The Long View on Presbyopia

Over the course of my career, I have been fortunate to witness and contribute to innovative developments in presbyopia correction, including laser refractive surgery, corneal procedures like conductive keratoplasty, and corneal onlays and inlays that have offered millions of patients the gift of spectacle independence.

What has been missing all along is a safe, effective, reversible, and noninvasive solution for the middle years – from approximately age 40 to whenever patients are ready for lens surgery. The onset of presbyopia in one’s 40s is the first real sign of aging for many people.  It is a particularly unwelcome shock for emmetropes and successful contact lens wearers, who suddenly find themselves wearing glasses for the first time.

In an ongoing quest to help patients in this age group, I was an early prescriber of pilocarpine 1.25% drops (Vuity, Allergan/AbbVie) and continue to offer them to patients.  Although some clinicians have not been actively offering Vuity, I take the long view. It is the first entrant to the market in an entirely new category. Just as with Restasis and Crystalens – the first in their own categories of dry eye therapies and premium IOLs – we have had to learn important lessons about miotic drops for presbyopia after launch. Additional entrants to the market – the second and third waves of innovation – will have the benefit of those lessons learned and will hopefully continue to advance the science to better serve patients.

Here are some of the still unmet needs in topical presbyopia correction that new agents may be able to address.

1. Minimize the number of drops
 

Certainly, a drop that lasts all day without re-instillation is desirable. I’m excited about the potential for Brimochol PF (Visus Therapeutics), a presbyopia-correcting drop containing carbachol and brimonidine, which together provide the duration of effect that may better meet patient needs. We could also see the introduction of a topical formulation that isn’t a drop at all: Eyenovia’s Optejet technology, which delivers a fine mist to the eyes, could alleviate the concerns of patients who don’t like using drops. The delivery technology is being tested with once-daily pilocarpine 2% (NCT05114486). I am interested to see whether a spray is effective and whether it can be delivered without smearing makeup.

2. Increase the responder rate
 

Manufacturers can secure approval of their presbyopia-correcting drops by demonstrating a statistically significant difference in the number of responders (people who achieve a three-line gain in near vision without losing distance vision) between the study drug and the control group. Presbyopia-correcting drops with a higher and longer responder rate are needed for doctors to feel more confident in routinely prescribing them.

3. Reduce symptoms
 

I think we’d all prefer to have a drop that doesn’t cause headaches, brow ache, stinging/ burning, or a sensation of dimness. In my experience, most of the unwanted symptoms associated with using pilocarpine drops go away after a few days of use, and patients who “power through” early symptoms often do just fine later on. However, brow ache as a symptom is also telling us that the ciliary body is stimulated by the drug, and that can have consequences for the retina. Phentolamine, the active ingredient in Nyxol (Ocuphire), blocks pupillary dilation, so it may be safer for high myopes – or former high myopes who have had LASIK already – to use without risking a retinal detachment (RD). The downside of phentolamine is that the drug causes significant redness for a few hours, so it is dosed at night to allow the hyperemia to dissipate overnight. As a monotherapy, it induces less miosis and near vision improvement than cholinergics. Ocuphire is testing Nyxol with and without a low-dose pilo “booster” that would be used the next morning. We need to see additional study data to know whether the disadvantage of a two-step drug regimen will be offset by greater safety.

Although often positioned as a “tolerability issue,” the symptom of redness is problematic because it conflicts with one of the reasons people are interested in a presbyopia-correcting drop in the first place. They want to look good! They don’t want any visible signs of aging or ocular redness. Pilocarpine has a direct effect on muscarinic receptors, providing a vasodilator effect that contributes to redness. Brimonidine, the second drug in Brimochol PF, is a sympatholytic alpha-2 agonist that whitens eyes, so it may have an advantage in addressing this common cosmetic issue with topical presbyopia drops. Brimonidine also has the advantage of preventing pupillary dilation and, by altering aqueous dynamics, increases the bioavailability of carbachol, thereby extending the duration of its pinhole effect.

Another contributor to redness and to stinging/burning symptoms is the low pH of some drops relative to the physiologic pH of human tears. In storage, pilocarpine is stable at a pH of 4.5 – far lower than the pH of tears (7.4). An incompatible pH can make drops uncomfortable, induce tearing, and reduce corneal permeability and bioavailability as well. The manufacturers of Vuity went to great lengths to ensure that, although their drop contains pilocarpine, it reaches a tolerable pH of 6.5 within a minute or two as the drop un-ionizes.  Aceclidine also requires an acidic pH for stability, and initial phase II results with topical aceclidine (NCT03201562) showed that 35–39 percent of patients experienced mild to moderate instillation site pain. Headache has also been reported with aceclidine despite some evidence there may be some degree of pupil selectivity demonstrated in iris and ciliary body explants (2). More recent safety data with topical aceclidine has yet to be presented publicly. As new presbyopia-correcting agents are introduced, it will be important to evaluate their overall tolerability profiles.

4. Turn back the clock on the lens
 

Best of all would be a way to treat the lens that reverses the protein misfolding and aggregation that causes presbyopia in midlife and eventually cataract in later years. Novartis evaluated UNR844, a lipoic acid choline ester that was reported to reduce disulfide bonds in the lens proteins to restore elasticity, but discontinued the program after poor phase II clinical trial results. Visus Therapeutics also has an interesting small molecule in early-stage development with the goal of preventing and reversing cataract and presbyopia. In preclinical studies, an α-crystallin inhibitor compound has been shown to restore the natural chaperone activity of native lenticular α-crystallins, restore lens elasticity, and reverse lens opacity in human lens explants (3).

The areas above are the four major items on my personal wish list for the next couple generations of presbyopia-correcting drops and disease-modifying agents to better serve our patients. I believe that we will see new products coming soon that address at least some of these unmet needs.

Pharmaceutical companies don’t bear all the responsibility for improving outcomes with topical presbyopia drops. We as clinicians have also learned that patient education and patient selection are absolutely critical. For example, miotic agents should only be prescribed by eye care providers who have performed a complete dilated exam to ensure that patients will benefit from drops and that they don’t have conditions that put them at higher risk of RD. We have to describe potential side effects and tell patients what to look for, when to return for a potentially serious complication, and how long to expect minor side effects to last.

For my patients who are appropriately counseled and highly motivated, Vuity has been quite successful. Patients love the reversibility and ease of a topical presbyopia solution. As science marches on, I believe this decade will be a watershed moment for the treatment of presbyopia.