Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension
Angelo P. Tanna, MD shares the biggest challenges ophthalmologists face when treating glaucoma and ocular hypertension. He discusses his recently published review of Rho Kinase Inhibitors as a novel treatment for Glaucoma and Ocular Hypertension.
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Learn more about Angelo P. Tanna, M.D.
Angelo Tanna, MD
Angelo P. Tanna, M.D. is Vice Chairman and Associate Professor of Ophthalmology and Director of the Glaucoma Service at the Northwestern University Feinberg School of Medicine in Chicago, Illinois, where he has served on the faculty since 1999. Dr. Tanna received his medical degree at the Columbia University College of Physicians and Surgeons in 1994.Learn more about Angelo P. Tanna, M.D.
Transcription:
Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension
Melanie Cole (Host): Welcome. This is Better Edge, a Northwestern Medicine podcast for physicians. I’m Melanie Cole. And today we’re discussing Rho-Kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Joining me is Dr. Angelo Tanna. He’s a Professor and Vice Chair in the Department of Ophthalmology and Director of the Glaucoma Service at Northwestern Medicine. Dr. Tanna, it’s a pleasure to have you join us today, tell us what’s new in pharmacotherapy and some of the biggest challenges ophthalmologists face in treating glaucoma and ocular hypertension.
Dr. Tanna: Well ophthalmologists are aware that there are two new agents that are available for our use clinically that have already been approved by the FDA for about two years now. One is netarsudil which is a Rho-Kinase inhibitor. The other is latanoprostene bunod. So, latanoprostene bunod has basically a latanoprost molecule attached to a nitric oxide delivery device if you will. So, this drug which goes by the brand name of Vyzulta once it’s in the cornea; is hydrolyzed into two components latanoprost acid and then once it gets into the eye, nitric oxide is released as well from butane dial mononitrate. So, the nitric oxide is thought to help lower the intraocular pressure in a mechanism different than how latanoprost itself works.
So, what we know from clinical trials, is that latanoprostene bunod lowers the intraocular pressure about a millimeter of mercury more that latanoprost. So, this is helpful, but this is not a big kind of impact that ophthalmologists are really looking for when they are trying to take care of a patient. We’re trying to get bigger degrees of intraocular pressure reduction. So, this small difference of the one millimeter of mercury is helpful, but on an individual patient level; maybe not all that profound.
So, there’s another drug netarsudil that also lowers the intraocular pressure but, in a mechanism, completely different than any other drug we’ve had before. It’s a rho-kinase inhibitor. And it works by acting on the trabecular meshwork and endothelial cells at the inner wall of Schlemm’s cannel by altering the cytoskeleton of these cells to relax the cytoskeleton and thereby improve outflow through the conventional or trabecular pathway.
Host: Dr. Tanna you recently published a review article in Ophthalmology of rho-kinase inhibitors. What else might they offer? Is there a possibility of neuroprotective activity, a favorable impact? You mentioned on ocular blood flow, even antifibrotic effect. Tell us a little bit about what else they may offer.
Dr. Tanna: Yeah, we don’t really have proof in humans that there’s a neuroprotective effect with rho-kinase inhibitors when used as an eyedrop. Because we don’t thing that enough of the drug would get to the relevant tissue. But at least in laboratory models, both in vitro and in vivo; there is evidence that rho-kinase inhibitors prevent apoptosis and are therefore neuroprotective. They also help with regeneration of axons in in vitro and in vivo models. So, there is hope that rho-kinase inhibitors can do more, but we just don’t have evidence that what we have available to us clinically is likely to accomplish that. So, there is a possibility though that there could be intracameral delivery of a rho-kinase inhibitor through some sort of long-acting device that could be implanted in the inter chamber for example. And that could change the game. That could allow us to tap into some of these other potential secondary benefits of rho-kinase inhibitors.
The other that you mentioned, we do know that rho-kinase inhibitors improve blood flow but it’s the same thing; it’s mostly in laboratory models. There is actually some human evidence for it with other rho-kinase inhibitors besides netarsudil. So, that too, is something that could be a benefit when the drug could ultimately be delivered intracamerally for example in a long-acting device. And then, you mentioned the antifibrotic activity. It does inhibit the activity of fibroblasts. When we do glaucoma surgery, our big enemy is scar tissue formation and rho-kinase inhibitors do prevent the transformation of fibroblasts to myofibroblasts and that’s a very important step in the scar tissue formation process that we don’t want after a trabeculectomy for example or even after [00:05:49] surgery. So, there are studies that are ongoing to look at the antifibrotic activity of rho-kinase inhibitors to see how that might be something we could take advantage of clinically to help improve our surgical outcomes.
Host: Are you typically using them alone or combined with other known ocular hypotensive medications doctor?
Dr. Tanna: Well, because of the side effect profile, there are substantial side effects with netarsudil mainly conjunctival hyperemia, some patients complain of blurry vision, pain, tearing. Because of these adverse effects, we tend to not use them first line or even second line. So, the most common place in my practice for rho-kinase inhibitors is for patients in whom we really are trying to get the pressure down in order to avoid having to do surgery. So, these patients are already often on many medications. That’s the primary use at least in my practice. There’s occasionally the rare patient in whom we’ve tried everything else and nothing else works and we might try a rho-kinase inhibitor. But that’s pretty uncommon.
Host: Do you have any new data to share from your continued research in this area?
Dr. Tanna: I do. So, we’ve done a retrospective study at Northwestern to look at all of our patients who have been treated with a rho-kinase inhibitor to see outcomes in terms of intraocular pressure and how well tolerated these drugs are. And we’ve submitted some of this stuff and it will be presented at ARVO this year in Baltimore in May. But we have some additional data that is not part of that abstract that I can share.
So, we looked at the pressure outcomes in patients in whom a rho-kinase inhibitor was added, specifically netarsudil because that’s all we have in the United States, after we had two baseline measurements. So, we only looked back at the patients in whom we had two measurements on different days of patients who are on a particular medication regimen. And once we added the netarsudil, we had to have one other pressure measurement. So, because if you look at patients in whom you only have one intraocular pressure and then one post treatment intraocular pressure in a retrospective study like a chart review; you have a problem with regression to the mean. So, what that means is, when we start a new medication on a patient; oftentimes it’s because the pressure just happens to be higher than we want that day and sometimes, it’s just random fluctuation. So, when the patient comes back for the next visit; just by chance, they are more likely to have a lower pressure because they go back to what they usually run at around the mean.
But by restricting our analysis to patients in whom we had two baseline measurements on two separate days; we reduced the confounding effect of regression. So, we have 307 eyes of patients in whom we added Rhopressa, netarsudil after two baseline measurements on a stable intraocular pressure lowering regimen and I’m going to focus just on the 86 eyes who were on three medications and 63 eyes that were on four medications prior to starting netarsudil. And what we observed in those two groups was a 2.9 millimeter of mercury reduction for the patients who were on three medicines and a 2.7 millimeter of mercury reduction for the patients who were on four medications before we started netarsudil. And the P values in both cases are very low. The P values are 0.0001 or less for both of those groups.
So, since we have a lot of observations and since the effect seems to pretty uniform; we high statistical significance that you get almost a 3 millimeter of mercury additional reduction of IOP on average in those patients who are already on multiple medicines. So, this is new information. We already have a lot of information in the published literature of how netarsudil works when you add it to a patient who is already on latanoprost because that’s part of the clinical trials that have been done in preparation for FDA approval for the fixed combination of netarsudil and latanoprost. That’s called ROCLATAN, so we don’t really have any evidence in the literature about how these drugs behave when you add them to existing regimens. Especially the commonly used regimens of three or four medications by the time you add the netarsudil.
So, I think that when we finally publish this, it will be very useful, new information that people will be able to take advantage. So, that’s a pretty good effect an extra 2.8 or 2.9 to 2.7, that range additional IOP lowering.
Host: Dr. Tanna, as we’re discussing the clinical impact of your projects and how you see it transferring to patient care; taken together, how do see the rho-kinase inhibitors having a broad theoretical therapeutic potential in glaucoma? Where do you see this going in the future?
Dr. Tanna: Well, if ophthalmologists know ahead of time that they can expect basically a 2.5 to almost 3 millimeter of mercury additional IOP lowering by adding netarsudil for patients who are already on three or four medications, and that’s on average by the way, so some people do even better; I think that that’s pretty encouraging and that would make it so that at least people would try this drug and what I found is that in about a quarter of patients, the drug really isn’t adequately tolerated and the patients don’t want to keep using it. But in something like half of the patients, we see a reasonable to excellent IOP lowering effect and tolerability of the drug, at least for the one year range. And I think so it can be used clinically to help at least delay and maybe avoid incisional surgery.
Host: As we wrap up, what would you like other providers to know about the class of rho-kinase inhibitors and optimizing treatment for patients and what you’re doing at Northwestern Medicine.
Dr. Tanna: Well I’d like people to know that if they prescribe this drug that they should expect a pretty large proportion of patients to have adverse effects. So, the physician really has to prepare the patient for the possibility of side effects like conjunctival hyperemia, blurry vision, pain and teary. I tell my patients that if they experience symptoms that they can’t tolerate, to go ahead and stop using the drug and to let us know and that they can expect resolution of the symptoms fairly quickly, usually within a day or two.
I also think that physicians need to know that even for patients who are on a lot of medications, three or four medications; there are some individuals in whom a pretty profound IOP lowering can occur with this drug. It’s not common, it might be 15% or so in whom the pressure might drop by 40%, but among the patients who can tolerate the drug and among the patients in whom such a big pressure lowering is realized; it is a very favorable effect for the patient. It does lead to the possibility for example, of preventing the need for incisional surgery.
The other thing that’s important is the cornea as it pertains to rho-kinase inhibitors. Physicians know that a common side effect associated with the use of rho-kinase inhibitors is cornea verticillata. There’s also another corneal abnormality that has been observed and has been reported at the Academy there was a group that reported a corneal endothelial abnormality that occurs with the use of Rhopressa. And we’ve observed this as well. We’ve seen with specular microscopy that at least in two patients that we have, that the normal hexagonal shape of the corneal endothelial cells can be lost and there’s irregularity of the corneal endothelium in these patients that can even be visualized with slit lamp biomicroscopy. So, although it’s rare, or at least very uncommon, we’ve also found it’s reversible. We found that in one patient when we discontinued the netarsudil by two months, which is the next time we looked; specular microscopy showed normal corneal endothelial cells.
So, that’s something to be aware of on the horizon. There might be an effect on the cornea that we have to be aware of and in terms of the long-term effects of this, I think we know from the clinical trials that it’s unlikely that there’s any long-term safety effect related to the corneal endothelium. But it’s another thing to keep in mind and that we likely will be getting more information on the horizon.
Host: Thank you so much Dr. Tanna for joining us today and sharing your incredible expertise. This is Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information on the latest advances in medicine please visit our website at www.nm.org to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. I’m Melanie Cole.
Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension
Melanie Cole (Host): Welcome. This is Better Edge, a Northwestern Medicine podcast for physicians. I’m Melanie Cole. And today we’re discussing Rho-Kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Joining me is Dr. Angelo Tanna. He’s a Professor and Vice Chair in the Department of Ophthalmology and Director of the Glaucoma Service at Northwestern Medicine. Dr. Tanna, it’s a pleasure to have you join us today, tell us what’s new in pharmacotherapy and some of the biggest challenges ophthalmologists face in treating glaucoma and ocular hypertension.
Dr. Tanna: Well ophthalmologists are aware that there are two new agents that are available for our use clinically that have already been approved by the FDA for about two years now. One is netarsudil which is a Rho-Kinase inhibitor. The other is latanoprostene bunod. So, latanoprostene bunod has basically a latanoprost molecule attached to a nitric oxide delivery device if you will. So, this drug which goes by the brand name of Vyzulta once it’s in the cornea; is hydrolyzed into two components latanoprost acid and then once it gets into the eye, nitric oxide is released as well from butane dial mononitrate. So, the nitric oxide is thought to help lower the intraocular pressure in a mechanism different than how latanoprost itself works.
So, what we know from clinical trials, is that latanoprostene bunod lowers the intraocular pressure about a millimeter of mercury more that latanoprost. So, this is helpful, but this is not a big kind of impact that ophthalmologists are really looking for when they are trying to take care of a patient. We’re trying to get bigger degrees of intraocular pressure reduction. So, this small difference of the one millimeter of mercury is helpful, but on an individual patient level; maybe not all that profound.
So, there’s another drug netarsudil that also lowers the intraocular pressure but, in a mechanism, completely different than any other drug we’ve had before. It’s a rho-kinase inhibitor. And it works by acting on the trabecular meshwork and endothelial cells at the inner wall of Schlemm’s cannel by altering the cytoskeleton of these cells to relax the cytoskeleton and thereby improve outflow through the conventional or trabecular pathway.
Host: Dr. Tanna you recently published a review article in Ophthalmology of rho-kinase inhibitors. What else might they offer? Is there a possibility of neuroprotective activity, a favorable impact? You mentioned on ocular blood flow, even antifibrotic effect. Tell us a little bit about what else they may offer.
Dr. Tanna: Yeah, we don’t really have proof in humans that there’s a neuroprotective effect with rho-kinase inhibitors when used as an eyedrop. Because we don’t thing that enough of the drug would get to the relevant tissue. But at least in laboratory models, both in vitro and in vivo; there is evidence that rho-kinase inhibitors prevent apoptosis and are therefore neuroprotective. They also help with regeneration of axons in in vitro and in vivo models. So, there is hope that rho-kinase inhibitors can do more, but we just don’t have evidence that what we have available to us clinically is likely to accomplish that. So, there is a possibility though that there could be intracameral delivery of a rho-kinase inhibitor through some sort of long-acting device that could be implanted in the inter chamber for example. And that could change the game. That could allow us to tap into some of these other potential secondary benefits of rho-kinase inhibitors.
The other that you mentioned, we do know that rho-kinase inhibitors improve blood flow but it’s the same thing; it’s mostly in laboratory models. There is actually some human evidence for it with other rho-kinase inhibitors besides netarsudil. So, that too, is something that could be a benefit when the drug could ultimately be delivered intracamerally for example in a long-acting device. And then, you mentioned the antifibrotic activity. It does inhibit the activity of fibroblasts. When we do glaucoma surgery, our big enemy is scar tissue formation and rho-kinase inhibitors do prevent the transformation of fibroblasts to myofibroblasts and that’s a very important step in the scar tissue formation process that we don’t want after a trabeculectomy for example or even after [00:05:49] surgery. So, there are studies that are ongoing to look at the antifibrotic activity of rho-kinase inhibitors to see how that might be something we could take advantage of clinically to help improve our surgical outcomes.
Host: Are you typically using them alone or combined with other known ocular hypotensive medications doctor?
Dr. Tanna: Well, because of the side effect profile, there are substantial side effects with netarsudil mainly conjunctival hyperemia, some patients complain of blurry vision, pain, tearing. Because of these adverse effects, we tend to not use them first line or even second line. So, the most common place in my practice for rho-kinase inhibitors is for patients in whom we really are trying to get the pressure down in order to avoid having to do surgery. So, these patients are already often on many medications. That’s the primary use at least in my practice. There’s occasionally the rare patient in whom we’ve tried everything else and nothing else works and we might try a rho-kinase inhibitor. But that’s pretty uncommon.
Host: Do you have any new data to share from your continued research in this area?
Dr. Tanna: I do. So, we’ve done a retrospective study at Northwestern to look at all of our patients who have been treated with a rho-kinase inhibitor to see outcomes in terms of intraocular pressure and how well tolerated these drugs are. And we’ve submitted some of this stuff and it will be presented at ARVO this year in Baltimore in May. But we have some additional data that is not part of that abstract that I can share.
So, we looked at the pressure outcomes in patients in whom a rho-kinase inhibitor was added, specifically netarsudil because that’s all we have in the United States, after we had two baseline measurements. So, we only looked back at the patients in whom we had two measurements on different days of patients who are on a particular medication regimen. And once we added the netarsudil, we had to have one other pressure measurement. So, because if you look at patients in whom you only have one intraocular pressure and then one post treatment intraocular pressure in a retrospective study like a chart review; you have a problem with regression to the mean. So, what that means is, when we start a new medication on a patient; oftentimes it’s because the pressure just happens to be higher than we want that day and sometimes, it’s just random fluctuation. So, when the patient comes back for the next visit; just by chance, they are more likely to have a lower pressure because they go back to what they usually run at around the mean.
But by restricting our analysis to patients in whom we had two baseline measurements on two separate days; we reduced the confounding effect of regression. So, we have 307 eyes of patients in whom we added Rhopressa, netarsudil after two baseline measurements on a stable intraocular pressure lowering regimen and I’m going to focus just on the 86 eyes who were on three medications and 63 eyes that were on four medications prior to starting netarsudil. And what we observed in those two groups was a 2.9 millimeter of mercury reduction for the patients who were on three medicines and a 2.7 millimeter of mercury reduction for the patients who were on four medications before we started netarsudil. And the P values in both cases are very low. The P values are 0.0001 or less for both of those groups.
So, since we have a lot of observations and since the effect seems to pretty uniform; we high statistical significance that you get almost a 3 millimeter of mercury additional reduction of IOP on average in those patients who are already on multiple medicines. So, this is new information. We already have a lot of information in the published literature of how netarsudil works when you add it to a patient who is already on latanoprost because that’s part of the clinical trials that have been done in preparation for FDA approval for the fixed combination of netarsudil and latanoprost. That’s called ROCLATAN, so we don’t really have any evidence in the literature about how these drugs behave when you add them to existing regimens. Especially the commonly used regimens of three or four medications by the time you add the netarsudil.
So, I think that when we finally publish this, it will be very useful, new information that people will be able to take advantage. So, that’s a pretty good effect an extra 2.8 or 2.9 to 2.7, that range additional IOP lowering.
Host: Dr. Tanna, as we’re discussing the clinical impact of your projects and how you see it transferring to patient care; taken together, how do see the rho-kinase inhibitors having a broad theoretical therapeutic potential in glaucoma? Where do you see this going in the future?
Dr. Tanna: Well, if ophthalmologists know ahead of time that they can expect basically a 2.5 to almost 3 millimeter of mercury additional IOP lowering by adding netarsudil for patients who are already on three or four medications, and that’s on average by the way, so some people do even better; I think that that’s pretty encouraging and that would make it so that at least people would try this drug and what I found is that in about a quarter of patients, the drug really isn’t adequately tolerated and the patients don’t want to keep using it. But in something like half of the patients, we see a reasonable to excellent IOP lowering effect and tolerability of the drug, at least for the one year range. And I think so it can be used clinically to help at least delay and maybe avoid incisional surgery.
Host: As we wrap up, what would you like other providers to know about the class of rho-kinase inhibitors and optimizing treatment for patients and what you’re doing at Northwestern Medicine.
Dr. Tanna: Well I’d like people to know that if they prescribe this drug that they should expect a pretty large proportion of patients to have adverse effects. So, the physician really has to prepare the patient for the possibility of side effects like conjunctival hyperemia, blurry vision, pain and teary. I tell my patients that if they experience symptoms that they can’t tolerate, to go ahead and stop using the drug and to let us know and that they can expect resolution of the symptoms fairly quickly, usually within a day or two.
I also think that physicians need to know that even for patients who are on a lot of medications, three or four medications; there are some individuals in whom a pretty profound IOP lowering can occur with this drug. It’s not common, it might be 15% or so in whom the pressure might drop by 40%, but among the patients who can tolerate the drug and among the patients in whom such a big pressure lowering is realized; it is a very favorable effect for the patient. It does lead to the possibility for example, of preventing the need for incisional surgery.
The other thing that’s important is the cornea as it pertains to rho-kinase inhibitors. Physicians know that a common side effect associated with the use of rho-kinase inhibitors is cornea verticillata. There’s also another corneal abnormality that has been observed and has been reported at the Academy there was a group that reported a corneal endothelial abnormality that occurs with the use of Rhopressa. And we’ve observed this as well. We’ve seen with specular microscopy that at least in two patients that we have, that the normal hexagonal shape of the corneal endothelial cells can be lost and there’s irregularity of the corneal endothelium in these patients that can even be visualized with slit lamp biomicroscopy. So, although it’s rare, or at least very uncommon, we’ve also found it’s reversible. We found that in one patient when we discontinued the netarsudil by two months, which is the next time we looked; specular microscopy showed normal corneal endothelial cells.
So, that’s something to be aware of on the horizon. There might be an effect on the cornea that we have to be aware of and in terms of the long-term effects of this, I think we know from the clinical trials that it’s unlikely that there’s any long-term safety effect related to the corneal endothelium. But it’s another thing to keep in mind and that we likely will be getting more information on the horizon.
Host: Thank you so much Dr. Tanna for joining us today and sharing your incredible expertise. This is Better Edge, a Northwestern Medicine podcast for physicians. To refer your patient or for more information on the latest advances in medicine please visit our website at www.nm.org to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Northwestern Medicine podcasts. I’m Melanie Cole.