New options are on horizon for presbyopia-correcting drops

Digital Edition, Ophthalmology Times: May 2021, Volume 46, Issue 8

Therapeutic choices beneficial for patients may be available in 1 to 3 years.

Special to Ophthalmology Times®

Presbyopia is a natural consequence of aging. It affects more than 1 billion individuals globally and approximately 123 million in the United States.

Over the years, many surgical approaches to the correction of presbyopia have been attempted, but none has yet become widely adopted for patients without significant cataract.

A review of available and emerging treatments for presbyopia was recently published.1 Finding a truly good solution for this problem has long been the holy grail of ophthalmology because the demand—and the potential rewards—are great.

Companies have begun testing topical therapies for the temporary correction of presbyopia.

Related: Presbyopia: Rethinking approach to better fit patients' needs

Several of these drugs may be approved over the next 1 to 3 years, opening up a new treatment avenue for patients who want to be less dependent on reading glasses.

Most of the drops being evaluated aim to modulate the pupil for better near vision. There will likely be significant differences among them in duration, tolerability, and other factors.

Below are various topical agents and clinical results available to date.

Pilocarpine is a cholinergic muscarinic receptor agonist well-established in managing pupillary miosis and is the most commonly employed agent in emerging presbyopia therapeutics.

What distinguishes the new presbyopia formulations from currently available generic pilocarpine is the lower concentration (in most cases, ≤ 1% vs up to 6% in generic pilocarpine) and that the investigational agents rely on sophisticated delivery vehicles that are better at modulating how much of the active ingredient gets to the ocular tissues.

Several companies have pilocarpine-based drops in clinical trials:

>AbbVie/Allergan (AGN-190584).Two phase 3 clinical trials (Gemini I and II) with a total of 750 participants have been completed. No published studies are available but public reports note that primary end points in both studies2,3 were met, with more patients in the treatment group versus the vehicle-controlled group gaining 3 or more lines of mesopic high contrast binocular distance-corrected near visual acuity (DCNVA) at 3 hours over 30 days of bilateral single-dose use.4

Headache, conjunctival hyperemia, blurred vision, and eye pain were each reported by 3% or fewer of the patients treated with AGN-190584. A New Drug Application has been submitted to the FDA and approval is anticipated in late 2021.

>Orasis (CSF-1). A phase 2 study5 with 166 participants was completed in 2019 with reportedly good tolerability of the drop and statistically significant gains of 3 or more lines of DCNVA when dosed twice daily.6 A phase 3 study of 300 participants has recently begun.7

>Eyenovia/B+L (MicroLine). This company has a novel microdose dispenser (Optejet) that sprays the drug at the eye. A phase 3 trial in which 84 participants’ DCNVA will be tested 2 hours after dosing with 1% or 2% pilocarpine is underway.8

Related: Avoiding IOL refinements after presbyopia-correction surgery

Pilocarpine + phentolamine
Ocuphire Pharma is evaluating a kit that combines a weak but long-acting evening dose of the nonselective α-1/α-2 adrenergic antagonist phentolamine 0.75% with a morning dose of pilocarpine 0.4%.

Synergistically activating the iris sphincter muscle while inhibiting the iris dilator muscle allows for lower concentrations of the active ingredients and may reduce the likelihood of adverse reactions.

A bA phase 2 study of 152 participants whose near vision will be tested for up to 6 hours post dose is underway.9

Similar to pilocarpine, aceclidine is also a parasympathomimetic cholinergic muscarinic receptor agonist.

A phase 2 study of an aceclidine-based miotic treatment for presbyopia in 58 participants was completed by Presbyopia Therapies in 2018.10


At the time, the company reported that 47% of study eyes gained 3 or more lines of near vision and 92% gained at least 2 or more lines 1 hour after instillation, a statistically significant benefit over placebo.11

Approximately half the eyes maintained a 2 or greater line improvement for up to 7 hours. Little information has been released about the drop since, and no additional studies have been registered.

Fixed-combination carbachol/brimonidine tartrate
Brimochol is a fixed combination of carbachol and brimonidine invented by Herbert Kaufman, MD, and now under development by Visus Therapeutics for the treatment of presbyopia.

Carbachol previously has been shown to be a more potent cholinergic miotic than pilocarpine.12 Combining it with brimonidine, which prevents pupil dilation and may inhibit ciliary muscle contraction, achieves synergistic effects and may reduce the severity of adverse effects.

Related: Researchers reaching for the stars to cure presbyopia

Brimonidine also whitens eyes,13 which may prevent the redness typically associated with miotics. Four peer-reviewed studies evaluating this combination have been published in the literature.14-17

One of these demonstrated superiority of the fixed combination over the individual components,14 something that is essential for FDA approval of any fixed-combination drop.

Results of the most recent study, in 2019, showed a 12-hour duration of effect on near vision in 57 participants without any reported symptoms of headache or brow ache.17 A phase 2 crossover study in 45 phakic and pseudophakic patients dosed once daily with 1 of 2 different Brimochol formulations or carbachol monotherapy has recently begun.18

Lipoic acid choline ester chloride
Unlike the other drops that act by modulating the pupil, Novartis is developing UNR844, a lipoic acid choline ester chloride that acts on disulfide bonds between crystalline lens proteins.

The idea is that by hydrolyzing the disulfide bonds, this drug would soften the lens and restore some accommodative ability.

Related: Technology puts focus on presbyopia laser correction

Results of an early phase 1/2 study found an improvement in DCNVA of 8.1 letters in the treated group vs 4.3 letters in the placebo group.19

A phase 2 controlled trial evaluating safety and efficacy after 3 months of twice-daily dosing treatment in early presbyopes (age 45-55) also has been completed, with a gain of 6.1 letters in the treatment group vs 4.5 letters in the placebo group.

In addition, 25% of the treatment group vs 16% of the placebo group achieved 75 or more letters in total. The most common adverse events reported were dysgeusia and headache, in 5% and 3% of treated participants, respectively.19

Thus far, study sponsors have reported only functional effects on vision from this lens-softening agent, rather than any lens outcomes such as change in accommodation.

Also, as trials are attempting to reverse presbyopic lens changes, it seems likely that such a drop would be used in younger individuals to prevent lenticular changes in the first place. This would increase the burden of proving the lens is safe for long-term use.

Related: Curvature-changing IOL: New frontier in cataract and presbyopia surgeries

This is a fascinating therapeutic category, but I think ophthalmologists are going to want to see a great deal more data, including whether these drops work consistently across the entire lens.

Factors to consider
As presbyopia-correcting drugs come to market, 1 of the most important factors for both physician and patient acceptance will be efficacy—how well the patient can read and use a computer.

Everybody likes to see J1 clinical trial results, but most individuals don’t actually need to be able to read J1.

A drop that can provide J6 or better for 8-12 hours, to cover most of a person’s working hours, would be a big advance for patients.

Although most of the pupil-modulating drops in development are being tested for use in both eyes, patients may experiment with using the drops monocularly and binocularly.

Related: How pinhole camera effect in small-aperture implant corrects presbyopia

The newer drops will have vehicles that are kinder to dry eyes or will make use of sustained-delivery nanomicelle technology.

Some presbyopia-correcting drops may be available in preservative-free formulations, which will make them more realistic for patients with preexisting ocular surface disease.

That was true for glaucoma patients who had been on 4% or 6% pilocarpine for years, but it may not be an issue with the much lower concentrations of pilocarpine that are being developed for presbyopia.

Although there are quite a few presbyopia-correcting drops in development, there will likely be room for all—or at least several—of them.

It will be relatively easy for patients to try several types and for practitioners to customize drop choice to patients’ lifestyles and ocular needs.


About the author

Marguerite B. McDonald, MD
McDonald is a clinical professor of ophthalmology at New York University in Manhattan and Tulane University in New Orleans, Louisiana. McDonald is in private practice at OCLI Vision in Garden City, Manhasset, and Oceanside, New York. She is a consultant to Allergan, Visus Therapeutics, and Ocuphire Pharma, and she has stock ownership in Ocuphire Pharma.



1. McDonald MB, Mychajlyszyn A, Mychajlyszyn D, Klyce SD. Advances in corneal, surgical and pharmacological approaches to the treatment of presbyopia. J Refractive Surg 2021; In press.

2. Allergan. A Phase 3 Efficacy Study of AGN-190584 in Participants with Presbyopia. 28 February 2019. Available at: Accessed: 22 April 2021.

3. AbbVie. Allergan, an AbbVie Company, Announces Positive Phase 3 Topline Results for Investigational AGN-190584 for the Treatment of Presbyopia. PR NewsWire. 28 October 2020. Available at: Accessed 22 April 2021.

4. Orasis Pharmaceuticals Ltd. A Multi-Center, Double-Masked Evaluation of the Efficacy and Safety of CSF-1 in the Treatment of Presbyopia. 21 March 2019. Available at: Accessed 22 April 2021.

5. Orasis Pharmaceuticals Announces CSF-1 Eye Drop Successfully Met Primary Endpoint in Phase 2b Clinical Study in Presbyopia. Orasis Pharmaceuticals. 10 October 2019. Available at: Accessed 22 April 2021.

6. Orasis Pharmaceuticals Ltd. An Evaluation of the Efficacy and Safety of CSF-1 in the Temporary Correction of Presbyopia (NEAR-1) (NEAR-1). 28 October 2020. Available at: Accessed 22 April 2021.

7. Eyenovia Inc. Safety & Efficacy of Pilocarpine Eye Solutions for Temporary Improvement of Near Vision in Presbyopic Adults (VISION-1). 8 December 2020. Available at: Accessed 22 April 2021.

8. Ocuphire Pharma, Inc. Safety and Efficacy of Nyxol With Pilocarpine Eye Drops in Subjects with Presbyopia. 19 December 2020. Available at: Accessed 22 April 2021.

9. Presbyopia Therapies, LLC. Evaluation of the Efficacy and Safety of PRX-100 in the Treatment of Early to Moderate Presbyopia. 8 September 2015. Available at: Accessed 22 April 2021.

10. Presbyopia Therapies. Presbyopia Therapies Announces Primary Safety and Efficacy Endpoints met in a Phase 11b study of its Tropical PRX Ophthalmic Solution for the Treatment of Presbyopia. PR Newswire. 30 July 2018. Available at: Accessed 22 April 2021.

11. Stamper R, Lieberman M, Drake M. Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas (8th Edition). Mosby, China, June 2009.

12. Bausch + Lomb. LUMIFY. Prescribing information. U.S. Food and Drug Administration. 22 December 2017. Available at: Accessed 22 April 2021.

13. Abdelkader A, Kaufman HE. Clinical outcomes of combined versus separate carbachol and brimonidine drops in correcting presbyopia. Eye Vis (Lond). 2016;3:31. doi:10.1186/s40662-016-0065-3.

14. Abdelkader A. Improved presbyopic vision with miotics. Eye Contact Lens. 2015;41(5):323-327. doi:10.1097/ICL.0000000000000137.

15. Abdelkader A. A novel pharmacological treatment of pseudophakic presbyopia. Int J Ophthalmic Res. 2018;4(2):291-294.

16. Abdelkader A. Influence of different concentrations of carbachol drops on the outcome of presbyopia treatment – a randomized study. Int J Ophthalmic Res. 2019;5(1):317-320.

17. Visus Therapeutics. Safety and Efficacy Study of BRIMOCHOLTM , BRIMOCHOLTMF, and Carbachol in Subjects with Emmetropic Phakic and Psedophakic Presbyopia. 1 March 2021. Available at: Accessed 22 April 2021.

18. 1, Accessed 4/2/21.

19., Accessed 4/2/21.

download issueDownload Issue : Ophthalmology Times: May 2021