Article

Presbyopia Progress in Pharmaceuticals

WITH THE LANDSCAPE OF PRESBYOPIA treatments changing, the prospects of topical presbyopia options are growing, and more companies are joining the table.

VUITY AGN 190584 (Allergan/AbbVie)

VUITY (pilocarpine hydrochloride ophthalmic solution 1.25%) is the first available topical eye drop treatment of presbyopia to hit pharmacy shelves nationwide. Increasing depth of focus via pupil constriction, VUITY improves near and intermediate vision in as little as 15 minutes, lasting up to 6 hours with once daily dosing.1

FDA approval of VUITY was based on data from GEMINI-1 and GEMINI-2, two pivotal phase(P) 3 studies that evaluated the efficacy, safety, and tolerability of VUITY in 750 participants.1 Both P3 studies met the primary endpoints with a statistically significant proportion of participants gaining 3 lines of improvement at near, without losing more than 1 line of corrected distance visual acuity (CDVA) at day 30, hour 3, versus placebo.1

VUITY made it through the FDA approval process earlier than anticipated in December 2021. Future safety and efficacy studies regarding long-term use (more than 30 days) and frequency of dosing (BID vs QD) will be beneficial information to obtain for patients and doctors who may be hesitant to use or prescribe low-dose pilocarpine as an alternative treatment option for presbyopia.

CSF-1 (Orasis)

Likely second to market, CSF-1 (a low-dose pilocarpine ophthalmic solution) is a topical presbyopia option that will be available in a preservative-free formulation with a proprietary vehicle. The pilocarpine formulation offered by Orasis Pharmaceuticals is sub-glaucoma range and clinical trials are measuring the novel CSF-1 formulation with BID dosing.2

A P2b double-masked, multi-center, repeated-administration clinical trial was completed in 2019 to evaluate the efficacy, safety, and comfort in 156 patients. Results shows CSF-1 is well tolerated among patients.2 Two P3 studies, NEAR-1 and NEAR-2, were launched in late 2020 and include 600 patients.

As of March 2022, the P3 trials are moving into the final stages of clinical development and it is hoped they will confirm primary endpoint goals of a 3-line improvement in distance-corrected near vision acuity (DCNVA) without loss of best-corrected distance visual acuity (BCDVA). Results of Orasis’ P3 trials will likely be released in 2022.2

MICROLINE (Eyenovia)

Offering a proprietary high-precision dispenser (Optejet) with Microdose Array Print (MAP) technology, Eyenovia’s pilocarpine spray provides a unique presbyopia treatment option. Designed for less waste, decreased exposure to preservatives, and convenient administration (no need to tilt head back), this unique MAP technology has the potential to be paired with smart devices for dosage reminders.3

In May 2021, Eyenovia announced positive results of the first P3 study, VISION-1, evaluating the safety and efficacy of the company’s 1% and 2% pilocarpine MicroLine formulations. The MicroLine primary endpoint of improved high-contrast binocular corrected distance visual acuity (CDVA) in low light conditions 2 hours after treatment was achieved with MicroLine 2%.3

The first patients for the second P3 study, VISION-2, have been enrolled and top-line data is expected mid-2022.3

NYXOL + LOW-DOSE PILOCARPINE (Ocuphire)

Ocuphire’s Nyxol (phentolamine mesylate ophthalmic solution) is a non-selective adrenergic antagonist offered in a preservative-free formulation that acts on the iris dilator muscle, decreasing pupil diameter.4,5 By creating a ‘pinhole effect,’ the smaller pupil leads to increased depth of focus.4 The combination of Nyxol with low-dose pilocarpine (LDP) may provide an option for the treatment of presbyopia that includes rapid onset of action and sustained duration of effect.4

In the P2 trial, VEGA-1, Ocuphire validated the effects of Nyxol dosed in the evening and a LDP (that activates the iris sphincter muscle) dosed during the daytime.4,5 With 61% of subjects gaining 3 lines of near vision at 1 hour, Ocuphire achieved primary endpoints of P2 and showed a favorable safety profile.4,5

Ocuphire plans to initiate the P3 trial for presbyopia, VEGA-2, in the first half of 2022.

In addition to the synergistic effects with pilocarpine, Ocuphire will also focus on Nyxol’s pupil modulating effects to pharmacologically reverse induced mydriasis and to treat dim light vision disturbances related to peripheral optical aberrations.5

LNZ100/LNZ101 (Lenz Therapeutics)

Aceclidine (a muscarinic acetylcholine receptor agonist) is a parasympathomimetic miotic that alters pupil size by targeting the iris sphincter.6 The LNZ100 and LNZ101 ophthalmic formulations by Lenz Therapeutics demonstrate the ability to influence the pupil size with minimal effect on the ciliary muscle (compared to pilocarpine and carbachol).6

Completing P2b trials with 58 participants, the primary endpoint of a 3-line improvement in DCNVA at 45cm at 1 hour post-treatment was achieved in 47.2% of study eyes, with 91.7% gaining at least 2 lines of near vision improvement.6 The onset of action was shown to be around 30 minutes and the duration of action around 4 hours, with up to half showing maintained improvement for up to 7 hours.6

Lenz Therapeutics is gearing up for P3 plans to begin in 2022 and hopes that aceclidine’s unique mechanism of action supports targeting a broader range of presbyopia patients, from ages 45 to 70.6

BRIMOCHOL (Visus Therapeutics)

Visus brings Brimochol topical ophthalmic solution to the presbyopia market. With a combination of carbachol (a cholinergic agent) and brimonidine tartrate (alpha-2 agonist), Brimochol demonstrates a synergistic effect.7,8 Utilizing the two active ingredients to constrict the iris sphincter and inhibit the iris dilator contraction, Brimochol helps to create a pinhole effect.7,8

With carbachol as the most potent approved cholinergic for pupil constriction, the addition of brimonidine is being studied to increase bioavailability of carbachol for 8-12 hours, to help mitigate effects of headache/myopic shift by inhibiting contraction of ciliary muscle, and to help prevent pupil dilation under myopic conditions.8,9

Visus is underway with P2 with two proprietary formulations of Brimochol, measuring data in both emmetropic phakic and pseudophakic presbyopia.8,9

DIOPTIN UNR844-CHLORIDE (Novartis)

Not all topical presbyopia treatments will be used to stimulate miosis. Uniquely working directly on the flexibility and accommodative ability of the crystalline lens, DIOPTIN (lipoic acid choline ester [LACE] 1.5% ophthalmic solution) penetrates the cornea and breaks down into choline and lipoic acid to reduce disulfide bonds.10 Over time, this restricts the lens from changing shape via ciliary muscle contraction and relaxation.10 Preliminary findings showed statistically significant improvement in sustained near visual acuity up to 10 days after treatment.10

The primary objective of the P2 study was to assess the efficacy of UNR844-Cl with binocular distance corrected near visual acuity (DCNVA) with an endpoint goal of a change in binocular DCVNA compared to baseline at 3 months.10 Due to a high variability in DCNVA measures of both treatment and placebo groups, no statistical significance was found and the primary endpoint was not met.10

Further P2b dose-finding studies are underway in 2022 in hopes to find strategies to mitigate future DCNA variability.10

GLK-302 (Glaukos)

As of January 2022, Glaukos announced enrollment has begun in their P2 trials of GLK-302. Focusing on their patented iLution ophthalmic topical cream-based drug formulation, Glaukos hopes to bring to the table an effective, dropless option to treat presbyopia.11 The topical cream is applied to the outer surface of the eyelids for transdermal delivery of pilocarpine through the dermis of the eyelid to the eye.11

Glaukos has also announced the enrollment of P2 trials of GLK-301, which utilizes the iLution patented cream-based pilocarpine formulation, but for the treatment of signs and symptoms of dry eye disease.11

References

  1. VUITY™ (pilocarpine HCI ophthalmic solution) 1.25%, the First and Only FDA-Approved Eye Drop to Treat Age-Related Blurry Near Vision (Presbyopia), is Now Available. https://news.abbvie.com/news/press-releases/vuity-pilocarpine-hci-ophthalmic-solution-125-first-and-only-fda-approved-eye-drop-to-treat-age-related-blurry-near-vision-presbyopia-is-now-available.htm
  2. Orasis website. https://www.orasis-pharma.com/
  3. Eyenovia Announces First Patient Enrolled in Phase 3 VISION-2 Trial of MicroLine for Presbyopia. https://www.globenewswire.com/news-release/2021/11/04/2327426/0/en/Eyenovia-Announces-First-Patient-Enrolled-in-Phase-3-VISION-2-Trial-of-MicroLine-for-Presbyopia.html
  4. Ocuphire’s VEGA-1 Phase 2 Trial in Presbyopia Meets Primary and Secondary Endpoints. https://www.ocuphire.com/news-media/press-releases/detail/344/ocuphires-vega-1-phase-2-trial-in-presbyopia-meets
  5. Ocuphire Announces Enrollment of First Patients in Second Phase 3 Pivotal Trial (MIRA-3) for Nyxol® in Reversal of Mydriasis (RM). https://www.ocuphire.com/news-media/press-releases/detail/357/ocuphire-announces-enrollment-of-first-patients-in-second
  6. Presbyopia Therapies Announces Primary Safety and Efficacy Endpoints Met in a Phase IIb study of its Topical PRX Ophthalmic Solution for the Treatment of Presbyopia. https://www.prnewswire.com/news-releases/presbyopia-therapies-announces-primary-safety-and-efficacy-endpoints-met-in-a-phase-iib-study-of-its-topical-prx-ophthalmic-solution-for-the-treatment-of-presbyopia-300688070.html
  7. Visus Therapeutics Initiates Phase 2 Clinical Trial of Brimochol for the Treatment of Presbyopia. https://uploads-ssl.webflow.com/5eea6cf86d23885e6fe09eb2/605be3ce5d20506c04b99ca9_Visus%20Therapeutics_PRESS%20RELEASE_FirstPatientPh2_FINAL%20FOR%20BW%20UPLOAD%203.24.2021.pdf
  8. Visus Therapeutics Reports Positive Phase 2 results for Three Presbyopia Formulations. https://www.healio.com/news/ophthalmology/20211201/visus-therapeutics-reports-positive-phase-2-results-for-three-presbyopia-formulations
  9. Advances in Corneal Surgical and Pharmacological Approaches to the Treatment of Presbyopia. https://journals.healio.com/doi/abs/10.3928/1081597X-20210408-04
  10. A Dose-ranging Study to Evaluate the Safety and Efficacy of UNR844 in Subjects With Presbyopia. https://clinicaltrials.gov/ct2/show/NCT04806503
  11. Glaukos Announces First Patient Enrolled in Phase 2 Clinical Trials for Presbyopia and Dry Eye Disease. https://eyewire.news/news/glaukos-announces-first-patient-enrolled-in-phase-2-clinical-trial-for-presbyopia