Treating Presbyopia: Cheaters May No Longer Prosper

Projected to affect over two billion people worldwide in the next decade, presbyopia is a global problem that cannot be ignored.^1,2 Unavoidable for those in the aging population, presbyopia encompasses a gigantic market with a significant unmet patient need. With the increasing aging population, optometrists and ophthalmologists should shift their focus to offering new alternative options to combat presbyopia.

Anatomy of Presbyopia

Although there are many theories regarding the exact mechanism of presbyopia, the general consensus involves the anterior central lens capsule steepening during accommodation.¹ A progressive decline in accommodative capacity due to the increased stiffness of the crystalline lens manifests as difficulty reading at certain focal lengths.^1,3 With the gradual loss of the ability to focus on near objects, presbyopia becomes noticeable in our early to mid-40s and continues to worsen until around age 65.^1,3

Accommodation has significant effects on the pupil response, vergence response, and binocularity.¹ Therefore, actions such as squinting to see near objects, holding reading materials further away, and requiring more light to read all typically occur at the onset of presbyopia and are some of the first signs of aging.³

Once patients reach their 40s, it is not abnormal to require more light in order to see well, and adding brighter lights to workspaces or reading areas can help.³ As a presbyopic patient squints to read or perform tasks that require close focus, the result can be headaches, migraines, and fatigue.⁴ When near tasks are performed for an extended amount of time, symptoms of eye strain may become a routine part of the day, if left uncorrected.

Demographics of Presbyopia

Inevitably occurring in many individuals over the age of 45, presbyopia is a diagnosis we can often see coming. With millions of people spending excess time on the computer in response to the COVID-19 pandemic, patients across the globe have been relying on their near and intermediate vision more than ever.

Affecting approximately 25% of the world’s population, review and analysis have shown that approximately 826 million people (95% CI, 686-960 million people) with presbyopia have near visual impairment because they had no, or inadequate, vision correction in 2015.² Unfortunately, lack of awareness and poor affordability are major global obstacles, and the prevalence of unmanaged presbyopia is as high as 34% in developed countries.¹ It is hard to imagine that there are still millions of people in the world who do not have access to options to correct their near vision impairment. There is a significant unmet need in access to care for this unavoidable issue.

Social and Psychological Experience with Presbyopia

Presbyopic patients understandably experience a psychological impact. Long gone are the days of being able to read effortlessly, and the sudden dependence on near correction can feel burdensome. Having to rely on visual correction for most near tasks can seem daunting.

Currently, the options to treat presbyopia are limited and do not restore accommodation.³ Non-invasive options consist of bifocal or multifocal progressive addition lenses and monofocal or bifocal contact lenses. Surgical correction of presbyopia is finite, and patients may feel frustrated with the lack of options.

Additional hurdles presbyopic patients face include the limited utility of contact lenses and not being candidates for refractive surgery, leaving them with only one option: spectacle correction. There are also many patients who are candidates for contact lenses but unable to tolerate monovision or multifocal lenses. The treatment option for presbyopia is not a one-size-fits-all approach. The more options available to present to the patient, the better.

THE OPPORTUNITY

Presbyopia currently affects 1.8 billion people worldwide and over 120 million in the United States.^2,5 When compared with dry eye, which affects approximately 16 million, it’s clear that eye care has an obligation to address this condition.⁶ The need for focus is ever-present, and the limitations in human anatomy have inspired a multitude of corrections, procedures, surgeries, and pharmaceuticals.

As optometrists are the primary ocular physicians and perform 85% of all eye exams, our role in addressing this anatomical failure is paramount.⁷ Correcting vision is the heart of optometry, and as vision correction evolves, so must optometry evolve to engage, embrace, and advance options to correct our patients’ visual conditions.

Just as not every pair of glasses fits every face, not every option for presbyopia correction will fit every patient. What may work for one patient may not work for the next. As we know, a comprehensive discussion, case history, and understanding of the patient’s visual demands can increase success when recommending treatment options. However, we always welcome an innovative non-surgical option. This new arrow in the quiver may be the one that works better for some patients or for certain activities. Additionally, some presbyopia-correcting options may work better together than alone. Just as some multifocal contact lens patients also use reading glasses in certain settings, some patients may benefit from having an additional option to boost their near vision in certain situations, such as low light or for fine detailed work. Synergy is a huge advantage for treatment options and should be acknowledged and discussed with patients. There are levels of treatment options, and some presbyopes may require more help in certain situations and less help in others.

The LiGHT study showed us that there are options for glaucoma therapy in that both SLT and medications are viable paths for treatment.⁸ In the United States, however, it tends to be more common to prescribe medication as opposed to laser therapy for the initial treatment of glaucoma. The culture of embracing pharmaceutical therapy is commonplace in our world. For example, most dry eye patients try over-the-counter drops for several years before discussing their condition with their doctors. From pediatric pink eye to dry eye to glaucoma, drops have become the go-to for treating ocular conditions. Why should presbyopia be any different?

Instead, we have allowed surgical interventions and optical modifications like monovision to try to conquer this condition. Drop therapy allows for much more flexibility and reversibility than our current options. This option is one that is already embraced by our patients and our society, and therefore needs to be embraced by the eyecare industry, specifically optometry.

We have all experienced the patient in their 40s who is having their very first eye exam. They’ve never needed glasses and therefore never needed to see an eye doctor. We’ve also seen the patient who comes in for help when some ocular pathology is too far gone. The prevalence of presbyopia and glaucoma both increase after age 40, with age being a significant risk factor for each. By engaging with this patient population and offering new, better options, we can not only help patients see better at near, but also educate them on the need for ongoing medical screenings and hopefully detect sight-threatening conditions like glaucoma earlier and more often.

As the opportunity to offer patients a non-surgical, pharmacological option for presbyopia emerges, it is critical that optometrists seize the chance to provide these options and use this opportunity to educate communities about the importance of comprehensive eye exams. Addressing a huge unmet need for people with presbyopia is likely to increase optometric demand, and this demand can help diagnose both ocular and systemic medical conditions earlier. The hope is that people with presbyopia will flood our offices, enabling more regular eye exams for our patients and their friends and families, so that we can diagnose these conditions earlier and more people can see better for the rest of their lives.

BALANCING EFFICACY, SAFETY, AND COMFORT

Finding the perfect balance of efficacy, safety, and comfort should be imperative for patients, providers, and companies striving to design a lifestyle drug for people with presbyopia. Particularly for presbyopes, innovative new products in the pipeline cannot compromise on safety or comfort, as this is a quality-of-life choice.

Efficacy is the cost of entry for any new pharmacologic, but what is important in this new space will be the ability to demonstrate no impact on distance and night vision. Because this is the formal FDA criteria for presbyopia-correcting eye drops, we will begin to understand whether new entrants can do this upon approval. Regarding pharmaceutical options for presbyopia, patients will not be as eager to fix their near vision if that involves sacrificing the quality of their distance and night vision.

Product safety is an important consideration for eye doctors as well, and because this is a quality-of-life drug, there can be no compromise. Especially because presbyopes have a high likelihood of dry eye disease, a preservative-free entrant will be key to ensuring the health of the ocular surface.

Patients want the freedom to choose how and when they will use presbyopia drops, so the drop must be comfortable upon administration. Presbyopes have high expectations and will not tolerate side effects like headache, brow ache, or eye redness. If any eye drop causes burning and stinging, patients won’t be compliant.

Miotics Out in Front

Given the enormous market opportunity, there are many companies developing presbyopia-correcting eye drops. Pharmacologically speaking, miotics are going to be a major player in presbyopia management going forward due to their pinhole effect. In their traditional glaucoma use, miotics work by contraction of the ciliary muscle, tightening the trabecular meshwork, and allowing increased outflow of aqueous through traditional pathways.

Miosis results from the action of these drugs on the pupillary sphincter, creating a pinhole effect. This pinhole effect allows depth-of-field enhancement without any associated accommodative distance blur. Improving near vision at the expense of distance vision likely would not be well received by patients. It could also lead to potential distance issues, such as driving safety, and recreational concerns where distance visual acuity is often critical (e.g., hunting, fishing, golfing). Likewise, improving near visual acuity that is accompanied by ocular discomfort, redness, dry eye, or other ocular or systemic side effects will not achieve the desired efficacy-safety balance patients desire. Therefore, it will be imperative that improvement of near visual acuity in these presbyopes is accompanied by the same level of ocular comfort and distance visual acuity that patients enjoy and expect.

Orasis (OR-uh-sis) Pharmaceuticals has a novel presbyopia-correcting eye drop, a proprietary combination of low-dose pilocarpine and multi-faceted vehicle, and is enrolling 600 patients in their Phase 3 clinical trials, NEAR-1 and NEAR-2. The primary endpoint of these studies is 3-line improvement in near visual acuity without loss of 1-line or more in best distance corrected visual acuity. The Phase 2b study met the primary endpoint: 3-line improvement in near vision (ETDRS chart) with no reduction of distance or night vision. Adverse events were mild and temporary, the drug was well tolerated, and no eye redness was observed. The preservative-free formulation ensures no further compromise of the ocular surface.

Allergan, an AbbVie company, also has a presbyopia-correcting eye drop in development. AGN-190584 is an investigational formulation of pilocarpine, a cholinergic muscarinic receptor agonist, that is being studied for treating symptoms associated with presbyopia as a topical, once-daily drop delivered by a proprietary vehicle. Two Phase 3 trials, GEMINI 1 and GEMINI 2, are evaluating the drop’s safety and efficacy in study participants with presbyopia. Allergan announced positive top line results of GEMINI 1 and 2, which will be the basis for a new drug application submission to the FDA in the first half of this year.⁹

Eyenovia announced enrollment for Phase 3 VISION-1 study of MicroLine, its proprietary pilocarpine formulation delivered via its Optejet dispenser, for improvement in near vision in patients with presbyopia. The VISION trials are double-masked, placebo-controlled, cross-over with approximately 100 participants.¹⁰ The primary endpoint is same-day improvement of binocular distance corrected near visual acuity. MicroLine is designed for use “on demand” for symptomatic improvement of near vision impairment secondary to presbyopia.

Miotics to Follow

Ocuphire Pharma is enrolling patients in a Phase 2 clinical trial, VEGA-1, to investigate Nyxol, its preservative-free ophthalmic solution containing 0.75% phentolamine or 1% phentolamine mesylate, a nonselective alpha-adrenergic antagonist that inhibits the contraction of the smooth muscle of the iris. In multiple Phase 2 trials, Nyxol reduced pupil diameter, resulting in better contrast sensitivity and visual acuity. Nyxol is being developed for dim or night vision disturbances, reversal of pharmacologically-induced mydriasis, and presbyopia.¹¹

Presbyopia Therapies completed their Phase 2 study, a single-center, double-masked evaluation of the efficacy and safety of PRX-100 in the treatment of early to moderate presbyopia, in 2018. The active ingredient in this presbyopia-correcting drop is aceclidine. The drop causes miosis without the usual accommodative effect, thus improving near vision without reducing distance vision with the pinhole effect. Onset is within 30 minutes, and the effects last 4 to 5 hours. During the trial, almost 50% of the subjects gained 3 lines of distance corrected near visual acuity and more than 90% gained 2 lines.¹²

Visus Therapeutics Inc. announced its launch and clinical development program for a novel eye drop designed to restore the loss of near vision associated with presbyopia. Visus’ lead product candidate is Brimochol, a proprietary formulation that combines two well-studied, FDA-approved pharmaceuticals: carbachol and brimonidine tartrate. Five clinical studies have been conducted evaluating the safety and efficacy of Brimochol. In the most recent clinical study of 57 patients, Brimochol demonstrated statistically significant improvement in near visual acuity of 5 lines or greater, with the effects lasting at least 12 hours. The same study found that Brimochol was well tolerated with no reports of headache or brow ache in this proprietary combination. Phase 2 trials are slated to commence in early 2021.¹³

A Look Ahead

UNR844 from Novartis Pharmaceuticals is a lens modifying agent. It is an ester of naturally occurring R-Lipoic acid and choline. UNR844 penetrates the cornea, where it is metabolized into choline and R-Lipoic acid. Enzymes within lens fiber cells are thought to chemically reduce R-Lipoic acid to the active dihydrolipoic acid, which may reduce disulfide bonds between lens proteins, thus restoring elasticity in the lens. UNR844 treatment resulted in improvement in near vision versus placebo in patients with presbyopia in the Phase 1/2 EV-C-002 study. It was well tolerated in all studies and no safety concerns were identified.