Presbyopia is a ubiquitous and progressive symptom of aging that was previously only treatable with reading glasses, contacts or surgery, but patients now have a new option to help their aging eyes: eye drops.

The FDA approval of Vuity (pilocarpine hydrochloride ophthalmic solution 1.25%, Allergan) in 2021 marked a paradigm shift in presbyopia treatment with a new noninvasive approach.

“There is a large number of presbyopes in the U.S., maybe close to 120 million,” Jay S. Pepose, MD, PhD, founder and medical director of Pepose Vision Institute in St. Louis, said. “To have a pharmacological treatment for these presbyopic patients is a huge deal, especially for patients who either are risk averse to surgery or aren’t ready or willing to wear reading glasses.”

The addition of Vuity to the treatment armamentarium for presbyopia is only the beginning of a significant change. The pipeline consists of several other presbyopia-correcting drops, and while they all work similarly, certain drops may work better for specific patients. However, none of the drops are one size fits all, and it is too early to tell, but they may not be effective indefinitely.

“We’ve had access to Vuity for a number of months now post-FDA approval, and we’re learning more and more with the real-world data in terms of patient selection and our best practices,” OSN Presbyopia Section Editor George O. Waring IV, MD, FACS, said. “The wonderful thing about this opportunity with treating presbyopia is that we have so many people to help, and we also have so many ways to help people.”

Presbyopia is a broad problem in terms of quality of life and safety issues, particularly among older people, OSN Presbyopia Board Member Daniel H. Chang, MD, said.

“Presbyopia is undertreated,” Chang said. “Patients often concede to unsatisfactory treatments or workarounds and eventually give up hope. They may try reading glasses or bifocals and they may ‘not mind’ or ‘get used’ to them, but aside from a surgical solution, I’ve rarely encountered a patient who truly loved their presbyopia treatment. Now we have a brand new and different option for these patients, a less cumbersome and less invasive medical treatment.”

Reading glasses are the primary treatment for presbyopia, but for some, especially younger presbyopes, glasses are not an option.

“Those that are in denial who refuse to wear reading glasses are one of the key target populations for a presbyopia-correcting drop,” Healio/OSN Board Member Darrell E. White, MD, said. “Most of these patients are younger presbyopes who are also just not ready or willing to undergo refractive surgery. I see these drops as a stepping-stone to earlier surgical intervention.”

According to Sheri L. Rowen, MD, FACS, medical director of NVISION Eye Center in Newport Beach, California, presbyopia drops are a gateway to correction for early presbyopes who suddenly find themselves incapacitated because they cannot see the way they used to.

“These patients include a presbyope who has never worn glasses or a patient who is adequately fitted with contact lenses for either myopia or hyperopia and now must wear another appliance on that. For these patients, drops are a great option,” she said.

Cost may be a prohibitive factor with drops. The cost of Vuity is approximately $80 a month, according to White, compared with approximately $10 for a pair of reading glasses. However, the cost of refractive surgery per eye ranges from $5,000 to $10,000 he said, so for most patients, $80 per month for Vuity is worth the cost.

“These drops are a gateway drug to eventually having elective procedures,” White said. “Will people wait until they have a true cataract? Or will they pull the trigger on refractive lens exchange at age 52 because the drops don’t work as well as they did when they were 42? If they’re accustomed to not wearing the glasses, they may go ahead and pay for the elective surgery.”

Pilocarpine, the main agent in Vuity and several of the drops in the pipeline, has been used for years as a treatment for glaucoma at higher concentrations. It is a miotic that constricts the pupil and creates a pinhole effect that increases the depth of field.

“The way that pilocarpine and other agents in this arena are being utilized, and the imagination and creativity involved, is extraordinary,” White said. “They work by changing the shape and size of the pupil so that it increases the depth of focus in the eye, exactly like a traditional SLR camera. If you increase the f-stop, you reduce the aperture to which the light goes in to hit the film. It gives you more depth in your photo. These drops give you more depth to your vision.”

Vuity was approved based on data from the phase 3 GEMINI 1 and GEMINI 2 studies, in which patients administered one drop per eye per day. However, the effect of the drug wears off, which might make a two-drop per day option ideal for some patients. According to Pepose, AbbVie/Allergan has successfully completed trials for a twice-daily Vuity dosing regimen.

Another two-drop daily option is in the pipeline: CSF-1 (pilocarpine hydrochloride 0.4%, Orasis Pharmaceuticals). Like Vuity, CSF-1 is a miotic that exploits the pinhole effect to increase depth and vision.

The phase 3 NEAR-1 and NEAR-2 trials of CSF-1 are completed with positive results. This drop comprises a preservative-free, low-concentration version of pilocarpine with a proprietary vehicle.

In the phase 3 VISION-1 study, a 2% pilocarpine-based drop, MicroLine (Eyenovia), achieved its primary endpoint. This formulation uses a proprietary dispenser called Optejet to spray the drug on the eye, which eliminates overdosing and waste.

“One of the potential advantages of MicroLine is titrating the amount of the drug delivered,” Waring said. “This agent is also intended to be used for more of an acute indication and for a more transient and short-term effect. It is currently in phase 3 trials.”

A single agent and combination treatment in the pipeline consists of novel preservative-free drop Nyxol (phentolamine mesylate, Ocuphire Pharma), which is administered at night, and low-dose 0.4% pilocarpine, which is administered in the morning. Nyxol inhibits the iris dilator, and it can be used alone or in combination with pilocarpine. Ocuphire has completed the well-controlled multicenter 150-patient VEGA-1 phase 2 trial with positive efficacy and safety results, and phase 3 trials are expected to initiate later this year.

“Nyxol takes a differentiated approach by working on the iris dilator muscle,” Pepose said. “The benefit of Nyxol is that it has a long 24-hour duration of action, and it’s administered at night, so patients benefit immediately upon awakening with minimal side effects. Since Nyxol does not engage the ciliary muscle, it does not increase the risk of retinal detachment. Near vision has improved in the morning, and patients who require an additional boost at near can add the low-dose pilocarpine. In addition, no patients experienced headache or browache or had loss of their distance vision.”

A non-pilocarpine drop in a phase 3 trial is aceclidine (Lenz Therapeutics). Data from a phase 2 trial showed that within 30 minutes of treatment, half of patients experienced a reading improvement of three lines or more; 81% of patients improved their reading vision by two lines or more.

Aceclidine is a parasympathomimetic miotic that is used to treat glaucoma in stronger concentrations. According to Waring, it targets the iris sphincter and avoids the ciliary muscle, which helps avoid myopic shift.

Another agent in the pipeline that can potentially help avoid the side effects of miotic drops is Brimochol (Visus Therapeutics). This combination drop include carbachol, a cholinergic agent, and brimonidine tartrate, an alpha-2 agonist. It is currently in phase 3 trials.

“These two agents work together to create a pinhole effect and decrease pupil size,” Waring said. “This mitigates the potential side effects of miotics and potentially prolongs the duration of action.”

One agent takes a different approach than miotics and instead softens the lens. Dioptin (Novartis), also known as UNR844, penetrates the cornea and works to reduce the disulfide bonds in the lens using lipoic acid choline ester. In a study of 75 patients with presbyopia, UNR844 demonstrated safety and efficacy, including improvements in distance corrected near visual acuity that were sustained up to 7 months after dosing. Phase 2 studies are currently underway.

In the past, pilocarpine has been associated with retinal detachment, which is potentially a side effect in patients using the agent for presbyopia. In May, a paper published in the American Journal of Ophthalmology highlighted three cases of retinal detachment in two patients who used Vuity for the treatment of presbyopia.

Chang said that the risk for retinal detachment has been associated with long-term use of higher concentrations of pilocarpine. However, he said that this has not been widely studied.

“An eye drop that may cause retinal detachments can be a scary prospect, but we have to remember that the incidence is rare,” Chang said. “I’d compare it to a fear of flying. Each time there is an airplane crash, it’s all over the news, but in reality, flying is far safer than driving. A rare but potentially serious side effect associated with an eye drop could deter doctors from even offering this treatment.”

He said that it is reasonable to be cautious and screen for patients who may be at a higher risk for retinal detachment. For example, in the GEMINI study of Vuity, patients underwent a fundus examination, and the study did not include patients with more than –4 D of myopia. Physicians should consider starting with a similar profile when prescribing the drops.

“This does not mean that the drops won’t work for high myopes. It just means that these patients are at higher risk for retinal detachment,” Chang said. “How much of a risk, we do not know yet, but as a surgeon used to navigating risks and benefits, I would not shy away from using pilocarpine or its analogues in the future simply because of the risk for a very rare side effect. Just like how driving is actually more dangerous than flying, common treatments for presbyopia like multifocal glasses and monovision can not only have a significant effect on people’s lifestyles but also have the potential safety concerns of increased trips and falls. I believe the benefits of the medical treatment of presbyopia far outweigh the risk.”

Another consideration is whether presbyopia-correcting drops are appropriate for those with pseudophakic presbyopia who already present with a baseline higher risk for retinal detachment, Chang said.

Using the pilocarpine drops would be an on-label use for pseudophakic presbyopia, considering its broad label, according to Pepose. He said these drops have a lot of potential in pseudophakic presbyopia, which affects approximately 8.7 million people in the United States.

“There is a large group of patients, the pseudophakes, who had cataract surgery 10 to 15 years ago when there wasn’t a big array of choices. Some of them are also looking for a treatment. This is an opportunity for us to help these patients,” Pepose said. “Many of the pseudophakes have monofocal lenses, and they want to improve their near vision, but they may not be good candidates for laser vision enhancement. In addition, miosis creates more tolerance to residual astigmatism. In patients who are not good candidates for laser vision enhancements, this is a nonsurgical vision enhancement.”

Rowen said that those with pseudophakic presbyopia may benefit from presbyopia-correcting drops, but getting the right amount of pupil modulation will be key. This population may also be better suited for a lower concentration of pilocarpine.

“I love the concept of this treatment being available for pseudophakes and being able to potentially help correct problems from multifocal lenses,” Rowen said. “But we need to find the right patients and the right strength of pilocarpine. Other agents in the pipeline may be better suited for these patients as well.”

Presbyopia-correcting drops are an exciting advancement in the field for ophthalmologists and patients alike, but managing expectations is critical.

“If you have appropriate expectations, presbyopia-correcting drops are certainly a worthwhile thing,” White said. “Right now, it’s super important to temper the expectations of patients. The drug is working well for younger presbyopes in the 42- to 52-year-old age range. We need to be careful about tempering enthusiasm of the market and setting reasonable expectations.”

White said patients should use Vuity for at least a week before deciding whether to continue the treatment in the long term.

“Patients shouldn’t make their decision based on just a few drops from a sample,” he said. “They should stick with it for at least a week since most of the side effects that happen with Vuity often go away after about a week of continued use.”

“Studies have shown that Vuity works better when you use it regularly and consecutively,” Chang said. “If you use it once, it works. If you use it for 7 days, it works better. If you use it for 30 days, it actually works slightly better.”

Some patients wonder if these drops will be a long-term option, which Rowen called a “billion-dollar question.”

“There will be a point where drops alone might not overcome the natural progression of presbyopia,” Rowen said. “At that point, a mini-monovision combined with the drops may be effective and extend the lifespan of the drops. Eventually, however, the lens gets harder and harder, becoming the dysfunctional lens, or cataract changes set in, and the process ends at a refractive lens exchange or eventually cataract surgery. At the moment, this formulation will not fulfill an older presbyope’s dream. We will have to see what happens with the later formulations.”

These unknowns do not hamper the excitement that surrounds the noninvasive medical option for this long-known problem with limited treatment options. But White reiterated the need for tempering expectations.

“Like all new products, especially new products in a marketspace that didn’t exist before, setting appropriate expectations makes it much more likely that not only the product but the entire space will thrive,” White said.

The general consensus is that younger presbyopes in their 40s and early 50s are the best candidates for presbyopia-correcting drops.

“When you’re in your 60s and 70s, lenses show cataractous changes, and you have great surgical options to simultaneously and permanently treat the cataract, the refractive error and associated presbyopia,” Pepose said. “But there’s a gap between younger presbyopes in their 40s and presbyopes in their 50s and 60s. These drops bridge that gap.”

Click here to read the Point/Counter to this Cover Story.

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