Pursuing the Holy Grail of Presbyopia Treatment

Rich pipeline suggests new options are on the horizon and beyond. Cheryl Guttman Krader reports from ASCRS Refractive Day 2021

Nearly two billion people on Earth are presbyopic, and the number continues to increase.

With a variety of investigational approaches for treating presbyopia advancing along the regulatory approval pathway, the question arises: Where do we stand now with regard to presbyopia treatment?

Delivering the Steinert Refractive Lecture at the ASCRS in Las Vegas, USA, Marguerite B McDonald MD, borrowed a quote from Winston Churchill that she said offers the perfect answer.

“‘Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning,’” Dr McDonald quoted.

In her presentation, Dr McDonald highlighted the limitations of currently available presbyopia treatments and other abandoned treatments. Most of her talk reviewed pharmacological, surgical, and contact lens-based approaches in clinical development.

TOPICAL DROPS Pharmacological approaches to treating presbyopia with topical drops are represented by an array of products based on pupil constriction to increase depth of focus, and a single modality aimed to soften the crystalline lens to improve accommodation. Currently, eight companies are developing a pupil constricting agent for treating presbyopia, and most contain pilocarpine.

“What is new about these treatments is that they contain a much lower concentration of pilocarpine than what was ever used for glaucoma, and they formulate it in sophisticated delivery vehicles,” Dr McDonald said.

Of the pilocarpine-based drops, AGN190584 (Allergan) is farthest along the pathway to regulatory approval as its New Drug Application is undergoing US FDA review. AGN-190584, administered bilaterally once daily for 30 days, was investigated in two phase-three clinical trials that enrolled 750 patients. Both studies met their primary endpoint, showing that a significantly greater proportion of patients using AGN-190584 versus placebo-treated controls gained at least three lines of mesopic high contrast binocular distancecorrected near visual acuity at three hours.

The near vision benefit was achieved without any negative impact on distance vision. The most common side effects associated with AGN-190584 were headache, conjunctival hyperaemia, and blurred visual acuity, each occurring in less than 3% of treated patients. The adverse events were generally mild and did not lead to treatment discontinuation, Dr McDonald said.

CSF-1 (Orasis), another pilocarpine-based agent, achieved positive results in a phase two study where it was administered twice daily. Two phase-three studies investigating CSF-1 with 600 patients are now underway.

MicroLine (Eyenovia) sprays pilocarpine onto the eye with microarray print technology (Optejet). At the completion of a smaller phase-three trial evaluating pilocarpine concentrations of 1% and 2%, 70% of patients indicated interest in using the product if it was approved. There are phase three registration trials planned for 2021.

Another company, Kedalion Therapeutics, also uses novel technology (AcuStream) to deliver pilocarpine for treating presbyopia. A phase two study is investigating 1% and 2% pilocarpine concentrations.

Pilocarpine is a component in a two-drug kit being developed as a treatment for presbyopia (Ocuphire). This approach combines a low dose of pilocarpine (0.4%) administered in the morning with an evening dose of phentolamine 0.75% (Nyxol)—a moderate and long-acting nonselective alpha-adrenergic antagonist.

“The combination synergistically activates the iris sphincter muscle and inhibits the iris dilator muscle. It also allows for the active ingredients to be used in lower concentrations, which may decrease the likelihood of adverse events,” Dr McDonald explained.

A phase two study including 152 patients met its primary endpoint and key secondary endpoints and showed the combination treatment had a favourable safety profile. There are plans for phase three registration trials.

PRX-100 (Lenz Therapeutics, formerly Presbyopia Therapies) pairs aceclidine, a parasympathomimetic cholinergic muscarinic receptor agonist, with tropicamide to induce strong miosis without accommodative distance blur. It demonstrated efficacy in a phase two study. Further development stalled while the company reorganises.

BRIMOCHOL™ (Visus Therapeutics) is a fixed combination agent designed to gain synergistic efficacy with a possible safety benefit. It contains carbachol (a potent cholinergic

miotic agent) and brimonidine, which may help prevent the redness associated with all miotics. The brimonidine preserves pupil dilation, may inhibit ciliary muscle contraction, and whitens the eyes. A phase two study is comparing two BRIMOCHOL formulations against carbachol monotherapy. One other combination topical treatment for presbyopia (EyeFocus) contains a miotic, an alpha-1 agonist, one or more histamine-1 antagonists, and an NSAID (OSRX).

UNR844 (lipoic acid choline ester, Novartis), the lens softening agent, acts to hydrolyse the disulphide bonds between crystalline lens proteins. In a phase two trial enrolling early presbyopes (ages 45 to 55 years) treated twice daily for three months, UNR844 was associated with modest improvements in near vision compared to placebo along with dysgeusia and headache in 5% and 3% of users, respectively.

“While the trials investigating UNR844 are attempting to reverse presbyopic lens changes, it seems this agent would more likely be used in younger patients as a preventive strategy,” Dr McDonald said.

“The long-term safety of using this treatment for decades and whether the treatment works consistently across the entire lens are questions that need to be answered.”

SURGICAL APPROACHES Thermal keratoplasty treatments for presbyopia using the holmium:YAG laser or radiofrequency energy have been available in the US for years but were never widely adopted. Optimal Keratoplasty (Opti-K, NTK Enterprises), which has the CE mark and was under investigation in a US clinical trial, seems to overcome the drawbacks of previous approaches, Dr McDonald said.

Performed with an infrared thulium fibre laser under topical anaesthesia, Opti-K is a non-invasive, rapid procedure that causes minimal discomfort and involves no downtime. Although the treatment effect regresses completely in one to two years as the presbyopic refraction changes, Opti-K can be safely repeated, unlike other thermal keratoplasty procedures.

“Opti-K also avoids the risks of other existing surgical treatments for presbyopia that are associated with the need for flap creation, stromal implant placements, and epithelial barrier disruption,” Dr McDonald said.

“A drop of topical steroid administered at the end of the procedure is the only postoperative medication needed. Among almost 1,400 eyes treated in clinical trials, there have been no cases of an induced cylinder of greater than 1D or loss of BSCVA of two lines or more at the one-year follow-up.”

Looking further into the future, Dr McDonald discussed laserinduced refractive index change (LIRIC, Clerio Vision), a femtosecond laser technique in development to alter the refractive index of the cornea, intraocular lenses (IOLs), and contact lenses.

Achieving change in a highly localised fashion, the cornea treatment modifies collagen fibril density without causing tissue ablation. One-month data from nine patients showed significant improvement in near vision and clear corneas with no light scatter, wound healing response, or inflammation.

“With this non-invasive treatment, there is no need for postoperative antibiotic or steroid drops. Animal studies show it has almost no effect on corneal nerves, suggesting it may be unlikely to cause dry eye,” Dr McDonald said.

Applied to an IOL, LIRIC can convert a monofocal optic to a multifocal design or vice versa. It is also being developed to create diffractive contact lenses.

“Because tear film mucus and debris accumulate in surface echelettes, presbyopia-correcting contact lenses have been trapped in the ’90s with a refractive design. LIRIC enables diffractive technology because it embeds the echelettes within the lens and can create a lens with any add power, not just the limited choices of existing contact lenses,” Dr McDonald said.

Marguerite B McDonald MD is a Clinical Professor of Ophthalmology at New York University Lagone Medical Center, New York, USA margueritemcdmd@aol.com