommodation. The combination and ratio of drugs aids both near and distance vision. Image: Presbyopia Therapies

Modified Lens Shape
The late Argentinian ophthalmologist Jorge Benozzi, MD, developed a presbyopia treatment that combines different concentrations of pilocarpine and diclofenac.9 The rationale of using pilocarpine is the same as with other strategies for using a parasympathetic agonist for presbyopia—stimulating ciliary muscle contractions to modify the shape and position of the lens. While the associated ciliary body contraction and accommodation can negatively impact distance vision, diclofenac, an NSAID, is intended to moderate the full amount of miosis and ciliary body contraction.9 The NSAID also is intended to prevent uveal tract inflammation from chronic dosing of pilocarpine, which can otherwise lead to posterior synechiae and a fixed pupil (Figure 4).9

In a study of this method, researchers treated both eyes of 100 patients for five years.9 All patients showed near vision of J1 and distance vision of 20/20 when the drops were instilled at six-hour intervals daily. Some side effects reported in the study include ocular burning and discomfort after drop instillation in 20 patients, with one abandoning treatment as a result. Another four patients also discontinued treatment due to fear of chronic drop instillation.

Now known as Benozzi Method, the treatment has been available in Argentina since 2009 and, according to Giovanna Benozzi, MD (Dr. Benozzi's daughter), 25,000 patients have been successfully treated.10 "We use different combinations depending on each patient, restoring accommodation binocularly at all distances over time," she says. "We have found no important adverse effects in all the years of treatment."

Presbyopia Post-LASIK
Another proprietary drop, PresbiPlus, includes a mixture of two parasympathomimetics with one parasympatholytic. It is instilled bilaterally twice daily to stimulate accommodation and pupillary constriction. A clinical trial that followed patients for one year showed that 90% could see J4 to J1 after using the drops with no adverse reactions.11

According to Roberto Pinelli, MD, scientific director of Switzerland Eye Research Institute and the developer of PresbyPlus, "I currently use PresbyPlus for my patients after femtosecond PresbyLASIK to maintain accommodation. While most of my current research is directed towards femtosecond PresbyLASIK, development of PresbyPlus remains active and ongoing." Dr. Pinelli also says that topical pharmacologic treatment of presbyopia holds promise for ODs in expanding their role in comanagement following LASIK.

Restoring the Lens
Unlike eye drops that attempt to stimulate miosis or accommodation, UNR844 uses a completely different treatment approach for presbyopia. Previously called EV06 ophthalmic solution (lipoic acid choline ester or LACE, 1.5%), UNR844 is now set to go through Phase II and III development. According to Novartis, the drug "is being studied for topical administration to restore the natural flexibility and accommodating power of the lens." 

This prodrug is designed to penetrate the cornea and then break down into lipoic acid and choline, two naturally occurring substances.13,14 Lipoic acid is then metabolized into dihydrolipoic acid within the crystalline lens fiber cells, where it reduces protein disulfide bonds to soften the lens and restore accommodative amplitude.

Phase I-II study of UNR844 in 75 patients (50 using LACE 1.5% and 25 using placebo) over 90 days showed that the drug was safe and well tolerated with no treatment-related study discontinuations. Additionally, all patients showed improvement in distance-corrected near vision acuity (DCNVA) efficacy measures starting at day 15.14 By day 91, 82% of patients had 20/40 DCNVA or better in the LACE group compared with 48% in the placebo group, with baseline values of 30% and 28%, respectively. Similarly, 60% of LACE-treated subjects had 20/32 DCNVA or better at day 91 compared with only 24% in placebo; the baseline value for this measure in both groups was 8%. Finally, 36% of LACE-treated subjects had 20/20 and 20/25 DCNVA at day 91 compared with 16% in placebo, with the baseline value for this measure in both groups at 0%. 

UNR844 is expected to be used for bilateral therapy with twice daily instillation. Novartis plans to file for marketing approval in 2021.12

Eventually, LACE or a similar preparation may also help slow or even reverse nuclear sclerosis, which is thought to result from the same chemical process underlying presbyopia, according to Richard Lindstrom, MD, a board member and equity owner of Encore Vision, which developed EV06 prior to acquisition by Novartis.15

Fig. 4. According to Giovanna Benozzi, MD, chronic dosing of pilocarpine alone may lead to posterior synechiae and a fixed pupil, as shown here. Diclofenac, used in Benozzi Method, is intended to prevent this complication. Photo: Walt Whitley, OD, MBA, and John Sheppard, MD, MMsc
Fig. 4. According to Giovanna Benozzi, MD, chronic dosing of pilocarpine alone may lead to posterior synechiae and a fixed pupil, as shown here. Diclofenac, used in Benozzi Method, is intended to prevent this complication. Photo: Walt Whitley, OD, MBA, and John Sheppard, MD, MMsc

The Implications
The many efforts to develop eye drops for presbyopia foreshadow the likelihood of a safe and effective treatment within the next few years to complement eyeglasses, contact lenses and surgery. This is wonderful news for the growing presbyope population.

The consumer demand for an eye drop for presbyopia is high enough that it has supported the sale of non-prescriptive drops that allegedly fix this issue, such as Bright Eyes Drops (The Ethos Group) and Blur Relief (The Relief Products) homeopathic eye drops, which sell for $99.97 and $10.99 per bottle, respectively.16,17 While the evidence-based support for homeopathic drops in treating presbyopia is not at a level that most eye care professionals require, the pharmacologic treatments under development, with regulatory approvals demonstrating safety and efficacy, will likely earn the favor of many eye doctors.

For ODs, the commercialization of viable topical drops for presbyopia may provide a way to increase demand for their prescribing services and offset eroding contact lens and eyeglasses sales. They could provide patients with therapeutic samples of the combination drops for presbyopia even during routine examination due to the rapid onset of action and the fact that the effect will wear off within a day. This would be unlike therapeutic sampling of topical antibiotics for bacterial conjunctivitis, where the sample alone may achieve resolution without the need to fill a written prescription. Instead, patients would simply get a preview of the drops' efficacy before deciding whether it would be worthwhile to fill the prescription. The combination drops would also largely serve as an adjunct to existing treatment for presbyopia rather than a replacement, preserving the existing roles for glasses, contact lenses and surgery.

In addition to improving near vision, topical presbyopia drops may also address aberrations dependent on pupil size, including mild levels of myopia, hyperopia and astigmatism. Likewise, they may help patients with symptomatic higher-order aberrations, including those arising from past refractive eye surgery.  

ODs will need to check their state therapeutics laws to be sure they will have the authority to prescribe eye drops for presbyopia. If there is ambiguity or no provision to allow their prescribing, now is the time to act so therapeutic privileges can be amended to encompass this future pharmaceutical category. 

As an example, while Latisse (bimatoprost 0.03%, Allergan) received FDA approval in December of 2008, California ODs with therapeutic certification were not given explicit privileges to prescribe a drug for hypotrichosis. That finally changed on January 1, 2018 with Assembly Bill 443 going into effect. Moving forward, this same bill allows therapeutically certified ODs in California to prescribe non-controlled medications and use non-invasive medical devices as they are invented for conditions they already treat. This means that pharmacologic treatment for presbyopia will be within the prescribing privileges of certified California ODs upon approval. Hopefully, other states without provisions for optometric privileges in pharmacological presbyopia treatment can avoid a similar situation California ODs experienced with Latisse. The possibility of presbyopia eye drops hitting the market in the not-too-distant future is an encouraging sign for eye care providers the world over.

Dr. Chou practices in San Diego, where he directs a referral-based keratoconus clinic and serves as an expert witness for litigation involving optometric standard of care.

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