For most people, presbyopia is inescapable once they reach their early to mid-40s. The first step in treating this natural, age-related condition, in which eyes gradually lose their ability to focus on nearby objects, has long been either spectacles or contact lenses. However, both modalities can be inconvenient for some patients, and contact lens wearers can become intolerant and develop infections or dry eyes from wearing the lenses. Surgical procedures that treat presbyopia include intraocular lens (IOL) implantation, corneal inlays, and laser procedures — all of which can be difficult to reverse.

So, pharmacologic solutions that reduce the burden of presbyopia represent an opportunity for eyecare providers. The compounds discussed here include drops that affect the depth of focus by inducing pupillary miosis, or excessive constriction of the pupil. To date, only one of these has been approved for use by the FDA, with others still under development. The Table presents an overview of these formulations.

Increasing depth of focus

Essential characteristics

Presbyopia-correcting pharmacologic agents work by exerting 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.

Vuity 1.25%

Allergan launched the first presbyopia drop on the US market, gaining FDA approval in late 2021. Vuity (pilocarpine HCl ophthalmic solution) 1.25% is a topical drop intended to increase depth of focus. It is instilled once daily in both eyes or in the nondominant eye alone. According to Allergan, the drug is well tolerated and has a fast onset of action. Vuity improves the quality of patients’ near visual acuity for several hours after instillation, even in mesopic conditions.¹

Vuity’s FDA labeling includes the following recent update: Rare cases of retinal detachment and retinal tear have been reported with miotics, including Vuity. Individuals with preexisting retinal disease are at increased risk. Therefore, examination of the retina is advised prior to the initiation of therapy. Patients should be advised to seek immediate medical care with sudden onset of flashing lights, floaters, or vision loss.¹

CSF-1

ORASIS Pharmaceuticals’ CSF-1, a 0.4% pilocarpine formulation, will be available in a preservative-free dose in a proprietary vehicle. Phase 3 studies with a primary endpoint of 3-line improvement in distance-corrected near vision acuity (DCNVA) without loss of best-corrected distance visual acuity (BCDVA) are completed, and a New Drug Application (NDA) has been filed with the FDA.²

CSF-1 is being tested as a formulation administered twice daily in both eyes. A Phase 2b, multicenter, double-masked, repeated-administration clinical trial evaluated the drug’s safety and efficacy. 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.³

MicroLine

Eyenovia’s MicroLine — pilocarpine micro-array print (MAP) — completed its fourth Phase 3 trial late last year. The VISION-2 study evaluated the safety and efficacy of Eyenovia’s 2% MAP formulation administered via the company’s proprietary Optejet device. The formulation met its primary endpoint with a statistically significant proportion of subjects treated showing a 15-letter or more improvement in distance-corrected near visual acuity with less than a 5-letter loss in distance acuity vs placebo in low light conditions at 2 hours after treatment.⁴ Adverse events were reported in fewer than 3% of patients, and all were mild and/or transient.⁴

LNZ 100/101

LENZ Therapeutics offerings aceclidine and aceclidine + brimonidine (LNZ 100 and LNZ 101, respectively), feature a method of action that works as a parasympathomimetic miotic. Outside the United States, it is available for narrow-angle glaucoma. LNZ100/101 has completed a Phase 2B trial and has commenced the Phase 3 trial with once-daily dosing. The primary endpoint, as in all these agents, is a 3-line improvement in DCNVA at 1.47 ft at 1-hour post-treatment.⁵

The drug has a 30-minute onset of action with a claim of duration up to 10 hours. Side effects will need to be evaluated, as will duration of action.

Nyxol

Ocuphire’s drug candidate Nyxol (0.75% phentolamine ophthalmic solution) is a preservative-free eyedrop that decreases pupil diameter by inhibiting the iris dilator muscle, creating a pinhole effect of the pupil. In the VEGA-1 Phase 2 clinical trial, 29% of presbyopic subjects treated with Nyxol alone compared to 12% in placebo at 12 hours post-dose of Nyxol as well as 61% of presbyopic subjects treated with Nyxol + low-dose pilocarpine at 1 hour post-dose of LDP compared with 14% of subjects on placebo improved 15 letters or greater (≥3 lines) in photopic binocular near vision.⁶

Ocuphire recently completed enrollment of a Phase 2 presbyopia study, with a primary endpoint of the percentage of subjects with ≥3-line improvement in binocular photopic DCNVA at 1 hour. The company is evaluating the efficacy of a kit combination of Nyxol dosed in the evening and low-dose 0.4% 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.⁷ Low-dose pilocarpine can allow for the miotic effects of pilocarpine with low side effect profile.⁸

Brimochol PF

Visus Therapeutics is testing brimochol PF, a combination drop of 2.75% carbachol and 0.1% brimonidine, hoping to show a synergistic effect of the two 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.⁹

As with all the other miotics, but especially because carbachol is the most potent cholinergic for pupil constriction, the night vision assessments will be pertinent to follow.

Reason for hope

All the aforementioned drops have shown great promise, each in their own way, for eye-care providers to finally be able to address many levels of presbyopia without devices or surgical intervention. Hopefully, following FDA review, there will be many approved 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 glasses or contact lenses. All these options will require safety, tolerability, ease of use, and low side effect profiles to be used en masse. OP

REFERENCES

1. AbbVie. VUITY PRESCRIBING INFORMATION. https://www.rxabbvie.com/pdf/vuity_pi.pdf. Accessed Feb. 7, 2023.
2. Orasis Pharmaceuticals. Results of novel eye drop candidate, CSF-1, for the treatment of presbyopia. https://www.orasis-pharma.com/orasis-pharmaceuticals-announces-positive-phase-3-topline-results-of-novel-eye-drop-candidate-csf-1-for-the-treatment-of-presbyopia/ . Accessed Feb. 7, 2023.
3. 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/orasis-pharmaceuticals-announces-csf-1-eye-drop-successfully-met-primary-endpoint-in-phase-2b-clinical-study-in-presbyopia/ . Accessed Feb. 16, 2023.
4. Eyenovia. Eyenovia announces positive results from VISION-2 Phase 3 study of Microline as a potential on-demand treatment for presbyopia. Oct. 20, 2022. https://eyenovia.com/eyenovia-announces-positive-results-from-vision-2-phase-3-study-of-microline-as-a-potential-on-demand-treatment-for-presbyopia/ . Accessed Feb. 7, 2023.
5. LENZ Therapeutics. LENZ Therapeutics announces positive topline data from INSIGHT, Phase 2 study. https://lenz-tx.com/2022/10/lenz-therapeutics-announces-positive-topline-data-from-phase-2-insight-trial-of-lnz100-and-lnz101-to-treat-presbyopia . Accessed Feb. 7, 2023.
6. Ocuphire Pharma. Ocuphire’s VEGA-1 Phase 2 Trial in Presbyopia Meets Primary and Secondary Endpoints. https://www.ocuphire.com/news-media/press-releases/detail/344/ocuphires-vega-1-phase-2-trial-in-presbyopia-meets. Accessed March 23, 2023.
7. 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.
8. 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 .
9. Visus Therapeutics initiates phase 3 clinical trials of Brimochol PF for the treatment of presbyopia. https://uploads-ssl.webflow.com/61088b48cbb6c4347abaaca5/62395f3d2797244ba46ec3f7_Visus%20Brimochol%20Phase%203%20Initiated_FINAL_03212022.pdf . Accessed Feb. 7, 2023.

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 for many FDA trials.

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