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  • Clinical Update

    Presbyopia-Correcting Eyedrops Move Ahead

    By Mike Mott, Contributing Writer, interviewing John P. Berdahl, MD, Eric D. Donnenfeld, MD, and Jay S. Pepose, MD, PhD

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    With at least 2 billion people affected globally, presby­opia is the world’s leading cause of visual loss. In the United States alone, close to 130 million adults live with the progressive eye condition, a number that is expected to surpass 150 million within the next two decades.1,2

    A technical challenge. Despite these statistics, current treatment options are relatively limited and somewhat flawed. Glasses and contact lenses are more common than surgical alternatives such as monovision LASIK, multifocal corneal ablations, intracorneal inlays, and refractive lens exchange, said John P. Berdahl, MD, at Vance Thompson Vision in Sioux Falls, South Dakota. And patients may be bothered by eyestrain, night vision disturbances, glare and halo, and a reduction in quality of vision.

    “We really have yet to design a lens or manipulate optics in a way that’s as effective as our naturally occurring flexible lens, and that’s why presbyopia remains one of the biggest technical challenges we face,” Dr. Berdahl said.

    An untapped market. There’s also another reason why a solution is con­sidered one of ophthalmology’s Holy Grails, said Dr. Berdahl. Consider the sheer size of the presbyopic market, he said: “It is enormous. It’s basically every person in the world over age 50. There are very few markets, if any, that are this large.”

    And U.S. pharmaceutical companies have taken notice. With several years of research completed, they’re inching toward regulatory approval and ready­ing the marketplace for a potential major breakthrough: topical therapies utilizing miotics and lens softening for noninvasive, real-time correction of presbyopia.

    New Era
    NEW ERA. Whether they act as miotics or lens softeners, eyedrops for presbyopia are poised to reshape the refractive landscape.

    The Pinhole Approach

    A large majority of the new pharma­ceutical drops under investigation are within the category of pupillary miotics. Miosis is achieved through the use of specific muscarinic agonists such as pilocarpine, carbachol, or aceclidine, said Eric D. Donnenfeld, MD, at Oph­thalmic Consultants of Long Island in Garden City, New York.

    “By reducing the size of the pupil in this manner, you create a pinhole effect that creates depth of field without impairing the peripheral field,” Dr. Donnenfeld said. “This is an exciting approach because it not only provides more near vision but also can improve distance vision, and it’s all reversible.”

    Pilocarpine. The first drug that’s likely to be approved by the FDA for the correction of presbyopia is AGN-190584 (AbbVie), a once-daily formu­lation of pilocarpine 1.25%. In a recent phase 3 clinical study, a statistically significant greater proportion of partic­ipants treated with the drop gained 3 or more lines in distance-corrected near visual acuity (DCNVA) under low-light conditions than with the placebo. Additional endpoints evalu­ated showed that 75% of participants treated with AGN-190584 achieved at least a 2-line improvement in mesopic DCNVA.3

    “AGN-190584 also demonstrates good durability,” said Jay S. Pepose, MD, PhD, at the Pepose Vision Institute in St. Louis. “What’s particularly im­pressive is that these effects had a rapid onset of around 15 minutes and lasted up to six hours,” Dr. Pepose said. “Ad­verse events, including tearing, blurred vision and headache, were reported more commonly in the treatment than placebo group, but the latter [events] were mostly mild and transient, and no patient discontinued treatment because of them.”

    Phentolamine + low-dose pilocar­pine. Ocuphire is using a combination of phentolamine 0.75% (Nyxol, a non­selective alpha-1/alpha-2 adrenergic antagonist) with low-dose pilocarpine 0.4% to induce miosis. In a phase 2 clinical trial, 61% of presbyopic par­ticipants experienced at least a 3-line improvement in daytime binocular near vision compared with 28% of the placebo group. These results were achieved within 30 minutes and were sustained through at least six hours.4

    Of note, this drug raises the poten­tial for tunable pupil modulation, said Dr. Pepose. “There’s a dual approach being taken here between the phentol­amine, which inhibits the iris dilator muscle, and the pilocarpine, which activates the pupillary sphincter,” he said. “And each of these drugs has a very different half-life—24 versus six hours. So there’s some possibility for customization here in that you can pro­vide a range of pupillary modulation by adjusting the timing of the drugs, providing synergy to phentolamine’s 24- to 36-hour moderate miotic effect.” This is relevant in that most patients function under different lighting condi­tions throughout the day and also need to be able to drive home in dim light, he added.

    Ocuphire plans on initiating phase 3 trials in 2022.

    Carbachol/brimonidine tartrate. Another contender is Brimochol (Vis­us), a fixed combination of carbachol and brimonidine tartrate. Although on­going phase 2 trial results have not been reported, the formulation does appear to have durability, Dr. Donnenfeld said. “As a miotic, the cholinergic agent car­bachol has a significantly longer-acting effect than pilocarpine,” he said, “and here it’s combined with brimonidine, an alpha-2 sympathomimetic, which prevents pupillary dilation and also inhibits ciliary body contraction.” This combination increases the half-life of the carbachol and extends its bioavail­ability even further, potentially up to a minimum of eight hours.

    Visus is planning to finish a phase 2 trial before end of this year.

    Pilocarpine via novel dispenser. MicroLine (Eyenovia) is another pilocarpine-based presbyopic drug, but what’s unique is the delivery vehicle, said Dr. Pepose. “A microdose mist of pilocarpine 2% is administered hori­zontally via the company’s proprietary piezo-print dispenser.” The dispenser reduces the amount of drug volume by 80%, potentially eliminating the excess overdosing and drug waste commonly associated with conventional eyedrops.

    Earlier this year, Eyenovia announced results from a phase 3 trial, which showed promise in terms of both safety and efficacy, said Dr. Pepose. Although spe­cifics were not provided, a higher pro­portion of participants achieved at least a 3-line improvement in DCNVA using MicroLine compared with placebo, and more than 70% self-reported a mean­ingful improvement in near vision.5

    Next up: Eyenovia is conducting a second phase 3 trial later this year, with results expected mid-2022.

    Rounding out the field. Two addi­tional miotic-based pharmaceutical offerings are also making their way through the approval pipeline. CSF-1 (Orasis) is a low-dose pilocarpine formulation currently being tested in two phase 3 studies. In a 2019 phase 2 trial, the formulation demonstrated at least a 3-line gain in DCNVA as well as no reduction of distance or night vision in participants using the drop.6

    In addition, Presbyopia Therapies has reemerged as Lenz Therapeutics following results from a 2018 phase 2 clinical study in which more than 47% of eyes treated with the company’s PRX formulation gained at least 3 lines of improvement at one hour, with almost half maintaining at least 2 lines after seven hours.7 “What sets this product apart from the competition is the use of aceclidine,” said Dr. Pepose. “This induces miosis without the myopic shift and accommodative effect often­times associated with other cholinergic agonists, which can impair distance vision.” The company is gearing up for a new trial in the future; no timeline has been disclosed.

    Lens Softening

    As an alternative to increasing the depth of field via miosis, the UNR844 eye­drop (Novartis) stands alone in the arena of lens softening for the tempo­rary relief of presbyopia.

    Restoring elasticity. In essence, this strategy aims to restore the elasticity of the lens that’s been lost due to the effects of aging, said Dr. Pepose. “This is a prodrug designed to penetrate the cornea, and it breaks down into two components, lipoic acid and choline, which are hydrolyzed by the esterases in the tear film and reduced into dihydro­lipoic acid within the lens fiber cells.”

    This antioxidant then hydrolyzes, breaking down the disulfide bonds be­tween the lens crystalline proteins that form over time. “By allowing cytosol to regain its ability to flow more freely, you’re pharmaceutically reversing the lens oxidative process and restoring the lens elasticity,” Dr. Pepose said. “This results in the return of accommodative amplitude because now the lens can change shape and curvature.”

    Research update. UNR844 has moved from experimental studies to human trials over the last several years, but it’s likely farther away from FDA approval than most of the miotic alter­natives, said Dr. Donnenfeld.

    The latest studies are nonetheless promising, he added: Recent results from an independent phase 1/2 dosing and safety study showed that patients treated with UNR844 had statistically significant improvements in DCNVA compared with the placebo—results that continued to increase through day 91.8 However, these results were not repeated when Novartis conducted its own phase 2 safety and efficacy trial in which researchers saw only a 4-letter DCNVA increase in treated patients 45 to 55 years old compared with the placebo in a post hoc analysis.9

    Novartis started a dose-ranging study of UNR844 this summer; it is expected to be completed by early 2023.

    Patient Selection: Unknown Variables

    One unknown factor at this point: who is and who isn’t the best candidate for these treatment modalities, said Dr. Pepose.

    What about age? Age will likely play a factor, Dr. Pepose said: “Will lens softening really work in eyes that are already presbyopic and already have significant hardening of the lens? Or is it best suited for the treatment of early presbyopes in their late 30s and early 40s? We don’t have the age-stratified data just yet to know the answers.”

    There’s a similar age-related ques­tion regarding treatment with miotics, added Dr. Berdahl. “We don’t know which patients are going to do the best here, but there’s no evidence for ruling out anyone.”

    Nuances to consider. Dr. Berdahl imagines the best candidates will be those who are new to presbyopia—e.g., those patients with new-onset presby­opia and even maybe those with mild to moderate amounts of astigmatism who are not accustomed to wearing glasses. In addition, hyperopes and post-LASIK emmetropes in this same age range will likely appreciate these presbyopic drops based on the pub­lished study data, added Dr. Donnen­feld, as well as patients who have had previous cataract surgery.

    What about side effects? Side effects will also play a role in patient selection, said Dr. Pepose. Although not enough is known about the long-term use of lens-softening agents, there’s a history of adverse reactions to approved doses of muscarinic agonists such as pilocarpine, he said. These include the potential for brow ache, decreased night vision, redness and irritation, dry eye, and retinal tears in high myopes.

    “We’re still a bit unsure of the real-world effects of these miotic drops,” Dr. Pepose added. “It’s one thing to get through the FDA process, but it’s an­other thing to see how these treatments work for different types of presbyopes interacting in different daytime and nighttime conditions, when very small pupils and resulting low retinal illumi­nation can dramatically elevate neural contrast levels.”

    Looking Ahead

    Ultimately, the drops’ side effect profiles—along with cost and convenience—will drive clinicians’ recommendations and patients’ choices, said Dr. Pepose. As a result, the market will likely be one that’s fragmented, similar to glaucoma drops.

    “Once these treatments hit the U.S. market, we’ll really start to see the differentiation in terms of onset, du­ration, and adverse events,” Dr. Pepose said. “Some drops might just be better for certain lifestyles, in certain envi­ronments, and under certain lighting conditions. But there’s going to be a variety of products, and that’s great because there’s plenty of room in this new marketplace.”

    1 Fricke TR et al. Ophthalmology. 2018;125(10):1492-1499.

    2 Donaldson KE. J Refract Surg. 2021;37(S1):S17-S19.






    8 Korenfeld MS et al. Eye (Lond). Published online Jan. 29, 2021.



    Dr. Berdahl is a clinician and researcher at Vance Thompson Vision in Sioux Falls, S.D. Relevant financial disclosures: Allergan: C,L; Orasis: C.

    Dr. Donnenfeld is professor of ophthalmology at the NYU Grossman School of Medicine in New York City. He also practices at Ophthalmic Consultants of Long Island in Garden City, N.Y. Relevant financial disclosures: Allergan: C,L; Novartis: C; Orasis: C; Visus: C.

    Dr. Pepose is a professor of ophthalmology at the Washington School of Medicine and founder of the Pepose Vision Institute, both in St. Louis. Rel­evant financial disclosures: Allergan: C; Novartis: C; Ocuphire Pharma: C.

    For full disclosures and the disclosure key, see below.

    Full Financial Disclosures

    Dr. Berdahl Allergan: C,L; Aurea: C,O; Avedro: C; Bausch + Lomb: CorneaGen: C,L; Equinox: C,O; Glaukos: C,O; Orasis: C; RxSight: C.

    Dr. Donnenfeld Alcon: C; Allergan: C,L; Avellino: C; Bausch + Lomb: C; Beaver-Visitec International: C; BlephEx: C,O; Carl Zeiss: C; CorneaGen: C,O; Eyepoint Pharma: C; Glaukos: C; Ivantis: C; Johnson & Johnson: C; Katena: C,O; LacriScience: C,O; Mynosis: C,O; Novartis: C; Ocular Therapeutix: C; Omeros: C; Orasis: C; PRN: C,O; TLC Laser Center: C; Visus: C.

    Dr. Pepose AcuFocus: C,O; Allergan: C; Bausch + Lomb: C; Dompé: C; Johnson & Johnson: C; Kala: C; MG Therapeutics: O; Mimetogen: O; Novartis: C; Ocuphire Pharma: C; Ocunexis: C,O; Stuart Pharma­ceuticals: C,O; Sun Ophthalmics: C; TearLab: C.

    Disclosure Category



    Consultant/Advisor C Consultant fee, paid advisory boards, or fees for attending a meeting.
    Employee E Employed by a commercial company.
    Speakers bureau L Lecture fees or honoraria, travel fees or reimbursements when speaking at the invitation of a commercial company.
    Equity owner O Equity ownership/stock options in publicly or privately traded firms, excluding mutual funds.
    Patents/Royalty P Patents and/or royalties for intellectual property.
    Grant support S Grant support or other financial support to the investigator from all sources, including research support from government agencies (e.g., NIH), foundations, device manufacturers, and/or pharmaceutical companies.