Source: Healio Interviews.
Disclosures: Ang reports being a clinical investigator and consulting for Ace Vision Group, Bausch + Lomb, Johnson & Johnson Vision, PhysIOL and STAAR Surgical. Donnenfeld reports consulting for Allergan, Orasis Pharmaceuticals and Visus Therapeutics. Fram reports serving as a member of the medical advisory board for Orasis Pharmaceuticals. Jackson reports being a shareholder and global medical director for Ace Vision Group.
September 22, 2021
11 min read

Treatment landscape for presbyopia evolving toward noninvasive options

Source: Healio Interviews.
Disclosures: Ang reports being a clinical investigator and consulting for Ace Vision Group, Bausch + Lomb, Johnson & Johnson Vision, PhysIOL and STAAR Surgical. Donnenfeld reports consulting for Allergan, Orasis Pharmaceuticals and Visus Therapeutics. Fram reports serving as a member of the medical advisory board for Orasis Pharmaceuticals. Jackson reports being a shareholder and global medical director for Ace Vision Group.
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Noninvasive or minimally invasive approaches may be the solution for presbyopia before the onset of age-related cataract and a way to address the increasing need to perform close-range tasks.

“The treatments that are currently available have not met our needs,” OSN Cornea/External Disease Board Member Eric D. Donnenfeld, MD, said. “Glasses are an inconvenience. Contact lenses cause dry eye, and most people become intolerant after a while. Corneal inlays have not done well, and most of them have left the market in the United Sates. Finally, laser vision correction is not for everyone and has all the drawbacks of monovision. Multifocal IOLs are an excellent option but at a later stage when people develop cataract.”

Nicole Fram, MD
Noninvasive, safe and effective options are needed to bridge the gap between the first symptoms of presbyopia and the implantation of an IOL, according to Nicole Fram, MD.

Source: Nicole Fram, MD

The COVID-19 pandemic has introduced new models of smart working with video display terminals, increasing the number of hours people need to rely on spectacles. At the same time, foggy spectacle lenses while wearing face masks can be frustrating.

“We have seen refractive surgery volume increase significantly with a primary motivation of wanting to get independence from spectacles due to the fogging of the lenses as a result of wearing a mask. But past the age of 40, LASIK with mini-monovision is not going to work for everybody,” Nicole Fram, MD, said.

The pandemic and the subsequent use of masks, which is likely here to stay for a long time, have further highlighted an unmet need in ophthalmology, she said.

“With many of our presbyopic patients, we just throw our hands up and say good luck, wait until you need cataract surgery. Fortunately, there are some great lens-based solutions once we turn 60, but we need a bridge,” Fram said.

“Ultimately, what we are looking for is a treatment that is effective, comfortable, reversible and has minimal to no complications,” Donnenfeld said.

Drops currently under evaluation

Presbyopia-correcting drops check all those boxes and promise to be a true paradigm shift, a huge opportunity and a simple solution that everyone can try with no risk and a high chance to be satisfied, Donnenfeld said.

The products that are currently near to reaching the market, or at least the final stages of clinical testing, are miotics that exploit the pinhole effect to increase depth of vision.

In July, Allergan released the full results of the phase 3 GEMINI 1 clinical study, evaluating the efficacy, safety and tolerability of AGN-190584 (pilocarpine 1.25%) ophthalmic solution. A new drug application has been submitted to the FDA and is currently under review.

“This is the first medication that almost certainly will be approved by the end of the year,” Donnenfeld said. “CSF-1 (Orasis Pharmaceuticals), a lower-dose preservative-free pilocarpine formulation, will be closely following after completion of the phase 3 NEAR-1 and NEAR-2 trials.”

Eric D. Donnenfeld
Eric D. Donnenfeld

MicroLine (Eyenovia) has also achieved the primary endpoint in the phase 3 VISION-1 trial. It is a pilocarpine formulation that uses a unique proprietary dispenser (Optejet) to spray the drug on the eye, eliminating the overdosing and waste of typical eye drop administration.

Two other products use combined formulations. Nyxol (Ocuphire Pharma) uses a combination of phentolamine mesylate and low-dose pilocarpine.

“Patients take the phentolamine at night and the pilocarpine in the morning. This combination has been shown successful in prolonging the duration of the presbyopia-correcting effect,” Donnenfeld said.

Brimochol (Visus Therapeutics) is a proprietary combination of carbachol and brimonidine that is currently undergoing a phase 2 trial.

“Carbachol is a miotic agent with longer duration as compared with pilocarpine, and the addition of brimonidine reduces aqueous production and allows it to remain in the eye for a longer period of time. Also, brimonidine causes whitening of the eye, whereas other drops cause redness and irritation,” Donnenfeld said.

Finally, aceclidine (Lenz Thera­peutics) is another miotic drop that showed promising improvement in near vision in a phase 2 trial.

“Aceclidine may have an advantage because it causes less ciliary muscle contraction, which may cause less myopic shift,” Donnenfeld said.

A completely different mechanism of action is exploited by Dioptin (Novartis), a lens-softening medication currently in a phase 2 trial.

“It uncross-links the lens, making it more flexible so that it can change shape with the normal movements of accommodation. This drug is still a long way away from approval, and we are waiting for more data, but it is an exciting concept,” Donnenfeld said.

Multiple options for different needs

Multiple options with different nuances in terms of concentration, combination of active ingredients, ways of administration and duration of action will give patients the chance to find the best strategy for their individual needs.

“Patients will be in control of their therapy. In their early presbyopic phase, in the early 40s, they may want something that is shorter acting because they may need to wear glasses only toward the end of the day. Longer-acting drops will be best for patients at a more advanced presbyopic age,” Fram said.

The Eyenovia dispenser, which sprays small droplets on the eye surface, may be something more amenable for people who do not like putting drops in their eyes.

“A common thing I hear from my female patients is that drops mess up makeup, so the spray might be a better option,” Fram said.

“Patients will enjoy having the flexibility of choosing the drop that works best for them,” Donnenfeld said. “The effect of pilocarpine lasts 2 to 6 hours, depending on concentration. Carbachol lasts 8 to 12 hours. Phentolamine in combination with pilocarpine will give the chance to have a continuous effect with one drop in the morning and one at night. The different formulations will help expand the market, and patients will choose the one that meets their needs.”

Minimizing side effects

Drops used for other purposes, such as glaucoma, have been associated with poor adherence, partly due to the burden of multiple administrations. However, motivation and the immediate effect of drops for presbyopia will positively affect compliance.

“People may give them up if the side effects outweigh the benefits, but this should not be the case with drops for presbyopia. Trials are showing that side effects are minimal, and satisfaction is high. Personally, I am one of those people who would trade a mild headache for no reading glasses,” Fram said.

The side effects of pilocarpine-based drops can be red eye and headache associated with the mechanism of action of miotics. In addition, dry eye may occur as a cumulative toxic effect of pilocarpine over the years.

“Low-dose preservative-free formulations should minimize these effects. In addition, we are not dealing with the high 4% concentration four times a day that is used in glaucoma,” Fram said.

In the Brimochol compound, a low dose of brimonidine will help medicate the red eye and also the ciliary spasm that may be associated with carbachol. However, people can be allergic to brimonidine.

“The company is aware of this and is now trying to lower the concentration of brimonidine,” she said.

A sweet spot of all miotic drops is that the constriction response may vary from eye to eye, depending on how the iris sphincter reacts.

“With all of these medications, they need to figure out a formulation that doesn’t narrow the pupil below 2.3 mm. Nighttime driving and best corrected distance vision cannot be compromised for the sake of reading your phone,” Fram said.

Expanding the market

“From my perspective as a refractive surgeon, emmetropic presbyopes are excellent candidates, but drops may serve well also those who had previous refractive surgery and are looking for solutions to maintain the excellent vision they have acquired through laser vision correction. These patients will gravitate toward these medications in a significant way,” Donnenfeld said.

Surprisingly, pseudophakic patients with monofocal IOLs have been shown in trials to have significant improvement in near vision by using presbyopic drops and may be a good market as well, he said.

He looks forward to the FDA approval of the Allergan ophthalmic solution.

“The company has full knowledge on how to launch a new product, and this will open up the market for other products to come,” he said.

Laser scleral microporation

Laser scleral microporation (LSM, Ace Vision Group) is another promising minimally invasive technology for presbyopia awaiting to enter the market in the near future. The Visiolite system uses an Er:YAG laser in four quadrants of the sclera to create tiny micropores in a patented mathematical matrix.

“We create four quadrants of scleral uncross-linking to release the rigidity that inhibits the accommodation process in presbyopic age. This decreased ocular rigidity improves accommodative biomechanics and results in restored ciliary muscle forces, which improves dynamic range of focus for all ranges of vision,” Healio/OSN Board Member Mitchell A. Jackson, MD, said.

The procedure is performed transconjunctivally, taking 14 seconds per quadrant and 56 seconds per eye, and time will be further reduced by the next generation of the laser, which is nearly ready and uses refined algorithms based on artificial intelligence in a touchless procedure taking less than 2 minutes to complete, he said.

Mitchell A. Jackson
Mitchell A. Jackson

The procedure is currently undergoing IRB registered pilot studies in two clinical sites in the Philippines and Panama with the Visiolite Gen I laser, and the FDA clinical studies using the Visiolite Gen II laser are expected to begin next year.

Results so far are promising, Jackson said. Patients gain at least two to three lines of distance corrected intermediate vision and three to four lines of distance corrected near vision. At least 86% of patients are achieving 20/40 or better at near, which exceeds what the FDA standards require for presbyopia-correcting lenses.

“On the first postoperative day, patients who were wearing reading gasses in the waiting room before surgery come back and read without glasses. They can actually do this as soon as they get off the operating table,” Jackson said. “One of my patients, a bartender, the next night was reading all orders in the dark at the bar without glasses.”

Studies show promising outcomes

Robert Edward Ang, MD, is treating patients at the Asian Eye Center in the Philippines within the ongoing pilot study.

“We were initially targeting 25 patients. Now we are targeting 50, of which 30 are already enrolled. We have the results for 22 who have passed 3 months of follow-up. Some have reached 6 months, and two have reached 1 year. We have perfected the technique and now do it very fast. There is no pain, and all patients report comfort the day of surgery. Some foreign body sensation may be experienced on the following day but quickly wears off,” he said.

Robert Edward Ang
Robert Edward Ang

Importantly, distance vision is not affected. The best results are for intermediate vision, which improves from 0.4 to 0.00 or 0.1 to 0.2 logMAR. Near vision uncorrected is J2 or J3 in both eyes.

“Patients report a significant improvement in their quality of life because in our country people use mobile devices to do everything they do, and this procedure allows them to read their cell phone without glasses. Intermediate vision is very important to our patients, yet some people cannot read very small print in dark conditions. I am very careful to warn my patients that this is a rejuvenation procedure and not a vision-correcting procedure targeting a specific vision correction. This procedure is like making you reverse aging to around 40 to 42 years old, not to 20 years old. Because LSM is not on the visual axis our patients have no reports of glare and halo, there are no adverse events so far like vision loss or infection, and cosmetic appearance is very good. Some people have a bit of redness in the treatment area, which is hardly noticeable,” Ang said.

Many advantages

According to Ang, LSM is one of the most promising techniques for presbyopia because it tackles the root of the problem, partially restoring the conditions for the eye to accommodate, and holds innumerable advantages.

“The main advantage is that it does not touch the cornea and has no impact on the visual axis. Any other presbyopia-correcting procedure — from presbyLASIK or LASIK monovision to corneal inlays and also multifocal IOL implantation — interferes with the visual axis, and this has an impact on quality of vision, particularly distance vision. I can confidently tell my patients that their far vision will be unaffected,” he said.

He said that unlike other procedures, which include monovision or pseudoaccommodation, LSM does not require neuroadaptation. The challenges of adapting to new non-physiological neural strategies are overcome, and no glare and halos are induced.

“It is a bilateral procedure, so you don’t have to play with enhancing the nondominant eye for more near vision while making sure the dominant eye remains good for far and hoping that the patient will adapt and be happy. Here you have no problem with adjustment, neuroadaptation and stereoacuity,” Ang said.

A further advantage of this procedure is that it will not cause problems with IOL power calculation when the time comes for cataract surgery, he said.

One drawback in Gen I laser

In his opinion, there is only one drawback to LSM. Because every person is different in the way presbyopia progresses, the treatment may lead to more or less improvement according to the stage at which it is performed in each patient.

“Someone at a more advanced stage may have a less pronounced effect as compared with someone younger, and currently we don’t have a way to measure preoperatively how the person will respond. The treatment is the same for everyone,” he said. “The Gen II laser will give us the capability to customize the procedure for each patient at any age.”

“LSM rejuvenates the rigid scleral tissue making it more compliant during ciliary muscle contraction, but you need to exercise this new ability. I tell my patients they must think of the first postoperative period as going to the gym and doing reading exercises every day. If they do this, the response improves a lot over time. They see better after 1 week and even better after 1 month,” he said. “This seems like a very acceptable price to pay for a treatment that has no other downside.”

Changing landscape of presbyopia

“The only side effect we discovered, and positively surprised us, is that it lowers IOP. We are now performing specific IOP studies in patients with glaucoma, so we might have a dual indication down the road: presbyopia and glaucoma,” Jackson said.

LSM is a procedure for emmetropic presbyopes but can also serve patients who have previously undergone laser refractive surgery.

“We have treated a subpopulation of patients with previous LASIK or PRK in our study, and although the approval will be for emmetropic presbyopes, our results so far show that previous refractive surgery is not at all a contraindication. I believe it will be used in those patients a lot after approval,” Jackson said.

He also sees a possible combination with presbyopic drops for some patients who may wish to boost the accommodative effect of LSM with the pseudo­accommodative effect of miotics. Drops are a good option, in his opinion, but he sees them more as an early, temporary solution or a complementary treatment, particularly for pseudophakic patients with monofocal IOLs.

However, the landscape of presbyopia correction is changing for the best toward less invasive, more therapeutic, more comfortable and user-friendly solutions, he said.

“What I foresee is that patients with presbyopia will come to see me a little scared, as usual, and I’ll tell them it is the ‘AGE syndrome,’ which I also suffer from. Patients always like to try nonsurgical solutions first, so I’ll tell them to try the drops. Some of them will be happy and continue; some will not like the side effects and may not be willing to keep paying for them. At that point, I will be able to offer them LSM, which is a more permanent treatment, and some might like to combine it with drops. Years later, they will develop cataract, and I hope that the time might come when we can implant an accommodating IOL,” Jackson said.

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