New options are on the horizon for presbyopia-correcting drops

Ophthalmology Times EuropeOphthalmology Times Europe September 2021
Volume 17
Issue 07

For ophthalmologists, finding the ideal solution for presbyopia has long been the ‘holy grail’ of the field.

New options are on the horizon for presbyopia-correcting drops

Presbyopia is a natural consequence of ageing. 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 the condition have been attempted, but none has yet become widely adopted for patients without significant cataract.

Dr Marguerite B. McDonald

Dr Marguerite B. McDonald

A review of available and emerging treatments for presbyopia was recently published.1 Finding the ultimate 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. Several of these drugs may be approved over the next 1 to 3 years, opening a new treatment avenue for patients who wish to be less dependent on reading glasses.

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

Candidates and trial results

There are various topical agents and clinical results available to date, discussed as follows.


Pilocarpine is a cholinergic muscarinic receptor agonist well established in managing pupillary miosis and is the most 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 reaches 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 endpoints in both studies2,3 were met, with more patients in the treatment group vs the vehicle-controlled group gaining three 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 hyperaemia, 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 US Food and Drug Administration (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 three or more lines of DCNVA when dosed twice daily.6 There was no impact on distance or night vision. A Phase 3 study of 300 participants has recently begun.

Eyenovia (Microline)

This company has a novel microdose dispenser (Optejet) that sprays the drug at the eye. A Phase 3 trial in which 84 subjects’ DCNVA were tested 2 hours after treatment with 1% or 2% pilocarpine1 showed that a statistically significant proportion of patients treated had a three-line or more increase in DCNVA vs placebo in low light 2 hours after treatment.7

Pilocarpine + phentolamine

Ocuphire Pharma is evaluating a kit that combines a moderate and long-acting evening dose of the non-selective a-1/a-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 Phase 2 study in 152 patients whose NVA was tested for up to 6 hours post-dose met its primary endpoint with statistical significance at 1 hour. More than half (61%) of patients treated with Nyxol plus low-dose pilocarpine gained 15 letters (three lines) in near VA.8


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 three or more lines of near vision and 92% gained at least two or more lines 1 hour after instillation, a statistically significant benefit over placebo.9

Approximately half the eyes maintained a two-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, although the company has reorganised and is moving forward under its new name, Lenz.10

Fixed-combination carbachol/brimonidine tartrate

Brimochol is a fixed combination of carbachol and brimonidine invented by Dr Herbert Kaufman and now under development by Visus Therapeutics for the treatment of presbyopia. Carbachol has previously been shown to be a more potent cholinergic miotic than pilocarpine.11 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.

Brimonidine also whitens eyes,12 which may prevent the redness typically associated with miotics. Four peer-reviewed studies evaluating this combination have been published in the literature, though using different formulations than are currently being tested by the company.14-16 One of these demonstrated superiority of the fixed combination over the individual components,13 something that is essential for FDA approval of any fixed-combination drop.17

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.16 A Phase 2 crossover study in 45 phakic and pseudophakic patients dosed once daily with one of two different Brimochol formulations or carbachol monotherapy has recently begun.17

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 disulphide bonds between crystalline lens proteins. The idea is that by hydrolysing the disulphide bonds, this drug would soften the lens and restore some accommodative ability.

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.18 A Phase 2 controlled trial evaluating safety and efficacy after 3 months of twice-daily dosing treatment in early presbyopes (aged 45–55) has also 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. 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 that the lens is safe for long-term use. 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, one 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 do not 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 advancement 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. The newer drops will likely 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 comfortable for patients with pre-existing ocular surface disease. This was true for glaucoma patients who had been on 4% or 6% pilocarpine for years, which had a high concentration of the active ingredient and were preserved, 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 probably 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 customise drop choice to patients’ lifestyles and ocular needs.

Marguerite B. McDonald, MD
Prof. McDonald is a clinical professor of ophthalmology at New York University in Manhattan, New York, US, and Tulane University in New Orleans, Louisiana, US. She is in private practice at OCLI Vision in Garden City, New York, Manhasset, New York, 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 Refract Surg. 2021; 37[Suppl]:S20-S27.
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 Ltd. 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 topical 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. Drug Approval Package: Lumify (brimonidine tartrate). U.S. Food and Drug Administration. Application Number: 208144. Approval Date: 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.
14. Abdelkader A. Improved presbyopic vision with miotics. Eye Contact Lens. 2015;41:323-327.
15. Abdelkader A. A novel pharmacological treatment of pseudophakic presbyopia. Int J Ophthalmic Res. 2018;4:291-294.
16. Abdelkader A. Influence of different concentrations of carbachol drops on the outcome of presbyopia treatment – a randomized study. Int J Ophthalmic Res. 2019;5:317-320.
17. Visus Therapeutics. Safety and efficacy study of brimocholtm, brimocholtmf, and carbachol in subjects with emmetropic phakic and pseudophakic presbyopia. 1 March 2021. Available at: Accessed 19 July 2021.
18. Novartis Pharmaceuticals. A study of safety and efficacy of UNR844 chloride (UNR844-Cl) eye drops in subjects with presbyopia. 18 January 2019. Available at: Accessed 22 April 2021.
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