W. Lloyd Clark, MD

Aflibercept 8 mg Shows Durability at 3 Years in Wet AMD with W. Lloyd Clark, MD

Aflibercept 8 mg (EYLEA HD) achieved positive results at 3 years among patients with 

neovascular (wet) age-related macular degeneration (nAMD)

 in an extension study of the Phase 3 PULSAR trial.

Announced by Regeneron Pharmaceuticals on February 8, 2025, these findings, presented at Angiogenesis, Exudation, and Degeneration 2025, revealed most patients treated with aflibercept 8 mg continued to experience improvements in vision and anatomy, with extended dosing intervals.

“In the PULSAR extension, a large percentage of patients can be extended out to 4 months or even longer, with good disease control,” W. Lloyd Clark, MD, Palmetto Retinal Center, and assistant clinical professor of ophthalmology at the University of South Carolina School of Medicine told 

“This really does represent the next incremental improvement in the chronic treatment of patients with wet AMD.”

 approved aflibercept 8 mg for wet age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy in August 2023.

 Wet AMD occurs after the growth of abnormal blood vessels leak fluid under the macula, with nearly 1.4 million people in the US at risk of vision loss from AMD.

The PULSAR trial was a double-masked, active-controlled pivotal trial in patients with wet AMD, reporting 88% of all patients on aflibercept 8 mg maintaining ≥3-month dosing intervals at the end of 2 years. After its completion, an optional extension study began at Week 96, with all participants receiving aflibercept 8 mg across Week 156. Dosing intervals in the extension study could be reduced or extended by 2-week increments based on certain criteria, with a minimum interval of every 2 months and a maximum of every 6 months.

Among those who completed the full 3 years of treatment (n = 375), nearly 60% had a last assigned dosing interval of ≥4 months. Approximately 40% and 24% had a final assigned dosing interval of ≥5 months and 6 months at the end of 3 years. Visual and anatomic improvements, including reductions in retinal thickness, were sustained through year 3 in the extension.

Those in the comparator arm were treated with aflibercept (EYLEA) as a fixed 2-month dosing regimen for 96 weeks and could switch to a 3-month dosing interval with aflibercept 8 mg until Week 156. Among those who completed the extension (n = 186) after switching, these data showed maintenance of vision and anatomic improvements, with 79% and 43% on an assigned dosing interval of ≥3 and ≥4 months, respectively.

The safety of aflibercept 8 mg was similar to aflibercept across 3 years and remained generally consistent with the known profile from pivotal trials. Ocular treatment-emergent adverse events (TEAEs) were reported in ≥4% of all patients, including cataracts, retinal hemorrhage, reduction of visual acuity, vitreous floaters, and increase of intraocular pressure. The rate of intraocular inflammation was 2.4% for the patients who switched from aflibercept to aflibercept, and 1.9% for those randomized at baseline.

“These patients typically stay on treatment for life and I’ve got patients in my clinic that have been on injections pushing 20 years,” Clark told 

. “If we can reduce the number of treatment visits for these patients, it will significantly increase their quality of life. These patients with wet AMD are typically more compliant and so they welcome the idea of coming less frequently.”

Relevant disclosures for Clark include Amgen, Genentech/Roche, Regeneron, and others.

Three-year results for Eylea HD® (aflibercept) injection 8 mg in patients with wet age-related macular degeneration demonstrate continued durable vision gains and anatomic improvements with extended dosing intervals. Regeneron Pharmaceuticals Inc. February 8, 2025. Accessed February 20, 2025. https://newsroom.regeneron.com/news-releases/news-release-details/three-year-results-eylea-hdr-aflibercept-injection-8-mg-patients.

Campbell P. Aflibercept 8 mg (eylea HD) approved by FDA for wet AMD, DME, and Diabetic retinopathy. HCP Live. August 23, 2023. Accessed February 19, 2025. https://www.hcplive.com/view/aflibercept-8mg-eylea-hd-approved-by-fda-for-wamd-dme-and-diabetic-retinopathy.

Ruia S, Kaufman EJ. Macular Degeneration. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560778/

Videos

Clark describes visual and anatomic improvements with aflibercept 8 mg in the PULSAR extension study, with most patients achieving extended dosing regimens.

Aflibercept 8 mg Noninferior for RVO in QUASAR with W. Lloyd Clark, MD

Positive results from the Phase 3 QUASAR trial demonstrate the noninferiority of aflibercept 8 mg (EYLEA HD) administered every 8 weeks to aflibercept 2 mg (EYLEA) dosed every 4 weeks for treating 

macular edema secondary to retinal vein occlusion (RVO)

Announced by Regeneron Pharmaceuticals on February 8, 2025, these findings, presented at Angiogenesis, Exudation, and Degeneration 2025, will support the submission of a supplemental Biologics License Application (sBLA) in Q1 2025.

“A higher concentration of VEGF inhibition might be beneficial because we have seen situations where there’s an unmet need in people with active disease on monthly therapy,” W. Lloyd Clark, MD, Palmetto Retinal Center, and assistant clinical professor of ophthalmology at the University of South Carolina School of Medicine told 

. “One of the key takeaways from QUASAR is that we do see an additional benefit, not only in terms of durability but also efficacy and the ability to get these eyes under control with less frequent injections.”

A common cause of vision loss in adults, RVO is the second most frequent retinal vascular disease, occurring when there is a blockage in a retinal vein, leading to restricted blood flow and increased pressure in the eye. Those with RVO can experience sudden blurry vision or loss of vision, with ultimate serious complications such as macular edema.2

The US Food and Drug Administration approved aflibercept 8 mg for wet age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy in August 2023.

 QUASAR is a global double-masked, active-controlled Phase 3 trial evaluating the efficacy and safety of aflibercept 8 mg in eyes with macular edema secondary to RVO, including central RVO (CRVO), branch RVO (BRVO), or hemiretinal RVO (HRVO).

Patients were randomized into three groups to receive either aflibercept every 8 weeks after 3 initial monthly doses, aflibercept 8 mg every 8 weeks after 5 initial monthly doses, or aflibercept 2 mg every 4 weeks. The trial’s primary endpoint was the mean change in best-corrected visual acuity (BCVA) through week 36, as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score.

An analysis of QUASAR showed the trial met its primary endpoint, with both treatment cohorts of aflibercept 8 mg every 8 weeks achieving non-inferior BCVA gains to aflibercept 2 mg every 4 weeks. These results were consistent across patients with BRVO, CRVO, and HRVO. At 36 weeks, 88% of patients sustained an 8-week aflibercept 8 mg dosing schedule after 3 loading doses, increasing to 93% after 5 loading doses.

Aflibercept 8 mg’s safety remained consistent with the known profile from pivotal trials, including low rates of intraocular inflammation (0.5%). Ocular treatment-emergent adverse events (TEAEs) were reported in ≥5% of all aflibercept 8 mg-treated patients, including increased ocular pressure (5%) and a single case each of endophthalmitis and retinal vasculitis.

“We’ve got ~15 years of clinical experience with the aflibercept molecule for the 2 mg formulation. Now, we’ve got a good body of evidence of 8 mg experience as well, and it appears that the safety profile of the 8 mg formulation is very similar to the 2 mg,” Clark told 

. “Our confidence in the safety of the molecule appears to be pretty much irrespective of the concentration.”

Disclosures: Relevant disclosures for Clark include Amgen, Genentech/Roche, Regeneron, and others.

Eylea HD® (aflibercept) injection 8 mg positive phase 3 results in patients with macular edema following retinal vein occlusion presented at Angiogenesis meeting. Regeneron Pharmaceuticals Inc. February 8, 2025. Accessed February 19, 2025. 

https://newsroom.regeneron.com/news-releases/news-release-details/eylea-hdr-aflibercept-injection-8-mg-positive-phase-3-results

Blair K, Czyz CN. Central Retinal Vein Occlusion. [Updated 2023 May 1]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK525985/

Let’s shift gears for a few minutes to talk about safety. This came up earlier, we’ve been incredibly fortunate to have 2 agents come to us, in a fairly quick period of time, that have been incredibly effective and very safe for our patients, then stood the test of time for 15 years or so. Diana, are there specific considerations for your patients with diabetes as it pertains to safety? Are there factors that you discuss with them? Or do you approach them in a way similar to patients who need anti-VEGF therapy for other indications?

: We’ve learned over the past decade that interatrial VEGF inhibitors, such as aflibercept and ranibizumab, are extremely safe and effective. We’ve seen that across patient populations, whether it’s patients with diabetes, elderly patients with wet age-related macular degeneration [AMD], or patients with retinal vein occlusion, that the safety profile is consistent across these populations. I’m confident in recommending these treatments for patients with diabetic eye disease.

Let’s look forward into the future. There are a number of different agents for a variety of indications. We have biosimilars coming to the market. What’s going to be most important for you as you consider new therapeutic options in this space? Is it going to be the idea that we’re going to see dramatic improvements in efficacy? Or has safety suddenly become the No. 1 issue, given some of our recent experiences with new agents?

 I must say this has been a disappointing part of our field. We’ve had previous biologics that we looked at that were very efficacious, and because of the rates of inflammation, they did not get approved. It seems as though as we progress in our field, and we have longer-acting agents, this is something that has been a recurring thing. I’m hoping going forward our pipeline is pretty robust. We talked about the KIS-301 antibody biopolymer conjugate earlier today. We may have a PDS [port delivery system] that may be beneficial. There are other agents that may have great efficacy, and they may be a little bit more tolerable to the eye. The studies are ongoing, the preliminary data look good. If we can get the efficacy piece, and to decrease patient burden, to not have the inflammatory piece, that’s really great. It also may be true that it’s about time that we started having these discussions with patients about being comfortable with adverse effects. It’s amazing how cancer physicians prescribe all sorts of medicines, people lose their hair, they get ulcers, all these issues, and if they extend your life for 6 months, it’s a success. But we, as ophthalmologists, don’t like talking about intraocular pressure. We don’t like talking about cataracts. These are reversible, these are things that are treatable. If we’re going to try to maximize the efficacy in our patients by decreasing the unmet need, which is burden, we may have to start talking about some of the adverse effects that we often treat.

: Joe mentioned future agents KSI-301 and the PDS implant. The common thread with those 2 is that they appear to offer the opportunity for significant reductions in treatment burden with perhaps the same clinical efficacy as monthly injections of anti-VEGF therapy. It’s all the good that we get with progressive therapy with reduced treatment burden. That’s obviously an important unmet need in our space. What else would you identify as an unmet need? Or where should we move going forward to push the ball forward in terms of treating our patients?

 Longer term, our goals are obviously to improve efficacy. We care about vision at the end of the day. And ideally, we’d like a few therapeutic targets that we can potentially pair with our VEGF inhibitors to get improved visual acuity gains; reduced treatment burden obviously is a big thing. As far as what’s immediately on the horizon, as you alluded to, is going to be improving durability, reducing treatment burden while maintaining the same degree of vision gains. That being said, we’ve all experienced this in the last year, safety trumps everything now. That pendulum has swung to that extreme due to what we saw with brolucizumab. We saw what happened with abicipar as well. Biosimilars are right around the horizon. There are some potential theoretical and well-founded concerns about their safety in terms of the purification process of how these antibodies are made. Safety is the primary concern now. After that, hopefully, some of these new, longer-duration treatments are going to allow us to reduce injection burden. And deeper into the pipeline, when we look at some of the newer therapeutic targets, we’ll be able to even potentially improve vision further, or at least address some of these parts of the disease process, AMD atrophy for example, where we don’t have any treatment at all.

 And Diana, how about you? What’s the future look like for us as retinal physicians, and for our patients in managing retinal disease? What do we need to take better care of our patients?

: The future is very optimistic and bright because of new agents that are likely going to meet the burden of treatment and reduce the frequency of injections. Having the discussion of treating diabetic retinopathy when there is no vision loss yet, being more proactive, is going to be important. Because, as retina specialists, we do have approved agents that are safe and that can turn back the hands of time and decrease the risk of vision-threatening complications. There is going to be a paradigm shift in the future, and having these discussions will help facilitate that.

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Key opinion leaders emphasize important considerations when discussing the safety of anti-VEGF agents with patients and highlight unmet needs in nonproliferative diabetic retinopathy treatments.

Initiating Conversations with Patients about Anti-VEGF Agents

 Ehsan, we’ve got a lot of data on regression, a reduction in the rates of vision-threatening complications using anti-VEGF agents infrequently as every 4 months. This is not particularly aggressive treatment. There doesn’t appear to be today widespread adoption of this type of management in patients that have the threat for vision loss in diabetes. How does this work for you in clinical practice? How do you apply this data as you see patients with diabetic eye disease?

There are so much great data to unpack from PANORAMA and from Protocol W. As you alluded to, there’s been slow uptake in our field. Although anytime you’re dealing with something that’s potentially paradigm shifting in terms of the way we handle or manage a condition that we used to observe, there’s going to be a gradual phase-in and phase-out to start adopting these therapies. At this point in my practice, I’m fairly comfortable offering anti-VEGF therapy to my patients with severe NPDR [nonproliferative diabetic retinopathy]. If there’s a mistake that colleagues who are a bit averse to it may be making, it’s not even having that discussion with patients. In my practice, I’m all about educating my patients, letting them know what’s available, trying to get them to engage, understanding their disease process, and letting them know that treatment options are available. Here are some studies, here’s what they showed. And I let them be an active decision maker in that process, rather than me practicing paternalistic medicine and saying, “I’m not even going to say anything to this patient other than, ‘Come back in 3 or 4 months.’”

That type of care with diabetic retinopathy potentially lends itself to increased noncompliance more than anything in the long run. I’ve been pleasantly surprised that when I share these data from Protocol W and from PANORAMA, and the findings essentially corroborate one another, that our risk of progressing to vision-threatening complications is substantially reduced. I’ve been pleasantly surprised at the number of patients who want to do therapy.

There are a couple of take-home points from that. No. 1, consistency is more important than frequency. What I mean by that is, we saw in year 2 from PANORAMA, the every-8-weeks arm that switched to as-needed treatment, their level of DRSS [Diabetic Retinopathy Severity Scale] improvement fell off a cliff. It doesn’t get talked about much because that was an as-needed treatment arm. Remember that in year 1 that you had an 80%, 2-step improvement. In year 2, that dropped all the way down to 50%. And the reason was patients were being undertreated and they got an average of 1.8 injections of the 6 eligible injections. Whereas that every-4-month arm group essentially maintained their 2-step improvement. It was 65% in year 1 and 62% in year 2 across much less injections.

The way I look at it is, consistency is more important than the frequency. If we can get a patient to a regular interval that’s comfortable for them, that they’re compliant with, whether it’s 4 months or 6 months, then that’s great. Part of this is also the psychology. I think about things as if I were that patient. I don’t have retinopathy, and I hope I never do, but I think about it in terms of going to the dentist. If I’m going to a clinical care provider, and that visit is being tied to something procedural, then I’m far more likely to be compliant with that visit, knowing that something is being proactively done for me. Rather than just showing up, somebody looking at something and saying, everything is fine.

When push comes to shove, if I have something else going on, as Joe alluded to, diabetes is not entirely a disease of noncompliance. We have patients who care very much about their visits but are forced to choose. They’re working class, so they can’t take that many days off. They may have to juggle seeing the eye care provider with the kidney doctor, with the cardiologist, maybe they’re hospitalized. Sometimes they just end up missing these appointments, not because they don’t want to be there but because they’re forced to. If I can tie in a procedure, my belief is—and we have some real-world data forthcoming that suggest that—adherence to visits ends up increasing when we’re tying that injection to it.

I’ll end with 1 anecdote of a patient I saw earlier this week. We talked about turning back the hands of time. This was probably 1 of my earlier patients who elected to want to start treating his severe NPDR. His right eye had severe NPDR, and his left eye was moderate. We said we’d just start therapy. He had no DME [diabetic macular edema], by the way; his vision was 20/20. He was an engineer, very educated, and wanted to know everything about diabetes. I remember him the first time he came to see me. He presented the PANORAMA paper printed up. He brought it to me, and he wanted to start therapy, and we did so with his right eye. I tried to do my own algorithm, where I extended his treatment. I eventually lost him for over a year.

He came back just this week. His right eye was still at about a severe NPDR state, and the FA [fluorescein angiography] looked somewhat comparable to before. But his fellow eye that was moderate had progressive proliferative diabetic retinopathy with vitreous hemorrhage during that interval period. And it’s just an N-of-1, it’s just 1 anecdote, but that’s the type of patient I’m thinking about. Because you could have the most compliant patient in the world, but diabetes is a terrible multisystem disease that will inevitably cause someone to become noncompliant and miss a visit. But by treating that patient, did we potentially lengthen the leash and help prevent a terrible outcome from coming by the time they do inevitably get back to us?

Joe, these are very powerful data. What do you think it’s going to take for us to change the way we think as a retina community to begin to prevent vision loss vs treating the end-stage complications? Are there data that we need? Is there just time? Are there factors you can identify that may change this line of thinking in the future?

 For 1, training younger physicians to understand the disease is important. When I was training, if it didn’t change an outcome—and at that time it was vision—then we didn’t institute that therapy. I was always trained to look at vision as an outcome. Now we’re talking about trying to change the disease process, so to speak, where vision is not effective, which is a little harder to gauge. By training younger physicians in understanding the historical standpoint of eyes, because the data are prevalent. The progression of retinopathy hasn’t changed since we had been doing the studies in the 1970s. That has been consistent. And if you have an eye that has moderate disease, we know what the rate of progression is over the next 5 years. We know what the rate of progression is—you have severe disease if it’s untreated. And when you have sight-related problems, you know what the progression is. From a historical standpoint, that needs to be told to younger physicians. That’s No. 1.

No. 2, for me, it took a patient to have that outcome where it happened on my watch, and because they missed an appointment, for whatever reason, they got worse. I don’t want that to happen again. When I talk to patients with these issues, she always comes up in my mind. The other eye we were able to save. She also has proliferative disease. She’s still 20/20 in that eye, but in the eye that developed the tractional detachment, we never gained vision better than hand motion. And she never misses an appointment now. She’s 3 years out. She’s constantly undergoing therapy, and the impact that we’ve made on her is important.

When you have personal testimonies, when you have personal patients, that’s a sounding bar that helps us to make a change. It makes the paradigm shift, which may go against what you were originally taught. For me, I’ve learned every day with my patients, and that discussion with my patients is critical; knowing more about their lifestyles, and how this disease is a little different from what we see with our patients with AMD [age-related macular degeneration] who are normally brought in by a caregiver. These are individuals, these are our colleagues, and these are people who work next to you. That’s the reason I find this disease so fascinating. There’s not 1 thing you can point to, but personal stories, and having your patients not do well, is a strong testament to changing your behavior so it won’t happen again. If you can decrease that, it’s just imperative.

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Drs Ehsan Rahimy and Joseph M. Coney analyze the implications of clinical trial data on the management of nonproliferative diabetic retinopathy.

W. Lloyd Clark, MD

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