Despite all the advances in pharmaceutical eyecare over the years for a myriad of eye conditions, including glaucoma, dry eye, and ocular allergy, presbyopia has stood out as a significant unmet need.
With the entry of Vuity (Pilocarpine ophthalmic solution 1.25%, Allergan [An Abbvie Company]) in October 2021 and a slew of other companies to follow suit in the presbyopia race over the next several years, patients finally have hope.
Presbyopia usually affects folks around the age of 40, progressively gets worse, and evolves every decade until even 100 years old. Activities of daily living (ADLs), including reading, surfing iPads, perusing nutritional labels, and texting, can be greatly impacted in presbyopic patients.
Before this first pharmaceutical approval, the only options for patients included progressive addition lenses (PALs), multifocal contact lenses, over-the-counter reading glasses, and surgical solutions.
Overview of presbyopia prevalence and classification
It is reported that over 1 billion people worldwide have presbyopia, with treatment burden alone costing well over $31 billion USD. In patients under the age of 50 with presbyopia (which internationally represents nearly 245 million people working-age presbyopes), this refractive error led to over $11 billion USD in annual productivity loss.1
As presbyopia was hardly spoken about at national meetings until recently, it was not even classified. Recently, a panel of ophthalmologists and optometrists led by Marguerite B. McDonald, MD, convened to do just that—suggest a way to classify presbyopia.
The authors proposed the following:2
- Mild presbyopia as requiring <1.25D of add power
- Moderate presbyopia as requiring between >+1.25D and +2.00D add power
- Advanced presbyopia as requiring >+2.00D of add power
Mechanism of action of presbyopia drops
It helps to understand the mechanism of action and differences between the presbyopia drops in order to better manage expectations and who may benefit from each drop. All of the drops are pupil-modulating by utilizing the pinhole effect.
The pinhole effect is a method of pseudoaccommodation via miosis and pupil size reduction without ciliary muscle engagement, working to increase the depth of field while avoiding distance vision loss. Xu et al. studied pupil size as it relates to photopic, mesopic, and scotopic conditions, finding that as the pupil size decreased, there was an increase in reading vision improvement.3,4
However, if the pupil was too small, the patient began to lose contrast and lines of near vision. The researchers reported that there is a “sweet spot” at 30% miosis from the patient’s natural pupil size.
Results from the clinical trials for Vuity
Pilocarpine HCl ophthalmic solution 1.25% (Vuity, Allergan [An AbbVie Company]) is the first FDA-approved topical drop to pharmacologically treat presbyopia. In March 2023, it was approved by the FDA for a twice-daily dosing option along with its original approval as a once-daily treatment obtained in October 2021.5 Dosing at either QD or BID, the second dose may be administered 3 to 6 hours after the first, extending the duration of effect of Vuity for up to 9 hours.
The phase 3 VIRGO trial that led to BID dosing approval met the primary endpoint proportion of participants required that gained 3 lines or more in mesopic, high contrast, binocular distance corrected near visual acuity (DCNVA), with no more than 5 letter loss in low light corrected distance visual acuity (CDVA) at Day 14, Hour 9 (3 hours after the second drop) versus placebo.5
The most common adverse reactions reported in >5% of participants were headache and eye irritation. Ocular adverse reactions reported in 1 to 5% of participants were visual impairment, eye pain, blurred vision, and vitreous floaters. No reports of retinal detachment were found during the trial.
Latest presbyopia drop approvals
Qlosi
Qlosi (Orasis Pharmaceuticals) utilizes a low dose, preservative-free ophthalmic solution of pilocarpine HCl 0.4%, a cholinergic agonist indicated for the treatment of presbyopia in adults. At this time of publication, the medication has been approved by the FDA in October 2023 for daily or up to twice each day administration. Qlosi is expected to be available in the first half of 2024.
With a preservative-free near-neutral pH formula that contains lubricating agents, it has been designed to provide flexible dosing with the option to dose a second time if needed 3 hours after the initial dose, extending the potential efficacy from 20 minutes after administration to up to 8 hours.7
Referring back to the Phase 3 clinical studies, NEAR-1 and NEAR-2, involved over 600 patients evaluating the efficacy and safety of CSF-1. Both trials met their primary and key secondary endpoints on Day 8, achieving statistically significant 3-line or more gain in DCNVA and no loss of 1-line or more in distance visual acuity (DVA).8,9
Only 2.6% of study participants reported moderate treatment-related adverse events, with the most common being headache (6.8%) and instillation site pain (5.8%).8,9
Presbyopia drops in the pipeline
Brimochol preservative-free
Brimochol PF (Visus Therapeutics) is a preservative-free (PF) combination ophthalmic solution of carbachol 2.75%, a miotic agent for pupil constriction, and brimonidine tartrate 0.1%, which inhibits iris dilator muscle contraction.6
Brimonidine is also believed to possibly inhibit ciliary muscle contraction, thereby assisting to decrease associated side effects, as well as act as a vasoconstrictor leading to increased bioavailability and duration of action of the carbachol molecule.6
Phase 3 pivotal BRIO-I trial met its primary endpoint, achieving >15 letter gain in binocular DCNVA without a loss of ≥5 letters at distance, starting at Hour 1 and maintaining across all time points through Hour 6.6 The drug was well-tolerated by trial subjects, with no significant adverse events.6
LNZ100 and LNZ101
LNZ100 (Aceclidine 1.75%) and LNZ101 (Aceclidine 1.75% + brimonidine) (Lenz Therapeutics) leverage the novel active ingredient Aceclidine, which targets the iris sphincter muscle to promote pupil constriction while avoiding overstimulation of the ciliary muscle and resultant myopic shift.10
While currently gearing up for phase 3 clinical trials, the phase 2 INSIGHT trial for both LNZ100 and LNZ101 achieved their primary endpoint of >3 lines improvement in near visual acuity (NVA) without losing >1 line in DVA at 1 hour in 71% and 56% of treated subjects respectively.10
Both were also found to maintain this improvement in 37% of LNZ100 and 48% of LNZ101 treated subjects at the 10-hour post-instillation point. Patient feedback noted both formulations were well-tolerated and no serious drug-related adverse events.10
MicroLine
MicroLine (Eyenovia) utilizes an ophthalmic solution of 2% Pilocarpine HCl that is micro-dosed with their patented Optejet microdose array print technology. The company released its VISION-2 Phase 3 study data in October 2022 but has yet to announce it has filed an NDA with the FDA.11
The primary endpoint of >15-letter improvement in DCNVA, with <5-letter loss in distance acuity, was met in a statistically significant number of subjects treated with MicroLine versus placebo, as measured in low light conditions at two hours post-treatment.11
MicroLine was also found to be well-tolerated with mild/transient adverse events reported in <3% of patients.11
Nyxol
Nyxol (phentolamine 0.75%) (Ocuphire Pharma, partnered with Viatris) is combined in a preservative-free ophthalmic solution with 0.4% pilocarpine.12 Nyxol itself works as a non-selective alpha-adrenergic antagonist, inhibiting the contraction of smooth muscle within the iris.
Of note, with or without low-dose pilocarpine (LDP), this formulation can elicit a pinhole effect to help with presbyopia. The phase 2 VEGA-1 trial met its primary endpoint with an improvement of 15 letters or more (≥3 lines) in photopic binocular vision at 1 hour in 61% of patients treated with Nyxol plus LDP compared to only 28% of placebo patients.12
Moreover, patients in the Nyxol and/or LDP arm were observed to not have a reduction in distance BCVA or headaches, with effects lasting up to 6 hours after instillation.12
A potential alternative mechanism of action in development
Recently, Novartis discontinued FDA trials for the drug UNR844 Dioptin, a lipoic acid choline ester that was believed to improve crystalline lens elasticity and accommodation by reversing disulfide bonds within the lens. No other current FDA trials are ongoing utilizing the same lipoic acid lens softening technique, but there are a few companies investigating animal models.
Both ViewPoint Therapeutics, recently acquired by Visus Therapeutics, and Cellix are two companies currently exploring these alternative therapies. Time will tell if we will see the emergence of an alternative mechanism of action to regain accommodation and even possible nonsurgical treatment for cataracts.
A rundown of presbyopia drops in development
With multiple presbyopia correcting drops currently in various stages of the pipeline, it is important to remain both positive about the options coming and be aware of how to set the stage for when they arrive.
The addition of a whole new category to the treatment of presbyopia is important and opens up the playbook in therapeutic management opportunities for both practitioners and patients.
Table 1 outlines currently available presbyopia drops and those in the pipeline.
| Drop | Company | Approval Status | Concentration of Active Ingredient |
|---|---|---|---|
| Brimochol PF | Visus Therapeutics | Phase 3 - ongoing, recruiting | Carbachol 2.75% + brimonidine 0.1% |
| LNZ100, LNZ101 | Lenz Therapeutics | Phase 3 - ongoing, recruiting | Aceclidine 1.75% & Aceclidine 1.75% + brimonidine |
| MicroLine | Eyenovia | Phase 3 - completed | Pilocarpine 2% |
| Nyxol, Nyxol + Pilocarpine | Ocuphire Pharma (partnering with Viatris) | Phase 3 - ongoing, recruiting | 0.75% Phentolamine +/- pilocarpine 0.4% |
| Qlosi | Orasis Pharmaceuticals | FDA approved in October 2023 | Pilocarpine 0.4% |
| Vuity | Allergan | FDA-approved for QD dosing in October 2021 and BID dosing in March 2023 | Pilocarpine 1.25% |
Table 1: Courtesy of the authors.
With this thought in mind, it will require ECPs to adjust patient education and prescribing patterns. The great news is that ophthalmic medications are a familiar modality to both patient and practitioner, which could lead to earlier adoption.
As discussed, some of the formulations are actually reformulations of previously approved medications coupled with innovative drug delivery platforms, while others are completely new, novel drugs.
This could be considered a seminal moment for ECPs to offer a new treatment that may help to improve the patient’s quality of life both from a visual and a psychological standpoint. As will be discussed, it is imperative to set realistic expectations (including limitations) and the overall reality when it comes to treatment.
It is similar to multifocal contact lenses or intraocular lenses (IOLs) pertaining to patient education and discussion: underpromise, overdeliver, and be prepared to pivot.
Presbyopia-correcting drop patient case report
A good case example of a patient with a positive outcome using presbyopia-correcting drops is a 48-year-old Asian female who presented to the clinic noting difficulty with near vision while reading over the last 3 years and more recently decreased computer vision over the last 6 months.
This patient had been using a combination of over-the-counter readers and was prescribed a pair of progressive glasses, but was frustrated with the poor visual quality, neck strain, and constant need to take the glasses off and on.
Recommended treatment
Vuity had been available for only a few months at this time and was presented as an option along with the possibility of multifocal contact lenses. In discussing it with the patient, she liked the option to use the drop when needed and glasses when she didn’t. Prior to prescribing therapy, the patient received a dilated fundus exam, and expectations with the drop were set during this visit.
The patient was cautioned that she may experience some visual spasms during the first few administrations of the treatment and may have a low brow headache for the first few weeks of use, both of which should subside. She was encouraged to use the drop every day for 2 weeks to help determine how well it was working and in which situations she would prefer to use it.
Follow-up
The patient returned for a 1-month follow-up to discuss her experience. She was very happy with the use of the medication, finding that the side effects mentioned did occur and had disappeared as well. The vision with the use of the drop allowed her to work more comfortably on the computer and transition between near and intermediate vision.
She did, however, mention that the effects tended to wear off around 3 to 4 hours after instillation, and she was actually using the drop twice a day most of the time. While this was off-label at the time, this patient was a great example of who is considered the “ideal” candidate for presbyopia drops.
Thinking outside the box case #1: The contact lens wearer
A 54-year-old Native American female presents to the clinic habitually wearing contact lenses for her distance vision while using over-the-counter readers for reading and computer work. The patient feels like there has to be another option, considering she already tried both monovision and multifocal contact lenses in the past with adaptation challenges.
Recommended treatment
As expected, she was more than willing and receptive to the idea of trying alternative therapies. The patient was presented with the option of using Vuity along with her current contact lenses, placing the first drop 15 minutes prior to putting in her contact lenses. The patient elected to try this for a month at home to see if it would work for her.
Follow-up
The patient returned to the office having used the presbyopia-correcting medication for the month prior. She was extremely happy with the utilization of the drop along with her distance-correcting contact lenses.
She found that she was able to work without strain on her computer and read her cell phone while not noting lasting adaptation effects or reduced distance vision.
Thinking outside the box case #2: The golfer
A 63-year-old female golfer comes in for a cataract surgery consultation in 2022. She has difficulty with night-time vision, glare while driving and playing golf, use of her iPad, and small print. Her relevant past medical/ocular history is mild hypertension and hypothyroidism, for which she takes medications for both and has good control.
Her best-corrected vision is 20/60 in both eyes (BCVA with -1.00 -0.75 x 90 refractive error OU with glare testing at 20/100 OU). Her ocular surface reveals trace superficial punctate keratitis with normal intraocular pressures; lens exam illustrated 2+ NS/Cortical and 1+ PSC changes in both eyes. Retinal and macular exam were considered noncontributory, with some drusen in the mid-periphery. Of note, her axial length is 22.75 OD/22.81 OS.
Recommended treatment
After reviewing all options for cataract surgery, the patient opts for the latest in monofocal IOL technology with paired-limbal relaxing incisions (LRIs) in both eyes. Her aim is to have the best vision for distance, given her “golf game.” Her ocular surface is treated with preservative-free artificial tears QID several weeks before her planned cataract surgery in both eyes, 2 weeks apart.
Her surgery went well and as planned with the standard peri-operative drop therapy and consistent use of her artificial tears. Her uncorrected visual acuity (UCVA) weeks after both cataract surgery procedures is 20/20 OU, and she “loves” her distance vision with added commentary that she was anxious to get back on the golf course. She stated that her iPad vision is good but “could be better as well as her near vision.”
She is offered OTC “cheaters” as well as Vuity. After a risk-benefit-alternative discussion and survey of her full retinal exam, including any relevant retinal history for which she had none, the patient began using the treatment almost once/daily with good results for nearly 5 to 6 hours (note, at the time of the case, Vuity was not approved for twice-a-day or BID). For presbyopia issues beyond these hours, she would use her “fashionable” reading glasses as needed.
Follow-up
During her 3-month follow-up, she still reported an excellent state of vision and had a noncontributory anterior segment/retinal examination. She stated that her golf game got much better and that she could achieve functional reading with her presbyopia drops during her planned usage.
Treatment experience disclaimer
Not every patient will be a candidate or have positive results with the use of Vuity. It is important to keep in mind that new alternatives are soon joining the category of presbyopia-correcting drops.
Keeping the positivity and discussion open with patients regarding this class of medication will help to open the door to utilization and re-evaluation where current therapies may not have worked.
Presbyopia drop practice implementation
One of our primary jobs as ECPs is to continue to educate ourselves on the newest treatment options and present them to appropriate patients. Pharmacological treatments for presbyopia are just that: a new opportunity to treat our patients' near vision problems.
Similar to how we present other options to patients, we have to think about what will work best for those who might be in the chair—whether it be progressive or bifocal glasses, multifocal or monovision contact lenses, and/or presbyopia-correcting drops.
It is imperative to remember that these drops are not replacing glasses and contact lenses with the perspective they are complementary therapy to what exists already. As more presbyopia drops enter the market, ECPs will have to think about patient selection with thought given to activities of daily life and the level of the patient's lens dysfunction journey.
Involving staff in the process of evaluating presbyopic patients
Depending on the flow of your office, it can be helpful to engage your staff in this discussion and once again reinforce patient selection. Implementing an activity of daily living questionnaire before the exam or at check-in may be helpful to find where the patient is having difficulties with vision and open up discussion.
Staff can use this to gather more information regarding computer and reading distances, identifying which patients may be struggling with their current solutions or lack thereof.
If the staff has been empowered to routinely dilate patients prior to being seen by the ECP, make sure that they are checking the patient’s pupil size in both mesopic and scotopic conditions. As discussed earlier, pupil size is an important piece of data when considering who will benefit from utilizing presbyopia drops.
Providing patients with a trial run of presbyopia drops
Trialing the drop in-office may work in some instances, but not all. Since it is recommended that patients receiving presbyopia-correcting drops receive a dilated fundus exam prior to prescribing, trialing on the same day is not likely.
A single use of the drop is also not a true representation of how the medication will work for the patient. With Vuity, many patients experience a ciliary spasm with the first usage and up to 2 weeks for certain patients. This will possibly be the case with some of the other medications.
Because of this and for other reasons, it is better to educate the patient in the office on what to expect and then send them home with a prescription to use every day for a minimum of 2 weeks to truly understand if the medication will work for them given their history and case presentation.
Examples of in-office discussions with a presbyopic patient
Below is a sample conversation between an ECP and a patient.
The ECP begins with: “Patient XYZ, based on our discussion, I think that this particular presbyopia-correcting drop will be very helpful. It works by constricting your pupils and increasing your ability to see up close, while not affecting your distance vision.
Now, there are multiple drops that could achieve this visual balance, but in my professional medical opinion, I believe this particular one will work best for you. If, for some reason, it doesn’t, don’t worry; we will try another, very similar to how we work together to land on the right contact lens fit for your vision and overall comfort.
When you go home today, I would like you to start tomorrow by using this drop every day for the next 2 weeks. Instill the drop in the morning before leaving for work [and then use a second drop approximately 3 to 4 hours later].”
In response, the patient asks the ECP, “Is there anything I should expect after first using the medication? What about side effects?”
The ECP responds with the following thoughts: “During the first few uses, you may feel like your vision is going a little 'wonky,' this is normal it is your muscles may contract. For the initial 2 weeks, you may have slight frontal headaches, which we have come to understand is rather normal because we are working the muscles in your eyes differently than they have been in the past.
Similar to working out a new muscle at the gym, it will stop being sore with continued use. During the next month, until I see you at the follow-up, pay attention to how this is working for you and in what situations you are finding it helpful or when it is not working well. When you come back, we can discuss this and the next steps if needed.”
Best practices in presbyopia pharmacological management
As the presbyopia landscape continues to evolve since the launch of the first presbyopia-correcting treatment in 2021, organizations like the FDA and the American Society of Cataract and Refractive Surgery (ASCRS) have weighed in with guidelines for practitioners to help guide their prescribing habits.
The ultimate conclusion is that an ECP-led delivery model for presbyopia treatment is essential. Patients need to be assessed for their gaps in presbyopia care (i.e., lifestyles), and every patient is required to have a full eye exam, including a refraction update as well as anterior and posterior segment surveillance.
Any patient with a history of high myopia, known recurrent ocular inflammatory diseases (i.e., uveitis), potential narrow angles, or peripheral retinal disorders at risk for the development of retinal detachment (RD), including lattice degeneration and/or retinal holes, should be advised against topical presbyopia therapies.*
Since these guidelines have evolved and ECPs have learned how to carefully select patients for pharmacological presbyopic treatment, the overall incidence of retinal issues seems to have abated.
Vuity Adverse Event Update: Throughout 2023, there were three cases of retinal detachment and four cases of retinal tears reported to the FDA.13
* If a patient were to experience flashes, floaters, or visual field loss (i.e., “curtains”) after administration of a presbyopia-correcting therapy, it is strongly recommended to seek the care of an ECP immediately to address these complaints.
Conclusion
Confidence in patient outcomes is based on individual case presentation, lifestyle needs, identifying the right candidates, managing expectations, conducting a thorough eye exam, and scheduling appropriate follow-up.
These are the keys to success for topical presbyopia therapy as this exciting landscape continues to progress and we learn more.
