Glaucoma Treatment Decisions and Reaction to Recently Released MORE Data
Nathan M. Radcliffe, Shan Lin, and Arkadiy Yadgarov discuss the results of the MORE study, which demonstrate significant intraocular pressure (IOP) reduction in glaucoma patients using Rocklatan, reducing the number of medications needed.
Nathan M. Radcliffe, MD:
It is fascinating to think about all this as we enter potentially the laser-first era, or an era in which patients will be offered laser first. And I think one of the reasons laser has taken this laser-first position is because it does act on the trabecular meshwork and in fact laser seems to work its best early, which reinforces some of the concepts we’ve been discussing, which is that treating glaucoma at its point of origin, the trabecular meshwork, seems to be a good way to approach the disease. We’ve probably all had the experience where you use a laser very late, decades into the disease, and it doesn’t work as well. So that maybe can inform our choices on using drops that address the trabecular meshwork, earlier on as well.
Arkadiy Yadgarov, MD:
Yeah.
Nathan M. Radcliffe, MD:
Yeah, and so whether a laser is wearing off and now you need an agent, still might make sense to address the trabecular meshwork. Anything to add to that line of thinking as we enter this era?
Arkadiy Yadgarov, MD:
Yeah, I think the hottest topic is interventional glaucoma, I think is the hottest topic, and partly I think a major reason for that, of course we’d like to intervene, but a huge reason is multiple medications is a burden. Medication reduction is something that all of us are striving for. Patients are not happy when they’re on 2 to 3, or 4 meds. I think SLT started there as a way to help reduce medicines, but now has found a new role which is, well, look, you can just start there. But glaucoma is a recurrent or a chronic disease and to me, I’m always thinking, “How do I reduce the amount of total medicines that this patient’s got to use?” Because I think it’s great when you have SLT first line, but it’s probably not always going to work, right?
Essentially, I think the way we should be thinking is, what do we do, whether it’s intervention, whether it’s medication, to keep as little amount of drops per day going? And I think that’s a good segue into really the MORE study because, if you have a patient on multiple medicines and let’s say they don’t want surgery or they don’t want SLT, how do we make life easier for them? That’s what I found very, very impressively, as a potential for doctors’ habits and doctors’ treatment paradigms, is there is a way still to make life easier for a patient. Instead of using multiple, multiple medications, to go ahead and try these trabecular outflow boosting medications, like netarsudil, and simply stop some of these [inaudible] suppressants, add a netarsudil or a Rocklatan and then you get phenomenal pressure reduction. So Shan, I wanted to ask you, what did you think of some of the MORE study results that were presented recently?
Shan Lin, MD:
With regard to SLT, I think that’s a very apropos question now that there’s more data about the efficacy of SLT, perhaps as a first line therapy, and as all of you know, there’s also going to be the availability perhaps of a much more rapid form of SLT coming up. And so, in regard to that, where is it that medications come in? Arkadiy’s, his thoughts are right, spot on. Can we try to help the patient reduce the medication burden and the number of medication? Can we just have it as one bottle and be able to control their pressures together with the SLT?
So I’m going to speak in regard to that and there might be some thought. Well, SLT works on the outflow pathway, right? Is there going to be some reduced effect from having that as a mechanism of action and now you’re adding medications that also acted there? And so I would just want to address that, that in fact some preliminary data, looking at prostaglandins, there’s still an additive effect in most studies that I’ve seen. So I think that’s still going to be my first line therapy, talking about the medications that we’re talking about here that also have a trabecular meshwork activity and perhaps even distally with netarsudil. Preliminary data that I’ve seen also shows its additive and also I will tell you anecdotally when I, for example, put somebody on netarsudil after they’ve had an SLT, it still works. And the reason being, perhaps back to the mechanism of action, it’s acting through different mechanisms, acting through cyclic GMP, relaxing that contractility of the trabecular meshwork and therefore allowing greater outflow.
Secondarily, it’s also been theorized that because it acts more distally at the episcleral venous pressure level, it’s additive in that way as well. So I think, yes, I think all of that is coming together that even though we’re shifting a little bit to laser first and maybe even easier laser first, that we still have that strength of using perhaps a single agent afterward, and having that additivity of effect.
Nathan M. Radcliffe, MD:
I love it and agree with those thoughts. And it is interesting to think and you’re correct, we will have direct SLT laser hopefully in the near term, hopefully within the next coming one or two years, and it is all about medication or bottle reduction, compliance being one of the main barriers. And so we have the MORE study that provided data and I’ll just say is, by way of background, we saw with the Most study, which was a study of netarsudil or Rhopressa as an adjunct therapy or replacement therapy, we saw that it was very consistent no matter how it was used. And this is how I use netarsudil or Rhopressa, clinically, particularly for borderline pressures. It wouldn’t necessarily matter how many other adjunctive therapies the patient was on. I found it very reliable in terms of giving me four to five millimeters of pressure reduction and the Most study demonstrated that. Do one of you want to tell me about the MORE study and how the study was set up? And then we can discuss the findings.
Shan Lin, MD:
Well, I’d be happy to and I’m going to give just a brief summary, of it and give a little difference between the Most study and the MORE study. And the Most study, I think most people are familiar with that, was basically looking at is netarsudil additive to patients who are already on medication, be it latanoprost or latanoprost plus, that is they’re multiple medications. And as you mentioned the summary of that is that, yes, you get about a 20% additional IOP lowering by adding on netarsudil. The MORE study is actually taking it to an even higher level. You’re on latanoprost or you’re on latanoprost plus other medications, 1 more medication or 2 more medications. And if we replace that regimen with just Rocklatan, which has the latanoprost, but you’re also getting the additive effect of the netarsudil, how does that work? And how does that, in terms of patients’ additivity, in terms of their medications, their IOP reduction, in terms of any side effect profile.
So I took away from that that there’s an additional 15 to 20% lowering of intraocular pressure when you actually replace that original regimen with the Rocklatan, which is latanoprost and netarsudil. And that worked with both just people who were on latanoprost, who were on latanoprost plus one med, or latanoprost plus two meds. And that’s actually impressive that you actually had such significant lowering when you took patients who were on two or three meds and you were replacing it with basically just one bottle. And then, in terms of the side effect profile, the vast majority of the patients, by the way, in a survey showed that they would stay on that regimen.
There were increased amounts of hyperemia, not as much as you would see with just starting netarsudil. So it was about a 30% increase in the report of hyperemia and most of that, the vast majority of it, I believe, 80% of that was mild to trace. So most of the patients were able to tolerate it. The discontinuation rate was about four to 5% in each group, that is in people who are just on 1 drop, 2 drops, or 3 drops, and that was very impressive. I’ll tell you, when I first saw the data, I was impressed that you can replace multiple medications with just one med and still have about a 15 to 20% IOP drop.
Arkadiy Yadgarov, MD:
Yeah, I want to echo that last statement there. Again, I like to talk about doctors, but it’s all of us. We are so used to additive, we stack. Here’s your first medicine, well, you need more help, here’s a second medicine. You need more help, here’s a third medicine. And Most study was part of that thinking, right? Well, here’s an additional medicine you can add. I think the MORE study really has just completely impressed all of us because this is the first time you saw data where you get pressure lowering and reduction of medication with just an additional molecule on board. So I think it’s a massive type of paradigm shift we may have because of the MORE study where you have a lot of doctors that may want to add a medicine, you go, wait, hold on now. With this medicine you can actually replace, and I think that’s exciting, and I think there’s going to be a lot more uptake because of the MORE study.
Nathan M. Radcliffe, MD:
Yeah, and I have to agree. Again, you saw the consistency of Rocklatan, whether it was replacing latanoprost, replacing latanoprost plus one med, or replacing latanoprost plus two meds, you saw pretty consistent decreases in IOP. And I have to say that latanoprost plus two med group really surprise and impress me. It’s the ultimate consolidation. Even if you’re thinking about something that we aren’t necessarily talking about tonight, but preservative load, you’re going from five preserved drops a day down to one, compliance is going to be of remarkably easier for the patients. And perhaps that’s some of the advantages you saw, but we live in the real world and we want the pressure reduction. And as we’ve talked a little bit about, there are some hyperemia.
That’s the notable issue with netarsudil, and then we learned from a patient reported outcomes, a lot of patients were happy with their therapy. A lot of patients would continue with it. One of the lessons I’ve learned is basically assessing patients for their relative concern about hyperemia versus their relative concern about their IOP. I’d love to hear how you talk to patients about hyperemia in general, or hyperemia when you’re thinking of using Rocklatan or Rhopressa.
Shan Lin, MD:
I’m happy to start, yeah. Even at the beginning, knowing the side effect profile for netarsudil and the combined Rhopressa. The first thing I tell them is that expect redness. I think all of you tell your patients that because it is a relatively high hyperemia rate, but most of it’s mild. So I tell them to give it a few weeks because usually the vast majority of people, it gets better. And I think both of you have had that experience as well. Beginning it may be a little bit of a surprise to patients, but if you let them know ahead of time to expect this, then they’ll understand that that’s the agent working. You got it in your eye, it’s working and that it improves over time.
I’ll add another thing too is that I’ve had patients that I’ve tried and the small percentage that can’t tolerate it really and have to discontinue it, I’ve come back years later and I just had a patient last week who are now on two or three meds. I need to get their pressure lower and I retried them with a Rhopressa added on and they’re doing fine. And I think I’ve heard a lot of those kind of anecdotal cases from my colleagues, the data from the MORE study suggests that, that in fact the hyperemia rate is not as high as monotherapy, Rhopressa for example, or netarsudil. And anyway, just something that’s helpful to me, not having to go to surgery by just adding it all later on.
Arkadiy Yadgarov, MD:
Yeah, a couple of things. I would say, that prior to MORE study, right, the typical usage of netarsudil a lot of times was, here’s an additional bottle, right? And so if you had a patient who already had two bottles let’s say, and now you added a third bottle and there was increased redness, sometimes they would complain. What I found very unique about MORE study, which mimicked, and I’ll give you an anecdote. This is a patient who, it’s a couple of years ago, in fact, maybe even longer than that, back when Rocklatan first came out, and of course I wanted to try it on everybody. He was a classic, prime example of the MORE study. He was this young teacher who was on latanoprost, I believe, co-something and possibly on [inaudible], but he was using all this medication.
I said, “Look, there’s this medicine out there called Rocklatan. Why don’t we just try that? Because I know this is a lot going on.” He came back and his eyes, indeed, he went from a trace injection to maybe a one and a half plus injection. So it was noticeable. And I said, “Well, how are you doing?” He’s like, “Oh my God, I’m loving not to have to use all those medications.” And to me, I think that you’ll find the happiest patients in that cohort. It’s how do I reduce their medication burden? Because if you add another medicine, you’ve now made them use more medicine and added redness, it’s going to be a battle. You’re right. Look, well, your IOP’s better or, hey, give it some time. But you’ll have a lot more patients that are going, “Look, man, I’m on one bottle at night. My eye’s a little red, but I’m so much happier that I don’t have to take multiple medicines and run out of one bottle and find the other bottle.”
So I think the redness is something that we have to talk about. There is chair time involved, but I found it to be a lesser of a problem on return visits if you follow what the MORE study did, which is consolidate, reduce their medication load. I’m thinking through it, Shan, based on what you said, where the redness was not as bad in the MORE study. And I think part of that possibly is, is what Nate was talking about, BAK reduction. You’ve got a patient who’s on benzalkonium chloride multiple times throughout the day and now you’ve reduced that load. And so it’s possible that their trace to one plus stayed at trace to one plus.
So I think there’s just a lot to glean from the MORE study. I think it’s probably one of the most impressive type of results I’ve seen recently. And then in terms of chair time, I will just say that I think it’s important if you don’t spend the extra few minutes saying, “There may be redness, stick with it, give it a couple of weeks.” I think that’s imperative because it builds trust in the patient that you know what’s going on and then there’s no surprises.
Nathan M. Radcliffe, MD:
Yeah, Arkadiy and Shan, you mentioned this too, I think, A, when you warn a patient about a side effect, you’re altering that part of the equation of success equals outcome minus expectations. You’re helping set their expectations, and it’s a bizarre irony but when you warn a patient about a side effect and then they have the side effect, they actually say, “My doctor was right.” It actually builds confidence and trust in the relationship and it does remind them that you spent the time to talk to them about it too, which I think you were saying, Arkadiy, which is meaningful for all of us. And so the little extra time you spend can help both your patient achieve their goals and their success, and it can build the relationship a little bit.
So it’s important, in anything we do, but in this case it tends to be helpful. And then the nice part of that is we do feel confident in the pressure reduction you’re going to get, based on essentially any arm of the MORE or Most study showing a benefit, and often in that four millimeter, 20%, with some variability, but consistency across two studies with multiple arms in various situations. So I like the part where I can say, “Hey, you may get a little red, but I’m confident this is going to help your situation. Give us some time, come back on it, let me assess and then let’s decide where we want to go from there.”
So those things are very important, and additionally, you made this great point, which is if you’re new, if you’ve been nervous or maybe your first experience using Rhopressa or Rocklatan, you backed off, start with the latanoprost plus two drop group, consolidate them to Rocklatan. And what happens, I think generally, is you see that success, you have these incredible success stories, and then you move it to your comfort point. For some of us, that’s going to be primary therapy in a patient where we know they’re going to need two drops. For others, it may be first adjunct instead of adding a bottle, switch to Rocklatan. There’s so many, hundreds of thousands now, ways to treat glaucoma. We all find our place that works for our patients in our practice, but you’ve given all the ingredients and all the different thoughts for how we can move in that direction.
