Dr Regillo leads a discussion with retina specialists about the utility and limitations of anti-VEGF agents in the treatment of patients with AMD and DME.
Carl D. Regillo, MD, FACS: Dave, can you discuss the anti-VEGF [vascular endothelial growth factor] agents we have been using for the treatment of DME [diabetic macular edema] and neovascular AMD [age-related macular degeneration]?
David R. Lally, MD: We are fortunate we have multiple anti-VEGF therapies we employ in our clinics every day. Historically speaking, the first one that was approved, back in the early 2000s, was pegaptanib. It has reduced efficacy compared to the other one. If we move to bevacizumab, which is one of the original ones developed: Bevacizumab is an off-label recombinant humanized monoclonal antibody, and it blocks angiogenesis and vascular leakage by blocking a specific type of VEGF called VEGF-A. There are different types of VEGF. There are types A, B, C, and D, and bevacizumab specifically blocks the isoform of VEGF-A165. Coming from bevacizumab is ranibizumab, which is made by the same company, and it’s similar to bevacizumab. But instead of the molecule being an entire full-length antibody, it is a fragment of the antibody created by the same mouse antibody from bevacizumab. And ranibizumab also blocks VEGF-A. Moving on to more recent ones, we have aflibercept. This one is different. Aflibercept is a recombinant fusion protein; it traps VEGF molecules within the fusion protein. Early in development, this molecule was called a VEGF trap molecule. It blocks not only VEGF-A, but also blocks VEGF-B and has some blocking capability of placental growth factors. You’re hitting some different targets with a different type of molecule to block the VEGF inside the eye. One of the more recent is called brolucizumab. This is a small, humanized single-chain antibody fragment. If you have a full-length antibody and ranibizumab is a small fragment of the small arm chain of that antibody, brolucizumab is the smallest functional chain you can create that has anti-VEGF properties of binding and blocking VEGF-A. By making a smaller molecule, brolucizumab can increase the concentration of the molecule when we inject it inside the eye to try to trap more VEGF molecules. We have a lot of therapies that are FDA approved and some that are not FDA approved we are using in our clinics each day.
Carl D. Regillo, MD, FACS: These are all biologics. They are all injected intravitreally in a similar way. They are VEGF-A blockers, maybe aflibercept or few other targets that may or may not be beneficial. And they have evolved, but for the most part, their efficacy is the same. It was mentioned that these drugs are safe, and that’s true. Adverse effects or events associated with these drugs are minuscule. We sometimes worry about the rare infection by the act of individual injection, but it’s about 1 in 3000 per injection. For patients over many years, the cumulative rate or risk of endophthalmitis might be more. But it’s not an adverse effect of a drug. The drug sometimes causes intraocular inflammation, but the rates of that in clinical trials have been about 1% or 2%. Brolucizumab stands out with a slightly higher rate in other associated adverse effects and is not getting that much use, even though it seems to last a little longer than the others in clinical trials. For the most part, the drugs we have been using such as off-label bevacizumab, on-label ranibizumab, and on-label aflibercept are ones we have been using for the past 12 to 16 years and are very similar in their efficacy, safety, and durability.
We have some fantastic anti-VEGF therapeutics at our disposal. I’m going to ask about the limitations of these drugs and the challenges of using them for these disease states: DME, neovascular AMD. Blake, why don’t you start.
Blake Anthony Cooper, MD, MPH: It’s important to understand we’re working through 1 very specific pathway: inhibition of either the growth of new vessels or the permeability and leakage of those vessels. In diabetic retinopathy, we’re dealing with vessels within the layers of the retina that are breaking down and leaking. The disease state of diabetes could be an inflammatory disease state that anti-VEGF therapy may help but not fully cover the anti-inflammatory component of it. Whereas with age-related macular degeneration, growth of new vessels underneath the retina are leading to visual loss. It’s 1 avenue in which blood vessels can grow or leak fluid, and as we become smarter about how we treat things, it’s important to understand there are other pathways.
Carl D. Regillo, MD, FACS: Mike, what’s the problem then? These drugs work well, right?
Michael A. Klufas, MD: I would argue the opposite. We have set such a high bar with these anti-VEGF therapies, and so many combination trials over the past 5 years have not been superior to anti-VEGF monotherapy. That doesn’t mean we can’t do better, but the therapies are good. The real problem is the frequency of injection. This is not only an issue in terms of the patient having to come in frequently, but these clinics are busy. So we need more durable therapies, and that’s where a lot of the trials right now are headed. The second-biggest barrier I see is subretinal fibrosis or macular ischemia and diabetic macular edema. These therapies don’t address these 2 conditions. You could inject every month when you have subretinal fibrosis, but the visual acuity will still be poor. And we haven’t solved issues such as that. In terms of nonresponders, we have patients with fluid who might receive monthly injections, but often visual acuity improves. I don’t love to see that. We love looking at an OCT that’s improved over time, but if visual acuity has improved, that’s a starting point. I had a patient today in my clinic. He had some inflammation with an anti-VEGF agent in the past, and we switched him to ranibizumab. He has been on that for a year now, but he has persistent fluid, and it’s his only eye. We made the decision to switch to another agent because he feels like his vision is declining. We’ll see how he responds to the new agent, see whether we can reduce that fluid and potentially maintain vision for a longer period.
Carl D. Regillo, MD, FACS: There are several ways we can do better. We’ve mentioned how highly effective anti-VEGF therapy is and how safe it is, so those are high bars to improve upon. But you’re right; not every patient has good vision outcomes. There are other mechanisms of action as Blake mentioned that might be good targets as add-on therapy. But for the time being, anti-VEGF therapy is here to stay and represents not only the primary form of therapy but also the foundational therapy for things that might be added in the future. For what we have now, I think the lowest hanging fruit to improve upon is durability. These drugs work great but don’t last long. That’s the problem, and that’s why in the real world we get a lot of recurrences. It’s hard for patients to adhere to frequent office visits and injections. And the visual gains early on may be lost, especially with wet AMD. Dave, your thoughts about all this?
David R. Lally, MD: I agree with all the comments from the panel. The only other thing to bring up would be flexibility in terms of our treatment plan. There are FDA labels for certain drugs, and payers sometimes expect us to administer certain regimens for these patients and certain intervals of treatment with our therapies on the FDA label every 8 weeks, but I may want to treat my patient more frequently. Not every patient has the same need for these medications. Clinical trial regimens are picked and followed and we’re seeing results for the average patient, but the average patient is not the individual patient I am seeing in my office. Increased flexibility of therapies at the dosing regimen I feel is best for my patients would be helpful.
Michael A. Klufas, MD: During the pandemic we saw patients with AMD who didn’t come in, and they lost some vision. Sometimes we get it back; sometimes we don’t. It underscores the importance of regular follow-up.
Transcript Edited for Clarity