PRESBYOPIA AFFECTS MOST people who are 45 years of age or older. The well-established first step in treating this natural, age-related condition has been either spectacles or contact lenses. Both modalities can be inconvenient for patients, and users can become intolerant and develop infections or dry eyes from wearing contact lenses. Surgical procedures that treat presbyopia include intraocular lens (IOL) implantation, corneal inlays, and laser procedures—all of which can be invasive and difficult to reverse.

A pharmacologic solution to presbyopia could therefore be of great interest to eyecare providers and patients alike. We really have not developed an easy convenient remedy, but that is about to change.

The compounds to be discussed here include one that can affect the eye’s accommodative ability and others that affect the depth of focus. Table 1 shows the pipeline of formulations being tested in a nutshell.

Accommodative Ability

There is 1 compound currently being studied that addresses the accommodative ability of the eye. A youthful eye has normal protein sulfhydryl groups within the lens fiber cells that allow the lens to change shape through central displacement of cytosol. It has been proposed that, in the aging eye, oxidation-induced disulfide bonds form between crystalline lens proteins, barring the movement of cytosol and thus causing the lens to stiffen.

UNR844

Previously called EV06 ophthalmic solution, UNR844 (lipoic acid choline ester [LACE] 1.5%; Novartis) works directly on the flexibility and accommodative ability of the crystalline lens. This prodrug is designed to penetrate the cornea and break down into lipoic acid and choline. Lipoic acid is then hydrolyzed by esterase in the tear film and cornea and subsequently reduced into dihydrolipoic acid within the fiber cells of the crystalline lens, causing hydrolysis of the disulfide protein bonds. Cytosol regains the ability to flow freely, and the oxidative process may be reversed, thereby restoring the lens’ elasticity and accommodative amplitude by allowing it to change shape again (Figure 1).

Preliminary results are optimistic in that there is a statistically significant sustained improvement in near visual acuity up to day 210 following treatment. Phase 2B studies are now being started in mid-2021, and enrollment is under way.

Depth of Field: Multiple Agents Being Developed

Other presbyopia-correcting pharmacologic agents in development exert a pinhole effect to increase patients’ natural depth of field. I consider the five main requirements of miotics to be:

1. Comfort and tolerability on instillation
2. Fast onset and sufficient duration of action
3. Modulation of the pupil to an efficient size for added depth of focus without loss of contrast or nighttime visual acuity
4. An excellent safety profile
5. No degradation of distance visual acuity

AGN-190584

Allergan Pharmaceuticals will place the first presbyopia drop on the US market, hopefully launching by the end of 2021 or early 2022. AGN-190584 (Allergan) is a topical drop intended to increase depth of focus. It is instilled once daily in both eyes or in the nondominant eye alone. Phase 3 studies are complete and have been submitted to the FDA. This drug is reportedly well tolerated and has a fast onset of action. The company says the agent improves the quality of patients’ near visual acuity for several hours after instillation, even in mesopic conditions.

Allergan received a provisional patent for pilocarpine at a concentration ranging from 1% to 1.5% for the treatment of presbyopia, and this topical drop concentration will be formulated as pilocarpine 1.25%. The company expects to be the first to market with a presbyopia-correcting drug that has completed FDA trials. They have also developed new validated questionnaires (the Near Vision Presbyopia Task-based Questionnaire and the Presbyopia Impact and Coping Questionnaire) to properly test for near vision, which could possibly help in future presbyopia studies.

As we can see, AGN-190584 is a known and trusted compound that we should have in our hands quite soon. It is a safe and trusted drug, and we await durability results to assess how well our patients will tolerate the mild to moderate side effects.

CSF-1

For patients who will obtain an effect with a lower dose of pilocarpine, providing excellent tolerability, we can also look forward to ORASIS Pharmaceuticals’ CSF-1. This formulation will be available in a preservative-free sub-glaucoma dose in a proprietary vehicle. Phase 3 studies are currently under way, studying 600 patients (active vs vehicle) with a primary endpoint of 3-line improvement in distance-corrected near vision acuity (DCNVA) without loss of best-corrected distance visual acuity (BCDVA). CSF-1 is being tested as a formulation administered twice daily in both eyes. It will be a lower concentration of the same known and trusted compound in a comfortable vehicle. A phase 2b, multicenter, double-masked, repeated-administration clinical trial evaluated the drug’s safety and efficacy in 166 patients. In that study, CSF-1 reportedly demonstrated an exceptional safety and tolerability profile. Treatment achieved a statistically significant improvement (3 or more lines) in DCNVA. Importantly, the patients also showed no reduction in distance vision, at both regular and low luminance.¹

These side effect profiles do appear promising for long-term use, and we will evaluate these drops when we have access to them.

Prx-100

Aceclidine’s method of action works as a parasympathomimetic miotic used for narrow-angle glaucoma outside of the US. Liquid vision (PRX-100) by Lenz Therapeutics (formerly Presbyopia Therapies) has completed a phase 2B trial and is preparing to commence the phase 3 trial with once daily dosing. The primary endpoint, as in all of these agents, is a 3-line improvement in DCNVA at 45 cm at 1-hour post-treatment. The drug will be administered to 1 or both eyes preferably and have a 30 minute onset of action with a duration of approximately 4 hours. This is a novel compound for the US. It appears to have no negative effects on distance vision and does improve near vision. Side effects will need to be evaluated, as will duration of action.

The Eyenovia Optejet Delivery Dispenser

The Optejet delivery dispenser will be a new concept for us in consideration of microdosing with an eye spray vs drops. We do not have data to share, but this delivery device will certainly be interesting to follow.

Ocuphire’s Nyxol (0.75% phentolamine ophthalmic solution), an alpha-1 and alpha-2 receptor antagonist drug candidate, is a preservative-free eyedrop that decreases pupil diameter by acting on the iris dilator muscle. Nyxol alone has been shown in multiple randomized, double-masked, placebo-controlled, phase 2 trials (NCT: NCT03960866, NCT: NCT04004507, NCT: NCT04024891) to reduce pupil diameter size statistically significantly by 1 mm for at least 24 hours after a single evening application and to improve near visual acuity by 1 line (63.2% with treatment vs 20.0% with placebo).² Ocuphire has recently completed enrollment of a phase 2 presbyopia study, initiated in early 2021, that enrolled 150 subjects aged 40 to 64 years old, with a primary endpoint of the percentage of subjects with ≥3 line improvement in binocular photopic DCNVA at 1 hour. The pharmacologic approach by Ocuphire is to create a pinhole effect, whereby a smaller pupil leads to increased depth of focus. In the phase 2 study, Ocuphire is evaluating the efficacy of a kit combination of Nyxol dosed in the evening and low-dose pilocarpine (activating the iris sphincter muscle) dosed in the daytime, with which an additional 1 mm in pupil diameter is expected to achieve this pinhole effect. Evening dosing of Nyxol will allow for daytime efficacy possibly without mild to moderate transient redness from conjunctival vessel dilation.³ Moreover, low-dose pilocarpine can allow for the miotic effects of pilocarpine without the known side effects of brow ache/headache, accommodative spasm, and eye irritation.⁴ Separate from its expected synergistic effects with pilocarpine, Nyxol’s pupil modulating effects are also being evaluated in phase 3 trials to treat dim light vision disturbances related to peripheral optical aberrations and to reverse pharmacologically induced mydriasis.

Visus Therapeutics – Brimochol

Visus Therapeutics is testing a combination drop of carbachol and brimonidine, hoping to show a synergistic effect of the 2 drugs in a proprietary formulation. The dosing could be once a day with effects possibly lasting 8 hours, with the primary endpoint of proportion of subjects with 3-line gains in best uncorrected near visual acuity without losing 5 letters or more in distance visual acuity.

Prior attempts by other companies have been unable to prove the synergistic effect of combination drops, so we await the final verdict of a combination drop in these trials. Also, as with all of the other miotics but especially because carbachol is the most potent cholinergic for pupil constriction, the night vision assessments will be pertinent to follow.

All of the aforementioned pipeline drops have shown great promise, each in their own way, for us to finally be able to address many levels of presbyopia without devices or surgical intervention. We sincerely hope that there will be many to choose from, so we can titrate the effects for our patients, limit side effects, and offer relief to the millions who find themselves suddenly feeling old and unable to perform daily activities without the crutch of glasses or contact lenses. All will require safety, tolerability, ease of use, and low side effect profiles to be used en masse. ■

Acknowledgement

Special thanks to John Hovanesian, MD, for sharing some of his slides from his Hawaiian Eye presentation for this article.

References

1. Press release. Orasis Pharmaceuticals Announces CSF-1 Eye Drop Successfully Met Primary Endpoint in Phase 2b Clinical Study in Presbyopia. Available at: https://www.orasis-pharma.com/orasispharmaceuticals-announces-csf-1-eye-drop-successfully-metprimary-endpoint-in-phase-2b-clinical-study-in-presbyopia/
2. Pepose JS, Hartman PJ, DuBiner HB, et al. Phentolamine mesylate ophthalmic solution provides lasting pupil modulation and improves near visual acuity in presbyopic glaucoma patients in a randomized phase 2b clinical trial. Clin Ophthalmol. 2021;15:79-91. doi:10.2147/OPTH.s278169
3. Pepose JS, Pitlick B, Meyer A, et al. Phentolamine mesylate ophthalmic solution provides long lasting pupil modulation and improves visual acuity. Paper presented at: Annual meeting of the Association for Research in Vision and Ophthalmology; June 2020.
4. Pilocarpine FDA warning label. US Food and Drug Administration website. Accessed June 6, 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/200890s001lbl.pdf

Dr. Rowen serves as Medical Director at NVISION Eye Centers in Southern California. She is a board-certified physician who pioneered new treatments and techniques for cataract surgery, and serves as Principal Investigator.

Disclosures
Dr. Rowen’s financial disclosures relevant to this article are: Allergan (Consultant), Orasis Pharmaceuticals (Consultant), Novartis (Speaker and Consultant, PI in SAHARA and UNR844 phase 2B trial).