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Paradigm’s Retina Unplugged Podcast is a platform that brings retina experts together for engaging discussions on timely topics that are relevant to clinical practice. Retina care continues to advance rapidly. This podcast provides a highly flexible, accessible, and engaging way to stay up to date on the latest clinical developments in the field and further your education by hearing from those who are at the forefront of innovation.
Common Practice Dilemmas in the Age of Second-Generation Therapy
Introduction: The Current Clinic Capacity Crisis
Dr Weng: All right, well, we're going to kick off today with my good friend and colleague, Dr. Roger Goldberg. The introduction of this podcast is going to look at the current clinic capacity crisis. Roger, it's great to be with you always. You and I both work in very busy clinic settings. I thought we would start off just by talking about the current state of our clinics. I'm sure you'll agree that we have this ever-growing demand for retina treatment these days when it comes to clinic and retina services. I'd love to hear your thoughts; have you noticed this in San Francisco? What do you think are some of the factors driving this ever-growing demand?
Dr. Goldberg: Yes. Christina, great to be here with you. You and I have gotten to collaborate since, I think, residency interviews. This has been a great trajectory. What a fun first start to our careers this has been. It's great to be here with you. It is incredible. I joined my practice. I finished my fellowship in 2014. I think you were the same. You joined an academic practice. I joined a retina-only private practice. Different environments, but I suspect both of us feel like, every single year, we just keep getting busier and busier. We're hiring more doctors.
Of course, we think about in ophthalmology, in general, and retina clinic specifically. We take care of a lot of older patients. Obviously, the “A” of AMD [age-related macular degeneration] is the age-related part, but we know we also have this global pandemic of diabetes and retinal vascular diseases—the combination of an aging population, increased obesity, diabetes, high blood pressure, all these comorbid diseases. Then, honestly, part of it is we're just so fortunate to be able to help so many of these patients, too. I think if we didn't have treatments available, we may not be as busy; but because we've got treatments, we can really do something for these patients, which ends up being a great problem to have.
Dr Weng: Yes, it's a great point that you make. Different from other subspecialties, we also give a lot of recurrent therapy. With our injections, a lot of high-frequency treatments are being done all the time. You're right. We're so fortunate that they do work so well. That means that one new patient becomes really 13 appointment slots over the course of a year when you think of it that way.
It's really unsustainable for a lot of our patients. You see that, over time, that injection fatigue, if you will, becomes a real thing for them. A lot of times, they peter off. I do think that that contributes a lot to some of the reasons why we do see eventual vision loss in some of our patients with diseases that we otherwise should be able to keep stable these days. What are your thoughts on other barriers that exist?
Dr. Goldberg: Yes. It is really interesting because pretty much every real-world study that looks at how patients are doing IRL here— in real life—in our clinics, they aren't doing as well as what we saw in the clinical trials. There are probably a lot of factors that contribute to that. Certainly, the one that's been very clearly correlated is the number of injections a patient is able to receive and their vision outcomes. This has been seen both in the diabetic population as well as the AMD population because these first-generation agents, like ranibizumab and 2-milligram aflibercept, bevacizumab, of course, which is off-label, and now we have some biosimilars for these first-generation agents.
They really require monthly or every-other-month treatment. We just know in real life, patients aren't able to come in as often as they need to. I think there are a lot of barriers that contribute to that.
Obviously, we've got, geez, 10, 11 offices now, and even with this proliferation of satellite offices, patients still will have transportation challenges getting in. Oftentimes, they rely on somebody else to bring them in. Certainly, up front, there's a fear of injections. I like to think that after patients get their first injection or two, they realize, okay, they don't actually hurt. Then when you think about the diabetic patients, these patients have lots of other diseases, so they've got lots of other medical appointments. Those things pull them away. Oftentimes, they're working age, so they've got work commitments or other family commitments. All of these things lead to probably suboptimal outcomes when we look at the population as a whole.
Dr Weng: Yes, I love that you mentioned that. I will also say that there are provider factors as well. I think I had told you about this before, but one of our former residents here, now a fellow at Iowa, Nikki Simone, and myself, and some of our colleagues, looked at these intervals a little more carefully with patients who were receiving injections for all reasons, not just wet macular degeneration. We looked at intended intervals versus actual intervals. We found that nearly a quarter of injections were received at least one week later than originally intended. That provider-side factor actually accounted for over 15% of those delays. We are real people, too, with real lives. We have meetings to attend, other obligations that sometimes take us outside of the clinic. It's important to remember those as well.
Dr. Goldberg: Now, Christina, I know you don't take vacation, but those of us in private practice, man, sometimes we take some vacation, too.
Dr Weng: I certainly wish I could have that opportunity one of these days.
Dr. Goldberg: Yes, and we'll get into it. That's really insightful. One of the things that's so great about longer intervals between treatment is it gives you a little bit of flexibility. When a patient is really stuck on four weeks, it becomes really prohibitive of, geez, I'm on vacation, they're planning a trip, it can be really hard to manage. When you have a patient out to 8 weeks or 10 weeks, there's a little bit more wiggle room and flexibility to accommodate all these real-world factors. They get in the way of receiving the intended interval treatment schedule.
Dr Weng: You're so right. It really does give me comfort to know that, hey, if we have to delay their injection by a week or two, I love thinking about the fact that they're likely still covered, if you will. That really does, I think, give us a sense of relief, both the provider as well as the patient. I know you're going to lead into our next section with that.
The Impact of Second-Generation Treatments on Patients, Caregivers, and Retina Practices
Dr. Goldberg: Sure. Obviously, we hinted at it a little bit, but some of these second-generation or next-generation treatments and what their impacts are on care and on quality of care and on outcomes. First, when we say second-generation therapy, what are we talking about? Let's make sure we level set so everybody is on the same page. How are these different from the first-generation agents that have been around for one to two decades now?
Dr Weng: Yes, it's a great question. It's interesting how that term arose over the past few years as suddenly there was this influx of new agents into our toolboxes after quite a long time where we really only had three options to choose from. It's really exciting. When people are talking about second-generation drugs, we're mostly referring to faricimab and aflibercept 8 milligrams. These were approved by the FDA in a very similar timeframe: Faricimab in 2022 and aflibercept 8 milligrams in 2023, just about a year later.
Faricimab is ophthalmology's first bispecific molecule. It works by targeting not just VEGF-A, which has been a target for a long time, but also a protein called angiopoietin-2. Then aflibercept 8 milligrams; that's not a new term to anybody because we've had aflibercept 2 milligrams for quite some time. This is four-fold the molar dose of our standard first-generation aflibercept 2 milligrams.
Both of these next-generation or second-generation anti-VEGF agents do have similarities because they're both indicated to treat wet macular degeneration and diabetic macular edema. Faricimab is also approved for the treatment of retinal vein occlusion, and aflibercept 8 milligrams is also approved to treat diabetic retinopathy. The exciting part of these two is that both can be dosed up to every 16 weeks, which is a difference from our first-generation agents, which were on label to be used up to every 12 weeks. This might allow patients to go an extra month, which I think is really appreciated by them.
It's really fascinating because these agents we are now using in the real world for several years now, and I have really seen some nice effects with durability that's been able to be achieved by patients. They are able to reach higher and higher bars. Has that been your experience as well, Roger?
Dr. Goldberg: Yes, it certainly has. I think faricimab has been out a little bit longer than 8-milligram aflibercept. It's interesting. I think the retina specialists, myself included, we care a lot about the flexibility that the label offers. Because sometimes these really difficult-to-treat eyes, you get three loading doses every month with 8-milligram aflibercept. At least for now, after that third dose, you really have to extend the patient out to eight weeks, maybe plus or minus a week, so seven-plus weeks. I really like having the flexibility to be able to treat, honestly, like some patients do better with these next-generation agents. It doesn't necessarily mean all of them can get out to an every-other-month treatment interval.
We are recording this in mid-August of 2025. We just got news that there's been at least some delay for the approval of 8-milligram aflibercept for an RVO [retinal vein occlusion] indication, Q4-week dosing indication, and the prefilled syringe. It might be a few more months until those come, but hopefully, those will give 8-milligram aflibercept some additional flexibility that I think the community would welcome.
Now, you had mentioned that faricimab is a bispecific antibody. It blocks Ang-2, which then allows angiopoietin-1 to signal through the Tie2 receptor. It's a little bit confusing biology. A lot of us, when faricimab first launched, questioned, well, is the Ang-2 inhibition adding any additional benefit, or is it just the higher molar dose of VEGF inhibition that you get with faricimab? Because you do get increased VEGF inhibition in comparison to 2-milligram aflibercept.
I think there have been some really great analyses, particularly in DME [diabetic macular edema], where we see the benefit of Ang-2 inhibition. I'm most intrigued by the macular leakage data. When you look at the reduction in macular leakage after the loading dose in YOSEMITE and RHINE, which were the pivotal studies for faricimab and DME, we see a marked improvement. Both drugs improve macular leakage, but with faricimab, we saw almost a 50% further reduction in macular leakage versus 2-milligram aflibercept. You were able to almost double the proportion of patients who had total resolution of macular leakage after that loading dose phase, which was what the reading center called less than one square millimeter of macular leakage on a fluorescent angiogram.
The reason you could say, well, how do I know that's not from the increased molar dose of VEGF inhibition? Well, we saw in the PHOTON study, which was the pivotal study of 8-milligram aflibercept. In the head-to-head phase versus 2 milligram aflibercept, there was no difference in the amount of macular leakage reduction. Just increasing the molar dose of VEGF inhibition doesn't further reduce macular leakage, and it really highlights the benefit of Ang-2 inhibition. The way I think of macular leakage is like vascular stability. You're getting better vascular stability by adding the anti-Ang-2 effect of faricimab.
Dr Weng: Yes, I love that you highlighted all of that great data. I know you've presented a lot of that on podium, Roger.
I'll just speak briefly about aflibercept 8 milligrams and what we've seen from the clinical trials there. For example, to achieve the indication of aflibercept 8 milligrams for DME, there was a pivotal study called PHOTON that looked at the 8-milligram dose of aflibercept given either every 12 or every 16 weeks. They compared that directly with aflibercept 2 milligrams on a fixed eight-week trial. The bottom line is that the aflibercept 8 milligram arms, both of them combined, Q12 weeks and Q16 weeks, they found were noninferior to aflibercept Q8 weeks in terms of the mean change and best corrected visual acuity at week 48, which was the primary endpoint. There was also excellent anatomic response demonstrated by aflibercept 8 milligrams. Very importantly, it was well-tolerated with a comparable safety profile to that of the aflibercept 2 milligram arm.
It was exciting to see that 16% were eligible for Q20-week dosing by week 96, and almost a third were eligible for Q24-week dosing by that same timeframe. It is important to remember that the aflibercept 2 milligram arm was not provided with the opportunity to extend intervals, so we have to keep that in mind. It's not truly an apples-to-apples comparison, but that durability, I think, is fascinating to see. Would you agree?
Dr. Goldberg: Yes. I think those studies were really designed to show durability and to really, honestly, push the limits or test the limits of how far out you can extend patients, which is why in subsequent years, they went out to 20 and 24 weeks even. I will say that there have been some subgroup analyses that do show in the more difficult-to-treat eyes, aflibercept 8 milligram does seem to be performing anatomically better than the 2-milligram group.
What Are We Seeing in Clinical Practice?
Dr. Goldberg: Well, Christina, these clinical trial results are very encouraging, but I think there's always been this disconnect between what we see in clinical trials versus what we see in clinical practice in the real world. I'm curious, what's your sense? How are these next-generation agents, the data from the trials, translating into what you're seeing in the real world?
Dr Weng: Yes, that's a great question, Roger. As you know, there are definitely key differences between the patients you and I treat every day from those that were in these pivotal studies. Our patients, especially the ones with diabetes, tend to be a lot sicker in the real world. Additionally, some of the inclusion criteria, obviously, are going to be much stricter in some of these studies. You're right. It's so important to look at these.
Yes, there are a couple of real-world studies that I want to highlight here because I think they're very important for us to be able to contextualize how these second-generation agents are working from a day-to-day basis. The first one is called TRUCKEE, which is led by one of our colleagues and good friends, Arshad Khanani, out in Reno, NV.
The three-year results have recently been reported. They found that after three injections of faricimab in patients that were switched, the dosing intervals increased by seven and a half days, so almost a week additional in terms of the interval that they were able to achieve, and that interval, delta, if you will, continued to increase over time. After the patients got settled and had repeat injections of faricimab, sometimes they were even able to stretch out longer than that compared to what agent they were on before.
Additionally, some other notable results after three injections in those switched patients included a letter gain of 1.24 ETDRS [Early Treatment in Diabetic Retinopathy Study] letters that was maintained over time, a reduction in the central subfield thickness of almost 30 microns, and even reduction in those PED [pigment epithelial detachment] heights of over 20 microns. Very importantly, significant reductions in the total retinal fluid volume were also observed in all eyes and in aflibercept switched patients, demonstrating significant decreases in volume and increases in treatment interval after sustained treatments.
Additionally, I think these real-world studies, Roger, teach us a lot about safety in the real world. That's something we're always looking at closely because sometimes you won't necessarily see those signals until you have a critical mass of patients. That's where these real-world studies are very helpful. It was encouraging to see in TRUCKEE that there was a low rate of intraocular inflammation and endophthalmitis with one report of bilateral non-occlusive vasculitis. All events resolved, and vision returned to baseline in all cases.
Then the other set of real-world studies that is familiar to a lot of people are called the FARETINA real-world studies. That looked at faricimab in both wet macular degeneration as well as diabetic macular edema. These are retrospective real-world studies of the IRIS registry data, which is the largest real-world study of faricimab for the treatment of wet AMD and DME. They looked at over 47,000 eyes with wet macular degeneration. Most of those had been previously treated with first-generation agents. Then there were also over 15,000 eyes with DME, again, most previously treated in the past.
What they found was that faricimab led to stable vision and improved retinal fluid reduction in previously treated eyes. There were also fewer injections from the six-month point onwards, suggesting treatment interval extension, again, parallel to what we saw in the TRUCKEE study as well. Then low rates of intraocular inflammation and endophthalmitis, not exceeding the rates that we saw in clinical trials.
Roger, tell us, what do we know about aflibercept 8 milligrams in terms of real-world studies from that end with that other second-generation drug?
Dr. Goldberg: Yes, sure. Look, you've gotten to mention studies here with thousands of eyes with faricimab. The real-world data on aflibercept 8 milligram—of course, it came out a couple of years after faricimab—we have some real-world data that's just starting to come in, but not quite the large multi-thousand-patient datasets. In DME, there's been some real-world data from both the IRIS and Vestrum datasets looking at 1300 previously treated eyes with DME.
What they found was that in the eyes with high injection frequency, every four to six weeks, switching to 8-milligram aflibercept did lead to longer injection intervals, which does support the improved durability that we saw in PHOTON. In those studies, they didn't report the anatomic outcomes. Then there's been a study from the Spectrum dataset looking in wet AMD at real-world aflibercept use. Again, small study. We're talking about 104 patients with previously treated wet AMD. They did show some, what I might call modest reductions in central retinal thickness when you switch to 8-milligram aflibercept.
I think over the next year or two, we should get a lot more real-world 8-milligram aflibercept numbers. Again, you've just rattled off the faricimab real-world datasets, and I just introduced some of the 8-milligram aflibercept. Do the real-world datasets, seem to mimic what you're seeing in your practice? Based on all this, how do you use these second-generation therapies, and how is it impacting your practice?
Dr Weng: Yes, it's a great question. I think yes and no, in a way. I do think that the real-world experiences that I've had with these second-generation agents do corroborate the efficacy, do corroborate the safety that we've seen in the clinical trials. The durability, I absolutely have observed that as well, but perhaps might be a little bit more muted. I alluded to these reasons earlier already. Like I said, many of these patients that I'm using second-generation agents in are treatment-experienced, not treatment naive. As you know, most of the patients in these pivotal studies were treatment naive. In fact, for the wet macular degeneration trials, all of them were. Additionally, we have different patient populations. They're likely sicker in the real world.
And the third important one that I always like to highlight for everybody is that there are differences in the retreatment criteria also that we practice and align ourselves with when we're practicing day-to-day, versus those that were used in the clinical trials themselves. I think for all those reasons, we might see slight differences in terms of the efficacy, letter-for-letter outcomes, as well as the durability outcomes as well. However, all in all, I do think that we are seeing excellent effects of these second-generation agents.
Dr. Goldberg: One of the things I like, actually, and it's not really the patient population I started with, I think a lot of the real-world datasets that you and I just talked about reflect the fact that most of us, when a new therapy comes out, we take our most difficult-to-treat eyes, and those are the ones we're dipping our toes in with a new therapy. That's when you say, okay, those are probably not the patients who are going to be able to get out to three or four months when they were requiring monthly treatment, let's say with 2-milligram aflibercept. A more modest interval extension, even two weeks, can be a big benefit for those patients.
What I've noticed is I tended not to extend patients, particularly wet AMD patients, past every three months. I will say that all these data, both in the clinical trials and in the real world, have made me comfortable in the setting of these next-generation agents to go past that three-month point. I find some of the patients who do really well are the ones, actually, who are doing well, let's say, with a first-generation agent at a 10- to 12-week interval. When I switch them over, and now they're out to every four months, they're quite happy, too. That is quite a relief from a treatment burden and a clinic efficiency standpoint. It frees up a spot in the schedule for patients.
I think, although we tended to think early on a lot about those most needy, frequent flyer patients who need treatment every month, there's also benefit for the patients who are doing all right, but can do even better and extend the time between treatments with these next-generation agents.
Dr Weng: Yes, I couldn't agree more. I love that you made that point because you're absolutely right. We must not forget that even if patients are doing really well on a current first-generation agent, maybe they can be doing as well, if not better, with longer times in between those shots [with second-generation therapy]. Absolutely, I've followed suit as well, taking some of my patients who have been very stable on first-generation agents and have been curious to try some of these second-generation agents for them. They have done excellently. They really do appreciate that extra few weeks in between, and that can really have an additive effect over time in terms of the burden that comes with treatment, which is great for these patients in their 70s, 80s, and 90s, oftentimes.
Home OCT and Future Treatment Protocols
Dr. Goldberg: Christina, earlier, you snuck in a little line about how the retreatment criteria in the clinical trials are different than what we tolerate in clinical practice. I think that's most relevant in wet AMD, where probably most of us try not to tolerate fluid, particularly intraretinal fluid. In DME, we might tolerate a little bit of fluid. I'm curious. I know you chair the DRCR [Diabetic Retinopathy Clinical Research] Network Protocol AO study, which is investigating the use of home OCT [optical coherence tomography]. Tell us a little bit about that and how home OCT might impact a lot of what we're doing in managing our AMD and DME patients.
Dr Weng: Yes. Thanks, Roger. Also, thank you for being one of the sites for Protocol AO. I think that's one of the most exciting trials that's happening right now in the retina space in conjunction with the DRCR Network. You're absolutely right. For really the longest time I can think of, as we've been treating these diseases, most of us have really aimed to get the patient as dry as possible. That may be the approach that we should be taking, but I think we're at a really exciting time right now because the needle, I think, is starting to shift where we're wondering, is that really something we need to be doing to get patients bone dry from our injections? There's been, obviously, as you know, small studies over the years, a handful really hasn't been a lot of data, but to suggest that maybe we don't need to get patients as dry as we currently are aiming for these days. We don't know that yet. I think one of the important studies is Protocol AO. It's going to teach us a lot about fluid tolerance. I appreciate the chance to speak about this.
As many of the listeners probably are aware, the home OCT device is a novel technology that was FDA-cleared in the spring of 2024. I think what's really exciting is that this Protocol AO study is going to look at home OCT-guided treatment and compare it with what most of us are doing today in 2025, which is treat and extend. We're expecting the results to come sometime in the next few years.
I mean, imagine a time, Roger, when you might be able to inject a patient when and only when they need it, only when they have a certain threshold of fluid that we've decided is the appropriate amount to initiate treatment. We're going to learn that data from this study. We all have patients that are home-run patients, like those who dry up immediately after one or two injections and they never have another fluid recurrence. We have patients, as we've discussed earlier, that are on the opposite extreme, who need injections every month and maybe still have fluid when they come back every month.
I love the thought of being able to tailor that therapy based on that individual's needs with the home OCT technology.
Dr. Weng: Yes, I think it'll be interesting. I think we all really want home OCT. We want it to work. We want to be able to just see the patients when they need care. I do wonder, will we get to a point where instead of talking about adherence to injection schedules, we'll be talking about their adherence to scanning themselves at home? Because as you know, asking a patient to do something every day or every other day isn't an easy feat. It'll present opportunities for personalized medicine, just like you talked about, but probably with it will come other challenges that we may not even be able to predict right now.
They actually have a dedicated branch to compliance. That's compliance both for the patients to make sure they're scanning and for us as their providers to make sure that we're responding to the alerts. We're looking at all of that in Protocol AO. I really am excited to hopefully have some data to share the next time we talk.
Dr. Goldberg: Yes, that's great. I think that does mitigate some of the adherence risks. Like I said, it's on both the patient and the provider sides.
Dr Weng: Totally.
Dr. Goldberg: Very interesting.
Well Christina, thank you so much. This was, as always, great fun for us to get together and talk about one of our favorite things, which is retina and what's happening in the world of retina. When we think about these next-generation agents like faricimab and 8-milligram aflibercept, they really both offer the potential to significantly lower the treatment burden for our patients with retinal vascular disease. I think the real-world data is supportive of the findings we're seeing in the clinical trials with respect to durability and safety in clinical practice and amongst the much more heterogeneous patient population that we're treating in the real world versus what makes it into a clinical trial.
Of course, we always need to be thinking about the patient voice in these treatment decisions. I really appreciate getting to spend an hour with you. Thanks so much.
Dr Weng: Yes, thanks. Always fun, Roger, and thanks for your great thoughts. I also want to thank Paradigm for executing this podcast and the listeners for tuning in.