An estimated 1.8 billion people in the world are living with presbyopia, about 1/4 of the entire population. In the United States in 2020, there were 123 million presbyopes, with the condition’s prevalence at 83% to about 89% among adults 45 years of age and older.^1-3

Clearly, the market opportunities are enormous as patients increasingly seek freedom from eyeglasses and contact lenses, the traditional first-line options. Late last year, the FDA approved Vuity (1.25% pilocarpine ophthalmic solution, Allergan, an Abbvie company), the first — and so far, only — pharmaceutical drop to treat the condition. More such agents are sure to follow.

Here is a review of seven products at various stages of development. Some of these drops are early in development, so the results remain to be seen until they reach Phase 3 trials.

PRESERVATIVE-FREE LOW-DOSE PILOCARPINE

Orasis Pharmaceuticals’ CSF-1, a low-dose 0.4% preservative-free pilocarpine ophthalmic solution formulated in a proprietary vehicle, will likely be the second drop to market. The agent is being studied with b.i.d. dosing.

The phase 3 NEAR-1 and NEAR-2 clinical trials (N = 613) met their primary and key secondary endpoints on day 8, achieving statistically significant 3 line or more gain in distance-corrected near visual acuity (DCNVA) and no loss of 1 line or more in DVA. Pooled across the two studies, 40% and 50% of participants demonstrated these gains 1-hour post-dose one and 1-hour post-dose two, respectively (P <.0001), according to the company. The data will form the basis of the company’s FDA submission planned for later this year.

CSF-1 also achieved statistically significant 3-line improvement at all measured time points on days 1 and 15. On day 15, participants achieved statistically significant three-line or more improvement in DCNVA as early as 20 minutes and up to 8 hours post-dose one.

The agent demonstrated an excellent tolerability and safety profile, the company reports, with comparable redness and comfort vs vehicle, validating the preservative-free presentation and proprietary formulation of CSF-1. The most common treatment-related adverse events (AEs) of headache and instillation site pain occurred in 6.8% and 5.8% of participants, respectively. Only 2.6% of CSF-1 participants reported moderate treatment-related AEs. All other AEs were mild.

PROPRIETARY DELIVERY DEVICE

Eyenovia is investigating a 1% and 2% spray formulation of pilocarpine called MicroLine delivered via Optejet, its proprietary high-precision dispenser. Optejet leverages the company’s Microdose Array Print or MAP technology, which is designed for less waste, decreased exposure to preservatives and convenient administration. According to the company, MAP technology has the potential to be paired with smart devices for dosage reminders.

In May 2021, Eyenovia announced positive results the first Phase 3 trial, VISION-1, evaluating the safety and efficacy of the MicroLine formulations. MicroLine met its primary endpoint with a statistically significant proportion of subjects treated with the drug showing a three-line or more improvement in DCNVA vs placebo in low-light conditions at 2 hours post-treatment. The company reported that MicroLine was well tolerated with no serious AEs.

In a post-study survey, 70% of study participants reported strong interest in using MicroLine for near vision improvement should it be approved. These patients said they would expect to use the product three to four times per week on average, according to an Eyenovia news release. The VISION-2 Phase 3 trial is progressing as planned, the company notes, with topline data anticipated in the second half of this year.

Eyenovia plans to start production of registration batches as a requirement towards filing a new drug/device combination application (NDA) to the FDA.

HIGH RESPONSE RATE, LONG DURATION?

Visus Therapeutics Inc. recently launched the first of two pivotal Phase 3 trials (BRIO-I and BRIO-II) for Brimochol PF, its proprietary, preservative-free, fixed-dose combination of the cholinergic miotic agent carbachol and the alpha-2 agonist brimonidine tartrate. Brimonidine is also known to cosmetically whiten the eye.

The company had previously shared topline data from Phase 2 VIVID, which demonstrated two preservative-free formulations of Brimochol PF and Carbachol PF, were well tolerated and met clinical outcomes to support advancement into pivotal trials. The formulations in VIVID achieved the endpoint of three lines of improvement in binocular NVA without losing one line of distance vision with a minimum responder rate of 83% at 1 hour.

BRIO-I and BRIO-II are expected to enroll emmetropic phakic and pseudophakic presbyopic patients (approximately 170 and 500, respectively). The primary efficacy endpoint is the percentage of patients who gain three lines of improvement in binocular NVA without losing one line of distance vision. The first readout of this study is anticipated in the fourth quarter of this year, the company says.

IRIS DILATOR AND IRIS SPHINCTER MUSCLE ACTION

Ocuphire Pharma’s Nyxol is a preservative-free ophthalmic solution containing 0.75% phentolamine (or 1% phentolamine mesylate), a nonselective alpha-adrenergic antagonist that inhibits the contraction of smooth muscle of the iris. Earlier this year, the company reported statistically significant efficacy and durability with Nyxol and now plans to initiate the VEGA Phase 3 program this year investigating the agent alone and with low-dose pilocarpine as adjunctive treatment.

Phase 2 VEGA-1 evaluating the efficacy and safety of the combined treatment found that 61% of subjects gained ≥3 lines of photopic near vision at 1 hour compared with 28% of placebo-assigned subjects (P = .003). The study achieved primary endpoints and showed a favorable safety profile. Other key secondary endpoints met include rapid onset at 30 minutes and durable near vision improvement through at least 6 hours. A majority of subjects treated with the combination achieved near acuity of 20/30 or better, the investigators report, and sustained significant reduction in pupil diameter over at least 18 hours due the durability effects of phentolamine.

There were no serious AEs and no headaches, brow aches or blurry vision reported. Mild, transient conjunctival hyperemia was observed in less than 5% of subjects.

Ocuphire plans to proceed with the Phase 3 VEGA program to file NDAs for both Nyxol as a single drop and with low-dose pilocarpine as adjunctive treatment. Assuming successful trials, the company expects to file for FDA approval in 2023.

PUPIL-SELECTIVE MIOTIC

LENZ Therapeutics is developing two different formulations of aceclidine for the correction of presbyopia: drug candidates LNZ100 (1.75% aceclidine) and LNZ101 (1.75% aceclidine with brimonidine).

According to the company, both agents are in confirmatory Phase 2 trials with Phase 3 investigations slated to begin sometime during the second half of this year.

Aceclidine is differentiated by being the only pupil-selective miotic in development for this indication, the company claims, enabling a sub-2-mm pupil without overstimulating the ciliary muscle. The Phase 2 study met its primary endpoints for near vision improvement, LENZ reports, with 81% of subjects assigned to aceclidine only gaining at least two lines of near vision within 30 minutes, and 53% gaining at least three lines within that time frame (P <.0002 and P <.0001, respectively).

The company also reports that the Phase 2 study of 1.75% aceclidine met its endpoint for no impact to distance vision with a trend toward a net gain. There was no change in best-corrected normal-light DVA vs placebo at all time points and no change in best-corrected low-luminance DVA vs placebo at all time points.

The drug was well tolerated with the most common side effect being mild discomfort on instillation. The company reports that there were no serious AEs.

DIRECTLY ON THE CRYSTALLINE LENS

Novartis’ Dioptin — UNR844-Cl, 1.5% — is thought to act directly on the flexibility and accommodative ability of the crystalline lens.

The prodrug, lipoic acid choline ester 1.5%, is an antioxidant shown to chemically reduce lens disulfide bonds between crystalline lens proteins. Researchers say it might restore lens elasticity and dynamic refractive power during accommodation. Preliminary findings showed statistically significant improvement in sustained NVA up to 10 days after treatment.

A prospective, randomized, double-masked, and multicenter trial included 75 subjects with presbyopia randomized 2:1 to UNR844 or placebo. On days 1 to 7, all subjects were dosed unilaterally b.i.d. in their nondominant eye to ensure safety and tolerability prior to days 8 to 91, when dosing was changed to bilateral b.i.d., according to a report in Eye.⁴ Investigators assessed DCNVA and AEs. Patients who completed the study were recruited into a non-interventional follow-up that monitored them until 7 months after their final UNR844 exposure. The primary endpoints were safety and the mean change in DCNVA from baseline in the study eye.

No safety concerns were reported, and the drop was well-tolerated with no clinically relevant changes in BCDVA, pupil size, IOP or discontinuations due to AEs. DCNVA improved in the study eye in the UNR844 group compared to placebo during the 91 days of treatment (UNR844 vs placebo, mean change in LogMAR [SD]; -0.159 [0.120] vs -0.079 [0.116]). Bilateral DCNVA improved, with 53.1% UNR844 vs 21.7% placebo subjects gaining ≥10 letters. Improvements in DCNVA were sustained at 5 and 7 months after UNR844 dosing ceased. Phase 2b studies are now fully enrolled.

TRANSDERMAL CREAM-BASED FORMULATION

Glaukos announced early this year that it had enrolled the first patient into its Phase 2 clinical trial of GLK-302 (pilocarpine) for the treatment of presbyopia. It is the second drug candidate that makes use of the company’s patented iLution platform, which consists of cream-based drug formulations that are applied to the outer surface of the eyelid for drop-free transdermal drug delivery.

The Phase 2 trial is evaluating the safety and efficacy of three different dose levels of GLK-302 administered b.i.d. to the eyelid vs placebo over 28 days for improving mesopic, high-contrast, binocular DCNVA while not deteriorating binocular BCDVA in presbyopic patients. According to a news release, the company anticipates it will enroll approximately 120 patients in the United States. OM

REFERENCES

1. Fricke TR, Tahhan N, Resnikoff S, et al. Global prevalence of presbyopia and vision impairment from uncorrected presbyopia. Ophthalmology. 2018;125:1492-1499.
2. Understanding presbyopia’s symptoms, causes and treatments. Versant Health website. https://versanthealth.com/blog/understanding-presbyopias-symptoms-causes-and-treatments . Accessed July 1, 2022.
3. Berdahl J, Bala C, Dhariwal M, et al. Patient and economic burden of presbyopia: a systematic literature review. Clin Ophthalmol. 2020;14:3439-3450.
4. Korenfeld MS, Robertson SM, Stein JM. Topical lipoic acid choline ester eye drop for improvement of near visual acuity in subjects with presbyopia: a safety and preliminary efficacy trial. Eye (Lond). 2021;35:3292-3301.