WOW! WHAT A YEAR IN THE PRESBYOPIA PIPELINE.

The prospects of topical presbyopia options are growing, the marketing dynamics are shifting, and the landscape of treatment options is evolving.

VUITY (Allergan/AbbVie)

Serving 120,000 patients with 190,000 prescriptions filled, and counting, Vuity (pilocarpine hydrochloride ophthalmic solution 1.25%) made a splash in 2022 as the first available topical eye drop treatment for presbyopia.^1,2 As primary eye care providers responsible for managing the majority of refractive errors with spectacle and contact lens correction, it is no surprise that nearly 75% of Vuity prescriptions have been written by optometrists.^1,2

By increasing the depth of focus via pupil constriction, Vuity demonstrates improvement with near and intermediate vision in as little as 15 minutes, lasting up to 6 hours with once-daily dosing.² FDA approval of Vuity was based on two phase 3 studies (GEMINI-1 and GEMINI-2), in which the primary endpoints included 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.²

Allergan has announced positive topline results of an additional P3 trial (VIRGO) evaluating the efficacy and safety of twice-daily administration of Vuity, improving near vision without compromising distance vision at hour 9 (3 hours after the second drop) on day 14.² The final results have not yet been published.

CSF-1 (Orasis)

Orasis is on track to be next to market, with recent FDA acceptance of its NDA. CSF-1 (0.4% pilocarpine ophthalmic solution) is a preservative-free topical presbyopia treatment that will be available with a dosing schedule that provides the patient flexibility to add a second dose after 3 or 4 hours to extend the effect out to 8 hours, if desired.³ Two P3 studies (NEAR-1 and NEAR-2) have wrapped up with results showing CSF-1 to be well tolerated among patients, with a safety profile that does not compromise distance or night vision.³

The P3 trials confirmed the primary and key secondary endpoint goals of a 3-line or more improvement in distance-corrected near vision acuity (DCNVA) without loss of best-corrected distance visual acuity (BCDVA).³ Participants were dosed twice daily on both eyes at an interval of 2 hours between doses on days 1-8 and an interval of 3 hours on days 8-15.³ On day 15, participants achieved statistically significant 3-line improvement in as early as 20 minutes and lasting up to 8 hours after the first dose.³

Notably, these results were achieved with a minimal effective dose of pilocarpine, which is less than one-third the concentration of the only commercially available treatment.³ More new data on CSF-1 will be presented at SECO. Orasis anticipates an approval in quarter 4 of 2023 and plans to launch in early 2024.

MicroLine (Eyenovia)

Eyenovia offers a unique presbyopia treatment option that includes a proprietary spray dispenser (Optejet) with Microdose Array Print (MAP) technology. Allowing for less waste, decreased exposure to preservatives, and a convenient spray (no need to tilt the head back), this option provides an alternative administration of pilocarpine.^4,5

The third P3 study (VISION-1) evaluated the safety and efficacy of the 2 formulations, pilocarpine 1% and 2%.⁴ In October 2022, Eyenovia announced positive results of the fourth P3 trial (VISION-2) confirming the safety and efficacy of MAP with a primary endpoint of improved high-contrast binocular distance corrected visual acuity (DCVA) in low light conditions 2 hours after treatment using MicroLine 2%.⁵

Notably, proprietary market research by Eyenovia has also revealed that nearly 80% of patients 40-55 year old who otherwise would not have worn glasses would prefer the Optejet device over traditional drops.⁵

Brimochol (Visus Therapeutics)

Utilizing a synergistic effect, Brimochol brings together a combination of carbachol (a cholinergic agent) and brimonidine tartrate (an alpha-2 agonist).^6,7 The 2 active ingredients constrict the iris sphincter and inhibit iris dilator contraction, helping to create a pinhole effect.^6,7

After positive results of the P2 studies (VIVID), Visus announced P3 trials (BRIO-I and BRIO-II) to evaluate the safety and efficacy of Brimochol PF.^6,7 Measuring data in emmetropic phakic and pseudophakic presbyopia patients, the primary efficacy endpoint is the percentage of patients who gain 3 lines of improvement in binocular near visual acuity without losing 1 line of distance vision.^6,7

P3 studies are still ongoing. Visus is hopeful for a launch in 2025.

PHARMACOLOGIC	COMPANY		DEVELOPMENT STAGE
VUITY	Allergan/AbbVie		FDA approved (QD dosing). Trials for investigational BID dosing ongoing.
CSF-1	Orasis		P3 complete, NDA accepted by the FDA.
MicroLine	Eyenovia		P3 complete, awaiting NDA submission.
Brimochol	Visus		P3 ongoing.
Nyxol, and Nyxol + low-dose pilocarpine	Ocuphire Pharma		P3 planned, accepting enrollment. 1-year safety study planned.
LNZ100 LNZ101	Lenz Therapeutics		P2 complete, P3 planned.
Dioptin (UNR844-CHLORIDE)	Novartis		On hold.

Nyxol, and Nyxol + Low-dose Pilocarpine (Ocuphire Pharma)

Ocuphire has studied combinations of Nyxol 0.75% phentolamine (or 1% phentolamine mesylate) and 0.4% low-dose pilocarpine (LDP), in addition to Nyxol alone. Nyxol ophthalmic solution is a nonselective alpha adrenergic antagonist offered in a preservative-free formulation that acts on the iris dilator muscle, decreasing pupil diameter and inhibiting the contraction of the smooth muscle of the iris.^8,9 Creating a “pinhole effect,” the smaller pupil leads to increased depth of focus with rapid onset of action and sustained duration of effect.⁸

In the VEGA-1 P2 trial, Ocuphire validated the effects of Nyxol dosed before bedtime and LDP (which activates the iris sphincter muscle) dosed during the daytime.^8,9 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.^8,9 Positive results were also reported with Nyxol alone and more studies have been planned.^8,9

As of January 2023, Ocuphire had reported enrollment of the first patients for the VEGA-2 P3 trials.⁹ Following VEGA-2, Ocuphire plans to initiate a second P3 trial (VEGA-3) and a 1-year safety study (LYRA-1).^8,9

LNZ100 and LNZ101 (Lenz Therapeutics)

Headquartered in California, Lenz Therapeutics is undertaking testing for 2 investigational preservative-free formulations of aceclidine: LNZ100 (1.75% aceclidine) and LNZ101 (1.75% aceclidine + brimonidine).¹⁰

Aceclidine (a muscarinic acetylcholine receptor agonist) is a parasympathomimetic miotic that alters pupil size by targeting the iris sphincter.¹⁰ The formulation by Lenz Therapeutics demonstrates the ability to influence the pupil size with minimal effect on the ciliary muscle (compared to pilocarpine and carbachol).¹⁰

The topline results of the P2 trials (INSIGHT) included participants ranging in ages from 46 to 73, consisting of some patients with prior vision correction and pseudophakia.¹⁰ Both LNZ100 and LNZ101 achieved the primary endpoint of 3-line or greater improvement in near visual acuity, without losing 1 line or more in distance visual acuity at 1 hour.¹⁰ The primary endpoint was met in 71% and 56% of treated subjects, respectively, compared to 6% of vehicle-treated subjects.¹⁰ ■

References

1. Waring GO 4th, Price FW Jr, Wirta D, et al. Safety and Efficacy of AGN-190584 in Individuals With Presbyopia: The GEMINI 1 Phase 3 Randomized Clinical Trial. JAMA Ophthalmol. 2022;140(4):363-371. doi:10.1001/jamaophthalmol.2022.0059
2. Allergan, an AbbVie company, announces positive topline phase 3 results evaluating investigational twice-daily administration of VUITY™ (pilocarpine HCl ophthalmic solution) 1.25% in adults with age-related blurry near vision (presbyopia). AbbVie News Center. April 5, 2022. Accessed February 5, 2023. https://news.abbvie.com/news/press-releases/allergan-an-abbvie-company-announces-positive-topline-phase-3-results-evaluating-investigational-twice-daily-administration-vuity-pilocarpine-hci-ophthalmic-solution-125-in-adults-with-age-related-blurry-near-vision-presbyopia.htm
3. Orasis Pharmaceuticals. Accessed February 5, 2023. https://www.orasis-pharma.com/
4. Eyenovia announces positive topline results from VISION-1 phase 3 clinical study of MicroLine for the treatment of presbyopia. Eyenovia. May 25, 2021. Accessed February 5, 2023. https://eyenovia.com/eyenovia-announces-positive-topline-results-from-vision-1-phase-3-clinical-study-of-microline-for-the-treatment-of-presbyopia/
5. Eyenovia announces positive results from VISION-2 Phase 3 Study of MicroLine as a potential on-demand treatment for presbyopia. Eyenovia. October 20, 2022. Accessed February 5, 2023. https://eyenovia.com/eyenovia-announces-positive-results-from-vision-2-phase-3-study-of-microline-as-a-potential-on-demand-treatment-for-presbyopia/
6. Visus Therapeutics initiates phase 2 clinical trial of Brimochol for the treatment of presbyopia. Visus Therapeutics. March 25, 2021. Accessed February 5, 2023. https://uploads-ssl.webflow.com/5eea6cf86d23885e6fe09eb2/605be3ce5d20506c04b99ca9_Visus%20Therapeutics_PRESS%20RELEASE_FirstPatientPh2_FINAL%20FOR%20BW%20UPLOAD%203.24.2021.pdf
7. Visus Therapeutics reports positive phase 2 results for three presbyopia formulations. Ocular Surgery News. December 1, 2021. Accessed February 5, 2023. https://www.healio.com/news/ophthalmology/20211201/visus-therapeutics-reports-positive-phase-2-results-for-three-presbyopia-formulations
8. Ocuphire’s VEGA-1 phase 2 trial in presbyopia meets primary and secondary endpoints. Ocuphire Pharma. June 30, 2021. Accessed February 5, 2023. https://www.ocuphire.com/news-media/press-releases/detail/344/ocuphires-vega-1-phase-2-trial-in-presbyopia-meets
9. Nyxol Eye Drops. Ocuphire website product pipeline page. https://www.ocuphire.com/product-pipeline/nyxol
10. Lenz Therapeutics announces positive topline data from phase 2 INSIGHT trial of LNZ100 and LNZ101 to treat presbyopia. Lenz Therapeutics. October 18, 2022. Accessed February 5, 2023. https://lenz-tx.com/2022/10/lenz-therapeutics-announces-positive-topline-data-from-phase-2-insight-trial-of-lnz100-and-lnz101-to-treat-presbyopia/

Dr. Coats works in a large OD/MD practice in Arkansas. The majority of her clinical practice is dedicated to ocular disease, comprehensive eye care, perioperative care, and contact lenses, with a special interest in the ocular surface and dry eye disease.