Theodore Leng, MD, FACS

Switching to Aflibercept 8 mg in Treatment-Experienced Patients with Theodore Leng, MD, FACS

2025 Association for Research in Vision and Ophthalmology (ARVO) Annual Meeting

, Theodore Leng, MD, Director of Clinical and Translational Research and Director of Ophthalmic Diagnostics at Stanford University School of Medicine, presented an analysis of using aflibercept 8 mg in eyes with 

neovascular age-related macular degeneration (nAMD

) upon switching from other anti-VEGF agents.

“I’m really excited about this study because it is a real-world data study which allows us an insight into how aflibercept 8 mg is being used in the AMD and DME population since it launched,” Leng told 

. “The other exciting part about this study is that we combined data from two separate real-world data sets. And from that, we had data from almost 40,000 aflibercept 8 mg patients to provide early insights into the effectiveness of this medication in everyday clinical practice.”

The study created multiple cohorts of previously treated eyes with nAMD from electronic records in Intelligent Research in Sight (IRIS) and Vestrum Health Retina Database (Vestrum). Eyes initiating aflibercept 8 mg from August 18, 2023 to June 30, 2024 (IRIS) and August 18, 2023, to July 30, 2024 (Vestrum) were followed from initiation until last visit, real-world treatment (tx) switch, or missing tx laterality information.

Mean dosing intervals were calculated during the pre-aflibercept 8 mg switch period (≥6 months up to 1 year); loading phase, defined as the first 3 injections or 90 days, whichever occurred first; and post-loading phase, defined as the end of follow-up. Dosing intervals were examined before and after switching in a subset of eyes that were consistently anti-VEGF-treated prior to switch with average dosing intervals before switching of 4-≤6 or 6-≤8 weeks. Consistency was defined as tx for ≥6 months and average dosing intervals of ≤8 weeks.

The trial collected a total of 25,846 and 9480 eyes initiating aflibercept 8 mg from IRIS and Vestrum, respectively. The mean age of these patients was 81 years; roughly 40% were men and 49% had bilateral nAMD. Approximately 71% switched from aflibercept 2 mg and 18% from faricimab.

Consistently anti-VEGF treated eyes with ≥1 post-loading phase injection (IRIS n = 7256; Vestrum n = 1814), the last post-loading dosing interval was on average (mean standard deviation [SD]) 16 (18) and 18 (17) days longer than last observed interval prior to switch, respectively. Consistently anti-VEGF-treated eyes with average pre-switch injection intervals of 4-≤6 weeks in IRIS (n = 3577) and Vestrum (n = 801), dosing intervals were extended by 19 (17) and 21 (15) days, respectively. Eyes with an average pre-switch injection interval of 6-≤8 weeks in IRIS (n = 3628) and Vestrum (n = 1013), mean interval extension was 12 (19) and 16 (18) days, respectively.

Leng and colleagues noted that these data suggest dosing intervals could be extended by 2 or more weeks among nAMD eyes that had received consistent anti-VEGF treatment prior to beginning aflibercept 8 mg.

“Typically, the most common reason for switching is a lack of efficacy or suboptimal treatment response, or the desire to have longer treatment intervals between the injections. And so, while we did see less extension in the patients that were not being dosed as frequently, it was still a significant time increase in treatment,” Leng said. “If your goal is to have fewer visits, that can come from either the patient side or from a clinical flow operational side, from the physician side. Then even patients who are only going to get a few more weeks might still be worth to consider switching.”

Leng reports the following disclosures: Astellas, Boehringer Ingelheim, Regeneron Pharmaceuticals, Inc., Roche/Genentech, Topcon, Virtual Field

Leng, T, Sherman, S, Murdock, D, et al. Early insights from real-world use of aflibercept 8 mg among eyes with neovascular age-related macular degeneration (nAMD) switching from other anti-VEGF agents. Abstract presented at Association for Research in Vision and Ophthalmology in Salt Lake City, UT, from May 3 – May 8, 2025.

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An analysis of several datasets cataloguing the switch revealed that dosing can be extended up to 2 weeks for patients with nAMD who received prior anti-VEGF therapy.

Switching to Aflibercept 8 mg in Treatment-Experienced Patients with Ted Leng, MD

Dr Leng, what do you see for the future directions in treatments for patients with diabetic macular edema [DME]?

 Going back to a point made earlier about at-home monitoring, healthcare is becoming more distributed and more personalized in the patients’ homes, and care is going to meet the patients where they are eventually. Whether that’s going to a health center at a local pharmacy, or another retail chain and having monitoring done, or having the device on their tabletop and in their own homes where they have daily assessments to see if there is a need to treat based on visual acuity changes, that are based on structural changes on OCT [optical coherence tomography] devices. The durability question is an important one because patients can’t be expected to come in monthly forever, or even for the first year, as we’ve seen in real-world studies where the average number of treatments is 3 to 4, and we have optimal outcomes compared to the clinical trials. At this year’s American Society [American Society of Retina Specialists Annual Scientific Meeting], retina specialists met in San Antonio, Texas, in one of my sessions one of the colleagues presented a data analysis looking at their patients at their center and what percent of patients would qualify for a clinical trial. They found that 50% of the patients in their center met the inclusion and exclusion criteria for a clinical trial. That tells us that half of the patients that we see every day don’t meet entry criteria for these trials that we’re basing these results in our treatment modalities on. There is an unmet need in that half of the patients out there won’t be able to enter, and therefore shouldn’t be expected to have trial outcomes. What are we supposed to do for those patients? There are many different areas where there’s an innovation that’s needed. Fortunately, as a field, both on the physician side and the industry side, there’s many innovative people and new ideas being brought to the forefront. The gene therapies that they work on could potentially be lifelong treatments and essentially be a cure for many retinal vascular diseases. That’s an exciting area to focus on. This implant that Dr Rahimy mentioned earlier, the port delivery, has the potential to become a platform technology with which we could administer multiple different agents over time and be able to give combination therapy through this device. The future is bright and our patients will ultimately benefit from the innovation that’s going on in this field, whether that’s in our offices or in their homes.

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Dr Theodore Leng discusses what the future may hold for patients with diabetic macular edema.

The Future of Treatment for Diabetic Macular Edema

Recently, there were 2 large FDA [Food and Drug Administration] phase 3 clinical trials. These were global trials that looked safe and effective for treating patients with diabetic macular edema [DME] at treatment intervals that we have not seen with our current anti-VEGF [vascular endothelial growth factor] agents. Although faricimab is investigational, I think it will be under FDA review and could get FDA approval in the first quarter of 2022. This is an active area of research, and I’m going to turn to Dr Rahimy to discuss some of the other compounds in development. Dr Rahimy, what excites you about this space?

 One thing that was exciting about faricimab is that this is potentially a novel therapeutic target. Many of us view the ideal tomorrow as having multiple agents to choose from, to mix and match, and to get personalized treatment. We discuss personalized medicine and that’s what we’re aiming for our patients; to figure out what combinations of therapeutic targets we can match with therapy to get the best possible outcomes for the longest duration of time. It’s sobering and disappointing so far in retina, anytime a new therapeutic target has come close to getting to the market, we’ve been met with disappointing clinical trials. We hear our colleagues’, and sometimes I consider, “maybe this is as good as it gets. Maybe all we have really is VEGF and steroids, and maybe that’s what we need to consider.” You can see that reflected on the clinical trial. Faricimab targets Ang2 [angiopoietin-2], but many of these other, you could call them compounds or even surgical platforms, that are in development are not going after a new target per se. They’re trying to create a better, longer-lasting anti-VEGF. We have 1 that just got FDA approved, although not for diabetic macular edema was the port delivery system. That brand name on that is this female, that is essentially a surgical device that is implanted onto the eye, and it slowly micro releases ran up a vitreous mac into the vitreous cavity. It was just approved for AMD [age-related macular degeneration] and the clinical trials are ongoing for the treatment of DR [diabetic retinopathy] and DME. Other compounds in development, Kodiak Sciences have a drug KSI-301 that’s called an ABC, an antibody biopolymer conjugate. It’s basically an antibody fragment, and the concept is that there’s increased bioavailability and durability, it sticks around in the eye and works.

There are also our gene therapy platforms. Regenxbio has RGX-314, essentially you are transpecting cells with a virus and producing an internal factor, if you were to produce anti-VEGF continuously. The Regenx platform is to be administered via the suprachoroidal space, but it helps bring something like that into the office setting, whereas other gene therapies require us to take patients into the operating room. In previous iterations of this, when you look at what matters most in clinical trials it’s efficacy, durability, and safety. From an efficacy standpoint, even with faricimab, it’s important to note that nothing has been shown to be better in terms of visual acuity. We’re pretty much seeing the same type of acuity gains on average across the board. If something comes out that’s novel and has a visual benefit then we’ll go to that as a first line, assuming it’s safe for our patients. We want the best vision possible for patients, but thus far it’s been a difficult task to achieve because everything is coming out more or less around the same. Efforts have shifted towards this durability game. I say game because, and I think we’d all agree, there’s a lot of gamesmanship. Clinical trials and design often skew things slightly in favor of the investigational compound versus what’s readily available. As we’re playing this game of durability, these new agents must be compared to what’s called standard. What they’re doing is investigational. They’re allowing for longer treatment intervals beyond what we’re accustomed to, or what we’ve seen from our previous trial data, and it leaves us to wonder clinically, if what we have is applied to those same methods, would we have gotten something comparable? Retina specialists, in general, are wising up to this and a theme is, that there’s a growing disconnect between the clinical trial world and the real world. That’s reflected in real-world studies that show outcomes are nowhere near as good as the trials. Many of these different trial designs are coming out with longer durations, Q4, Q6 months. You’re left to wonder if this is inherent in your trial design. Maybe what we have out there can go that long. I have plenty of patients that can go for months, and six months on various therapies. I’m sure we all have it. That speaks to the heterogeneity of the disease.

Finally, safety, and I said that last because that is the most important thing. We saw this in our field over the course of the last year or so. There was a new entry to the market role, abciximab, which had safety signals, and in phase 3 clinical trials our field was eager to use it. Not everybody. Some of us had concerns and we were watching and waiting to see the approach. I usually do that whenever there’s anything new. On the other end, we saw unfortunate events of occlusive vasculitis. In some cases, patients didn’t get their vision back and that drug cannot be called a second line at this point. Nobody uses it anymore. On the heels of that, AbbVie had a compound. They submitted a pickup bar that got denied by the FDA, and that was supposed to be a longer duration anti-VEGF. The pendulum in society is swinging towards the extreme of safety. First, do no harm, that’s why we’re all doctors beyond this durability game. I’m not sure if it’s part of the discussion, but we are seeing biosimilars come out for the first FDA-approved biosimilar, Lucentis [ranibizumab]. I’m already hearing from colleagues in certain markets that insurances are mandating that they use that. That’s important because biosimilars are not subject to the same trial design in terms of rigorous phase 1, 2, 3 studies to prove safety and efficacy. These companies are basically reverse engineering what’s already out there, and when you’re dealing with monoclonal antibodies a lot of that protein purification processes are proprietary. They do not have to disclose that. It’ll be fascinating, and honestly, potentially concerning when we see what happens in the real world, because thus far most biosimilars have been infusions or subcutaneous injections. This is the first foray into the ophthalmic space, and we know that the eyes of very privileged. We’re already dealing with issues of safety and inflammation. I’m concerned that we’ll see that with some of these biosimilars, especially as our markets are mandated to use it before we’re allowed to do other drugs.

Dr. Ehsan Rahimy describes the emerging treatment options for diabetic macular edema.

Emerging Treatment Options for Diabetic Macular Edema

We have had a great discussion about anti-VEGF [vascular endothelial growth factor] agents and the standard of care. We’ve discussed how effective it is to preserve and improve vision in patients with diabetic macular edema [DME]. We discussed how anti-VEGF injections can prevent future complications of anti-VEGF agents; the ones we currently have can also reverse the diabetic retinopathy score. That sounds great, but we’re still not satisfied because an underlying theme is the treatment burden, as it’s hard to translate what we see in clinical trials with highly motivated patients into the real world where there are real-world challenges. For the last 15 minutes, we’ll discuss emerging treatment options that may help us reduce the treatment burden. Dr Coney, can you to talk about one in particular? Which we have 2 FDA [Food and Drug Administration] phase 3 clinical trials that say it’s effective and it appears safe for treating diabetic macular edema. This molecule is a bispecific monoclonal antibody called faricimab. Can tell us about it?

This is when good is not good enough. We have great therapies, but we still have an unmet need and unmet burden. We still have room to grow in this space. We discussed the multi-factorial pathophysiology of diabetes and diabetic retinopathy. Because we have this there is some potential for multi-targeted treatments that may affect different pathways to get better visual outcomes. There’s a molecule that we’ve been observing, it’s called faricimab, which is a single molecule with a dual mechanism of action, and it blocks this VEGFA [vascular endothelial growth factor A] that we’ve been discussing. We know that VEGF is elevated in individuals with both DME and diabetic retinopathy, but this antibody also has a different arm, which blocks Ang2 [angiopoietin-2], which has been shown to be regulated in the vitreous levels in individuals with diabetic retinopathy. Ang2 works through an inflammatory pathway called the Tie2 pathway. This is potentially important because it promotes vessels breakdown, which then leads to leakage and proliferation that we normally see in diabetes and elevated levels of Ang2. It’s also been associated with microvascular inflammation. For normal eyes there’s an Ang1 [angiopoietin-1] that promotes or activates the Ang2 pathway and this stabilizes vessels, but in disease or sick eyes, as we see in diabetes, diabetic macular edema, neovascular AMD [age-related macular degeneration], and even vein occlusions there’s this angiogenic switch where Ang2 levels in the eye cause an [INAUDIBLE] in the Tie2 receptor. This causes a lease to the destabilization, increased permeability, and increased inflammation in the eye. We have the ability now to block both VEGFA and Ang2. The goal is that this new molecule may provide more stability in the vessels, and more durability in terms of how long the drug lasts and the long-term outcome beyond using anti-VEGF.

Joseph M. Coney, MD, provides an overview of the drug faricimab for treating diabetic macular edema.

Theodore Leng, MD, FACS

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