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Spotlight

Presbyopia: A part of Aging and Challenges

Clinical

1rem

According to the company, the investigational, novel eye drop candidate was assigned a PDUFA goal date of October 22, 2023.

FDA accepts Orasis Pharmaceuticals' NDA for CSF-1 for treatment of presbyopia

According to Lento Bio, its collaboration with FSU will focus on medicinal chemistry and will help accelerate lead asset development, with board expansion focused on well-rounded scientific expertise.

Florida State University teaming up with ophthalmology drug developer

According to the company, the launch of the presbyopia phase 3 program is supported by positive clinical results that demonstrated durable efficacy and a favorable safety profile.


Ocuphire Pharma enrolls first patient in VEGA-2 phase 3 trial for presbyopia treatment 

Investigators test the efficacy of phentolamine alone and with low-dose pilocarpine. 

VEGA-1 Trial: Focusing on presbyopia

The deal with FamyGem Life Sciences covers the development and commercialization of Nyxol eye drops for the reversal of mydriasis, presbyopia and night vision issues. 

Ocuphire reaches license agreement for the development and commercialization of Nyxol

Dr Mah, what are the attributes of aceclidine that differentiate it from all the other agents out there?

 There are several. We’ll talk about the predicate drug, which is already FDA approved. It works. We know it works because the FDA approved it. I’ve prescribed it, and I’ve tried it as well. There are some shortcomings for the product, in my experience but also on the label. No. 1 is that it does cause that brow ache or the headache that we talked about. In the FDA clinical trials, it was a significant number of patients, about 20% to 25%. It’s relatively mild most of the time. Most of the time, it’s short lasting. That’s obviously a shortcoming.

No. 2 is that in the FDA clinical trials, the length of time where it was efficacious was 6 or 7 hours on average. When speaking to patients, it’s difficult. Patients want something that’s at least once a day. They say, “If it’s not going to be a 12-hour or 10-hour efficacy, then can I use it again?” That’s another shortcoming. A third shortcoming is that some of the adverse effects that we talked about are a little more concerning, as far as potential blinding disorders, like the retinal tears and detachments, which have been reported.

As far as aceclidine, compared with those 3 adverse effects, it doesn’t seem to cause that brow ache, because it’s a lot more selective for the pupil’s sphincter. In its phase 2 clinical trials, which are public information, it seems to last, at least the pupil effect, for 10 hours, which is something that patients have been complaining about or wanting. Lastly, because it doesn’t have the effects on the ciliary body, the hope is that you have no effects, or significantly fewer effects, on that vitreous pull and the retinal detachments from retinal tears. Time will tell about that. But those seem to be the benefits over what we have.

It seems that what we have available has certain limitations. In essence, they make us tailor its applications in certain ways to patients, whereas some of the newer agents, like aceclidine, might be something that can meet the lifestyle needs of our patients more significantly. Do you agree with that?

 We all live on smartphones. That’s the ultimate test for the public: how am I going to use this device every day without glasses? We all do it, I’m sure. We pick up our smartphones when we get to work—7 o’clock in the morning, 7:30 in the morning—and we want them to work. When we’re taking our lunch break, we want to check email, get some messages across, talk to our loved ones—we want them to work then. At the end of the day, you want them to work then. With a presbyopia miotic drop, it’s about quality of life. It’s about functioning in real life. That’s why aceclidine has raised the bar. It’s making a better quality-of-life drug, and it’s making tasks we do daily a little simpler than the other stuff.

Videos

Expert eye care specialists comment on the use of aceclidine as a selective miotic for the treatment of presbyopia.

Role of Aceclidine in Presbyopia Treatment

When we’re talking about reducing pupil size to affect near vision function, there are different ways you can look at it. You can look at absolute pupil size after the effect of a drug. You can look at a percentage reduction in the size of the pupil. Can you comment on the difference between them and why it’s important to reach a certain target?

 Ultimately, we have to get below a certain level of pupil size to achieve the highest-quality near vision that we can accomplish. Bringing it back to practical clinical talk to patients, we have to let these patients know that even though we’re bringing these pupils down to a certain size—to get that light in, to go parallel, to see clearly—you’re never going to get perfectly clear vision 100% of the time, like when you were 13, 14, 15 years old. But by getting the pupil below a certain level, that optimizes the optical pathway. The percentage reduction of the pupil size isn’t necessarily as important as getting it below a certain millimeter in diameter.

 Less than 2 mm is what we’re looking for. We’re using a drug to make a miotic pupil. If I say my drug reduces the pupil size by 50%, well if it starts at 10 mm, you’re only down to a 5 mm pupil. You’re not getting the effect you’re looking for. However, if your drug can achieve a certain small diameter, of less than 2 mm, you’re going to have an optimal pinhole effect for near vision. That’s where the overall size vs percentage decrease needs to be understood.

Andrew S. Morgenstern, OD, FAAO, FNAP, highlights the importance of reducing pupil size to a certain level to optimize near vision for patients with presbyopia.

ICYMI: Targeting Pupil Size for Presbyopia Management

We’re talking about presbyopia and things that happen to our focusing system as we age—the lens hardening, and so on. But the central point of our conversation is the role of eye drops, specifically miotics to affect pupil size to help individuals with presbyopia see better up close. Andy, how does that whole mechanism work? What’s the relationship between both the miosis and the pupil size change, as well as the effect on other elements of the eyes that some miotics might have?

 For those of you who aren’t comfortable with the term 

, we have 2 actions that happen with the pupil. The pupil can get smaller, which is miosis, or larger, which is mydriasis. Imagine the aperture of a camera: as the hole opens, more light comes in. The opposite happens when you have miosis: the pupil constricts, and less light comes in. An interesting thing happens with light. When the light comes through a small enough hole, it doesn’t act as a big wave anymore, but those light beams start to act in parallel. Because they come in parallel, they essentially have an infinite focal point, and they don’t blur. With miosis, we’re trying to take that pupil and constrict it, so we have enough parallel light rays and clear vision regardless of your ability to focus or how far away the target is that you’re looking at. It’s a pretty simplified way of using it.

All the stuff that we do is funny because a lot of people say, “I’m just going to go get an eye exam.” It’s amazing how much complexity there is to the focusing of light. Let’s be honest, the 3 of us specialize in something that’s the size of a golf ball, and some of us specialize in something even smaller than that. There are so many complex processes going on at the same time to make us see. We have to be able to take advantage of the physics of the eye. That pinhole optic is what we’re looking for to help us see up close.

Dr Mah, we know miotics make pupils smaller. What else do miotics do?

 That’s the rub here. We’re trying to develop something to help us expand that range of vision but that limits adverse events or complications. A lot of the issues with the miotics are that they also cause the ciliary body to contract or spasm and move. Some of the time it might be a little beneficial. You might get a bit of a myopic shift with that movement. However, with too much, you might get some headaches or brow aches, which are very common with some miotics.

No. 2 is the tension that the ciliary body can place onto the vitreous as it pulls can cause vitreous or retinal complications or issues such as PVDs [posterior vitreous detachments]. It could also cause retinal tears or detachment. With any product, surgery, or medical advancement, we’d like to enhance the benefits and maximize that but still try to lessen or eliminate any potential complications.

Expert eye care specialists discuss the role of miotic agents in targeting presbyopia in patients.

ICYMI: Using Miotic Agents for the Management of Presbyopia

This transcript has been edited for clarity:

Hi, I'm Dr. Jay Pepose, and I'm pleased to be here at the EyeCon 2022 meeting in Marco Island, Florida, where I'll be speaking about incorporating topical therapy in the treatment of presbyopia. I have really five pearls that I'm going to be discussing.

First is do no harm, you know, primum non nocere, which means, in this case, you know, the only approved drug right now is 1.25% pilocarpine, which engages this the not just the iris sphincter, but also the Surya muscle. And so we want to be sure that patients are examined, have a fundus exam, looking at the peripheral fundus looking for risk factors for retinal detachment and retinal tears. Also vitreous foveal traction. And so there are there have been reports now of some patients. Although there's no proven causality, there are some reports of patients developing retinal tears, five cases in the published literature, as well as vitreal foveal traction and 29 cases in the FDA website.

The second pearl is looking for dimming or decreased vision under low illumination at night. And I think it's best to warn patients that this could be a problem, particularly because if the retina illumination gets too low, neural contrast goes way down. And so probably it is best for them to experience this before they have to drive or do something that could be dangerous at night, operating some equipment. So that's the second pearl.

The third, of course, would be don't just try this once and say it doesn't work for me. Because in the studies and the clinical trials, the GEMINI I and II wanted to be efficacy in terms of the categorical data improvement of three lines of near distance corrected near vision without loss of one of distance was better at the two week and four week than then earlier on. And that turns out not to be related necessarily to more a smaller pupil, but perhaps neural adaptation or some other mechanism that that's not been elucidated. So it could be staying on the drug makes for higher efficacy.

Also staying on the drug, the fourth Pearl staying on the drug longer. Many patients have early side effects that say a headache, which may subside may only occur once it may be just mild and they may adapt to that.

The fifth Pearl is just to have a reasonable expectation. These patients may not all go out of glasses completely for near, but they may have a good effective intermediate vision, they may have good near vision, under certain circumstances, good lighting. If the patient is slightly hyperopic, they may not get the effect at near as much but they may improve distance and intermediate. If a patient has floaters or cataracts, it could make it worse. So I think of this as sort of adding about equivalent to about a 1.25 diopter add. And so for early presbyopes or moderate presbyopes, this may be very effective. And for later presbyopes, we may have to temper our expectations and give a realistic expectation, similar to how they counsel a patient for an EDOF lens, for example. So those are my five clinical pearls and pleasure to be here.

Jay Pepose, MD, PhD. presented Incorporating "Topical Therapy in the Treatment of Presbyopia" at EyeCon 2022 in Marco Island, Florida. 

Pearls for incorporating topical therapy in the treatment of presbyopia

 Mr Morgenstern, can you address what Dr Mah was referring to before in terms of the selectivity of some of the agents that are being looked at, in terms of isolating the effect on the pupil without some of the other effects?

 We have drugs in optometry and ophthalmology that do a great job. They work. They do good things for us, and they help us with so many diseases. We’re looking for the optimum zone. If we can get that pupil down to a certain size, that’s great. Not affecting the ciliary body and the ciliary muscle is helpful. We know it’s not with everybody, but it happens with the ciliary muscle and causes some aches in the eye. It could cause some headaches in people. That could be something. The drug is helping them see a little better, but if they’re getting some adverse effects from it, they may not want to use it as much. It’s an adverse effect. Drugs have adverse effects. This is nothing new. All drugs have some adverse effects. But as we look at new drug technologies, that pilocarpine was good. We think aceclidine is going to be a better product. It’s going to help us, we’re going to learn from what was in the past, and we’re going to modify it to get our patients to have better vision with fewer adverse effects. That’s the name of the game. It’s like that with every drug in every category in any part of the body. That’s not to say that it was bad. We’re just trying to get a better option for our patients.

Andrew S. Morgenstern discusses the selectivity of miotic agents in isolating the pupil while limiting adverse events for the management of presbyopia.

Miotic Selectivity in the Management of Presbyopia

There are several miotic agents available and approved or under investigation. Dr Mah, what are some of the similarities and differences with these agents?

 That’s a great question. There are many innovative ways that companies are trying to address miotics. The first 1 that was FDA approved was pilocarpine 1.25%. There’s another pilocarpine product coming through the FDA restoration process. It will probably be approved within the next year or 2, assuming everything continues to hit their signals. I believe it’s 1% pilocarpine. There are also agents like carbachol and brimonidine or a mix of them. These are all pretty strong miotics. They seem to affect the ciliary body in addition to causing that miosis of the pupil. Another agent, aceclidine, seems to affect only that pupil’s sphincter. It seems not to affect the ciliary body, and it seems to have a pretty powerful effect on the iris sphincter muscle.

A number of these agents seem to use elements that have been around for a long time, and we’re all familiar with them in different concentrations. There have been limitations, especially the ones that have come onto market. In my experience, they haven’t been able to achieve that critical pupil size in most of the patients we’ve seen. Therefore, it’s really limited in its efficacy. As you said, because of the effect on the ciliary body, the potential for other complications is there.

Francis S. Mah, MD, reviews miotic agents that are available or under investigation for the treatment of presbyopia.

Miotic Treatment Options for Presbyopia

For background, Andy, describe how the near-focusing system in the eye works.

 I’ll try to keep it as simple as possible. It’s a complex system in the eye. We always teach our student optometrists—externs, residents—and our patients that the eye is an extension of the brain. All the visual information coming in and going out is processed by the brain. This is a processing issue. But mechanically, inside the eye, we have a few mechanisms going on.

First, we have the crystalline lens. The crystalline lens, when we’re young, is an auto-focus lens. When we get that visual stimulation into the eye, into the brain, the brain tells the lens how much power to focus, so we can bring things into focus. A good example of that is when you wake up in the morning. You look at your alarm clock, and it takes you 3 or 4 seconds to adjust, just like an auto-focus camera would. But something else is going on because the lens and the accommodative ability, the focusing ability, is linked to an aperture in our eye called the pupil. You can’t separate the 2 actions from going on. Actually, there are 3 actions going on because the eyes are turning in to help us read. All of those mechanics inside the eye, stimulated by the brain, are how our focusing system works. Unfortunately, as we age, things change. But that’s basically how it works.

Dr Mah, why don’t you share with us what happens as we age? What happens to this wonderful and complex system?

 There’s still a little controversy as far as what exactly is happening with presbyopia or the loss of accommodation. Andy went through an excellent but very simplified description of it. It’s very complex, and that was an excellent simplification of it. There are a couple of thoughts as far as what’s happening with the loss of accommodation. There are 2 theories. The main theory most people accept is the Helmholtz theory. Essentially, the lens itself is an auto-focus lens. As we age—the process starts on the day we’re born—the lens slowly loses its flexibility. We don’t notice that loss of flexibility when we’re distance corrected until around 40 or 50 years old, when our arms aren’t long enough to hold that item we’re trying to read or look at from far enough away. That’s the main theory.

The other theory is the fact that the lens is becoming larger in addition to becoming stiffer. Although the ciliary body is moving, contracting, and relaxing, and the lens may still be a little flexible, it’s so large that the ciliary body can’t move enough to have that little remaining flexibility left over to cause accommodation.

Drs Andrew S. Morgenstern and Francis S. Mah provide insight on the functionality of ocular accommodation as an autofocus lens and how this is affected in patients with presbyopia.

Impact of Presbyopia on Mechanism of Ocular Accommodation

Francis S. Mah, MD, and Andrew S. Morgenstern, OD, FAAO, FNAP, review the impact of presbyopia on quality of life as well as current treatment options and unmet needs for disease management.

Overview of Presbyopia

I'm David Hutton of Ophthalmology Times. I'm joined today by Ben Bergo, CEO of Visus Therapeutics, who will be presenting at Eyecelerator at the American Academy of Ophthalmology 2022 annual meeting in Chicago. Thanks for joining us today. Tell us about your presentation and what's new at Visus.

Thank you, David. And thank you for the opportunity to provide this briefing on what I presented at Eyecelerator. As many of you will be aware, Visus Therapeutics is a clinical stage company. With a lead program in presbyopia and a rapidly expanding pipeline of novel multi-target ophthalmic drug candidates.

We announced at Eyecelerator that we acquired a new set of drug candidates actually for managing both presbyopia and cataract, but also provided just some further data and insights into what we're doing with our miotic eye drops under development. So at the moment, again in in phase , we 3 have two miotic eye drops in development.

We have brimochol PF, which is a preservative free combination drug to create a pinhole effect, and provide an improvement in near vision for patients globally. This is a combination of carbachol and brimonidine.
And we saw from our VIVID phase 2 study results along with durable improvement in near vision with this, with this drug candidate. And we also saw from those phase 2 results, a benefit of the combination over the monotherapy. So we saw that with the additional brimonidine. The combination dominated the monotherapy alone the carbachol alone.

I also presented the patient reported outcomes from this study. So importantly, at the end of each dosing day, we would ask subjects in the study: What did you think of the eyedrops? And they gave very, very good feedback on brimochol, and carbachol also. They said that they would see and want to use brimochol potentially, you know, 8 days out of 10. And that's after a full day in the clinic, you know 10 hours in the clinic. And that was, that was statistically significant.

So I provided some updates on again, that lead program. We are in the middle of those 2 phase 3s, BRIO-I and BRIO-II. BRIO-I, we'll be reading out its top line [results] in the first quarter of next year. It's 170 subjects in that study. And then the second study, BRIO-II, will move through to its read outs in the first half of next year too, and then we move forward to filing in the in the second half of next year.

So that's our miotic strategy that's creating again a pinhole to provide an improvement in near vision for people. The alternative approach obviously for many presbyopia, but also cataract, is to actually go after obviously the naturally occurring changes in the lens.

So again, as we age, our lens starts to harden, and we form, we form aggregates. And this hardening obviously prevents accomodation. We can't change the shape of that lens, because again, it's becoming harder with age. That first presents as presbyopia, but then secondly can move forward as those aggregates increase and we get opacity can, can move forward to cataract. And obviously, cataract is a major form of visual impairment globally.

So again, we've acquired acid compounds, to allow us to develop a disease-modifying drug. So a drug that would actually start to undo this protein misfolding in the lens and potentially slow down the progression of presbyopia an/or potentially reverse cataract in patients.

So we're incredibly excited by that development. This is giving us obviously two approaches to managing presbyopia and cataract and and I presented on that at Eyecelerator.

Excellent. Ultimately, what can these new therapeutics mean for patients?

So what it means for patients is, is choice, obviously, and what it means for them is potentially again, a disease-modifying drug. So as we're aware of these miotics are treating, obviously, the underlying change in lens function, and they're doing that by again, creating a pinhole effect. This other therapeutic candidate that we have under development would go after, again the lens itself and would be able to restore vision in that way.

So a lot of great news. Thank you for sharing it with us. Thank you very much appreciate you having me.

Ben Bergo, CEO of Visus Therapeutics, announced the acquisition of all patents and other assets of ViewPoint Therapeutics, which will accelerate development of novel alpha-crystallin chaperone compounds as a non-surgical treatment for age-related cataracts.

Visus Therapeutics CEO announces acquisition of ViewPoint Therapeutics to expand on cataract, presbyopia candidate

Cathleen McCabe, MD, recently discussed her presentation at the Women in Ophthalmology Summer Symposium, titled "GEMINI 1 and 2 pooled Phase 3 safety and efficacy: AGN-190584 primary and key secondary endpoints" 

McCabe discussed the trial, its results and the hope these drops could have for patients diagnosed with presbyopia.

Allergan, a subsidiary of AbbVie, announced last fall that the FDA had approved pilocarpine HCl Ophthalmic Solution 1.25% (Vuity) for the treatment of adult patients with presbyopia.

At the recent Women in Ophthalmology Summer Symposium, held in Monterey, California, Cathleen M. McCabe, MD, outlined how pilocarpine HCl Ophthalmic Solution 1.25%, the first and only FDA-approved eye drop to treat presbyopia could offer an opportunity for patients looking for spectacle independence.