Lecture: Targets of the Medication Pipeline: New and Emerging Glaucoma Treatments

During this live webinar, we will discuss newer therapeutic agents for the treatment of glaucoma. We will also discuss newer drug delivery methods as well as drugs/delivery methods in the pipeline. Questions received during registration and during the webinar will be discussed.

Lecturer: Dr. David Sola-Del Valle, Massachusetts Eye and Ear, Assistant Professor of Ophthalmology, Harvard Medical School, USA


Dr. David Sola-Del Valle: Good morning, everyone, at least for those of us joining from this part of the world. I’m in Boston, Massachusetts. Hopefully, you can all see my screen. David Sola-Del Valle. I’m a glaucoma specialist at Mass Eye and Ear. I’m an assistant professor at Harvard Medical School. I would like to thank Cybersight and Orbis for asking me here today. Today, I’ll talk about targets of the medication pipeline, new and emerging treatments. It’s a talk I’ve given a few times and I expanded it a bit for this talk today and I look forward to walking you through it. First, financial disclosure side. I was a speaker for the Allergan Xen Gel Stent for three months and this lecture does not talk about that. First, I want to start with an outline of the talk. I’m going to start with the newer medications. Especially, those that are already available in the United States. The mechanisms of action, the effectiveness, the pros and cons, the side effect profile. And I’ll talk about the new delivery systems and focus on the one that is approved in the U.S. and emerging ones. I plan to share a success story in a patient of mine with whom I have used some of these things and achieved great results. In the last five minutes, I will talk about new targets for glaucoma therapy, these are IOP-dependent and IOP-independent therapies that are not available in the United States, but basically the future of what is to come. The first medication I want to discuss is netarsudil. It’s one of my favorites. It’s available in the United States but it’s been available here for five years. One of the great things about netarsudil is the mechanism of action. It’s a three-prong mechanism of action. The Rho kinase inhibition relaxes the trabecular meshwork and increases the outflow through the trabecular meshwork. Reduces fluid production. And something that is unique about netarsudil and netarsudil containing medications is that the Rho kinase inhibition lowers the scleral venous pressure. This three-pronged mechanism makes it a powerful medication. This is a summary of the randomized clinical trials that led to the approval of netarsudil. Keep in mind, these are randomized clinical trials so the conditions are perfect. And they’re comparing netarsudil to other medications when used as mono-therapy, so it may not be indicative of what you’ll see in the real world. But the IOP reduction went from 3.4 to 6.8 mm of mercury. I wanted to share this research article from my lab, we published this last year. The data I just shared came from a randomized clinical trial so I was curious to look at the data here at Mass Eye and Ear of patients who we started on netarsudil. In the real world now, we use netarsudil as an adjunctive therapy. As you may imagine, netarsudil — there is no generic version. It’s only brand name. It’s an expensive medication. Requires prior authorization or PA approval in the US. So we don’t use it typically as monotheraphy or first-line therapy. We use it as adjunctive therapy. This is what the article meant to study, what happened to the patients where we used netarsudil as a third, fourth, fifth or a sixth agent in attempts to avoid surgery. Even as an adjunctive agent, netarsudil is a very powerful medication. It with lower IOP between 2.84 and 3 mm of mercury. Again, this is a third, fourth, fifth, or sixth agent added. And something interesting that came out of our research, there is 10 percent of patients that we started on netarsudil that had very pronounced IOP lowering effects. We termed these patients super-responders and they have prolonged IOP lowering of at least 20 percent and IOP lowering of more than 10 mm of mercury. You can imagine that is very powerful as bringing IOP from 30 to 20 and 20 to 10. That makes a big difference in some patients. Granted it’s only 10 percent but for the right patient it can sometimes do wonders. As you know, no medication is perfect and netarsudil is not perfect either. There is a side effect profile to it. I think the main side effect that we always talk about and it’s the main side effect of netarsudil is conjunctival hyperemia or red eye. Between 40 and 60 percent of patients will have a red eye. That said, you hear this and you immediately think, oh my goodness, my patients with not going to like it, they’re going to discontinue it. But my experience is if you coach the patient through the hyperemia and red eye, this improves over time. Usually takes 3 to 6 weeks in my experience. It doesn’t hurt or cause discomfort to the patient. It’s more the thing that their spouse or significant other will notice and comment on. If you coach a patient through it, the discontinuation rate in my clinic is very low. Honestly, it’s around 5, 10 percent. Despite the fact that 40 to 60 percent will get a red eye initially. The other interesting side effect and this happens up to 25 percent of patients. It’s cornea verticillata. There is a picture of that on the screen. It’s something pretty to look at but it doesn’t really affect vision. There is no one to one effect on visual acuity drop. Netarsudil is not the only medication that can cause cornea verticillata. As you look at this slide here, I’m saying 8 percent of patients have a visual acuity decline, it’s not from the visual verticillata it’s from dry eye and the side effects of the preservatives and netarsudil. As a summary slide and I’m going do this — I did this slide for each one of the three newer agents that are available in the US. Things I like and things that aren’t ideal. The things I like about netarsudil is the dosing. When you have glaucoma patients, adherence to medication regimens can be the most challenging thing. The least amount of times they have to put the drops in, the better, the more adherent they’re going to be. So once a night dosing is phenomenal. It’s just like the prostaglandin analogues that many of us use around the world. Netarsudil seems to work well at the full range of the spectrum. I talked about the super-responders where you get pressure drops of 10 points but it works well in the normal glaucoma patients where we want to bring them from 15 to 11 or 11 to 9 sometimes if they’re progressing. It’s a useful medication. The other interesting thing about netarsudil and rho kinase inhibitors, can cause trabecular meshwork remodeling. I have had patients after two or three years have to discontinue it because they had a reaction and the preservatives caught up with the eye so to speak. And I had to discontinue the medication. I monitored them closely but their IOP stayed low. I think it has to do with this trabecular meshwork remodeling. That is something very, very interesting to keep in mind. I showed you with data that it works well as an adjunctive agent. In terms of coverage, these three newer agents are still not generic. They’re branded medications in the US. You can imagine they’re expensive. But I will say of the three agents, this is the better covered by all insurance companies in the US. You still have to submit a prior authorization or PA for short here in the US for a lot of insurance companies but usually it does get approved and it’s affordable for patients which is nice. The last thing that I like about netarsudil is in a lot of my pregnant and breast-feeding patients this has been a lifesaver. As you know, there are very few drops that are 100% safe in pregnancy. Usually, I use brimonidine as the only completely safe pregnancy medication. But I have a list of pregnant women who have done really, really well with rhopressa and on the breast-feeding side of things, usually rhopressa can be continued during breast-feeding and I have had success stories. This is something to keep in mind once netarsudil becomes available elsewhere in the world. Nothing is perfect. I already talked about the red eye. The conjunctival hemorrhage that can happen. Scary looking but not dangerous. Don’t cause pain to the parent. But it’s something that other people look at and some patients may not be happy with it. An interesting side effect that I didn’t touch on is this reticular epithelial edema. I have pictures here showing that. This is especially true in patients with a compromised cornea, patients who had a corneal transplant, they are more prone to getting the side effect. The problem with the side effect opposed to the red eye is the patients do feel it. As you can imagine, it can affect, it does affect the quality of the visual opposed to the cornea verticillata which is less likely to do so. Things are not ideal, it’s a brand name. It can be expensive but it’s improving. The cap color, this varies a lot around the world. But here in the US with our patients, a lot of our patients use the cap color. Teal or yellow but they don’t know the name. They say I’m taking the purple drop twice a day. The cap color here in the US is white and we have drops like prednisolone that also have white caps so it can lead to confusion. The last thing that is not ideal about netarsudil is because it’s a branded medication still, there is no preservative free option. For patient who is are allergic to preservatives which I have found is more and more common unfortunately, I usually have to discontinue it if they’re having difficulties with it. I’m trying to make this a little interactive. I gave you information and data on netarsudil. I was hoping to poll the audience with a question. And I think the Cybersight team is going to help me here. Which of the following is true regarding netarsudil? Has a twofold mechanism for IOP lowering. B, there is a one-to-one correlation between cornea verticillata and drop in vision after netarsudil initiation. Netarsudil may cause trabecular meshwork remodeling. Or D, hyperemia and conjunctival hemorrhages are the least common side effect of netarsudil. And I think we’re going to give you 30 seconds I heard from the Cybersight team. And then we’ll discuss the correct answer and why the other ones are not the correct answer. Perfect. Most of you got the correct answer, netarsudil may cause the trabecular meshwork remodeling which may have IOP lowering effect later in treatment. A is not correct because there is a threefold mechanism of IOP lowering. You have to remember the rho kinase inhibition. There is not a one to one correlation between cornea verticillata and drop in vision. Sometimes the cornea verticillata can be pronounced and the vision will stay the same. And red eye and conjunctival hemorrhages are the most common side effects of netarsudil. But great job. Most of you got that. So the second agent newer agent available in the US is netarsudil latanoprost combination. It has netarsudil in it so the first three IOP lowering mechanisms are the same as netarsudil. But then it has latanoprost, so it’s increasing the scleral outflow. This has a four-pronged mechanism of action. It’s a very, very powerful agent. I wanted to share this data from the mercury one and mercury two trials. Mercury one was 12 monthses and mercury two is for 3 months. They found the fixed dose combination of netarsudil latanoprost one bottle one drop was superior to the individual components. Patients taking a drop of latanoprost and netarsudil had higher IOP than the patients taking just one drop combining the two. I thought that was a powerful statement. The IOP lowering was up to 3 mm of mercury better with the combination. For me this was unexpected because you would think it’s only one extra drop, people should be able to do a good job placing one drop and then another five minutes apart. But one extra drop can be — for some patients and you may lose some effectiveness. It speaks to how powerful this medication can be, the fixed dose netarsudil latanoprost combination. This is a summary of the randomized clinical trials that lead to its approval. These are perfect conditions. Randomized clinical trials. Here we’re looking at monotherapy which is very rare nowadays because this is just a brand name. But still the IOP reduction in these randomized clinical trials is between 5 and 8.6 mm of mercury which is very powerful IOP reduction. The things I like and things I don’t like. The main thing I like is it’s extremely powerful medication. We’re mixing latanoprost which most of us use as a first-line agent around the world because it works and has a good side effect profile and only one time at night. And you’re mixing it with another very powerful medication, netarsudil. I love that it’s one drop at night. You can’t beat that. just like netarsudil, it works really well for the full range of the IOP spectrum. The main problem I found in the United States is because there is no generic version and insurance companies can make the argument, well, latanoprost is covered and netarsudil is covered, have the patient use two. It’s hard to get coverage for it, it’s hard to justify the high price of the insurance. You to do a prior authorization or PA for short. It’s extra work for your staff and hard to get it approved and even when it’s approved, it can be very expensive. And the other thing is you’re combining two drops and getting the side effect profile from two medications. I talked about how 40 to 60 percent of patients on netarsudil alone had hyperemia, conjunctival hemorrhages. You’re going to go upwards of 60 percent in terms of hyperemia when you give the combined medication. If you coach them through it, it’s doable but it’s something to keep in mind. The other thing is you’re adding a prostaglandin analogue. In patients that you expect the prostaglandin analogue caused edema or inflammation, you may not want to use this medication. I talked about this, about the cap colors in the US. But the cap color here is also white so that leads to confusion. Netarsudil and others can have white caps. There are a lot of different medications that have the same color cap and for some patients this can be confusing. Because it’s a brand name, there is no preservative free option available. So this is the question regarding the fixed-dose combination of netarsudil latanoprost. I wanted to point out this question is about which one of these is false. The last one was which is true. Which one of the following is false. No. 1, netarsudil latanoprost has a four-fold mechanism for IOP lowering. B, netarsudil latanoprost side effects include conjunctival hyperemia and cornea verticillata. Netarsudil latanoprost allows for substantial IOP lowering with once daily dosing. And netarsudil latanoprost was shown to have less side effects than latanoprost. Which one of these four is false or not true. Again, we’ll give you 30 seconds to answer and then we will go over, we’ll go over the responses. The Cybersight team will let me know when everyone is done and we’ll review what you all said. Perfect. Most of you thought the right answer which was the last one. I will review this for everyone. No. 1, netarsudil latanoprost does have a four-fold mechanism of action. Remember, netarsudil has a three-pronged mechanism of action and you’re adding latanoprost so it works in four different ways. The side effect profile is similar to netarsudil because it has netarsudil in it. It does have the side effect profile of redness or hyperemia. Allows for substantial IOP lowering. I showed you data from mercury one and two trials showing the combination is even more powerful than the individual drops used together. And the one that is false is the last one because netarsudil and latanoprost both cause hyperemia so you have a higher likelihood of getting a red eye when you combine the two. So it’s not a surprise. Very good. Even is doing great. Most of you got the right answer. The third and last newer agent that is available in the United States is latanoprostene bunod. A lot of you may have heard Zulfa. It’s a prostaglandin analogue with a nitric oxide donating part to it. That allows for the scleral increase outflow that we know prostaglandin analogues can do but it increasing the outflow through the trabecular meshwork. This theoretically should be a more powerful medication. Again, this is a summary of the clinical trials that led to the approval of the latanoprostene bunod. The randomized clinical trials showed the IOP reduction in RTC, perfect conditions used as monotherapy which unfortunately is not real life. Showed that it lowered IOP between 2.5 and 9 mm of mercury. Again, a very powerful medication. We know that prostaglandin analogues are powerful and then you add in this nitric oxide component to it. This was not a surprise. Things I like about latanoprostene bunod, we expect it to be a powerful drug, and you’re adding something that is supposed to increase the mechanism of action and now it’s a twofold mechanism of action. It’s one time at night. That is something that I love about the three newer agents, only one drop at night. In terms of adherence, you can’t get better than that. These statements I’m going to make now are controversial, but it can have benefits like potentially anti-inflammatory, patients have done well with this medication when I put them on it. I will show you a patient in a second in whom I used this medication. Even though hyperemia can still be the No. 1 side effect, in fact, it is the No. 1 side effect, it’s slightly less than latanoprost and other prostaglandin analogs. So it’s something to keep in mind for patients that may not tolerate the red eye. Things are not perfect. The main thing glaucoma specialists in the US are caught on, is at least when we look at the voyager trial, you compare the approved latanoprostene bunon to latanoprost, it only did 1.23 mm of mercury additional IOP lowering. For some patients that may be great. Every mm of mercury matters. But at the end of the day, it may not make a big difference. When I have a patient who has a pressure of 20 and they need to be 12 because they are an advanced glaucoma patient, I’m not going to bother to try this because it’s not going to get them there. But I have had some surprises with some patients so keep that in mind. The main problem is, considering it may not be as powerful compared to latanoprost as we thought when we talked about the dual mechanism of it, the cost remains high with most insurances in the US. There is no generic, the P As, the prior authorizations are convoluted in the US. Many times they’re denied because the data shows that it may not lower IOP that much. That’s the main problem right now. So third question regarding latanoprostene bunod, which one of these is false or not true regarding latanoprostene bunod. Which of the following is false regarding this drug. It’s a nitric oxide donating molecule increasing trabecular mesh workout flow. It’s closely related to prostaglandin analogues and has latanoprost as one of the metabolites. Ocular hyperemia is the most common side effect. Or D, provides substantial IOP lowering over latanoprost more than 5 mm of mercury. Again, which one of these four is false or not true. And we’ll give you 30 seconds to answer and I’ll let the Cybersight team let me know when everyone is done and we’ll review the answers to the questions. Perfect. Everyone has been paying attention. Latanoprostene bunod showed it can give you up to 1.23 mm of mercury over latanoprost. There is no good data that states it can give you more than 5 mm of mercury. The others are true. I talked about the nitric oxide donating part and how it can explain the extra mm of mercury because it’s increasing trabecular meshwork out flow. It’s closely related to prostaglandin analogues and latanoprost as one of the metabolites and that may explain why in the Voyager trial you only saw that extra 1.2 mm of mercury because it’s in the same family. You can sometimes get less hyperemia or redness with this medication versus latanoprost, but it’s still the most common side effect of latanoprostene bunod. I love this table. This summarizes the mechanism of action of basically all the glaucoma medications available around the world which are the first four or five. But it also adds the three newer agents that are now approved in the U.S. And I love the summary goes through the four possible mechanisms of action and tells you which ones work with which medications. As you can see, of all of them, the most powerful is the fixed combination netarsudil latanoprost because it has the four-pronged approach to IOP lowering. Now, moving onto a drug delivery. Most of us around the world still use eye drops. That’s the main way. But I think the future of glaucoma is headed towards trying to find better ways of delivering our drugs and finding better drugs and I’ll get there, too. This is the first FDA approved sustained released drug implant for glaucoma in the U.S. It’s sustained release bimatoprost implant. It’s delivered by an intra-cameral injection. It’s approved for one-time administration. The company is trying to get approval now for a second dose. As of right now, for most patients, the average of IOP lowering is between 4 to 6 months. And I have seen some data at the American glaucoma society meeting where they looked at patients who got more than 3 and there is some concern that some patients may lose cells from three or more injections of this sustained released bimatoprost injection. For some patients it may do wonders. I will say before I go on, the average is 4 to 6 months, that is true. But in the trials, about 25 percent of patients had IOP lowering up to do years and I’ve seen that in some patients. In fact, I’m going to share that. In some patients it may do wonders to keep that in mind. One of the things I love about the sustained release bimatoprost is it’s a preservative free medication and it doesn’t involve drops. It’s a 30 second injection in the clinic and it can last on average 4 to 6 months or maybe two years if you’re lucky. So you don’t have to deal with the medication adherence problems. In some patients I had better than expected results and I’ll share one here. And sometimes I see that the bimatoprost implant may work better than the topical or better than multiple medications. I had patients on latanoprost and Tim roll and I got the same IOP lowering or better. In some patients you can get amazing results. Nothing is perfect and I consider myself a charming glaucoma specialists and some patients say I smile too much. But once I mention needle injection in the eye some patients get squirmish and that is understandable. I try to minimize it. It’s a tiny needle and it takes 30 seconds. But again, it’s a hump to get over with patients. The coverage situation, none of these are generic so getting insurance coverage can be challenging but it has been improving a lot recently. Starting January 2023, I have seen a huge improvement in coverage. Most of my patients are now eligible for the sustained release bimatoprost implant. So I’m doing more of these than I was in the past because the insurance wasn’t covering and it was expensive. But it’s only one time. If you get unlucky and it only lasts two to three months, which again the average is 5 to 6. You may have an unhappy patient because you’re stuck at the beginning and going back to the drawing board. Usually by the time you’re talking about sustained release bimatoprost, you’ve tried drops and other things. So it might be a stopgap between the drops and surgery. If it just lasts 2 or 3 months and the pressure goes up, you can’t do it again. It’s not FDA approved. You could have the patient pay out of pocket but not ideal because it’s very expensive. Something to keep in mind for the future, as I said the company is trying to get FDA approval for a second administration now but there is data when grow to three or more administrations you may end up compromising the endothelial cell count because of how close the pellet is to the endothelium. That can be an issue and something to keep in mind. So I think this might be the last question of the day. Which of the following, again, is false regarding the sustained release bimatoprost implants. Which is false, not true. It’s IOP lowering effects, typically, last 4 to 6 months on average. Endothelial cell loss may be the primary contraindication for multiple injections because of the proximity of the drug pellets to the corneal endothelium. C, the bimatoprost implant is delivered by an intra-cameral injection and it’s the first FDA approved sustained release glaucoma therapy in the United States. And the implant is FDA approved for multiple administrations. Which one of these is false and the Cybersight team is giving everyone 30 seconds to respond and then we’ll go over the answers. I don’t think I said the brand name. It’s Durista. Some of you may have heard that but I’m trying to stick to the generic names. Most of you, thank you, you’ve been listening to what I’m saying. The false one is that currently in the United States the FDA has not approved it for a second administration. Everything else is true. Typically, the IOP lowering effects will last 4 to 6 months. In the future, especially for 3 or more administrations, we may have to think about endothelial cell loss especially in patients that are prone to that. It’s an intra-cameral injection and I showed you pictures of that on the last slides. You guys are doing amazing. I wanted to share this success story. It’s all nice and good when we talk about randomized clinical trials and data but how can this work in a patient. I want to show you this very cool case. I followed this patient now from 2018 until yesterday, actually. Very auspicious that she came to clinic right before I was giving this talk. I followed her from ages 62 to 67. Caucasian woman. Has been a nurse for the last five years. About to retire. Moderate to severe NTG. This is her visual field from 2020. I’m focusing on the left eye for simplicity. Had a toric ICE1 procedure. That is cataract surgery and photocoagulation. That is one of the CMIG procedures and I do now the ICE2 procedure. She had that in 2017. Tried all the available drops. They were all ineffective or she was allergic to them. She had SLT and an ICE1 procedure, she was surgically avers. She was not excited about it. Her TMAX was 19. When I met her, her pressure was 14. IOPs between 14 and 19, it’s clear to me that she needed lower IOP. I wanted to bring her down to 10 if possible and lower it by 30 percent. At that point there was a new drug, this is back in 2018, at that point she was 62. She still had private insurance. She had been added to Medicare which is the healthcare we have here in the United States for the elderly. And so I started her on latanoprostene buton and she did beautiful until 2021 taking one drop at night. And got the IOP down to between 9 and 10. And the vision stayed stable. And then 2021 came and she turned 65. For those of you know how the U.S. healthcare system works, it’s convoluted and complicated, she turned 65. She got on Medicare and Medicare refused to cover latanoprostene bunon. I wrote letters. My staff did everything and we couldn’t get her approved. She was allergic to everything else. But Medicare approved the sustained release implant and I consented her and said this may only last 4 to 6 months. I did the implant in the left eye on April 9, 2021. I just saw her yesterday. Her pressure is 7 off glaucoma medications and she has a stable visual field. So it goes to show you for some patients the implant can do wonders and this is a perfect example where two years out from the implant and she couldn’t be happier. Her pressure is where it should be, fields are stable, not taking drops. This is a happy camper. I do have some patients like this. This is something to keep in mind. The newer therapies and the delivery systems can sometimes do wonders for the right patient. There’s other potential delivery methods. I’m not going to go into a lot of detail because none of these to my knowledge are FDA approved. I will mention the ocular ring, I think this is the closest to getting FDA approval. It’s a silicone polymer matrix insert placed on the surface and you can see in the picture how this looks. In the phase to trials when they looked at open angle glaucoma patients, it lowered IOP around 20 percent from baseline over 6 months. When they compared patients that received timolol twice daily, the ring wasn’t as powerful. I think this is a cool idea. Of all the things I looked at, I think this might be the closest thing outside of the eye dose which I didn’t include in the talk today. And then this medication is also not approved in the U.S. It’s an IOP lowering medication. It’s only approved in Japan. And it’s the omidenepag isopropyl, OMDI for short. It’s close to getting approval in the United States. I’m excited to try it. First of all, it’s shown to be non-inferior to latanoprost with a mean reduction of 6 mm of mercury. It’s a non-prostaglandin, prostanoid EP2 receptor metabolite. So it doesn’t have the side effects that we don’t like about latanoprost. Like periorbital atrophy, uveitis or sis toyed macular edema. Some of the things that the prostaglandin receptor activation is doing with latanoprost this drug won’t do and might work just as well in terms of IOP lowering. It’s not FDA approved to my knowledge. The last five minutes of the talk I’m going to leave you with research from my lab and Dr. Margeta’s lab. She is a basic science translational researcher and a wonderful clinician. And she and I have teamed up to look at Galectin3 inhibitor. There is a nice publication in immunity from her lab. Showed that intra-vitreal injection of this protects the retina and optic nerve from the degeneration in the setting of high IOP in mouse. This is the first IOP independent treatments for glaucoma which would be fabulous in my opinion. Basically, in her publication and there is a copy here, she showed that microglia, the resident immune cells and retina and optic nerve switched from a normal state to a neuro degenerative phenotype in glaucoma. Apoe3 induce galectin37. And interestingly, the mice that have the Apoe4 allele were protected against retinal ganglia cell lost. The APOE3 is inducing galactin3. From my standpoint, teaming up with her, we published this last year and we showed that in humans, human patients with glaucoma, galactin3 and apo lipoprotein are elevated. These are patients undergoing cataract surgery or cataract with glaucoma surgery with me and we collected their — and compared the two and saw that glaucoma patients had elevated both galectin3 and APOE. We did not sort them according to alleles but interesting result. We found that galactin3 and apoE were possible associated and apoe drives galactin3 elevation. How do you know that total protein is not responsible for the total elevation. We looked at the total protein and found no correlation. We also showed that both galectin3 elevation and apoe elevation is associated with the maximum — in the chart and that is an indication of sicker patients. Some take home points, first, we have powerful new medications, especially netarsudil in my opinion. And their used may be limited by side effect profile and insurance coverage but for some patients, it will do wonders. We have the sustained release implant as you saw with my patients can sometimes do wonders for some. One time administration, they’re working on the second administration. We’ll have to be careful with three or more administrations. Hopefully I showed you there are many things in the works in terms of delivery systems. I’m excited about the OMID. And I’m really excited about the idea that in the future we won’t have to worry so much about the numbers per se in glaucoma, because we’ll have some IOP independent medications that protect the optic nerve from elevated pressure. For those of you who hopefully I was trying to speak slowly so everyone can understand, but I wanted to talk about this article that we published last summer in glaucoma today. It’s a summary of this talk if you want to think of it that way. Zoe my scribe has been accepted to Harvard Medical School. I’m very proud of her. She helped write this article and it’s available online for free. If you want more details, this can be a good source. I want to thank everyone for sticking with me for the last 45 minutes. Special thanks to Dr. Margeta and Theresa Chen and Lucy Shen I’m seeing questions pop up. You can use my email. I would be remiss not to thank Dr. Helwe who is my research fellow from Lebanon and he helped me put together this presentation. And Falah. Feel free to reach out to me. I also would be remiss if I didn’t acknowledge my donors and collaborators. These are all patients or foundations who have supported my research and Dr. Margeta’s research. I couldn’t do what I do without them. So thank you so much. I’m going to stop sharing and I think there are some questions popping up. I’m going to go there now. We’re going to go one by one. This is what I did last year and hopefully that will work this year. The first question, what is your first line glaucoma medication for primary open angle glaucoma or primary open angle closure glaucoma. My first line agent is still latanoprost. It’s a combination of reasons. First, the one time at night dosing is fantastic. It’s still a very powerful medication and well tolerated. You get the most bang for your buck, that’s the way I describe it to patients. Obviously, there is a nuance to glaucoma. You have to think about blue-eyed patients or light eyed patients, warn them about the possible changing of the iris color. Patients who had maybe uveitis episode with latanoprost, you have to be careful. Sis toyed macular edema you have to be careful. For most patients, even angle closure patients, latanoprost can do wonders. Primary angle closure you have to, in my opinion do an LPI or cataract surgery first and open the angle. But even in the acute setting, after you did an LPI and try to temporize it before you remove the cataract, you can use latanoprost. So that’s still my first line. In the future, though, I will say, I’ve done some interviews about, this same topic, new targets in the medication pipeline? Student: They asked, would you do netarsudil as a first-line agent. Once there’s a generic form and a preservative free form, I think netarsudil might be maybe first line for me honestly over latanoprost. But again, it’s not just the reality. Latanoprost is still first line. What is your frank assessment of SLT as primary treatment. I published an article of this in the journal of ophthalmology. Again, I think for the right patient it’s a good treatment. I tend to still offer it to patients in the mild to moderate stages according to ICD10 criteria. Patients with elevated pressure, I think that is key. And my experience it doesn’t work well if your pressure is not elevated but if you have elevated pressure, IE, pressure over 21 and you’re in the mild to moderate stages and haven’t had ALT once or SLT once. I think SLT works beautifully. The article that my lab published in 2020 looked at 360 degrees of SLT and we found that 360 had more ILP lowering. Perhaps that is why I’m seeing better results than other people. I like to see Champaign bubbles in my shots so I go up in power depending on the pigmentation of the TM so I can get a good affect. The paper that we published in 2020, we looked at whether pigmentation correlated to IOP spikes than 180 and we did not see that. We looked at 300 or 400 patients. So my frank assessment is for the right patient it’s a wonderful drug. >> What are contraindications to the bimatoprost implant, can it be removed if found to be unstable in the AC? I would not do a bimatoprost implant — if there is any chance that implant is going to migrate to the posterior chamber, I would not do it. That said, I have done on pseudophakia patients. If they’re patients where you’re thinking that the zonules are going to be unstable, you can still do it in pseudo-phakia. I have been doing sustained release in patients that already tolerated some sort of prostaglandin analogue. I know they didn’t do well with latanoprost but doing well with tafluprostin that givers me hope that putting the implant in the eye won’t cause problems. I avoid it in patients where you know the prostaglandin analogue caused problems. I have some patients that are on latanoprost and the macular edema is worse and it’s a one-to-one correlation, in those patients I wouldn’t do it. I’m going to make the macular edema worse. Same with uveitis. In a patient whom you tried some prostaglandin and they did okay and they’re trying to get off the drop or they don’t like the preservative or can’t afford the others, I think those are the perfect patients. But in patients who did well on the latanoprostene bunod or doing okay on latanoprost timolol, the implant can be as good as two medications. I’ve never found, so moving onto the second part of the question, can the implant be removed if unstable? I have never found it to be unstable. Usually it falls, I see patients two weeks after the sustained release implant. Every single time it’s fallen down and stayed stable. I know they’ve told me it can be removed if I need to. But I’ve never had to do that. Is bimatoprost implant available in Asia? I don’t know. I’m happy to try to ask my implant rep and see. But the short answer is I don’t know. I apologize. What other conditions when you need to remove the implant? I haven’t had to yet, thankfully. I’ve been told it’s basically an anterior chamber wash out which I have done a lot of as a glaucoma specialist in the U.S. I don’t think it would be hard but I haven’t had to do that. Maximum, how many eye drops can be used before going to surgery? Great question and I think it depends on you and the patient. In a way it’s a very controversial question because it depends who you ask. Some of my colleagues here, if a patient is on three drops they go to surgery. I trained at — where I did my fellowship, I learned this, he said, David, you want to exhaust every possibility before you take a patient to surgery, that way the patient knows you tried to avoid surgery and if there is a complication they won’t hate you for the complication. That usually is what I try to do. If a patient has elevated IP or progression, I try to maximize tolerated medical therapy before going to surgery. But again, it depends. Some patients are honest and say, I’m not going to take a fourth drop. This is not going to work so what are the options. Okay, we can do surgery and these are the risks and benefits. It’s about your preference, patient preference, having great communication with the patient and consenting the patient appropriately before you proceed to surgery. This is a four-prong question. I will go one by one. What eye drops should start first line treatment of glaucoma. That was answered previously. I start with latanoprost and down the line once netarsudil is generic, that might be my first line. The second line now is brimonidine. Latanoprost is also thought to be neuro protective. And it depends on the patient characteristics. No. 2, if the patient disk is .5 to .8, IOP normal. Should we start AGM or what? I’m not sure what AGM is. I will say, I don’t necessarily guide myself too much by the ratio. I’m more of a fan, I try to be a stickler for staging my patients and each eye of each patient. I typically stage it mild, moderate, severe glaucoma. For me, a mild glaucoma patient has a thin nerve on OCT but a full field. Moderate is a visual field deficit superior or inferior but not in the center that corresponds to the OCT and the nerve. And severe is someone who has a para central defect or interior and superior defect. As you can imagine, the mild glaucoma patients who also tend to have smaller ratios but there is not always a one-to-one correlation which is why I’m hesitant to hang my hat on the ratio. The mild glaucoma patients I’m less aggressive with and the advanced ones I’m more aggressive with. I have seen a lot of patient disc is suspect and VFA is normal, IOP normal. What do we do with that type of patient. That’s so tough. Because OCT for me is so crucial. I have seen so many patients progress in OCT even at normal pressures before they have any visual field deficits. So I would say do everything you can to get an OCT. And outside of that, I think look at risk factors. If you don’t have an OCT and cannot get one in the future, then I would try to rely on family history. Do they have first degree relatives that went blind at normal pressures: A thin cornea. At that point you do have to rely a little on the cup disc. If you feel it’s suspicious, treat more than not treat. And monitor closely with the visual field. Not having an OCT, I’m very privileged to be at Boston and Harvard and we have the latest technology, I would find it very hard to practice without OCT. Both eye disc is 0.9 and IMSC, can we plan cataract surgery first. I’m not sure what IMSC is. If I understand the question, if you have an advanced glaucoma patient, can you do cataract surgery first? It’s controversial. I have some colleagues who will do cataract surgery by itself if the pressure is okay on drops. I’m in the camp that if you have advanced glaucoma, especially by visual field, OCT and ratio and you have a cataract, even if you’re controlled you should get a combined procedure. There are a lot of options in the United States. Maybe where you are you can only do Trabs. But in general if you can offer at least some glaucoma procedure to a patient who is on multiple drops and undergoing cataract surgery, that’s the thing you should do. Feel free to email me if you have follow up questions. What’s the maximum number of anti-glaucoma medications you use before performing glaucoma surgery. It depends on the patient and depends on the surgery. I answered this. I’m going to move on. Netarsudil can be given in inflammatory or secondary glaucomas? Yes. There is no contraindication using netarsudil and an inflammatory or secondary intravascular glaucoma. It can work well. The paper that we published last year looking at adjunctive therapy using netarsudil, the super-responders, I said the top ten percent of those patients are super-responders. Got a lowering of 10 or more. They did great. The other thing I will say about netarsudil that I didn’t touch on in the talk is my cornea colleagues have seen that sometimes it can help — corneal edema. The retinal colleagues have seen that netarsudil can help with macular edema. In the future netarsudil may be the first-line therapy if we can coach the patients through the hyperemia. The short answer is yes to all. Thank you. I appreciate that. What is your first line medication for an NTG patient. Still latanoprost. And I think this was maybe controversial in the past. But I remember having David green field come over and really hit the nail on the head. Latanoprost is also neuro protective and the first line. I would still go for prostaglandin analogues. Netarsudil may release latanoprost in my mind I think netarsudil may replace latanoprost in the future. But as of today, latanoprost is my first line assuming no contraindications. Can you comment on the use of PGAs in pseudo-phakics especially with the use of Durysta and Eybelis. So we still don’t have that in the U.S. At least not commonly. But anyway, I would say when it comes to durysta, I use them routinely in pseudo-phakic patients. I think it’s controversial whether they cause macular edema. I have seen some but I have patients that have macular edema and they do great on the prostaglandin analogues. If I have a history and patient where I saw a one to one correlation where it led to macular edema, of course I will avoid the prostaglandin analogues in the patient. I don’t want to inject a pellet that is going to worsen the vision. Once in a blue moon, I work with those patients and work with the retina specialist and they help me control the macular edema, or diabetic macular edema so we can keep them on the prostaglandin. Sometimes the pressure is doing great with the prostaglandin. If I take them off, the next step is surgery. Say advanced glaucoma patient and sometimes when I chat, this is why it’s important to obviously have smart colleagues you can work with. But sometimes I will chat with the retina colleagues and say the next step is a tube or a trab and they can increase the risk of macular edema. Should we just keep the patient on the prostaglandin and treat the macular edema. And sometimes they works well. Especially if you have a functioning tube. I published an article two years ago showing that intra-vitreal injections can help. Sometimes I leave them on the prostaglandin with the tube and give injections to treat the macular end. I think with pseudo-phakic you can do it. I’m excited to use it and I would use. It’s a non-prostaglandin receptor activator. I think the chances of getting into trouble are less than with the prostaglandin analogues. SLT for POAG. I talked a lot about this. I will answer the second part. Can you use it as first line, the answer is absolutely yes. There is great data showing that SLT can be used first line. I have offered it to patients. Some patients are still reluctant to pursue this first line but I think it can be offered. There is great evidence it works, it works better when you use it second line. The main problem is convincing patients to go for that instead of a drop. Despite me being a charming Harvard professor, they still want to try the drops. But for the patients that agreed to it, they have done beautifully and I would offer as first-line therapy. What is aphaloic patient — I don’t know — maybe they mean aphakic patients. I don’t know how to answer this question. I’m assuming they meant aphakia. You don’t have a lens on of the eye. They had cataract surgery and couldn’t place a lens safely in the eye. And they had pseudo-exfoliation glaucoma and a dislocated lens and it had to be removed. Feel free to email me. Vyzulta used in NTG can be superior. Yes, I think it is. The patient that I showed, my success story, the fact it’s a nitric oxide donating molecule makes it work better. I have seen that happen in a lot of patients where they weren’t well controlled with travoprost or the other prostaglandins and they did great with latanoprostene bunod. I think it’s worth a shot before you do anything else. Does the bimatoprost implant dissolve on its own or be removed surgically. It dissolves on its own and becomes smaller and smaller with time. I haven’t had to remove any surgically. One pellet has not been shown to cause damage to the endothelium or anything. You leave it alone after you inject it. In the case of acute angle closure crisis, what do you use? I use everything I can use. In an angle closure crisis, this is a situation where it’s a surgical treatment. You have to do a laser or LPI or remove the cataract to treat it. You have to temporize the patient to clear the cornea. Sometimes you can do the LPI or the cataract surgery safely. This is controversial, but for angle closure patients I use everything at my disposal. I have seen prostaglandin analogues work well. The key thing in angle closure, again, is if you have a steamy cornea that is swollen and cloudy, the medications aren’t going to penetrate. Sometimes you have to try to get rid of the steamy cornea first. I do it Dr. Ponberg style. Decompress the eye and hit them with drops and then do the cataract surgery. I use all of the medications that I can, including netarsudil and the prostaglandin analogues but angle closure is a surgical disease. I’m not sure I understand that question. If I didn’t get your question correctly, feel free to email. Do you use prostaglandin analogues as first line treatment in children. When do you stop? I trained and did surgery on newborns. In my practice I see children 7 and above. So I can only comment on that. I recently had a case of a 7 year-old with Doag and I used the prostaglandin analogues and had no problems. There is no contra indication in older children or younger children to my knowledge: I only see children 7 and above. But if you have high pressure, I think it’s worth a try. Anti-glaucoma medicine. Thank you for that. That wasn’t something I was, not something we use in the US. Can we use netarsudil and implant a congenital glaucoma. I haven’t used this myself. Most of my patients are 7 and older. We use it safely in pregnancy and with breast-feeding. I don’t see why you couldn’t use it. I don’t think the bimatoprost implant is approved for glaucoma. I can’t comment on that. What edge do prostaglandin analogs have over brimonidine in the treatment of NTG. I think the edge is that it tends to be more powerful in terms of IOP lowering and one time at night. That is why it’s still first line. I agree with you, brimonidine is second line: The side effect profile is better. So I think those are the three edges. Is there any relationship between intra-vortex vein pressure and progress in cupping in spite of good IOP control? Honestly, I can’t comment on this. It’s not something I looked at routinely. There might be, but honestly, I just don’t look at the intra-vortex vein pressure. I’m not sure, it’s not something I think about. I think when you’re talking about progression at lower IOPs, my approach is first make sure there is nothing else you’re missing. Sometimes I send these patients to the neuro ophthalmology colleagues to make sure nothing is missing. I look for disc hemorrhages. If I see one I know I’m treating NTG. And you have to remember pressure fluctuates in the eye. Up to 12 points in a day in patients with glaucoma. If you’re seeing progression at good IOP in the clinic, that can mean it spikes out of the office. The highest are usually midnight to 4 a.m. They are sleeping. That means they need more medication or need surgery to stabilize the eye fluctuations. How to manage neovascular glaucoma. First line anti-VEG F? It almost always is a surgical disease. In the short term, within a day or hours if you can get anti-VEG F in a patient with a tap to lower the pressure after you inject, that is helpful. You’re going to probably end up putting a tube or doing TPC. It’s good to try to do the anti-VEGF as soon as you can so do you don’t get as much bleeding with the procedure. In the short-term, yes, anti-VEG F. Once the cornea is not steamy, hit hard with all the drops you can and plan for surgery. I usually resort to a valve in these situations. What about intra-cameral implants? That’s the one that I talked about. That’s an intra-cameral implant. They’re great for the right patient. What are the special role in the NTG patients. What are the special role in NTG patients? I’m not sure I understand the question. We talked about NTG patients. It’s too broad of a question. If you have a more specific question, you can email me. I know, these medications are new and expensive, how do we get it from Africa or to Africa? When I was planning this webinar, this was brought up, David, can you try to make this as relevant as you can for the whole world. And trust me, if I could, I would just make netarsudil and all these medications available everywhere. Even in the United States we have difficulty getting it for our patients. I wish it wasn’t the case. I’m sorry, hopefully it will get there soon and I’m with you. Thank you, so much. I think those are all the questions. It’s been such a pleasure. Thank you, thank you, thank you. I think I’m giving another one of these in a couple months. Take care.

Last Updated: May 8, 2023

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