A First Look at Therapeutics for Presbyopia

An overview of the growing list of options for presbyopia management.

Speakers:

Gina Wesley, OD, FAAO, and Paul M. Karpecki, OD, FAAO

Release Date:

Educational Objectives:

After completing this activity, the participant should:
1. Better understand the presbyopic population today and its unique needs.
2. Have knowledge of existing presbyopia mitigation options.
3. Gain awareness of emerging pharmaceutical presbyopic candidates.
4. Understand the basic mechanisms of action for emerging presbyopic candidates.

Target Audience:

This activity is intended for optometrists who provide primary care optometry services, including but not limited to medical optometric services.

Faculty/Editorial Board:

Disclosure of Conflicts of Interest:

Review Education Group (REG) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to REG policy. REG is committed to providing its learners with high quality activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

Paul M. Karpecki, OD

Consulting fees from Akorn, Alcon, Aldeyra, Allergan/AbbVie, Azura, Bausch + Lomb, BioTissue, BlephEx, Bruder Healthcare, Bruno Pharma, Cambium Medical Technologies, Dompé, Eyedaptic, Eyedetec Medical, EyeGate Pharma, Eyevance, Gobiquity, Hubble, iCare USA, Imprimis, Ivantis, Jobson/WebMD, Johnson & Johnson Vision, Kala Pharmaceuticals, Keplr Vision, Konan Medical, Legrande, Lentechs, MacuLogix, Mallinckrodt Pharmaceuticals, Mitotech, Neurolens, Novartis, Oasis Medical, Ocuphire Pharma, Ocular Sciences, Oculus, OcuMedic, Omega Ophthalmics, Orasis, Osmotica Pharmaceuticals, Oyster Point Pharma, Regener-Eyes, Reichert Technologies, Rendia, RxSight, ScienceBased Health, Sentiss Pharma, Sight Sciences, Silk Technologies, Sun Pharmaceuticals, Surface Pharmaceuticals, Tarsus Medical, TearClear, Visant Medical, Visus Therapeutics, Vital Tears.

Fees for non-CME/CE services from Bausch + Lomb, Dompé, Eyevance, Kala Pharmaceuticals, Mallinkrodt Pharmaceuticals, Neurolens, Osmotica Pharmaceuticals, Sun Pharmaceuticals.

Contracted research with Ocuphire Pharma, Kala Pharmaceuticals, Sight Sciences, Surface Pharmaceuticals, Bruno Pharma.

Royalties from Eye Therapies.

Ownership interest in Allergan/AbbVie, Bausch + Lomb, BlephEx, Bruder Healthcare, Cambium Medical Technologies, Eyedaptic, Eyedetec, Gobiquity, Healthe, Ivantis, Kala Pharmaceuticals, Keplr Vision, Legrande, Lentechs, Mati Therapeutics, Mitotech, Neurolens, Ocuphire Pharma, Ocular Sciences, OcuMedic, Omega Ophthalmics, Orasis, Oyster Point Pharma, Regener-Eyes, RxSight, Sight Sciences, Silk Technologies, Tarsus Medical, TearClear, Visant Medical.

Gina Wesley, OD

Consulting fees from Bausch + Lomb, Alcon, CooperVision, Optovue, Orasis, Shire Pharmaceuticals, Johnson & Johnson Vision

Planners and Managers: REG planners and managers have nothing to disclose.

Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management.  Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

Presbyopia is front and center in most practices because it affects a wide age range of people, and patients are very vocal about their symptoms and how they affect their quality of life. After all, we are living long lives and presbyopia symptoms begin to appear around age 40.^1,2 As the world’s population grows older, optometrists must be prepared to intervene and treat patients in a manner that is practical, effective and personalized to the lifestyle needs of the individual. In this regard, optometrists have a huge opportunity to make a difference. In the United States alone, approximately 128 million people are presbyopic.^3,4,5 Globally, 1.8 billion people are affected.⁶ 

In the US, most presbyopic patients wear some sort of vision correction. But as most eyecare providers will attest, patients express tremendous frustration with most of the options they try, spectacles in particular. According to the Vision Council, almost 31 million adults purchase about 51.2 million pairs of readers per year.⁷ These are active patients who lead busy lives and who plan to work into their 70s. They also spend most of their days experiencing the negative effects of presbyopia. For example, Americans check their phones 96 times per day.⁸ That’s just one device. In total, US adults spend in excess of 11 hours daily interacting with media.^9,10 For those patients whose vision correction doesn’t allow them to easily switch visual functioning distance, this can be extremely frustrating. 

If you’re having conversations with these patients in your office, you know that they want and expect more. Yet, the limited options we have to improve their quality of life don’t do much in the way of engendering loyalty to our practices. Patients likely commiserate about this lack of choices with family and friends as they wait impatiently for new technology to end their frustration. This is why it is so important that we remain fully informed about new options for presbyopes—because patients may hear about them as soon as we do, so we must be prepared. We experienced this with cataract surgery, and it’s even more pronounced with presbyopia correction. 

This monograph aims to provide optometrists with the information needed to field patients’ questions, respond to their demands in a safe and clinically appropriate fashion, and prescribe or recommend solutions from the diverse and growing armamentarium of presbyopia-correcting options, ranging from spectacles and contact lenses to surgery and emerging pharmaceuticals. 

Indeed, we are well-versed in most presbyopia-correcting approaches. But as new therapies emerge, clinicians must also be prepared to guide and educate patients in this evolving treatment landscape. As pharmacologic agents for presbyopia become clinically approved for use in patients, we must quickly ready ourselves to make treatment decisions and counsel patients about their choices. 

THE PATIENT EXPERIENCE 

Dynamic vision is much more complicated than static vision. With ametropia, the cornea doesn’t change. You only need to correct for distance and accommodation provides the near. Presbyopia is dynamic and has multiple points of focus with moving components. Replicating or simulating this natural dynamic is challenging, and patients are very sensitive to the frequent changes they experience in their vision and ability to focus. They often relay to their eye doctor what appear to be overnight changes (e.g., they went to bed able to read a book and woke up needing a new prescription). These changes don’t happen that fast, but for many patients, that’s how it feels. This phenomenon highlights one of the most meaningful ways that we can help presbyopic patients; namely, preparing them for what’s about to happen. If we mention it ahead of time, patients are more likely to slowly notice the changes vs. experience what feels like rapid vision loss and extreme disappointment. 

Binocular vision issues drive many patient complaints in presbyopia patients. For example, consider the convergent insufficient patient who can no longer accommodate to compensate for their near point of convergence. When patients are convergent insufficient, their accommodation can help build the ratio necessary to be comfortable at near. But with age, these patients start to lose their hyperfocus ability to compensate and start to complain a bit more about asthenopia, often in their mid- to late-30s. Run a quick cover test on these patients and if you notice an issue, have an early conversation about expectations moving forward so they understand they may need help sooner than other presbyopes. 

Another group to pay extra attention to is post-LASIK former myopes with symptoms of asthenopia. Before surgery, these patients had built in, base-in prism in their minus lens glasses to help them with convergence issues, but post-LASIK, that’s suddenly gone. When these patients are in their late 30s, they often start experiencing near vision issues, which is a little sooner than you would think, but it makes sense because LASIK surgery has taken away their prismatic “crutch.” 

Finally, accommodative insufficient patients are likely to experience earlier symptoms. These patients never had the ability to focus properly at the appropriate time and age, and need more help sooner. Here again, we have to be ready to explain this to our patients because they don’t understand why they are feeling so much more uncomfortable than other people who are the same age. 

Patients with early-onset symptoms of presbyopia may be very motivated to achieve comfortable vision. This begins with a conversation about what’s happening physiologically and an explanation about what we can do to help. 

TREATMENT OPTION OVERVIEW 

As you know, there are a variety of vision correction options for presbyopes, including spectacles. Within the spectacle arena, there are reading glasses, progressives, bifocal/trifocal and anti-fatigue lenses. With contact lenses, we can choose between multifocals, which allow for continued binocularity, monovision as a fallback, or modified monovision using a combination of multifocal and spherical designs. In the surgical realm, we’ve considered accommodating lenses, multifocal IOLs, extended depth of focus IOLs, trifocal IOLs, adjustable IOLs, corneal inlays and scleral expansion. 

The IOL options have proven to be a frontrunner in this category and are increasingly selected as a presbyopia-correcting option for cataract patients. In some instances, as with contact lenses, monovision also is still utilized and can provide very sharp point near vision. However, this often comes at the expense of intermediate vision, which in this day and age is critical to functioning with our many handheld tools and devices. The challenge with most IOLs is that you only get one chance to get it right, and you don’t know for sure how the patient is going to react until after the lens is already in their eye. In other words, your biometry and other preoperative measurements have to be spot on, which can be challenging in a patient population with so much ocular surface disease because these tear films can create a lot variability in the eye’s refractive surface. 

Conversely, adjustable lenses are less reliant on preoperative measurements. Instead, you refine the prescription after the lens is in the eye. This is achieved using an adjustable beam light delivery device, which is used in-office and causes macromers in the path of the light to be photopolymerized. The unpolymerized macromers move into the exposed area causing precise shape and power change. Next, the entire lens is exposed to light to polymerize all of the remaining macromers. The outcome is a precise change in the lens power to match the patient’s individual prescription. In essence, refraction is optimized after healing is complete, and the patient gets to trial the refractive outcome. The light treatments are painless, noninvasive and last about 90 seconds. Most patients have two to three treatments, the first of which is at least 17 days after surgery. The subsequent treatments are for refinement purposes. Clinical trials show patients receiving the RxSight Light Adjusting Lens achieved uncorrected vision of 20/20 or better twice as often as those receiving a monofocal lens, and nearly 92% of patients receiving the light adjusting lens achieved results within 0.50D of the intended target.¹¹ 

One disadvantage of light-adjusting lens technology is that patients must wear UV protective glasses outdoors for the first few weeks until they decide that their vision is exactly as they want it and you lock in the final prescription. As soon as they are satisfied, you can finalize the prescription, and patients can discontinue wearing the UV protecting eyewear. 

In addition to spectacles, contact lenses and surgical techniques, a number of new pharmaceutical agents are being investigated for the treatment of presbyopia. They are based on one of two main mechanisms of action— pupil modulation or lens softening. Pupil modulation utilizes pupillary miotics, which exert a pinhole effect and increase the depth of field.¹² The lens softening approach is based on the assumption that lens stiffening and loss of flexibility are presbyopia’s main causes.¹³ As such, these drops selectively target and disrupt the disulfide bonds in the lens. 

LENS SOFTENING APPROACH 

A presbyopic lens can result from several different etiologies; however, excessive crosslinking is considered a leading potential cause of increased lens stiffening, which results in the loss of accommodative focusing power. In short, in order for the eye to focus on nearby objects, the lens must be flexible and viscous enough to change shape by thickening at its center in order to accommodate. Lens fiber cells are filled with a 30% solution of protein, known as cytosol (soluble) lens protein. A normal functioning lens fiber cell allows for cytosol displacement, thus facilitating accommodation and enabling the lens to focus on nearby objects. Oxidation is a normal challenge to all body tissues, including the lens fiber cells. Oxidation leads to crosslinking of cells and the aggregation of proteins. Normally, we have processes to break these bonds, but as we age, the enzymes that do this can’t keep up with the number of crosslinked proteins, so the aggregation builds up. This compromises the lens fiber cell’s ability to displace cytosol and, therefore, its ability to accommodate. 

The experimental drug in this category, UNR844 (lipoic acid choline ester [LACE] 1.5%, Novartis) is a prodrug that’s administered twice-daily. Previously called EV06 ophthalmic solution, this drop penetrates the cornea and is metabolized into choline and lipoic acid, two naturally occurring substances. Next, enzymes within lens fiber cells chemically reduce lipoic acid to active dihydrolipoic acid. Dihydrolipoic acid chemically reduces disulfide bonds. These disulfide bonds are cleaved, or chemically reduced, in lens fiber cells and the choline exerts a cationic surfactant action on protein aggregation. Crystallins are repaired and cytosol displacement is restored. As such, UNR844 may potentially restore the natural ability of the human crystalline lens to reduce aberrant chemical bonds and cross-links, thus regaining lens flexibility and restoring accommodation and focal power. This therapeutic approach should not disrupt the fiber structure of the lens or any natural proteins. Therefore, UNR844 will not likely result in optical distortions, which could potentially result from mechanical or laser treatment approaches. 

In a Phase 1/2 study, 50 patients received one drop twice daily.^14,15,16 At day 91, distance-corrected near visual acuity (DCNVA) was 20/40 in 82% of the treated patients and 20/32 in 68% of treated patients. Also of note, 22% of patients experienced an improvement of three lines after 90 consecutive days of twice-daily treatment. With increased use the improvement was sustained in 67% of patients at 7 months post-treatment.^17,18 

More recently, a Phase 2 study of 78 patients ages 45 to 55 years did not meet its primary objective insofar as there was no significant difference in mean change in DCNVA between UNR844 and placebo.¹⁹ The authors noted that this may be due to variability in DCNVA measures. When a post hoc non-parametric analysis was performed, the median difference between UNR844 and placebo was four letters, which is more in line with the earlier results. A Phase 2b dose-finding study is planned. 

PUPIL MODULATION APPROACH 

Dilated pupils narrow depth of focus and create blur. By making the pupil smaller, we allow for a range of depth of focus, and when we create a pinhole, we improve image quality by blocking stray light. Of course, we also restrict peripheral vision, making placement very important. Only a small pupil at, or extremely close to, the iris plane can extend depth of focus without restricting peripheral focus.²⁰ The traditional miotic is the muscarinic receptor agonist pilocarpine, which causes miosis and ciliary muscle contraction. 

Several pupil modulation drugs in the pipeline may receive approval in the next few years, some of which utilize pilocarpine, sometimes in combination with other agents. The leading miotics under investigation include: 

• AGN-190584. (1.25% pilocarpine, AbbVie/Allergan). After assessing different concentrations of pilocarpine with and without oxymetazoline, researchers have optimized a formulation upon which new Phase 3 trial data is based.21 Gemini 1 and Gemini 2 are placebo-controlled randomized trials that include a total of 750 patients.22,23 AGN-190584 or vehicle were administered once-daily bilaterally for 30 days. In both studies, the primary endpoints were met. Specifically, there was a statistically significant 3-line or more gain in distance-corrected near visual acuity out to day 30 at hour 3 in low-light conditions and without a loss of distance vision. No treatment-emergent serious adverse events were observed. 

• Brimochol (brimonidine and carbachol, Visus Therapeutics). This combination of carbachol, a parasympathomimetic, and brimonidine, an alpha-2 adrenergic agonist, has entered Phase 2 trials. It is unique in that the effect is believed to last 8 to 12 hours thanks to the higher dose carbachol.²⁴ However, headaches and brow aches are thought to be mitigated due to the combination with brimonidine. Five clinical studies have already been conducted, with the most recent reporting on 57 subjects and showing statistically significant improvement in near visual acuity of a 5 Jaeger-line or greater gain.²⁵ 

• CSF-1 (low-dose pilocarpine, Orasis Pharmaceuticals). With a concentration of less than 1% pilocarpine, this parasympathomimetic is currently in Phase 3 trials. Six hundred subjects are enrolled in two multicenter, double-masked, parallel-group clinical trials dubbed NEAR-1 and NEAR- 2 (300 subjects per study ).^26,27 A unique feature of CSF-1 is the vehicle, which is both lubricious and preservative-free, which may be beneficial given the prevalence of dry eye in aging populations. The primary and secondary outcomes of the Phase 3 investigations mimic those studied in phase 2b,²⁸ with some additions including the impact on night vision and other safety and tolerability measurements. In the earlier investigation of 166 patients on b.i.d. dosing, 47% achieved ≥3 line improvement and 80% achieved a ≥2 line improvement.²⁹ Treatment-related adverse events were mild and temporary, with no negative impact on distance or night vision. 

• MicroLine (1% or 2% pilocarpine, Eyenovia). Now in Phase 3 trials, this agent is administered via the company’s proprietary Optejet dispenser that delivers about 8 microliters of 1% or 2% pilocarpine.30 For reference, a typical drop is between 30 and 50 microliters. Earlier investigations have shown that a statistically significant proportion of subjects treated with MicroLine had a 3-line or more improvement in distance-corrected near visual acuity vs. placebo in low-light conditions at 2 hours post-treatment and that the drug was well-tolerated. All adverse events were mild. 

• Nyxol (0.75% phentolamine and 0.4% pilocarpine, Ocuphire Pharma). This combination drug began Phase 2 proof-of-concept trial enrollment in VEGA-1 earlier this year, with the expectation of reporting on data from 152 participants.³¹ It is believed that Nyxol (preservative-free phentolamine) can last a significant period of time to offset the shorter duration of the low-dose pilocarpine. Earlier studies indicate that Nyxol alone reduced pupil diameter by approximately 20% and significantly improved near visual acuity by one line for >24 hours after an evening instillation. 

• PRX-100 (aceclidine, LENZ Therapeutics). Aceclidine is a parasympathomimetic like pilocarpine. This muscarinic acetylcholine receptor agonist causes pupil constriction in the sphincter muscle of the iris and causes miosis without stimulating accommodation. In Phase 2b trials (n=58), this novel treatment was well-tolerated, with 47.2% of participants gaining 3 lines of near vision acuity and more than 90% gaining at least 2 lines of near visual acuity.^32,33 About half of the patients receiving the drug maintained the 2-line improvement for up to 7 hours following initial installation. According to the company, aceclidine can treat a broad range of refractive error, from -4.50D to +1.50D and up to 2.00D of astigmatism.³⁴ 

ADAPTING TO PRESBYOPIA 

Fundamentally, patients are seeking functional vision without too much hassle (which, of course, is relative). Some patients need 20/20 all the time to be happy, which may not be possible without making adjustments to how they interact with the environment. However, most patients are used to modifying their lighting or the fonts on their computers. The challenge for eye care providers is determining the right strategy for each individual patient. Unfortunately, this can be hit-or-miss before a patient is ready for cataract surgery. The promise of therapeutics opens up a whole new realm of possibilities that may be more convenient and aesthetically acceptable to many presbyopes. But, whatever option the patient chooses, it must be comfortable and safe. As new data emerges on drops, this should be top of mind. 

Optometrists have a long history of treating presbyopia with glasses and contact lenses, but for patients who are not willing or able to undergo surgical procedures, no pharmacologic treatments have been available. As this evolving pipeline develops, there is growing anticipation for this method of treatment. 

One way we can position ourselves is to make patients aware of the emerging possibilities and let them know that we are the leading experts in presbyopia treatment. In addition, we can let them know that soon we will have more options for more circumstances and lifestyle needs. That said, by no means does the introduction of drops imply that glasses and contact lenses are going away. On the contrary, therapeutics are additive. They are not going to work perfectly for every patient’s eyes in every situation. However, they may offer freedom that wasn’t previously available, which is welcome news for clinicians and patients alike.