Aging trends for presbyopia show a global prevalence of the “long-arm” condition at 1.1 billion people in 2015, with an estimation of reaching 1.8 billion people by 2050.^1,2 Additionally, approximately 80% of patients who have uncorrected presbyopia have difficulty performing near vision tasks, as found in a study focusing on quality of life by Berdahl et al.^1,3 This, in turn, leads to productivity loss estimated at $11 billion annually, within the United States.¹

Bifocals, progressive spectacle lenses, multifocal contact lenses, premium IOLs, corneal inlays and laser surgeries are currently available to meet these patients’ needs and, therefore, improve their quality of life and productivity. Pharmacologic solutions may soon join them as treatment options. As our patients look to us for the latest information on products and services that can benefit their vision and ocular health, here’s a look at these solutions, so we can, in turn, educate our patients on what’s in the pipeline.

PILOCARPINE-BASED TREATMENTS

Pilocarpine is a cholinergic agonist that works on the muscarinic 3 agonist pathway to cause miosis. Utilizing pilocarpine-based ocular therapeutics helps to create pinhole optics, which increases the depth of focus. A number of these treatments are in the pipeline:

• AGN-190584 (Allergan-Abbvie). This drop utilizes 1.25% pilocarpine. The GEMINI 1 clinical study evaluated 323 participants randomized in a one-to-one ratio of vehicle (placebo) to AGN-190584 (pilocarpine 1.25%). AGN-190584 was instilled bilaterally (in both eyes), once-daily, for 30 days in GEMINI 1 participants who have presbyopia. The primary and key secondary endpoints were met with a statistically significant greater proportion of participants treated with AGN-190584 who gained three lines or more (the ability to read three additional lines on a reading chart) in mesopic (in low light), high-contrast, binocular distance-corrected near VA (DCNVA) at day 30, hour three (22.5%, p < 0.0001) and hour six (9.7%, p = 0.0114) vs. the vehicle.

The results demonstrate AGN-190584 had a rapid onset of 15 minutes and a duration of up to six hours in mesopic DCNVA without loss of distance vision after administration at Day 30. Additional endpoints evaluated show that 75% of participants treated with AGN-190584 achieved a ≥2 two-line improvement in mesopic DCNVA; and 93% of participants achieved ≥20/40 vision in photopic (daylight) DCNVA. Improvements were also observed in distance-corrected intermediate VA (DCIVA) up to 10 hours at day 30. There were no treatment-emergent serious adverse events observed in any AGN-190584-treated participants, Allergan-Abbvie says. The most common treatment-emergent non-serious adverse event in AGN-190584-treated participants, occurring at a frequency of >5%, was headache. Most side effects were mild and transient in nature, with 1.2% of patients discontinuing use due to adverse events.

• CSF-1 (Orasis Pharmaceuticals). This is a proprietary, preservative-free formulation of low-dose pilocarpine. The parasympathomimetic creates a pinhole effect and, along with the proprietary vehicle and other formula elements, CSF-1 was designed to achieve tolerability and comfort. A Phase 2b clinical trial, comprised of 166 subjects, shows CSF-1, dosed twice a day for one week, successfully met the primary endpoint of statistically significant improvement in DCNVA of three lines or greater.⁴ In addition, all adverse events in this study were mild, temporary and self-resolving, Orasis Pharmaceuticals says. Two Phase 3 trials (NEAR-1 and NEAR-2) are underway and actively recruiting. (See bit.ly/3ycvfwA and bit.ly/3l6CUca , respectively.)

• MicroLine (Eyenovia). This is a 2% pilocarpine formulation that utilizes a microdose array print (MAP) therapeutic given via the company’s Optejet delivery dispenser.^5,6 The company says the dispenser allows for a smaller amount of solution to be dosed compared to the traditional eye dropper, preventing excessive overdosing that can cause systemic exposure and corneal toxicity. The VISION-1 Phase 3 study shows a higher proportion of participants met the primary endpoint of three lines or more improvement in near vision under mesopic lighting conditions at two hours after dosing, with the 2% formulation vs. the placebo; and significantly more participants who took the 2% pharmacologic solution gained two lines or more in near vision two hours after dosing vs. those who took the placebo.⁷ Effects on vision lasted at least three hours (the last measurement made in the trial) with one dose (MicroLine is dosed as needed). Eyenovia says ocular adverse events were trace-to-mild in severity and transient in nature, with fewer than 3% reporting headache and brow ache. The company is now recruiting for the Phase 3 trial VISION-2, which will enroll approximately 120 participants who will be randomized between 2% pilocarpine and placebo. Eyenovia says it expects topline data in mid-2022.

• Nyxol + LDP (Ocuphire Pharma Inc). This is comprised 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.⁸ The goal is to use both the iris dilator and the iris sphincter muscles moderately to improve near vision without any side effects associated with the use of pilocarpine, such as headaches and brow-aches. A Phase 2 trial (VEGA-1) reveals 61% of Nyxol + LDP subjects gained 15 letters or more (≥ 3 lines) in photopic binocular near vision at one hour vs. 28% of subjects using placebo (33% placebo-adjusted). Additionally, the formulation was effective at 30 minutes post-drop instillation and was maintained for at least six hours.⁹ The company reports mild, transient conjunctival hyperemia in <5% of subjects. Ocuphire now has plans for Phase 3 registration trials, it says. Nyxol will be dosed at night/bedtime, and pilocarpine will be dosed in the morning.

SEPARATE MIOTIC-BASED THERAPIES

Other therapies designed to cause miosis are:

• Brimochol (Visus Therapeutics). This drop contains carbachol, a cholinergic agent, and brimonidine, an alpha-2 agonist. Together these two actives decrease the pupil’s size, creating a sustained pinhole effect that allows only centrally focused light rays to enter the eye, thereby reducing blur and increasing depth of focus. Brimonidine tartrate also potentially mitigates miotic-induced side effects and prolongs carbachol’s duration of action, Visus Therapeutics says.¹⁰ Previous clinical trials demonstrate an onset of effect within 30 minutes that lasts at least eight hours with once-daily dosing.

A Phase 2 clinical trial was started in late March to assess the safety and efficacy of two proprietary formulations in patients who have emmetropic phakic and pseudophakic presbyopia. The company anticipates enrolling approximately 60 patients. The trial’s primary endpoint is the percentage of patients who gain three lines or more in near VA without losing distance vision. Trial results are expected in the second half of 2021.

• Aceclidine (LENZ Therapeutics). This is an aceclidine-based eye drop. Aceclidine is a parasympathomimetic that acts as a muscarinic receptor agonist, causing miosis by engaging the iris sphincter, while avoiding the ciliary muscle. Aceclidine helps to increase depth of focus, utilizing the pinhole effect, and its method of action is to avoid the ciliary muscle and associated myopic shift and side effects, the company says. Phase 2b trials, completed in 2018, show 53% of patients who received this pharmacologic solution via once-a-day dosing achieved the primary outcome of at least 3 lines in near VA at 30 minutes post-treatment.¹¹ Additionally, 81% gained at least two lines of near vision, and 50% of these patients noted this improvement lasting for up to seven hours.¹⁰ This formulation was well-tolerated, with no significant loss in monocular BCVA in study eyes, and had no serious adverse events, LENZ Therapeutics says. The company is now gearing up for Phase 3 studies.

CRYSTALLINE LENS-BASED TREATMENTS

The following formulation is designed to change the structure of the crystalline lens:

• UNR844 (Novartis). This drop is comprised of lipoic acid choline ester tosylate. UNR is theorized to disrupt the disulfide bonds found between crystalline lens proteins, resulting in a softer lens and, thus, facilitating accommodative ability.

A previous Phase 2a trial shows gains of 6.1 letters in the treatment group vs. 4.5 letters in the placebo group, with 43% of the treatment group gaining two lines of near vision compared with 18% placebo.

Novartis is currently recruiting for a Phase 2b clinical trial on UNR844. (See clinicaltrials.gov/ct2/show/NCT04806503 .)

PERFECT TIMING

With the continued growth in the number of presbyopic patients and as millennials enter into the equation, the introduction of more treatment options for this refractive condition, such as the pharmacologic solutions outlined above, couldn’t come at a better time. When we educate our patients on treatment advances, it binds them to our practices: They know they’ll get the most up-to-date care. OM

REFERENCES

1. Berdahl J, Bala C, Dhariwal M, Lemp-Hull J, Thakker D, Jawla S. Patient and Economic Burden of Presbyopia: A Systematic Literature Review. Clin Ophthalmol. 2020;14:3439-3450 https://doi.org/10.2147/OPTH.S269597
2. GBD 2019 Blindness and Vision Impairment Collaborators, on behalf of the Vision Loss Expert Group of the Global Burden of Disease Study. Trends in prevalence of blindness and distance and near vision impairment over 30 years: an analysis for the Global Burden of Disease Study. Lancet Glob Health 2020; published online Dec 1. https://doi.org/10.1016/S2214-109X(20)30425-3 .
3. Holden BA, Fricke TR, Ho SM, et al. Global vision impairment due to uncorrected presbyopia. Arch Ophthalmol. 2008;126(12):1731–1739. doi:10.1001/archopht.126.12.1731
4. Orasis Pharmaceuticals. Orasis Pharmaceuticals Announces CSF-1 Eye Drop Successfully Met Primary Endpoint in Phase 2b Clinical Study in Presbyopia. https://www.orasis-pharma.com/orasis-pharmaceuticals-announces-csf-1-eye-drop-successfully-met-primary-endpoint-in-phase-2b-clinical-study-in-presbyopia/ . Accessed July 28, 2021.
5. Eyenovia. Eyenovia Pipeline: MicroLine (Presbyopia). MicroLine is our proprietary pilocarpine formulation and candidate for the episodic treatment of presbyopia. https://eyenovia.com/pipeline/presbyopia/ . Accessed July 28, 2021.
6. Eyenovia. Eyenovia Announces Positive Topline Results from VISION-1 Phase 3 Clinical Study of MicroLine for the Treatment of Presbyopia. https://eyenovia.com/eyenovia-announces-positive-topline-results-from-vision-1-phase-3-clinical-study-of-microline-for-the-treatment-of-presbyopia/ . Accessed July 28, 2020.
7. Eyenovia News Release. Eyenovia Highlights Recent Progress in Three Phase 3 Programs, NDA Review Progress and License Agreement Totaling up to $100 million in Potential Pre-Commercial Revenue. https://ir.eyenovia.com/news-releases/news-release-details/eyenovia-highlights-recent-progress-three-phase-3-programs-nda . Accessed July 28, 2021.
8. Ocuphire Pharma. Nyxol Eye Drops: Beginning Phase 3 Development Through the 505(b)(2) Pathway. https://www.ocuphire.com/product-pipeline/nyxol . Accessed July 28, 2021.
9. Ocuphire Pharma. Press Releases. 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 July 28, 2021.
10. Visus Therapeutics. Visus Therapeutics Initiates Phase 2 Clinical Trial of Brimochol for the Treatment of Presbyopia. https://uploadsssl.webflow.com/5eea6cf86d23885e6fe09eb2/605be3ce5d20506c04b99ca9_Visus%20Therapeutics_PRESS%20RELEASE_FirstPatientPh2_FINAL%20FOR%20BW%20UPLOAD%203.24.2021.pdf . Accessed July 28, 2021.
11. Presbyopia Therapies Announces Primary Safety and Efficacy Endpoints Met in a Phase IIb Study of it’s Topical PRX Ophthalmic Solution for the Treatment of Presbyopia. www.prnewswire.com/news-releases/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-300688070.html . Accessed July 28, 2021.

DR. KOETTING practices at Virginia Eye Consultants, and she is adjunct faculty for Pacific University, MCPHS, Salus University, Southern College of Optometry and the University of the Incarnate Word. She has received consulting fees or honorariums from Oyster Point, Glaukos, Quidel, Horizon, Ocular Therapeutix and Eyevance.