John D. Sheppard, MD, MMSc

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Presbyopia affects billions of people globally, including approximately 128 million adults in the United States.

 Reading glasses are the most common solution for near vision correction. Although some people consider the desire to reduce dependence on reading glasses to be based purely on vanity or aesthetics, there are also significant functional benefits to eliminating glasses—as anyone who has looked through microscope oculars in glasses knows all too well.

There are 2 approaches to pharmacologic control of presbyopia. One involves alteration of lenticular metabolism to improve elasticity of the crystalline lens. There are a couple such lens-altering agents currently in the pipeline that hold great promise to reverse, or at least delay, the lenticular aging process. They will likely have an onset of action of months, making them viable for younger presbyopes or pre-presbyopes who are willing to use the drops on a regular basis until the desired physiochemical structural changes in the lens have occurred.

The other approach—the one that can best help our patients who are already well into presbyopia—is the use of pupil-modulating drops. Miotics, such as pilocarpine and carbachol, have a rapid onset of action that is within approximately 15 minutes. They act on the iris sphincter to constrict the pupil, creating a pinhole effect.

With the smaller pupil, only the most parallel central light rays are able to enter the eye. This minimizes a wide variety of aberrations, especially chromatic aberration, to sharpen distance vision. It also increases the depth of focus for improved near vision.

Pilocarpine 1.25% (Vuity; Allergan/AbbVie) was recently approved by the US Food and Drug Administration and will soon be available to consumers by prescription.

Several other miotic drops, mostly pilocarpine based, are in the pipeline and are likely to be introduced to the US market within 1 to 3 years. A key parameter for success of these miotic agents will be duration of action.

From all our experience with eye drops to treat dry eye and glaucoma, we know people dislike using drops multiple times per day, so it is clear that most presbyopic patients are going to want a single drop to last a full workday of 8 hours or so. In the GEMINI clinical trials that led to approval of pilocarpine 1.25%, between 26% and 31% of patients achieved the desired end point of a 3-line gain in near vision 

(without a 1-line loss of distance vision) at 3 hours. A smaller percentage of patients (16% to 18%) still had good near vision at 6 hours.

Carbachol is known to be the most potent and durable of the miotic class,3 so it may have advantages over pilocarpine when it comes to peak and duration of effect as a presbyopia-correcting agent. Carbachol is a cholinergic agonist that binds to and activates acetylcholine receptors, affecting both the iris sphincter and the ciliary body. When I was a resident, we routinely prescribed carbachol and pilocarpine for our patients diagnosed with glaucoma, but the carbachol needed to be dosed much less frequently (2 or 3 times per day) than pilocarpine (4 times per day). Carbachol may have an even greater miotic effect on younger presbyopes than in the older glaucoma patients we once prescribed it for, because younger patients have more pronounced sympathetic iris tone and thus more vigorous pupillary dilation.

Carbachol is the miotic agent in Visus Therapeutics Inc’s presbyopia-correcting drops. Three novel formulations, including 2 fixed-dose combinations of carbachol and brimonidine tartrate (Brimochol and Brimochol F) and a similarly formulated preservative-free carbachol, were recently tested in the company’s phase 2 VIVID clinical trial. All 3 formulations achieved a 3-line gain in binocular near visual acuity without losing one line of distance vision. A minimum of 82%, 52%, and 35% of subjects in the study met this end point at 3, 7, and 9 hours, respectively.

It may be that a synergistic combination of agents will promote the longest durability. For example, previous evidence suggests that combining brimonidine tartrate with carbachol could have additive contributions.4-6 Brimonidine, a sympatholytic α-2 agonist, prevents pupil dilation by inhibiting the contraction of the iris dilator muscle and may also inhibit contraction of the ciliary muscle. Thus, its activity is synergistic to pupillary constriction and potentially alleviates the customary dull ache or brow pain experienced by many patients on miotics.

Presumably, by altering aqueous dynamics, brimonidine has also been shown to increase the bioavailability of carbachol in the iris/ciliary body (ICB) in nonclinical studies in rabbits, resulting in a more prolonged miotic effect than carbachol alone.7 The peak concentration of carbachol in the ICB in rabbits, measured using liquid chromatography and tandem mass spectrometry, was nearly twice as high 2 hours post dose when combined with brimonidine than when carbachol was dosed on its own (32.8 ng/g vs 17.8 ng/g, 

 = .159) and the area under the curve (concentration over time) was higher at all time points.7 It remains to be seen how drug penetration and concentration will influence functional outcomes in larger human clinical trials as these combination agents move into phase 3 studies.


The mechanism of action of the investigational combination therapy Brimochol (carbachol 2.75% + brimonidine 0.1, Visus Therapeutics) relies on: Carbachol as the most potent and durable cholinergic for pupil constrictionto induce the pinhole effect to increase depth of field by acting on the muscarinic M3 receptor in the iris sphincter muscle; and, (2) Brimonidine as a selective α2 agonist to inhibit contraction of the iris dilator muscle by activating the α2 receptor and reduce cholinergic mediated hyperemia. The bioavailability of carbachol is also enhanced by α2 -mediated suppression of aqueous humor formation via α2 receptors located in the ciliary processes.

A reasonable question is whether drugs such as carbachol and pilocarpine, which have been prescribed as glaucoma therapies for their ability to increase trabecular meshwork outflow, will have unintended effects on IOP. Studies of pilocarpine in normal and healthy subjects indicate that an increase in IOP occurs initially, followed by a decrease in IOP.8 The initial IOP spike is thought to be due to the initial contraction of the ciliary body decreasing uveoscleral outflow. This may be of some concern in patients with undiagnosed ocular hypertension or glaucoma, as well as those prone to hypotony.

Clinical data with Brimochol suggest there are no clinically significant IOP fluctuations (phase 2, data on file). This may be because of functional antagonism between carbachol and brimonidine on aqueous humor dynamics. Brimonidine lowers IOP by 2 separate mechanisms of action: decrease of aqueous humor production and increase in uveoscleral outflow9 mediated by α-2 receptors in the ciliary processes10 and the ciliary muscle,11 respectively. Cholinergics can increase aqueous humor production12 and can presumably negate the effects of brimonidine on aqueous humor production. Cholinergics can also block IOP reduction mediated by uveoscleral flow enhancement via contraction of the ciliary muscle,13 thereby negating the uveoscleral flow effect of brimonidine.

Cataract surgeons may also be wondering whether long-term use of presbyopia-correcting miotic drops might affect pupil size during cataract surgery, making the procedure more difficult. I don’t expect this will be the case. We would expect the pupil size to be reduced by approximately half and only for part of the day, returning to normal each evening with typical use of presbyopia-correcting drops. There might also be an association between many presbyopia dilator drugs and idiopathic floppy iris syndrome. Pupillary recovery time data can allay concerns to some extent, but these questions will be answered only after widespread clinical use in the cataract age group.

A disadvantage of miotic agents—both pilocarpine and carbachol—is that their action on the ciliary body can cause ciliary spasm and unwanted associated adverse effects, such as brow pain and headache. These effects are known to resolve with the continued treatment of a patient. Miotic drops have also been associated with hyperemia.

Certainly, we know formulation and active pharmaceutical ingredient pharmacokinetics can dramatically alter the adverse effect profile. For example, pilocarpine is very acidic, which can make it irritate the eyes. To counteract that and improve tolerability, Vuity drops were designed to quickly adjust to physiologic pH (7.4). With the fixed-combination carbachol/brimonidine preparation from Visus Therapeutics, the drop is already at physiologic pH, and the presence of brimonidine should certainly help to counteract any ocular redness. After all, low-concentration brimonidine (0.025%) is the active ingredient in Lumify (Bausch + Lomb), which is now widely used for eye whitening. Brimonidine, when used in this way has fulfilled an unmet need in eye care to reduce redness without dependency and deleterious effect on the vasculature of the conjunctiva that we see with OTC vasoconstrictors.

We already have great surgical options for presbyopia correction using diffractive multifocal or extended depth of focus IOLs. I am excited about the ability to nonsurgically control presbyopia, and in doing so, extend the age range during which our profession can provide reduced dependence on reading glasses. We have much to learn about how these drops will perform in the real world, but the science behind them and the ease of access bodes well for their prolific use.

I expect that presbyopia-correcting drops will be prescribed and dispensed in offices, saving patients the step of going to the pharmacy. There will likely be patient-friendly mail orders, with recurrent delivery options to improve convenience and enhance the lifestyle of patients who are not yet surgical candidates. And of course, any concerns about safety or tolerability are greatly ameliorated by the fact that patients can simply stop using the drops if they experience any unwanted adverse effects.

1. Zebardast N, Friedman DS, Vitale S. The prevalence and demographic associations of presenting near-vision impairment among adults living in the United States. 

 2017;174:134-144. doi:10.1016/j.ajo.2016.11.004

2. US Census Bureau. Table 9. Washington: Population Division. 2014.

3. Stamper RL, Lieberman MF, Drake MV, eds. 

Becker-Shaffer’s Diagnosis and Therapy of the Glaucomas.

4. Suzuki G, Kunikane E, Shinno K, Kozai S, Kurata M, Kawamura A. Ocular and systemic pharmacokinetics of brimonidine and timolol after topical administration in rabbits: comparison between fixed-combination and single drugs. 

. 2020;9(1):115-125. doi:10.1007/s40123-020-00229-x

5. Burgalassi S, Chetoni P, Panichi L, Saettone MF. Prolonged, contemporaneous administration of pilocarpine and timolol increases the aqueous humor pilocarpine levels in rabbits. 

 1999;15(1):1-7. doi:10.1089/jop.1999.15.1

6. Abdelkader A, Kaufman HE. Clinical outcomes of combined versus separate carbachol and brimonidine drops in correcting presbyopia. 

7. Hom M, Verhoeven R, Burke J, Schiffman R. Pharmacokinetics and pharmacodynamics of Brimochol. Paper presented at American Academy of Optometry 2021.

8. Korczyn AD, Nemet P, Carel RS, Eyal A. Effect of pilocarpine on intraocular pressure in normal humans. 

. 1982;14(3):182-187. doi:10.1159/000265191

9. Toris CB, Gleason ML, Camras CB, Yablonski ME. Effect of brimonidine on aqueous humor dynamics in human eyes. 

1995;113(12):1514-1517. doi:10.1001/archopht.1995.01100120044006

10. Woldemussie E, Wijono M, Pow D. Localization of alpha 2 receptors in ocular tissues.

. 2007;24(5):745-756. doi:10.1017/S0952523807070605

11. Kubo C, Suzuki R. Involvement of prejunctional alpha 2-adrenoceptor in bovine ciliary muscle movement. 

 1992;8(3):225‑231. doi:10.1089/jop.1992.8.225

12. Nagataki S, Brubaker RP. Effect of pilocarpine on aqueous humor formation in human beings. 

1982;100(5):818-821. doi:10.1001/archopht.1982.01030030822020

13. Crawford K, Kaufman PL. Pilocarpine antagonizes prostaglandin F2 alpha-induced ocular hypotension in monkeys. Evidence for enhancement of uveoscleral outflow by prostaglandin F2 alpha. 

 1987;105(8):1112-1116. doi:10.1001/archopht.1987.01060080114039

Sheppard is the Mid-Atlantic medical director of Eyecare Partners, senior partner of Virginia Eye Consultants, professor of ophthalmology, microbiology, and molecular biology at Eastern Virginia Medical School, and clinical director of the Thomas R. Lee Center for Ocular Pharmacology. He is a consultant for Visus Therapeutics Inc, Novartis, Allergan/AbbVie, EyePoint Pharmaceuticals, Inc, Alcon, and Bausch + Lomb. Contact him at jsheppard@cvphealth.com.

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