In this roundtable discussion, John Berdahl, MD, Michael Greenwood, MD, and Russell Swan, MD, discuss the data and mechanism of action of newly approved glaucoma drugs as well as what’s in store for glaucoma specialists in terms of combination medications and drug-delivery systems.
Dr. Berdahl: The more tools in the toolkit for the person treating glaucoma, be it a glaucoma surgeon or not, the better for patients. We are looking for the right drug for the right patient with the right side-effect profile and the right IOP lowering. Dr. Greenwood, any insight into what you think about new data on outflow drugs and what’s coming down the pipeline?
Dr. Greenwood: We’re going to learn with time how well they perform in real-life practice compared to study data, and we’ll also learn how well patients tolerate them. The one thing that differentiates one drop from another is sometimes the side-effect profile. I think these drugs will do well because a lot of the new medications are combination or multimechanism medications, and offering patients a single drop decreases the number of medications or number of drops they need to take, which increases compliance.
Dr. Berdahl: There are a couple of things that I’m excited about regarding new drugs. One is how these medications will do in patients that have lower eye pressures to start with, particularly Vyzulta (latanoprostene bunod ophthalmic solution; Bausch + Lomb). I wonder if, with its potential mechanism of lowering episcleral venous pressure, that will help us treat patients that have lower starting eye pressures to reduce pressure further.
The other thing that I’m excited to see is how these new medications will work in combination with MIGS procedures. For example, if you’re doing a trabecular bypass and lowering episcleral venous pressure, is there going to be a synergistic effect? We don’t know that yet.
Dr. Greenwood, would you share your thoughts on compounding and how that will fit into the treatment protocol?
Dr. Greenwood: Yes. Overall, I think it’s a great thing, because it provides more options for patients and, of course, for clinicians. The fact that compounded medications are also cost effective creates competition in the market, and could potentially make all drugs more affordable. And they’ve also been able to do it in a preservative-free manner, and that’s impressive because historically, medications have used preservatives, which cause ocular surface disease. Eliminating that has been a win for patients and for doctors.
I’m all for additional options for doctors and patients. And so, I’m very grateful for companies that take the enormous risk that comes along with getting a new molecule approved for the treatment of any disease. The amount of money and effort and risk that goes into getting a new molecule approved is tremendous, and that’s where real pharmaceutical innovation occurs. Compounding pharmacies put existing molecules together in sometimes novel ways, which can result in fewer medications and less cost for patients. Generics can also provide a lower-cost option that also helps our profession move forward and give patients a choice of care.
Dr. Berdahl: Dr. Swan, would you share some of the data on the new drugs?
Dr. Swan: Vyzulta is a combination of latanoprost and nitric-oxide-donating moiety, and the first study investigating it was the VOYAGER study. That was a drug concentration study, where they studied both 0.024% and 0.04%. In that sample size, the lower concentration achieved the same 9-mmHg effect as the higher concentration.
The study that has gotten the most attention with regard to Vyzulta is the JUPITER study. What was unique about this study was the baseline IOP for patients in the study was between 19 mmHg and 20 mmHg. They were able to get a 4-point to 5-point effect over a year.
The reason there has been a lot of interest is that this would be a great target for normal-tension glaucoma, in addition to primary open-angle glaucoma The effect of the nitric oxide on decreasing episcleral venous pressure could have some added benefit in patients with normal-tension glaucoma who otherwise can be difficult to treat and get below or at a target IOP.
We also have Rhopressa (netarsudil 0.02%; Aerie Pharmaceuticals), and its sister drug, Roclatan (netarsudil 0.02% and latanoprost ophthalmic solution 0.005%, Aerie Pharmaceuticals). Netarsudil 0.02% has unique mechanisms of action as both a Rho-associated protein kinase (ROCK) inhibitor and a norepinephrine transport inhibitor. These are both novel pathways that haven’t been explored in a significant way. Data from the Rhopressa ROCKET studies showed a similar effect to timolol.
The data from the MERCURY studies of Roclatan, which studied a combination of netarsudil and latanoprost, are also very interesting. The MERCURY 1 study showed a beneficial combination effect. Probably the most impressive finding of the study was the percentage of patients who had IOP reduction of greater than 20%. In the latanoprost group, this target was achieved in 78%, and in the Roclatan group it was 88%. Also, 65% of patients receiving Roclatan achieved a 30% reduction compared to 37% with latanoprost. Even more impressive, at a 40% reduction, which you just don’t see with medications very often, 35% of patients achieved that drop with Roclatan compared to just 9% with latanoprost. I think the combination effect and the fact that you’re seeing higher percentages than we’ve even seen with the gold-standard prostaglandin-alone therapy, are really encouraging. As long as we can keep the side-effect profile low in terms of hyperemia and other issues, this will be a nice addition to the market.
Dr. Greenwood: And the Roclatan data are impressive because it gives a lot of potential for big bang out of one drop, which again reduces the need for multiple medications, multiple drops and helps avoid compliance issues.
Dr. Swan: The next wave of trials will likely study combination therapies. Simple Drops (Imprimis) are preservative-free combinations of generic medications. In a recent study presented at the ASCRS meeting evaluating the safety, efficacy, and patient satisfaction of 72 patients who were switched from commercially available glaucoma drops to Simple Drops, uncontrolled patients previously on multiple medications saw an average of 2 mmHg additional reduction in IOP with Simple Drops. Of the 72 patients in the study, 68 preferred the novel combination medication regimen and rated an average of 8.4/10 on a satisfaction scale.
In the United States we can order combination timolol, brimonidine, dorzolamide, and latanoprost and have 1 drop that our patients use that has all 4 medications. I think you’re going to see more pressure on pharmaceutical companies to pursue similar combinations. Although we don’t always discuss it, probably one of the biggest issues in glaucoma is compliance, and compliance with complex drop schedules. The simpler we can make it by having more efficacious medications that are also combination medications, the better for patients. It is probably also inevitable that drug-eluting devices will be studied with combination drugs as we get more data and it becomes easier to study.
Dr. Berdahl: Let’s talk about drug delivery. The next step is to try to reduce issues with compliance. There are 2 approaches to delivery. There’s external delivery, like punctal plugs, the bimatoprost periocular ring (Allergan), and other external approaches, and then there are intraocular approaches like iDose (Glaukos), bimatoprost SR (Allergan), or the Envisia approach, which places a nanoparticle in the anterior chamber. Both approaches may not have the same efficacy of an eye drop, but in my opinion it should be close. Also, the durability is different between the 2 approaches. I would say the minimum time for an extraocular approach is 3 months to make it feasible clinically, and for the intraocular approach the minimum is 6 months. However, a year or more would be desirable. But if we can make sure that we’re getting the drug in a consistent way to the patient, in a way that’s not dependent on compliance, that would be a win for patients and a win for glaucoma specialists.
Dr. Greenwood: I agree. I think taking the compliance out of patients’ hands literally and figuratively is extremely important. The biggest revolution for retina specialists recently was anti-VEGF medications. And now the biggest hurdle for patients is they have to come in every month to get these injections, and that’s the worst part of their week. They don’t just worry about that day. They worry about that whole week because they have to travel, they have to get a shot in the eye. So, the goal is to reduce the number of treatments needed – up to a year would be best. If a therapy were available that was close in efficacy to a drug that works 24 hours a day, but the patient didn’t have to worry about taking it every day, and their pressures were not fluctuating throughout the day, that would be beneficial.
Dr. Swan: I agree the ultimate question with any of these sustained-release delivery devices is how long of an effect can we get. We do have some data on some of these devices. A study of the bimatoprost ring showed a 6-month drop from baseline of 23.9 mmHg to 18.8 mmHg in the 50 eyes that they tried. And Ocular Therapeutix has a travoprost drug-eluting punctal plug (Dextenza) that showed an IOP decrease of between 4.5 mmHg and 5.7 mmHg, which I consider a one-drop effect. It was outperformed by the timolol arm that it was being compared to, but 91% of patients still had the plug retained at 60 days. Retention rates dropped to 48% by 90 days.
Interim phase 2 results of a study of the iDose travoprost implant (Glaukos) from an available interim cohort of 74 patients, 49 of whom received an implant, and 25 of whom were in the timolol control group, showed average IOP reductions for the implant during the first 12 months of approximately 30%. In addition, the mean number of glaucoma medications ranged from 0.54 to 0.56 at 12 months in the fast and slow iDose Travoprost elution implant groups, respectively, compared to 0.72 mean medications in the timolol group.
Dr. Berdahl: Dr. Greenwood, what are your thoughts on potential pitfalls that glaucoma specialists are going to encounter when implementing new drugs?
Dr. Greenwood: We have to lean heavily on clinical trial data and the experience of leaders in the field to learn the nuances of any new drug or technology. Then we have to learn through our own practice what works for our patients.
Dr. Berdahl: Dr. Swan, what do you think the key takeaway is for glaucoma specialists?
Dr. Swan: There’s a lot of excitement because we have new pathways for topical medications. The last time we had a major innovation in topical therapy was the advent of prostaglandins, which was quite some time ago. It’s important that providers be familiar with the mechanism of action of those new medications and think about how they might apply or be beneficial to their patients.
Secondly, I think it’s just important to know that while not available yet, in the very near future we’re going to have a lot of great sustained release drug delivery devices that may take a significant amount of the compliance issues that we’re all concerned and worried about with our patients and take those out of the picture. That combination is going to make it so that compliance becomes less and less of an issue and hopefully, our ability to get patients to goal becomes more and more possible. GP
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