Issue: August 2017
August 16, 2017
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Clinicians anticipate treating presbyopia with eye drops

Issue: August 2017
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New eye drop therapies under study may help delay presbyopia for the estimated 2 billion people worldwide who typically experience dramatic visual changes in their 40s and 50s.

The term “presbyopia” literally means “old eyes” in Latin.

“If you can get a 45-year-old to postpone the need to wear glasses until 50 or 55 years, most patients would be extremely excited about that prospect and would be willing to use drops during that entire period, if needed,” Bobby Christensen, OD, a private practitioner and senior vice president of clinical strategies at Vision Source, said in an interview with Primary Care Optometry News.

Years ago, Richard B. Mangan, OD, FAAO, who specializes in ocular disease and surgical comanagement, led many seminars to educate patients on their surgical refractive options, including laser vision correction.

Richard B. Mangan

“We found that the majority of people that attended the seminars were of presbyopic age and hoping for more than what LASIK alone could provide,” said Mangan, a member of the PCON Editorial Board. “This is just one reason why these therapies are such an important innovation. It’s something that, if it is an affordable eye drop, it’s going to be incredibly popular.”

It is the optometrist’s responsibility to improve, enhance and care for vision regardless of the treatment modality, according to PCON Editorial Board member Arthur Medina, OD, who practices in San Antonio.

“I don’t care if it’s with a refracting lens, surgical procedure or pharmacological, optometry is in the profession of treating for, caring for and advising patients of all of their options for vision improvement,” Medina told PCON.

David Cockrell

“I would think that any agent that is going to reduce or reverse presbyopia would fit in wonderfully,” according to David Cockrell, OD, FAAO, who owns a practice with his wife, Cherry Cockrell, OD, in Oklahoma. “Most patients do not want to be dependent upon near point addition, whether that’s a bifocal or reading glasses.”

Currently, presbyopia is managed in many ways, including glasses, contact lenses, multifocal IOLs, corneal inlays and monovision laser correction. Whether by surgery or through contact lenses, patients may elect to try a multifocal approach or a dissociated approach such as monovision, Mangan said.

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However, not all patients adjust well to monovision. For many, it can be nearly impossible, according to our experts.

“For some, cortical adaptation simply does not occur,” Mangan said.

He often sees presbyopes who are mentally resistant to monovision, whether through contacts or surgical correction.

“The biggest concern is that with optical devices available today, whether its glasses or contacts, there is not a perfect option,” Mangan said. “As for contact lenses, patients’ options are monovision or a multifocal contact lens. We are requiring patients to let their eyes function independently with monovision or deal with contrast sensitivity reduction or optical aberrations when we talk about multifocal contacts.”

With multifocality, the biggest problem is quality of vision, he added.

Christensen added that one of his most important pearls in managing presbyopia is there is no one-size-fits-all approach.

To gain the range of vision presbyopes desire, they must sacrifice quality of vision, Mangan said.

Richard B. Mangan, OD, believes an affordable drop therapy for presbyopia would be “incredibly popular” among patients.
Image: Mangan RB

“We find that the success rate of contacts is still not ideal,” he added. “We have newer presbyopia-correcting implants, which are showing promise, but patients still deal with dysphotopsia and glare, so much so that they have these lenses explanted.”

Cost is another issue that is significant for patients.

“The costs associated with multifocal contact lenses or surgery can be a significant barrier for some,” Mangan said. “And when it’s a more permanent change to the visual system, which we see with multifocal IOLs, for example, patients can become rather dissatisfied if they are not able to adapt to the new optics.”

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Legislative issues

While the up-and-coming drop therapies for presbyopia may seem to address many current clinical issues, a potential nonclinical issue is the fact that this type of treatment may not fit into some states’ classification for scope of practice.

“Doctors of optometry have topical prescriptive authority in all 50 states,” Deanna S. Alexander, OD, FAAO, American Optometric Association State Government Relations Committee chair, told PCON. “However, some statutes are written in a way that does not allow for all classifications of medications to be prescribed for treatment of ocular conditions.

Deanna S. Alexander

“It is important for states to work toward an open practice act that will allow for future changes in medicine and technology so our patients can benefit from the latest treatments of ocular conditions,” she continued.

Alexander said optometrists in most states will be able to prescribe this new type of therapy; however, some will need to update their state laws.

Presbyopia Therapies

A handful of companies are working on topical therapies to potentially extend the amount time that presbyopes can go without reading glasses.

A 30-year eye care industry veteran, Jim McCollum, co-founder of Presbyopia Therapies in Coronado, Calif., has such a treatment in the pipeline.

LiquidVision eye drops are meant to complement current treatment options and are not a permanent replacement for reading glasses, contacts or surgical options, he told PCON in an interview.

The therapy is based on discoveries from combining aceclidine (a miotic) with tropicamide (a cycloplegic), which may provide a powerful topical presbyopic treatment with improved near and distance vision for total depth of focus enhancement, he said.

Aceclidine creates a pinhole effect with a targeted pupil size of less than 2 mm. McCollum noted there have been no issues with night vision or diffraction.

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He also said that that pilocarpine is not used, as it may cause head- and brow aches when taken in certain doses.

“We initially tested pilocarpine but found that this drug didn’t provide enough miosis and can cause some blurry distance vision,” he said. “This led to the use of aceclidine, which is considered a stronger miotic than pilocarpine.”

Throughout testing, the researchers found that aceclidine alone may result in some accommodation, and this may cause blurry distance vision in some patients, according to McCollum. With the addition of tropicamide, accommodation is modulated.

“The key is the ratio and interaction between the two drugs,” McCollum said. “The potential result is both improved near and distance vision, with a total depth of focus enhancement.”

LiquidVision drops are fast-acting, have a 30-minute onset and a 4- to 5-hour duration from a single binocular dose. Because the treatment is binocular, no monovision challenges exist for patients, he said.

In the phase 2A proof-of-concept trial conducted in 2016, the results yielded improvement in uncorrected near visual acuity vs. placebo at multiple near distances and over multiple time points after a single dose, according to McCollum.

The drug was also well tolerated, with no serious adverse events.

McCollum stated that during the earliest anecdotal testing (outside of the U.S.), a few patients experienced some initial mild redness for about 15 minutes, then it completely dissipated.

The phase 2b trial, which is underway, is exploring a higher strength formulation with an enhanced protocol. McCollum noted that signs of a cataract would exclude a patient from enrolling in the phase 2b trial, but that this would be further evaluated in phase 3.

LiquidVision eye drops are able to produce both pinhole optics and moderate accommodation.
Image: McCollum J
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Top line data from the 2b trial will be available at the end of 2017 or early 2018, according to McCollum.

“LiquidVision is designed to be a daily or temporary treatment for presbyopia; it is a lifestyle enhancement,” he said.

“For the potential rapid commercial adoption and utilization by a large number of patients, Presbyopia Therapies believes a drop must be very fast-acting. Think of the ‘wow’ factor with LASIK. A fast-acting therapy would also allow the drop to be easily sampled in the office by the OD or MD,” McCollum explained.

If a patient needs the therapy to last beyond 4 or 5 hours, a second dose is recommended.

The estimated time frame for U.S. availability is about 4 years, according to McCollum.

“As with all drugs, after the phase 2b is complete, a phase 3 clinical trial will be conducted, and this typically takes about 3 years to entirely finish. Assuming positive results and the FDA approval of the New Drug Application, LiquidVision could be available in the U.S. in 2021,” he said.

Novartis and EV06

In December 2016, Novartis acquired Encore Vision to further develop EV06.

The ophthalmic solution (lipoic acid choline ester, 1.5%) improved bilateral distance-corrected, near vision compared with placebo in a 3-month, prospective, randomized, double-masked multicenter phase 1/2 trial.

Richard L. Lindstrom

EV06 is a prodrug that penetrates the cornea and is metabolized into an organic compound able to naturally “un-crosslink” the crystalline lens, making it more elastic, according to Richard L. Lindstrom, MD, a member of the PCON Editorial Board.

“The lipoic acid, which is a protein that is widely available in nature and has a strong track record of safety, is like an antioxidant,” he said in an interview.

Lindstrom explained that in the process of presbyopia, the collagen in the crosslinks make the cornea stiffer, as in a patient with keratoconus. Also, the normal aging process stiffens the lens of the eye, as does exposure to UV light.

‘To un-crosslink, we reduce the crosslink collagen bonds ... the dihydrazide is reduced between the lens proteins, creating lens microfluidics. It makes the lens more elastic,” Lindstrom said.

In a few years this drop could reverse presbyopia in a clinically meaningful amount, he said.

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“What I like about it is you have a pupil that works normally,” he added.

“Patients will have a perceived benefit with this drop; they will be motivated to take it,” Lindstrom said. “It will be like other medications where if the patient doesn’t take it, it will not be effective.”

At the American Society for Cataract and Refractive Surgery meeting in May, Lindstrom called EV06 the first therapy that can reverse presbyopia in a natural and safe fashion.

In the phase 1/2 trials, 50 patients experienced improved binocular near acuity, significant improvement was reported as early as 8 days and it continued over 3 months, with no loss of distance vision. Eighty-four percent of the patients gained at least one line and reached 20/40 or better, and more than half of the patients gained two lines or more, according to Lindstrom.

No patients in the study discontinued treatment, only a few reported mild irritation at instillation, and no changes in IOP or pupil diameter were reported.

By the time Novartis is ready for the FDA drug approval process, the formulation could be slightly higher, or the dosing indications could change, Lindstrom said. They will not know for certain until the research is complete, he added.

“In this therapy that changes the flexibility in the lens of the eye and where the patient resumes better accommodation, that would be a very big breakthrough,” Christensen said.

Other therapies in the pipeline

Carbachol 2.25% with brimonidine 0.2% is also in development for topical treatment of presbyopia.

“The choice of active principles was driven by the rationale of stimulating the parasympathetic innervation and increasing depth of focus through miosis,” according to Renna and fellow researchers in Eye and Vision, in a summary of topical therapies for presbyopia in development.

Results of this therapy showed a four-line mean improvement of uncorrected near visual acuity measured with the Jaeger scale 1 hour after the instillation of drops, which progressively regressed to one to two lines at 10 hours, without a worsening of the uncorrected far visual acuity at any time, according to researchers. No side effects were reported.

Another therapy, pilocarpine 0.247%, phenylephrine 0.78%, polyethyleneglycol 0.09%, nepafenac 0.023%, pheniramine 0.034% and naphazoline 0.003%, is currently filed under a European Patent Application.

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In a pilot study involving 14 presbyopic subjects between 41 and 55 years old, results showed a mean uncorrected near visual acuity improvement by about two to three lines in each eye and binocularly from a baseline mean of about J3.5 to about J1.5. Improvement of at least three lines was seen until 5 hours for seven patients, according to Renna and colleagues.

There was no loss in uncorrected distance visual acuity in each eye and binocularly.

PresbiDrops (FEPA-SAET Group) combines a parasympathomimetic agent with a nonsteroidal anti-inflammatory drug in an oil-based formulation. The purpose of the NSAID is to prolong the effect of the parasympathomimetic action

The J. Benozzi method uses pilocarpine 1% and diclofenac 0.1%. The authors reported that all patients prescribed the treatment showed near vision of J1 and far vision of 20/20, using the drops at 6-hour intervals daily.

Presbyeyedrops is a combination of two parasympathomimetics and a NSAID. In a pilot study one patient reported dryness, and one patient reported a burning feeling, according to Renna and colleagues.

PresbyPlus (Lugano) stimulates the ciliary muscle to accommodate and constrict the pupil. The therapy contains two parasympathomimetics and one parasympatholytic. The clinical trials showed 90% of subjects could see J4 to J1 within 1 year without adverse reactions, according to the researchers.

What does the future hold?

Bobby Christensen

Christensen predicts that the initial interest would be strong in such products. His long-term prognosis is that the therapies may be compromised because patients will not remember to take them, and only a small group would be willing to use the drops often.

The experts agree that pricing is a major concern and a significant factor in determining the impact of this new treatment method.

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“I foresee that the demographics are going to be a big part,” Christensen said. “If your office is in an affluent area, a patient is willing to pay $250 to $300, but in a less affluent area, drops over $150 that are not more permanent are going to be a tough sell.

Many unanswered questions remain, and these therapies are several years away from approval in the U.S., but the potential is promising for those suffering from or nearing presbyopia.

Medina believes optometrists need to treat presbyopia with whatever methodology is appropriate for the patient.

Arthur Medina

“Spectacle treatment and surgical inlays are exceptional options for many patients, and I think another one will be pharmacological,” he said. “There will not be any one treatment or procedure that fits all; optometrists must be well versed and involved in each one and always do what’s best for the patient.”

To illustrate a point about education and primary care, Medina said he often teases his colleagues that not many optometrists cut and grind the optics on the spectacle lens.

“They oversee the management of that process so they can best deliver those optics as a medical device to their patients,” he said. “I see it no different in many of the surgical procedures and now pharmacological treatments. I want optometry to actively participate, be knowledgeable and be involved.” – by Abigail Sutton

Disclosures: Alexander, Christensen, Cockrell, Mangan and Medina report no relevant financial disclosures. Lindstrom is a consultant to Novartis. McCollum is a co-founder of Presbyopia Therapies.