Ali Khan, MD, FACS, FASRS

Retina specialists highlight the safety data of both faricimab and high-dose aflibercept for use in treating nAMD and DME.

Safety of New Therapies in nAMD and DME

 Apart from extended durability, what else do you think that we need to achieve from these therapies to really be meaningful in regard to your practice and your patients?

I think safety is a big one. I think we’ve had experience with several recent drugs where safety concerns were brought up, perhaps after the clinical trials, and that I think is a big pause for most physicians, because the existing treatments we have are very safe in our hands. And I don’t think anyone wants the uncertainty or potential harmful effects of an unforeseen, perhaps inflammatory event that could cost a patient [their] vision. So I think safety after durability, of course, which is the primary end points in terms of these trials, there’s vision at a durable extended interval. But I think the safety concerns in the broader retina community are now paramount. That needs to be proven before I think people will truly adopt these drugs.

 Obviously, with any of these efficacy analyses, one of the other areas is potentially closure of the CNV [choroidal neovascularization] finally, or reduction of subretinal hyperreflective material, which we all think is the neovascular complex, which may benefit us to see that happen over time for sure from these drugs. And we talked about the safety profile of these drugs. Are there any new safety signals that were seen, any of these new drugs that have come out so far?

 Luckily, there wasn’t. So at least in the public trial data, there were similar rates of inflammation, which I think is the big one that most retina specialists are looking for nowadays between the comparator arms, which are aflibercept 2 mg every 8 weeks that had similar inflammatory events to the active arms of the trials, meaning the faricimab or the high-dose aflibercept. So hovering around 1% to 2% rates of inflammation and thromboembolic events, heart attack, stroke, no new safety signals in all of the trials. 

 I would agree with you that we’re so cautious right now [about] safety because we have what we’ve seen with brolucizumab in the past. Obviously, we’ve seen some events recently with the drugs and geographic atrophy, which has been concerning to us. Our heightened awareness is definitely there for these drugs. And so we’re really making sure that there are no safety signals. Thankfully, both of these drugs, both faricimab and high-dose aflibercept, have not shown any concern as far and they’ve been used in clinical practice.

Transcript is AI-generated and edited for clarity and readability.

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Key Clinical Findings From the PULSAR and PHOTON Trials for High-Dose Aflibercept

Recently, we’ve had the high-dose aflibercept 8 mg, which was approved by the FDA and PULSAR and PHOTON. What are some of the clinical outcomes from this trial that stand out to you?

So PULSAR and PHOTON, I think with the approval of faricimab, the 16-week mark became a very attractive time point that everyone’s looking at. So with the PULSAR and PHOTON looking at DME [diabetic macular edema] and neovascular AMD [age-related macular edema] with the high-dose aflibercept. In PULSAR, there was about 88% of patients who were on a 12-week or more dosing interval by the end of 2 years, which was a significant proportion. And then in PHOTON, that number was about 89% of patients were on a 12-week or more treatment interval. In these 2 trials, they even allowed criteria to go longer than 16 weeks. And in both trials, there was a decent percentage of patients who can actually achieve that. In the PULSAR trial, the [number of patients who] could reach up to even 24 weeks was approximately 28%. And about 27% in the PHOTON study for 24-week dosing. So it achieved a similar duration and level of interval that we’re noticing with the faricimab trial and potentially even a bit longer. And most of those intervals were maintained for the majority of those patients for the entire 2 years.

I think that you’re absolutely correct about that 12-week holy grail. And now it’s gone to 16 weeks and even 20 weeks. And like you said, I think the numbers speak for themselves both for PULSAR and PHOTON. What I think was interesting was that the week 20 was a durable agent into year 2, which I thought was very, very interesting because I didn’t expect it to go that long. I think honestly, we thought that most patients need to be monitored every 3 months as most. If we got 90% of people to 3 months, probably we would have a very durable agent that we could all use. And this actually went even 20 weeks, which I think is probably longer than we did. And I think in clinical practice, we might choose to just see these patients back quarterly regardless of that because in the fact, we want to make sure that we follow them, make sure they don’t have any sort of changes in their OCT [optical coherence tomography] or visual acuity that might be silent and not necessarily evident to the patient. So it’s important, I think, [that] we follow these individuals as closely as we can despite the great durability that we saw of these patients over time. In addition to the fixed-dosing arm, clinical trials for both these drugs used [a] treat-and-extend arm, can you discuss some of these prespecified criteria on shortening or extension of the intervals?

I think to help mirror clinical practice, both trials did have the treat-and-extend portion after year 1. So, in year 2, you were able to extend your interval and the prespecified criteria were based on OCT, central subfield thickness, visual acuity letters, and then for the neovascular AMD trial, also the presence of submacular hemorrhage, as you mentioned. So these were very tight criteria, so everyone was on the same page in terms of who can extend and who couldn’t.

And again, these could be up extensions to 4 weeks either way, either reduction or an extension. So I think those prespecified criteria were made, for both the faricimab trials and the high-dose aflibercept trials,…in a way that mirrors mostly what we do with clinical practice.

I would agree with you. I think that the ability for you to pick both anatomy and vision at any given time, and, by the way, investigator discretion in both studies was allowed to change the interval as well. So it just wasn’t based upon one and the other per se. It was also investigator discretion. So they could have determined if the patient met a criteria that they saw clinically or what have you, that they could actually change that based upon that. So that was, I think, a very important finding as well.

M. Ali Khan, MD, FACS, FASRS, reviews the PULSAR and PHOTON clinical trials of high-dose aflibercept for treatment of nAMD and DME.

Use of Faricimab in Clinical Practice in nAMD and DME

 We’ve obviously had the newer generation, anti-VEGFs [vascular endothelial growth factor] and Ang2 inhibitors together approved recently. We had recent approval of faricimab, which is a combined bispecific Ang2 anti-VEGF treatment. We had high-dose aflibercept approved as well, which was…8 mg of aflibercept compared to the 2 mg standard dosing. I think that faricimab was first on the scene, and we’ll talk about that a little bit more in detail. I would like to get your clinical insights as far as how it’s played out in your practice. And what I can tell you about the studies in LUCERNE, which are the neovascular AMD [age-related macular edema] trials and the YOSEMITE and RHINE trials, which were the DME [diabetic macular edema] trials, is that they were able to show with a comparator to aflibercept given every 8 weeks that they were able to treat-and-extend these patients with a set force paradigm to a significant extent. And in fact, 75% or 78% of patients were able to achieve a Q12 week [every 12 weeks] or beyond interval of retreatment into year 2. And I’d just like to ask you, given some of this baseline data from YOSEMITE and RHINE and TENAYA and LUCERNE, which we saw similar numbers and rates of 70% to 80 % Q12 and beyond, what are you seeing in clinical practice? Are these patients getting that durability or is it because you’re using one of those for recalcitrant patients more often than not and then treating those patients and may not see the same benefit per se?

 Yeah, I think that’s the big distinction. Are we really [working with] treatment-naive patients or are we [treating] patients who have previously been on high burden anti-VEGF of other agents prior? So for the kind of the initial [treatment-naive population], I think we all have a little less experience because of the relatively newer drug, but I have been able to see patients extend out to the 12 week or more interval. And I think partially because in the trials, the extension was 4 weeks at a time, which is quite a bit longer than I think what most of us do in clinical practice with treat-and-extend, usually 1 to 2 weeks at a time. So I’ve been a little bit more liberal about how far I will extend in between visits, usually 2 weeks or so at least. But for the recalcitrant cases, I think it’s still tough. I mean, I think these are just high anti-VEGF burden patients and even though we’re adding an additional blockade of Ang2, many of these patients have stayed at least on a 6- to 8-week interval similar to what they were before. There’s still some anatomic changes that I feel like I’m seeing anecdotally, but the interval is still tough to extend because of their visual acuity for me. So I think the recalcitrant traces are tough for any drug, to be perfectly honest, but for the treatment-naive, I think we are seeing some longer intervals.

 I couldn’t agree more. In my practice, too, I started dosing faricimab and I did get a week or 2 extension, I think in those patients who are most recalcitrant, but in the treatment-naive population, I don’t think I have enough experience to talk about [it] this far. There have been some real-world clinical trials have shown some…benefit at extending intervals earlier in patients for those conditions. But yet we don’t have enough data; I think a [we need] year out yet to see that difference there.

Drs Rishi P. Singh and M. Ali Khan review the real-world experience of using faricimab to treat nAMD and DME, as well as its durability compared to clinical trials.

Extending Treatment Intervals in nAMD and DME

 presentation titled “Extending Treatment Intervals With Durable Therapies for Neovascular AMD and Diabetic Macular Edema.” I am Dr Rishi Singh, staff physician and president of Cleveland Clinic Martin Hospital and Cleveland Clinic, [in] Florida. And joining me today is my colleague and friend, Dr Ali Khan. He’s a vitreoretinal surgeon in Granite Bay, California. Welcome, Ali.

Our discussion today will focus on therapies that promise to reduce the treatment burden with extended durability. And we’ll highlight some of the recent clinical trial data and safety for these therapies. We’ve been very fortunate, as in retina for so many years to have anti-VEGF [vascular endothelial growth factor] therapy for primary therapy for our patients for both neovascular AMD [age-related macular degeneration] and diabetic macular edema [DME]. I know that both of us as retina specialists have encountered durability issues with these drugs.Many of our patients can’t be extended very fast. Some of them have to be unfortunately reduced in their interval of retreatment to get an effective improvement in visual acuity and anatomical improvement. And we’re going to talk about some of those opportunities today, but also talk about some of the newer therapies that we have that are more recently FDA approved that will help us manage these patients over time. So let’s talk about, first, Dr Khan, the patient burden. What are the factors in which you sort of talk to patients about the burden of these anti-VEGF treatments in general late clinical practice?

 I think it’s a big part of it. I think the initial discussion you have with any patient you start treatment on, one of the first questions is, “How many of these am I going to need and for how long?” So treat-and-extend has become, I think, the protocol of choice for many retina specialists, simply because you can explain to the patient, “We’re going to treat you monthly for a little while and then depending on how you respond, we’ll try to go longer and we’ll go as long as we possibly can in between your visits, but a lot will depend on your vision and your pictures,” meaning their OCT [optical coherence tomography] images. So I explain the patients, we’re going to have to do this for as long as we need to. For diabetics, it’s easier to tell them, “Look, over time, we tend to expect fewer injections,” but for the neovascular AMD [nAMD] patients, I do give them a heads-up that this might be years and as long as we need to and the goal being your vision. So it takes a little while to break them into the idea that they might need this for a while, which is why the durability issue is particularly important. Some of these people are working age or they have caregivers who need to bring them, so they’re often always worried about how they can get [into the office]. Getting a durable treatment for as long as possible, I think, is what most patients want.

We always want to strive to treat our patients less. I don’t think any retina specialist goes into this saying, “I want to see you frequently.” I use that phrase that you did just kind of use that in a different way. I say, “I’m going to get to know you very well through this treatment approach,” because obviously there are a lot of treatments to be given for this condition, and we’re always trying to [give] fewer injections. We want to have the less probability of these anti-VEGF–related ocular [adverse] effects and potentially inflammation in various rare cases, but certainly we know that there’s a correlation between high frequency of injections and certainly complications of these treatments. You talked a little bit about that treat-and-extend strategy—can you talk to us about what factors you use in determining treat-and-extend for somebody who may be in practice now or just new to practice. What is the sort of way in which we use treat-and-extend mechanisms, the definitions by which we define it to really apply to our patients in practice?

 It can be quite variable in practice what people truly use as their criteria, which I think is why many of the more recent clinical trials have very strict criteria for why they allow patients to go longer within the trials, which I think is a good idea to standardize things. For me personally, I look at their visual acuity, and again we’re using Snellen visual acuity so there’s some variability there visit to visit, but mainly the OCT. Honestly I think if there’s fluid that’s clinically evident on the OCT image, that’s reason enough for me to either shorten the interval and, conversely, if the OCT looks good in terms of any residual fluid, to extend the interval. Lastly, there’s symptoms, and some patients who tell me “By a day or 2 before my injection, I’m starting to notice my vision change.” And even if the OCT looks clean and their vision seems stable, I will take that into account to decide whether or not to truly extend them. So a combination of their OCT vision and symptoms, but OCT being probably the biggest decider for me.

 I think you’re right about that. And I think you pointed out the fact that sometimes vision does play a role in these discussions because we all know that the OCT is only mostly correlated with activity; not always correlated, but mostly correlated with activity. Clearly, there could be people with a dry retina and still have an active coronary neovascular complex present there. So, what we think is what we’re managing on the OCT, which we think is a very valuable tool, is valuable for the most part of what we do, but certainly there are outliers in that. And the other part of this that I think also factors into this is clinical exam. So if you see the presence or absence of subretinal hemorrhage, the presence would mean that you may consider even shortening the interval further; the absence of which [means] you would continue to extend the patients over time. So that’s another kind of factor to look at clinically to make sure that you’re following the right paradigm.

Rishi P. Singh, MD, and M. Ali Khan, MD, FACS, FASRS, discuss the need for extending treatment durability for neovascular age-related macular degeneration [nAMD] and diabetic macular edema [DME], as well as approaches to applying treat-and-extend strategies.

Ali Khan, MD, FACS, FASRS

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