Impact of Newer Prostaglandin Analogs on Treatment of Glaucoma
Nathan M. Radcliffe, Shan Lin, and Arkadiy Yadgarov explore how recent innovations in prostaglandin therapy are reshaping our approach to managing glaucoma.
Nathan M. Radcliffe, MD:
Hello and welcome to our discussion of latest developments with glaucoma treatments, including the prostaglandins and the latest prostaglandins and combinations. I’m here with my fantastic glaucoma colleagues, Shan Lin, who is the co-research director at the Glaucoma Center of San Francisco. Welcome, Shan. Hi.
Shan Lin, MD:
Thank you. Thank you for having me.
Nathan M. Radcliffe, MD:
Thanks for being here. And Arkadiy Yadgarov in private practice, glaucoma specialist in Atlanta.
Arkadiy Yadgarov, MD:
Yes. Thank you for having me.
Nathan M. Radcliffe, MD:
Thanks for coming.
So it’s been a reasonably interesting time over the past number of years managing glaucoma because we’ve gotten new treatment options, including a new class of IOP lowering therapies, which it’s been a long time since we’ve had a new class. And while the Rho kinase inhibitors have been available to us now for a few years, we’ve finally had some experience with them. And they’ve opened up not just a new class of medications, but also a new pathway of reducing IOP through reducing resistance at the trabecular meshwork.
At the same time, we’ve had developments within the prostaglandin analog class, including latanoprostene bunod, which also has some additional mechanism at the trabecular meshwork, allowing additional outflow. And these agents have been shown to be more effective than just the traditional prostaglandin analogs that we’ve been using now for many years.
So maybe we could just start and just take a look at how the overall treatment options for these single agent therapies, single bottle therapies, has changed the way we practice over the past 5 or so years. Arkadiy, how’s this been for you?
Arkadiy Yadgarov, MD:
Yeah. I think doctors are creatures of habit, and just like you’ve said, these are newer drugs. And I think what I find surprising is it’s not as much uptake of these two medications as I would’ve thought. We’ve had prostaglandins and aqueous suppressants for decades. And although these aren’t brand new, they’re fairly new. I find that a lot of doctors still go with the old guard, latanoprost, timolol, brimonidine. And both of these agents, latanoprostene bunod and netarsudil, are completely new chapters of glaucoma treatment. And the way I think about is they’re not just IOP lowering medicines, they’re trabecular meshwork medicines. And we need to think more and more about mechanism of action. Because I think we lose the big picture. We still think of pressure, but it’s pressure, but where it matters, which is the trabecular meshwork.
So I’m very keen on that. And so it’s very early in my treatment paradigm is how do we make sure that, especially in younger patients, how do we preserve that trabecular meshwork and treat it? And I think that’s where these two medicines come in very handy.
Shan Lin, MD:
Well, I can just support that. My basic science research early in my career was in the trabecular meshwork. And together with John Samples, I co-founded the Meshwork Society Meeting. It’s still going on. I think we’re at 25 years. And David Epstein, who is one of the co-founders of the company for Airie for Rhopressa, now also Rocklatan, was somebody who came every year. And we were trying to find… The whole point is all this research to find something to treat where the actual disease process is. Or as Arkadiy says, here we are treating glaucoma almost like indirectly decreasing the amount of fluid production, but that’s not where the problem is. It’s really where the outflow obstruction is, particularly the trabecular meshwork.
So it was so heartening to see the first drug, and so far the only drug out there that is targeting the trabecular meshwork with the disease processes. And a drug that’s effective as well, very effective. We’re going to be talking about some of the additivity, together with prostaglandins of this drug. And you have the added bonus, as we’ll talk about with the episcleral venous pressure. And so now you’re both upstream and downstream, you’re decreasing the resistance to outflow. So it’s really great to see.
Nathan M. Radcliffe, MD:
Yeah, thanks Shan. And I would ask you maybe if you could help folks who are maybe dipping their toes in the water, getting to know latanoprostene bunod versus netarsudil, or even Rocklatan, what are some of the key distinguishing features in their mechanism and how they work in the trabecular meshwork?
Shan Lin, MD:
Yeah. We’ll start with Rocklatan, or Rhopressa, the active agent that is acting at the trabecular meshwork. Now you’ve got a ROCK inhibitor. And this, I won’t go too much into the weeds, but basically what it’s doing is acting at the trabecular meshwork to make it more permeable. And that’s where the disease process is. It’s actually, through primary open-angle glaucoma, become less permeable. So now you’re acting at those cells and making them more permeable through the ROCK inhibition and cyclic AMP pathway. And therefore, we’re actually, again, treating a disease process. And then you also have the added benefit, because it dilates vessels, of acting more distally at the episcleral veins. And so you have a dual mechanism of action.
In terms of latanoprostene bunod, that’s a compound that is partly latanoprost, which we’re all familiar with, is a PGA, acts through the uveoscleral pathway. It’s also broken down to the BuNO compound, which actually then gets metabolized into a nitric oxide acting agent. And that acts at the trabecular meshwork as well. And through that mechanism, it also adds a little bit of boost at the trabecular meshwork by decreasing the resistance there.
So you now have 2 agents, again, that are very helpful. And so we’re going to be talking about those 2 in contrast. But it’s great to have these agents in our hands to treat our patients perhaps just in one bottle instead of multiple bottles.
Nathan M. Radcliffe, MD:
Great. So do we have any initial thoughts on what might lead you to choose one pathway over the other? Is there anything differentiating? I did see some interesting data presented a few years ago at the American Glaucoma Society that did show that when netarsudil was added to eyes that had had a goniotomy, there was still significant IOP reduction. I don’t know if we think that’s because of the episcleral venous pressure reduction, or whether it’s just still helping other parts of the meshwork that are still there.
Shan Lin, MD:
Yeah, I’m happy to speak on that as well. I think there’s a published paper already on that, a small study, where [inaudible] There’s so many MIGS being done. I think all of us on this call do MIGS including the participants. And so when you enter the trabecular meshwork or you move part of the trabecular meshwork, what would be a great drug, for example, that could be additive or enhancing? So there’s a recent paper showing that in fact having a drug like Rhopressa, one that acts distally at the episcleral veins, collector channels, episcleral veins, actually seems to have an additive effect in MIGS compared to using a drug that has a different mechanism of action. So there may be some additivity there, as you were mentioning.
Arkadiy Yadgarov, MD:
I think that’s actually a huge potential space for a whole new avenue of glaucoma. I mean, there’s such a huge MIGS revolution right now that if there’s anything that we can do to improve results, including things that work on the EVP, which I think Shan is correct, if you’ve removed part of the trabecular meshwork (TM) at that point, the biggest limiting step is going to be the EVP at that point. And so if we can improve upon that with an agent like netarsudil, I think that’s a huge potential for therapy.
Nathan M. Radcliffe, MD:
One of the things that strikes me is how many of us meet patients who are already on latanoprost? Maybe they were started by the doctor who sent them in. Do either of you have any tips, triggers, kind of cues when you see a patient when you’re thinking of making that change, versus just sticking with the agent they came to you on?
Arkadiy Yadgarov, MD:
Look, I think in the ideal world, no one really should be on latanoprost. They should be on either latanoprostene bunod, which is latanoprost plus, you’ve got nitric oxide donating and proven trabecular meshwork, or there should be latanoprost plus Rhopressa. In other words, there should be something in that treatment paradigm that’s acting on the trabecular meshwork. I think latanoprostene bunod is probably a easier initial step because it’s something that has latanoprostene plus nitric oxide all in one, and has a very similar profile from just a adverse effect and a chair time to latanoprost. So I think that’s an easy place to start. I feel like everybody should start there in some way. But of course, access sometimes is part of the problem.
But I think if you have a patient who’s got borderline pressures, they’re on latanoprost, I think the way we really need to start educating other doctors and really thinking about things is let’s not add an aqueous suppressant. Let’s add either a netarsudil agent or a combination netarsudil latanoprost or latanoprostene bunod.
And I think, well, which one do you go with is an interesting next step question. And part of it has to do with how much more pressure lowering. And I think the rule of thumb with glaucoma is there’s no free lunches. The more IOP efficacy you get sometimes comes with a little bit of disadvantages, whatever they may be. And that includes glaucoma surgeries, as you know.
So I think with latanoprostene bunod, it’s a great agent if you need maybe a point lowering, one to two points. You’re almost at your IOP target, but you’re not quite there. In my mind to some degree, even if you’re at your IOP target, and it’s such an easy switch that I think it’s something that I think makes sense. But if you’re more than a couple of points away, I think you’re not going to see as much IOP lowering as you would with a netarsudil agent. I mean, the amount of power that a netarsudil delivers in terms of IOP lowering is… I mean, I know you’ve seen it. I know Shan’s seen it. Anybody who uses netarsudil can speak to how impressive it can be. You will three to five millimeters of mercury extra just from an additional molecule at night. But there’s got to be a little chair time with that in terms of the adverse event profile.
Nathan M. Radcliffe, MD:
Yes. Shan, anything to add with that? I agree completely, Arkadiy, with all the points you just made.
Shan Lin, MD:
Yeah. I think Arkadiy has summarized it very well in terms of the efficacy aspect, as well as the adverse events aspect that we have to take into consideration. And just again, back to the mechanism of action, it’s great with both compounds. We do with the combination of netarsudil with [inaudible] have this sort of… You’re hitting many different levels downstream, both upstream at the trabecular meshwork. You’re also hitting downstream at the collector channels and episcleral veins. But you’re also having a different mechanism of action with your latanoprost with the uveoscleral. So you’re really hitting many levels with the combination, latanoprost and netarsudil.
Arkadiy Yadgarov, MD:
I will add, I mean, uveoscleral is great and all, but to me, the prime drug, if it ever does get formulated, would be just a trabecular outflow drug. We shouldn’t be acting on anything other than that.
So I think as with anything, there’s initial iterations, and this is the kind of initial step toward trabecular outflow. But I would imagine that there will come a time where we simply give a nitric oxide medicine or a powerful first-line Rho kinase inhibitor. But it’s something that I think we’ll eventually get there without needing.
But I agree with you, currently latanoprost still is a first-line most powerful agent, and these other two new medicines that we’re talking about really are great adjuncts or next steps.
