PRESBYOPIA IS A PHYSIOLOGICAL accommodative insufficiency associated with aging of the eye that progressively worsens the ability of the crystalline lens to focus on near objects. Like death, taxes and cataracts, it is one of the few near certainties of life. Presbyopia classically presents around the age of 40, and currently affects an estimated 1.8 billion people globally (128 million in the U.S. alone). As the eye ages, the natural lens becomes progressively less flexible, eventually compromising near vision. Common symptoms include eyestrain and headaches that are worsened by near tasks, difficulty reading small print and a need for more light when reading. But you already knew all that.

More importantly, with the ubiquity of presbyopia, it is no surprise that discovering a novel way to correct it has been likened to finding the holy grail of the eye care world. Presbyopia can be currently managed with contact lenses, eyeglasses and surgery. Wouldn’t it be nice to have an age reversing eye drop? We can, and we will. Broadly, these drops can be classified into two categories: miotic agents intended to increase depth of focus by decreasing pupil size to an ideal 1.5 to 2.5 mm PD, and compounds intended to soften the crystalline lens. Of these two options, miotics are far closer to coming to market.

Miotics

• Abbvie/Allergan AGN-190584

One of the newest preservative-free miotic drops is AGN-190584 from Abbvie/Allergan. It consists of low concentration pilocarpine (1.25%), and includes a proprietary multi-faceted vehicle with the goal of creating exceptional near visual acuity without a reduction of distance acuity or night vision. While its primary mechanism of action is through pupil constriction, AGN-190584 also aims to maintain pupillary response to different lighting conditions—an effect known as dynamic pupil modulation. Currently, the drop has completed a phase 3 clinical trial (GEMINI I), and has been submitted to the FDA for approval after meeting both its primary and secondary efficacy endpoints.

In the phase 3 trial, 323 participants were randomized in a one-to-one ratio to AGN-190584 vs. vehicle (placebo). With a once-daily dosing system, a statistically significant proportion of patients was able to gain three lines or more of mesopic, high contrast, binocular Distance Corrected Near Visual Acuity (DCNVA) at day 30, hour 3 and hour 6. It showed a rapid onset of 15 minutes and a duration of up to 6 hours without loss of distance vision. In addition, 75% of patients in the treatment group achieved >2 line improvement in mesopic DCNVA, 93% achieved >20/40 vision in photopic DCNVA, and improvements were observed in intermediate acuity for up to 10 hours. Constricted pupil sizes over time are expected to return to baseline within 24 hours with minimal to no side effects, and no tachyphylaxis was found. Side effects of the drop include headaches, conjunctival hyperemia, visual blur, and eye pain. Overall, patients who had received AGN-190584 had a reduction in the use of presbyopia-related coping behaviors such as squinting or changing the size of electronic screens, compared with those who received vehicle. In addition, it is preservative free and would be a good option for patients with concurrent ocular surface disease.

• Eyenovia MicroLine

Eyenovia MicroLine is another presbyopia drop in a phase 3 clinical trial. The VISION-1 study evaluated the safety and efficacy of the company’s 1 and 2% pilocarpine Micro-Array Print formulations vs. placebo, administered by a proprietary dispenser, the Optejet. The results showed statistically significant improvements in DCNVA in low light conditions at 2 hours post-treatment. MicroLine was well tolerated with no serious adverse events. The dispenser delivers the solution in a well-distributed mist, offering convenience, cleanliness and a reduced chance of systemic absorption.

• Orasis CSF-1

This drop has been dosed twice a day in testing, and no negative impact on distance or night vision has been reported. The major benefit of Orasis CSF-1 is that it is titratable; which means patients are not trapped into an extended duration of effect should they choose to revert back to their reading glasses or stop the drop due to side effects. In addition, it is also preservative free and may be a better option for patients with presbyopia and dry eye disease. The primary endpoint is a 3 line improvement in near visual acuity with minimal loss of best corrected distance vision. The secondary endpoint is a 2 line improvement in near with slight impact on night vision along with various safety and tolerability measurements. It has recently demonstrated good safety, efficacy and comfort in its phase 2b study, and is currently enrolling participants in its phase 3 clinical trials, NEAR-1 and NEAR-2.

• Ocuphire Pharma Nyxol + Low-Dose Pilocarpine

Ocuphire recently completed its phase 2 proof of concept trial (VEGA-1) to evaluate a combination of Nyxol (PF phentolamine 0.75%) and low-dose pilocarpine in the treatment of presbyopia. It is one of the only drops to combine a cholinergic agonist with an alpha adrenergic antagonist, and thus acts on both the iris sphincter and iris dilator muscles. Its primary and secondary endpoint compares the amount of letter gain in photopic distance and corrected vision along with its duration of action and side effects. It met its primary and secondary efficacy endpoints, and is expected to be moving on to phase 3 soon.

• OSRX Pharmaceuticals Eyefocus

This is a compounded miotic eye drop—available in EyeFocus and EyeFocus+ strengths—which contains low concentrations of pilocarpine, phenylephrine, pheniramine and ketorolac. The company recently completed a proof-of-concept study in nine patients aged 44-64, and early results appear promising.

• Lenz Therapeutics (formerly Presbyopia Therapies) PRX-100/Liquid Vision

Liquid Vision uses aceclidine, a novel chemical entity in the U.S., to cause pupillary constriction without induced myopia (improving near vision without impairing distance). Its phase 2b study showed a rapid onset at 30 minutes as well as a duration of at least 7 hours, and a phase 3 trial is expected soon.

• Visus Therapeutics Brimochol

Brimochol is a proprietary combination of carbachol and brimonidine that is currently enrolling 40 patients in its phase 2 trial, with results expected towards the end of the year. It appears that carbachol may have a longer duration of action than pilocarpine, leading to treatments that may last up to 8 hours. Also, the addition of brimonidine has reportedly mitigated some of the adverse effects seen with miotics (headaches, hyperemia and brow aches). Two phase 3 studies enrolling up to 500 patients are expected in the near future.

Lens Softening

There are currently two companies attempting to tackle the root cause of presbyopia by developing products designed to soften the crystalline lens.

• Novartis Dioptin

Novartis is currently planning a phase 2b dose-finding trial for Dioptin, an ester of naturally occurring R-lipoic acid and choline that penetrates through the cornea and acts to reduce disulfide bonds between lens proteins, ideally restoring lens elasticity that has been lost with age. A phase 2 study of 78 subjects did not meet primary efficacy endpoints, but research is ongoing.

• Viewpoint Therapeutics VP1-001

Viewpoint Therapeutics is in preclinical investigations evaluating the molecule VP1-001 as a way to stabilize the protein alpha-crystallin, ideally working to treat both presbyopia and cataracts. Alpha-crystallin is a crucial component of the natural lens, with an important role in maintaining transparency and flexibility. It tends to destabilize with age, leading to light scatter and lens rigidity.

Meeting the Need

Presbyopia-correcting drops are on the horizon, and have the potential to become a potent tool in the treatment of one of the most common conditions optometrists face.

There is an unmet need for a topical drop to improve near vision from early presbyopes to pseudophakes. Contraindications include high myopes and a history of retinal tears, due to the pharmacological action of pilocarpine. As clinicians, we are excited and anxious to see how we will be able to utilize these tools to improve the lives of our patients. Overall, studies have shown significant improvement in near vision with presbyopia drops. ■

Dr. Kading owns three practices in the Seattle area (Specialty Eye), focusing on dry eye disease, specialty lenses and front of the eye conditions. He performs research as part of the post-graduate residency that he hosts in Seattle, and lectures internationally.

Dr. Schmauder is the current binocular vision and contact lens fellow at Specialty Eye in Seattle. She graduated from Pacific University College of Optometry in 2021 and enjoys exploring the lovely Pacific Northwest.

Dr. Huang is the current ocular surface and cornea & contact lens resident at Specialty Eye, emphasizing front of the eye disease, dry eye treatment and fitting specialty contact lenses for complex eye diseases.

The authors would like to thank each of the companies for their contribution to our understanding of their forthcoming presbyopia medications.