How often have you had a patient sit in your chair and say “I’m starting to have a little trouble seeing up close, doc!” And if you dare respond back and mention the words “getting old,” “40s,” “bifocals,” you may be met with a stink eye or chuckle, and suddenly they’re cured of their ailment and it’s “not THAT big a deal.” Fortunately, there’s hope in some emerging topical treatments and we may no longer have to worry about those dreaded old people glasses.
Presbyopia (AKA accommodative loss) starts to affect people in their 4th decade of life. We’re quite familiar with treatment through bifocals, progressives, monovision/multifocal contacts, and premium IOLs. Back in the day, you may have laughed when patients wanted you to prescribe a drop to cure aging eyes. But now, a lot of companies are investing top dollar in some groundbreaking research for these exact treatments. This article will highlight some of these medications, and where they currently stand.
There are two mechanisms of actions that companies are targeting: 1) accommodation, 2) pupillary miosis to increase depth of field. Here’s a few products that are gaining traction in this emerging field:
Dioptan (UNR844) by Novartis
In a young eye, lens accommodation occurs by displacement of cytosol centrally. When the eye ages, oxidation stiffens the crystalline proteins to disulfides and prevents cytosol from moving through. UNR844 (formerly known as EV06) is composed of a lipoic acid choline ester which breaks down further into choline and lipoic acid that penetrates into the cornea, and causes hydrolysis of proteins to reduce disulfide bonds. This creates a free flow of cytosol centrally and once again allows the lens to change shape.
In phase 1 of animal studies, the drop was applied to one lens tid for five weeks. Results showed a 40% increase in elasticity compared to the untreated lens. In phase 1/2 of human studies, lipoic acid choline ester chloride soln 1.5% vs placebo was dosed in each eye bid for three months. Seventy participants were selected, aged 45-55 years of age with hyperopia, myopia, and emmetropia. There was a statistically significant improvement in near vision of two lines or greater in participants vs placebo. Phase 2 clinical trials were just completed at the end of December 2019, and results are yet to be announced.
The second mechanism of action causes a pinhole effect which increases the depth of field. Parasympathomimetic (cholinergic) drugs are known to have certain side effects with overstimulation of the ciliary muscle and pupillary sphincter: accommodative spasm, brow ache, myopic shifts, anterior segment inflammation, among others. And visually speaking - decreased contrast sensitivity, and limited peripheral night vision are also an issue against optimal vision. It is believed that the perfect topical agent needs to create a stable pupil size of 1.6 mm for several hours with no side effects. This is all largely being explored by a few different companies: Allergan, Presbyopia Therapies, and Orasis Pharmaceuticals.
Anatomical interlude
Let's review a bit of anatomy so we can understand how the next few drugs will work.
Accommodation is done by the ciliary muscle, lens, and zonular fibers. The ciliary muscle is innervated by parasympathetic fibers from cranial nerve V (nasociliary branch) to alter the shape and position of the lens causing accommodation. It is also dually innervated by some sympathetic fibers to inhibit accommodation. The ciliary muscle contains muscarinic-3 acetylcholine receptors (M3). The iris is also under heavy innervation by the parasympathetic system, and cholinergic stimulation of its M3 receptors causes miosis.
On the other hand, the iris dilator muscle is sympathetically innervated and contains alpha-adrenergic receptors. When these receptors are antagonized, it allows the parasympathetic innervation of the sphincter muscle to take over and cause miosis.
Oxymetazoline (AGN-199201) and AGN-190584 by Allergan
AGN-199201 is oxymetazoline, an alpha-sympathomimetic agent, whereas AGN-190584 is an unknown agent. Oxymetazoline’s alpha-adrenergic action causes mydriasis by acting on the iris dilator muscle. This may seem counterintuitive since we need a miotic pupil for depth of focus, but it may be that oxymetazoline is used to weaken the adverse effects caused by AGN-190584.
Allergan is moving apace with launching this medication which claims to produce miosis and increases depth of focus without affecting accommodation. Phase 2 trials showed promising results where greater than 70% of participants received one drop of AGN-190584 followed by one drop of AGN-199201 vehicle in the non-dominant eye, and two drops of AGN-199201 vehicle in the dominant eye. They experienced a two line improvement in VA. Phase 3 trials were completed in late 2019, and Allergan’s goal is to obtain approval in 2021. The drops have been well tolerated and studies show improvements in near vision in the dark without compromising distance.
Liquid Vision (PRX-100) by Presbyopia Therapies
PRX-100 is a topical solution that contains aceclidine in one arm, and aceclidine with low-dose tropicamide in the other. This is a proprietary blend of a muscarinic agonist and a muscarinic antagonist. Aceclidine is less potent than pilocarpine. And tropicamide is thought to be chosen due it’s propensity to attach to iris M3 receptors (versus ciliary M3 receptors like other antimuscarinic agents). This will dilate the pupil without affecting accommodation, and relieve side effects like pupillary spasm, ciliary contraction and in turn resolve issues like brow ache. (This is also why we prescribe cyclopentolate, another antimuscarinic agent, for uveitis or corneal abrasion to reduce aching pain from ciliary and iris spasm.)
This combination is reported to effectively cause miosis without stimulating accommodation. The onset of action is reported in less than 30 minutes. In phase 2b trials, PRX-100 showed a 3 line or greater improvement in monocular distance corrected near acuity in patients aged 48-64 years. The drug was well tolerated and effects were noted up to seven hours after initial instillation.
Presbi-Drops (CSF-1) by Orasis
What is unique about this formula is that it is a combination of a parasympathomimetic agent with a nonsteroidal anti-inflammatory in an oil-based formulation. The NSAID is hoped to overcome discomfort from ciliary spasm, and minimize risk of uveitis. Current data shows a boost in near vision by 2-3 line improvements in high and low illumination, without impacting distance vision. The company has finished phase 2b trials and are analyzing the data, which will be presented at an upcoming medical meeting.
Other Treatments
Electrostimulation:
An unconventional idea found by Ocufit that provides a low voltage pulse to passively contract the ciliary muscle. Studies show promising short term results (2 months) for near and intermediate visual acuity in emmetropic presbyopic patients ranging from 40-50 years old.
Optimal Keratoplasty:
Heat coagulation of the corneal stroma alters the corneal curvature. With the use of a special applanation ring, Opti-K confines thermal elevation into the anterior corneal stroma and preserves the epithelium and produces multiple intervals of Sturm. This phenomenon causes improvement in near vision, and distance for hyperopic patients. The peak lasts up to 45 days, with decline between three to six months. Post-laser recovery is immediate, and patients may return to a routine lifestyle the next day.
In closing...
These upcoming years will be exciting with new developments underway. At some point, we’ll have to factor in how insurance companies will cover for these drops. Let’s hope that these options will be affordable and accessible to people across the globe. Who knows if at some point these drops will be available over the counter. We also need to think about how to perform dilations on a miotic pupil—perhaps we can just chuck them over to retina (jk) or just lay off the miotics the day of the appointment. Patients in their 60s will still need to consider surgical options which also have continued succession. As optometrists, we are going to be at the forefront when discussing and/or prescribing these medications.
