Drip drop, tick tock: Are presbyopia drops turning back the clock?
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Hickory Dickory Dock, a well-known nursery rhyme, is a nonsense poem in which children mimic the sound of a clock chiming at the relevant point in the song, intending to introduce the fundamentals of telling time.
As far back as we can remember as premium surgeons, time still remains important, especially for our aging presbyopic population of patients. Presbyopia is ubiquitous with an average age of onset of 40 to 45 years, a global prevalence of 1.8 billion and a U.S. prevalence of 120+ million. This sizable market has become an opportunity for a new class of presbyopia therapy: Eye drops.
Several companies have developed formulations that affect either pupil or lens modulation. The optimal presbyopia solution is one that is effective, comfortable/tolerable and safe, with many in various FDA clinical study stages and one coming to market later this year. One recent market research study showed for a presbyopia drop to be tolerated best by the market, 73% of those queried preferred a drop duration of at least 7 hours for temporary correction of near vision. Below I will discuss three companies’ formulations and early results, if publicly available, on pupil modulation by increasing depth of field and one company’s approach on lens modulation by increasing lens elasticity.
Pupil modulation approach
Orasis has formulated a low-concentration pilocarpine with a proprietary multifaceted vehicle with twice-daily dosing. CSF-1 has shown statistically significant improvement with three or more lines in near vision improvement in 47% of subjects vs. 16% who received vehicle in a phase 2b study, with no negative impact on distance and night vision and high safety and tolerability. Phase 3 study enrollment began in the third quarter 2020 with the NEAR-1 and NEAR-2 studies.
Visus Therapeutics has introduced its own formulation using Brimochol (carbachol 3% and brimonidine tartrate 0.2%) in a once-daily drop with a duration of functional near vision of J2 effect lasting 8 or more hours. By combining a miotic with brimonidine, a sympatholytic alpha-2 agonist that inhibits ciliary body contraction, the negative side effects associated with miotics (browache, reduced distance vision) are mitigated, and the pinhole effect generated by carbachol is prolonged. Other benefits with a pH of 7.4 allow for minimal to no burning and stinging and less redness with the addition of brimonidine. Phase 3 pivotal trial enrollment is slated to start in this year’s third quarter.
Allergan’s novel, fast-equilibrating ophthalmic vehicle of a low concentration of pilocarpine produced less ocular blur and discomfort and a well-tolerated alternative to currently available ocular pilocarpine medications. In an October 2020 press release of phase 3 topline results, investigational AGM-190584 (pilocarpine 1.25%) met its primary endpoint. GEMINI 1 and GEMINI 2 revealed three lines or more of gained statistically significant mesopic low light binocular distance corrected near visual acuity at day 30 hour 3 vs. vehicle. Regulatory submission is expected early this year, and it should be the first commercial presbyopia eye drop to reach the U.S. market.
Lens modulation approach
Lens stiffening and increasing lens protein disulfide content with age have led to the Novartis UNR844 eye drop to be potentially the first-in-class treatment for presbyopia. The prodrug UNR844 is an ester of naturally occurring R-lipoic acid and choline, and as lipoic acid choline ester penetrates the cornea, it is metabolized into choline and R-lipoic acid. Enzymes within the lens fiber cells chemically reduce R-lipoic acid to the active dihydrolipoic acid, the latter acting to reduce disulfide bonds between lens proteins, thus restoring lens elasticity. Lipoic acid choline ester increases lens elasticity in 8-month-old mice treated topically with 5% UNR844 three times daily for 5 weeks.
EV-C-002 and EV-C-003, prospective, randomized, double-masked, placebo-controlled multicenter studies followed by an observational follow-up period (no treatment) for 7 months in subjects successfully completing treatment, showed improved bilateral near vision vs. baseline at 3 months. UNR844 was well tolerated and had no safety concerns in these studies. A further phase 2 study provided a signal of the intended clinical activity, but there was high variability in the results. Further non-parametric analyses suggested that UNR844 has clinical activity. Novartis is proceeding with the clinical development of UNR844 and will conduct a phase 2b dose-finding study with close attention to distance corrected near visual acuity variability.
Regardless of the mechanism of action, the clock keeps ticking as we all age and come closer to presbyopia; however, eye drop therapy will become a viable option in the battle against presbyopia especially before the true development of cataracts and the future need for premium IOLs. Continue to stay safe during the pandemic era, and pray for that clock to end soon.
- References:
- Abdelkader A. Int J Ophthalmic Res. 2019;doi:10.17554/j.issn.2409-5680.2019.05.89.
- Burke Healthcare Research April 2020, n = 1,000, fielded March 31 through April 9th, 2020 amongst U.S. adults ages 40-80, geographically balanced to U.S. Census.
- Garner WH, et al. Invest Ophthalmol Vis Sci. 2016;doi:10.1167/iovs.15-18413.
- Heys KR, et al. Mol Vis. 2004;10:956-963.
- Kubo C, et al. J Ocul Pharmacol. 1992;doi:10.1089/jop.1992.8.225.
- Suzuki G, et al. Ophthalmol Ther. 2020;doi:10.1007/s40123-020-00229-x.
- Takemoto L. Exp Eye Res. 1996;doi:10.1006/exer.1996.0149.
- For more information:
- Mitchell A. Jackson, MD, can be reached at Jacksoneye, 300 N. Milwaukee Ave., Suite L, Lake Villa, IL 60046; email: mjlaserdoc@msn.com.
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