Variability of Frequency Dosing for Anti-VEGF Agents in the Treatment of Wet AMD

Dr Coney discusses the variability of frequency dosing with anti-VEGF therapy in patients with wet AMD and DME, and Dr Sheth expands on Ang-2 and its contribution to the development of vascular instability in wet AMD.

Jim Kenney, RPh, MBA: Dr Coney, we talked about the frequency of dosing for the anti-VEGF [vascular endothelial growth factor] agents, and sometimes the treatments can be at odds with the real-world use and the label dosing. Can you discuss the variability of the dosing frequency with the current anti-VEGF agents and maybe different clinical factors that might go into your decision-making upon a certain agent or a treatment schedule?

Joseph Coney, MD, FASRS, FACS: Jim, I think it’s really important for us to understand how we got here, and particularly how. I look at clinical trials and incorporate what we learned [there into] what we see in my clinical settings. There is a disconnect between what we see in clinical trials and real-world data in terms of visual outcomes. And I think a lot of these are set on how the clinical trial is designed. Our clinical trials are always designed to maximize efficacy and decrease the amount of noise to see if a drug actually is very beneficial. When we look at clinical trials, these individuals have preset inclusion and exclusion criteria. They’re monitored very closely. There’s very little loss to follow up on. The lesion size or certain types. These are things we try to maximize in trials, but in the real world, I think it’s very difficult because we treat all types of lesions. These are varying sizes of hemorrhages. There’s subretinal fibrosis, there’s pigment epithelial detachment. These patients are normally excluded. I think that’s one of the disconnects between how we look at what we see in the real world and what we see in randomized clinical trials. And then the amount of vision that we check is different. In the clinical trials, we do ETDRS [Early Treatment Diabetic Retinopathy Study] and then we use Snellen [visual acuity charts]most times in our centers. With that being said, I think the most important thing, what I look at from the clinical trials, is how often am I hitting a grand slam with certain patients, and then for the 30% to 40% of individuals who are not responding well, what kind of cocktail can I put them on to keep them as dry as possible and decrease the amount of fluid? I look at the lesion size. I think that’s really, really important. If there is a RAP [retinal angiomatous proliferation] component or there’s a polypoidal component, I think that the level of visual acuity is important. How much blood they have is important and, again, the health of the other eye. This helps me early on to determine what I may feel is a greater need or greater burden. Then I look at their response to their therapy. If they’re not responding to the first 2, 3, or 4 injections, I’m pretty quickly trying to go to a different agent. These are things that I think I’ve learned more over time. I think that a lot of our clinical trials have shown that after those first 3 or 4 injections, most times that can assess…where that patient is going to be over that year. These are the things that I look at. The variability of dosing corresponds to what I normally see after the first few injections. Then over time, I try to either treat and extend, which I find the most beneficial in order to try to customize or individualize their therapy based on that particular response.

Jim Kenney, RPh, MBA: Dr Sheth, the implications of VEGF have long been understood; we’ve discussed it’s almost 20 years that we’ve been using them. However, angiopoietin-2, or Ang2 levels, may also play a role in the disease. Now we have a new marker, if you will, from the payer side that we’ve got to worry about. What is Ang2, and how does it contribute to the development of vascular instability and wet AMD [age-related macular degeneration]?

Veeral Sheth, MD, MBA, FACS, FASRS: That’s a great question. Before I answer that, I think Joe [Dr Coney] said something—there was a seed in what he just said that connects this, which is that even in our best clinical trials, there’s still a good percentage of patients who aren’t home runs, who don’t benefit in a way that we hope they will or expect they will. The question is why. What is it about those patients? I think what we’re starting to understand, especially as data on treating Ang2 and addressing Ang2 comes out, [is that] we’re seeing that there probably is something driving these diseases, both AMD and DME [diabetic macular edema] beyond VEGF. We’ve been looking for the last decade or so for that other process or other processes that might be important. I think what we’ve found, especially as data for faricimab is starting to come out, is that this Ang2 component may very well be important because what we do know about Ang2 is that it promotes an aspect of vascular stability that these patients don’t have, especially with our diabetics but certainly with our AMD patients as well. Addressing that vascular permeability issue, that vascular stability issue by addressing the Ang2 component of the disease may very well help us improve upon what we’ve seen with just anti-VEGFs alone. I think for us, we’ve been treating with this just kind of one target for the longest time, whereas we’ve seen our colleagues in cancer therapeutics or blood pressure or diabetes, where they’re looking at multiple targets and getting so much better response from their patients when they start looking at these multiple agents, treating these multiple pathways, and then building synergies with that. I think what we’re seeing now and hopefully what we’ll continue to see as the R&D [research and development] develops is that we will be able to target other aspects of the disease, get better results, and potentially build on that durability. To your point earlier, we do not have to treat these people as often; we’re treating them less often but getting better results.

Jim Kenney, RPh, MBA: If you had to figure a percentage of your patients who don’t respond currently to the VEGFs, what percentage would you put on that? That, I think, would be helpful for payers to know in terms of whether we should put a 3- to 6-month check-in on these to make sure they’re working.

Veeral Sheth, MD, MBA, FACS, FASRS: Yes. I think the data’s there. I think we’ve seen this in multiple studies that somewhere between 40% and 60% of our patients still have residual fluid despite frequent anti-VEGF therapy. I think protocol T is a great example where we treat patients monthly or every 4 weeks, and even after 6 cycles of that, we’re still seeing a lot of patients with residual fluid. I think there’s a decent number of patients out there. To your point of when we check in, maybe that’s when. Maybe it’s a few months into their therapy where we’re still seeing residual fluid.

Jim Kenney, RPh, MBA: Well, that’s a high percentage, so clearly that’s a lot of unmet need. What percentage of that population do we anticipate a new agent like Ang2 might address? Do we have any sense based on early data?

Veeral Sheth, MD, MBA, FACS, FASRS: I think if you look at the data from the faricimab studies, I think you’re starting to see improvements in those numbers. If you look at head-to-head vs anti-VEGF, you’re seeing fewer patients at 16 weeks, for example, in some of the phase 2 studies with residual fluid compared to anti-VEGF. I think it’s probably 10% or 20% improvement that we’re seeing if you look at some of the phase 2 studies, so certainly [there’s] movement in the right direction.

Transcript edited for clarity.

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