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Clinical Focus

In this podcast, John Kitchens, MD, is joined by Peter Kaiser, MD. They discuss higher molar dose and share pearls and their clinical best practices.

What are the challenges when treating patients with higher molar doses? How can clinicians help patients transition to a higher dose? Listen and find out today.

Don't miss the full podcast – or the key takeaways below.

Increasing aflibercept dose for longer drug duration in eyes.

A deep dive into how increasing aflibercept dose improves drug durability in the eye

Modeling suggests slower ocular clearance with higher dose of aflibercept

Drug half-life and dosing for anti-VEGF treatments in ophthalmology.

How the half-life of aflibercept is determined in the eye using PK sampling and modeling

Highlights of studies include dose regimen modifications and durability of drug in second year

Accelerating aflibercept dosing intervals for wet AMD patients.

Designing clinical studies translating the "treat and extend" approach to the real world

Potential benefits of longer-acting eye medication, including increased efficiency and reduced burden on healthcare providers

Potential biomarkers that indicate a need for frequent VEGF injections in wet AMD patients

Emphasising the importance of early treatment with the strongest medication for type three lesions to prevent permanent vision loss

John Kitchens, MD, and Peter Kaiser, MD, discuss drug duration, accelerating dosing intervals, and other pearls for aflibercept dosing in wet AMD.

Implementing Higher Molar Dose in Your Clinical Practice

According to the company, the axitinib injectable suspension achieved all primary and secondary outcomes and maintained stable visual acuity and anatomical control over 9 months. There were no ocular or treatment-related serious adverse events.

Clearside Biomedical releases positive topline results from ODYSSEY Phase 2b Trial of suprachoroidal axitinib injectable suspension in wet AMD 

Aleksandra Rachitskaya, MD, FASRS, speaks about the Vit-Buckle Society at the 2024 EURETINA Congress.

EURETINA 2024: The Vit-Buckle Society makes its EURETINA debut

4D Molecular Therapeutics has announced data based on the longest interim follow-up from Phase 1/2 PRISM clinical trial and 4FRONT Phase 3 study design. 

4DMT shares data from Phase 1/2 PRISM clinical trial, 4FRONT Phase 3 study design

Gene therapy offers a promising alternative by potentially providing long-lasting effects from a single treatment.

The current state of gene therapy in managing neovascular macular degeneration

This certification covers AI based regulatory requirements for the company's platform for AI imaging and diagnostic tools.

Diagnos Inc. meets compliance requirements for ISO 13485 standard

At the 2023 ASRS annual meeting, Dante Pieramici, MD, spoke with our team to share information on OPT-302, or sozinibercept, for the treatment of neovascular AMD and other retinal vascular diseases.

- This transcript has been edited for clarity.

Hi, I'm Dante Pieramici, a partner at the California Retina Consultants in Santa Barbara, California. I'm here in beautiful Seattle, and the rest of the country is boiling right now, but we have nice weather here in Seattle for the American Society of Retina Specialists meeting.

It was my pleasure to give a talk on OPT-302, or sozinibercept, the treatment of neovascular AMD and other retinal vascular diseases. My talk was a pooled analysis of the Phase 1/2 trials looking at pharmacokinetic data obtained from the serum as well as a pooled safety analysis. You know, OPT-302 is a as a trap protein inhibitor of VEGF-C and -D. It's a fusion protein, and we, what we've learned is that when you inhibit VEGF-A there's an compensatory upregulation of VEGF-C and -D. And this may lead to additional problems. So a more rational approach would be to inhibit VEGF-A as well as -C and -D. And so a combination approach with OPT-302 may be a very good way to go.

In phase 2 clinical data that included over 366 patients, showed that we got superior visual results with a combination blockage of both WEGF-A, -C, and -D, as compared to monotherapy VEGF-A blockage, as well as better anatomical results. And this is particularly true in patients that had minimally classic or a neovascularisation, where at 6 months, there was a 6 letter difference between the groups.

And the study that I presented here we looked at pharmacokinetics, and the pharmacokinetics of the drug are very similar to that of aflibercept in his bio-distribution as well as its absorption. We found that in this serum that last has a serum half life of about 7 days, and using the serum analysis, we developed an ocular model that demonstrated that the half life in the vitreous is about 4 and a half days. So very similar to other interventional anti-VEGF agents that are being used currently in our practice.

In the pool safety analysis, which included about 600 patients, we really find no additional safety signal in the combination approach, compared to the monotherapy anti-VEGF either for ocular safety or systemic safety, very infrequent inflammatory events, no vasculitis type events. So very well-tolerated with this combination approach. This drug is currently in phase 3 clinical trials the SHORE and COAST trial, looking at combination anti-VEGF suppression combined with sozinibercept, compared to monotherapy VEGF-A suppression. And the hopes are that this combination approach will have superior visual results in this phase 3 clinical trial. And we'll know the results sometime in the next couple of years. So I'm very excited about the potentials of this drug for our patients to actually get better results than we have over the years. Thank you very much.

Videos

At the 2023 ASRS annual meeting, Dante Pieramici, MD, spoke with our team to share information on OPT-302, or sozinibercept, for the treatment of neovascular AMD and other retinal vascular diseases. 

ASRS 2023: Dante Pieramici, MD, provides update on OPT-302, or sozinibercept,

Thanks to all of you for this very informed discussion. Before we conclude, I’d like to get final thoughts from each of you. Dr Adrienne Scott?

I think it’s an amazing time to be a retina specialist. I’m at a point in my career where I can remember when all we had were certain laser treatments and photodynamic therapy and just hoped a patient didn’t lose vision or hoped we could slow their vision loss. Now it’s exciting that we seem to have this wealth of things in our armamentarium to offer patients. But the jury’s still out, and then the ultimate elephant in all our rooms is the insurance payers and the ultimate cost to the health care systems with all these different products. But it’s an exciting time. I’m thrilled to be practicing with so many choices.

I’ve been practicing retina care longer than anyone here on this panel. And I’ve lived the bad old days of managing these common vision-threatening and blinding disorders pre-anti-VEGF [anti–vascular endothelial growth factor therapy] here, and the world is a lot better right now. And we’re continuing to make very good progress at a very good rate. Obviously, when anti-VEGFs hit the scene, it was a major transformation in helping our patients, and we’re still doing better. It seems like every year or two we get either a new therapy or a new approach or thinking that improves our patients’ quality of life, and that’s very exciting. I think we’re going to continue to make great progress in the future.

On the opposite side of the spectrum, as a young retina specialist, I would say it’s an exciting time because we have multiple dynamic plays in effect. We have reference drugs that have been on the market for almost 10 years now. We have biosimilar agents that are being introduced to rival or complement these reference drugs. We have gene therapy, which hopefully will transform how we treat in terms of treatment burden. On top of that, we have this AI [artificial intelligence], big-data component. So, as a young retina specialist, having these different avenues to be able to look at the field is very inspiring, and I think it inspires young retina specialists to go into the field.

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Nathan Steinle, MD; Adrienne Scott, MD; Carl Regillo, MD, FACS, FASRS; and Prethy Rao, MD, MPH, share final thoughts on the changing treatment landscape of neovascular AMD and DME. 

Key Takeaways on Managing Neovascular AMD and DME

Another interesting topic we could talk about is dry age-related macular degeneration [AMD]. I used to think when I went to the conferences, they always put the worst topics at the very end, right? It used to be pediatrics, and then it’d be uveitis. At the very end, it would be dry AMD. And now dry AMD has moved to the front. It’s one of the very hot topics we’re talking about now. Just as of last month, we have an FDA-approved agent for dry AMD. Have you made the transition to treating dry AMD? Tell me your thoughts.

Again, very fascinating. These are groups of patients who never had any therapies. We’ve been speaking about patients with wet AMD who are now getting excellent vision outcomes, more so than before these agents were available. And the GA [geographic atrophy] folks were left behind. So, to me, it’s exciting to be able to at least tell the patients there are developments, and I think our patients get encouraged when they know that there may be treatments for their disease, which we said there’s no treatment for and told them to take these arid supplements but without any hopes of really impacting their disease.

So, I haven’t used these GA therapies as of yet. At my institution, Johns Hopkins University in Baltimore, Maryland, it usually takes a while to get new medications in our hands. But that works to our advantage sometimes, since we are waiting, watching to see what’s going on in the real world. I’ve been speaking about it with patients and trying to assess their excitement for the drugs. And there’s been quite a mixed response. You have some people who are quite enthusiastic and can’t wait to use it, and then you have some patients who say, “Well, is it going to make my vision better?” And I have to answer, “No it hasn’t been shown to do that.” And that decreases their excitement quite a bit.

How about over here? For pegcetacoplan, what are your thoughts?

I’m very excited about the medication, in terms like Dr Scott said. Historically, we’ve had not much treatment except the arid supplement. Now we’re giving patients hope that there is treatment for dry AMD in terms of slowing the process. I am having discussions with patients about it being an option. I think in terms of implementation, it’s harder to convince patients, like Dr Scott was saying. Your vision is not getting better.

The beauty of anti-VEGF [anti–vascular endothelial growth factor] treatment for neovascular AMD is that their vision gets better. They have that motivation to maintain their vision. But in the patients who are seeing fairly well, it’s hard to convince them to get an injection in their eye. And the hard part is that we don’t know for how long the treatment lasts. We have clinical trials that say up to 2 years, but after that, what happens? Do we still do it? How often do we do it? Do we shift to more of a treat-and-extend regimen, where we’re doing it every 4 or 5 months? So, it’s hard to talk about that with patients.

For sure, yes. There’s a 3-year GALE extension trial going on, so we’ll have 5-year data at some point, but yes, it’s down the road for sure. Dr Regillo, what are your thoughts?

When we talk about AMD as a whole, when we say dry [AMD], we’re talking about the advanced dry form, right? Geographic atrophy is the form that will typically cause some degree of symptoms and visual acuity loss. For most of our patients, they have early/intermediate dry AMD, and many of them will never convert to wet AMD. Many of them will never get GA. But with our patients living longer, they’ll either convert to wet AMD and get GA later or just simply get GA later if they grow old enough to get it or depending on the characteristics of their disease. So as everyone’s saying, we haven’t had an effective treatment for GA to alter the natural history of this slowly but relentlessly progressing condition.

I’m very excited that for the first time, we have a drug that can, to a small degree, slow the rate of growth of geographic atrophy. It’s logical to treat early if we can, before the GA affects vision or knocks visual acuity down. But even in patients who have lost some vision, it still could be beneficial to slow the rate of growth of GA. We have the one approved agent, pegcetacoplan, which is a complement inhibitor that blocks C3 synthetic peptides that were injected intravitreally. And based on the results of the clinical study, we talked about the frequency of injections. It’s going to be a fixed regimen. There’s no way to monitor the response to therapy. You can only hope that the patient’s going to behave on average as they did in the studies, with a slight reduction in the rate of growth, and monitor them for adverse events, which I’m sure you’ll get into.

But it has some downsides. I’ve already started to treat patients with this drug, and for the most part, I’m telling them it’s going to be every month or 2. And most seem to prefer 2 months, knowing that every 2 months worked almost as well as every month, but with half the adverse events. So, phrasing it that way, most end up choosing every 2 months. I think that’s how I’m going to utilize the drug for the most part. I’m sure there’ll be exceptions.

Talk to me a little about the safety profile for pegcetacoplan and what concerns you have.

I think the IOI [idiopathic orbital inflammatory] events are a significant concern. I think it was around 2% or 3% in the clinical trial. We’ll see how that plays out in the real world. It is still promising, so I still think it’s something we should offer patients, with the caveat that we might have that safety signal as well. So, we’ll see just over time.

And how about this conversion from dry to wet AMD? What do you think the mechanism is, and what are your thoughts?

Well, I can tell you we don’t know the mechanism. But it’s not unique to blocking C3. It looks like it’s also a phenomenon that occurs with blocking C5, which is the other agent, avacincaptad, that has the potential to get FDA approved later this year because it had successful registration studies reducing the rate of GA growth. It had a similar efficacy and similar safety profile. But it is an issue, and every patient needs to know that if you have dry AMD with GA, which is the patient population we’re talking about treating, the risk of turning wet AMD based on these pivotal studies with these 2 drugs, is in the range of about 3% to 4% per year. And that’s going to increase by blocking complement, at least C3, C5. They need to know that if they’re starting on a course of therapy for their GA, they have to accept the trade-off that they may have a higher rate of conversion to corneal vascularization and the potential to get dual treatments, one for each condition. Or they may elect to stop the GA treatment, knowing that the wet AMD is the bigger, more acute threat to the vision.

But nonetheless in the clinical trials at the phase 3 level, we were allowed to treat wet AMD as we typically would in practice and continue to treat GA. And patients, in general, did quite well who converted. So, in practice, I anticipate that in the very near future, I’ll be doing dual therapy with 2 injections in these patients. And I’ve had a good reception to the notion of doing treatments in patients with GA, a select group that either have their vision imminently threatened or are already starting to be affected by GA. They’re willing and able to undergo a course of regular, frequent treatments.

Do you think the role of having this subretinal fluid phenomenon and having a complete drying effect and contributing to the GA will affect how you treat their neovascular component? Are you OK with tolerating a little bit more fluid in those patients?

Well, the one thing I will say is I’m not going to treat just CNV [choroidal neovascularization]. I’m going to treat actual exuding CNV. And even in practice without GA, I don’t treat CNV unless it’s actually leaking, it’s active, and therefore showing clinical manifestations of exudation. So, I’ll do the same here. If they’re starting to exude, I’ll treat them with anti-VEGF in hopes of maintaining the best possible vision outcome.

Dr Steinle, I’m interested in your thoughts.

How do you feel about the geographic atrophy therapies?

Good question. I’ve been an early adopter in this one, so I have a number of patients who now are on treatment for dry AMDs. And the reception in my clinics has been phenomenal, honestly. It’s been an easy approach for patients, and they’re desperate for therapy. And my regimen so far, because on-label it’s approved for acute 25 to 60 days, is 1 to 2 months. And I’ve been splitting the difference at 6 weeks and just going right down the middle. Based on most of my feedback from patients, they can tolerate about every 6 weeks, and that seems to be well tolerated so far.

My concerns are 2-fold, one of which is a conversion from dry to wet AMD. And the second we don’t talk about a lot is the volume. It’s a 100-μl dosing, and so to do that so frequently in these patients over and over again, it’s a viscous substance. And so, you’re injecting it in the order of injecting syrup. It’s really thick. In the trials, we’ll have to watch in the real world how those frequent injections over time with 100 μl play out. And then to Dr Regillo’s point that if the patients did convert to wet AMD, they were treated the same day of first anti-VEGF-A and then getting the pegcetacoplan. So that’s 150 μl put in the eye in a single visit. That’s a lot of volume, so those are my concerns. But there are patients definitely willing to go through it, for sure.

It’s interesting because this age group, they’re older and it’s very rare for them not to know somebody who is getting an injection in their eye and knowing that it’s relatively well tolerated. I get very little pushback when I say, “Oh, by the way, there’s a treatment. This is what it could accomplish. This is the risk, and it’s an injection in the eye.” And I have yet to get, “I don’t want that.”

You’re absolutely right. I think a big hurdle in the past is that patients just didn’t know the concept of getting an injection in the eye. And now I think in the older population, they have a lot of friends who are going through some of the therapies. Very true. One question for you really quick before we wrap up here. If you have a patient who has wet AMD now and you’re treating them and you’re starting to see a little area of GA off to the side, those are the tricky ones. What are your thoughts? Would you start applying pegcetacoplan to those patients in addition to anti-VEGF?

Yes. Still, my mind goes to the most rapidly growing, the process that’s most likely to be most detrimental to vision most quickly. So, my priority is going to be treating choroidal neovascularization. That said, I don’t have the GA treatments in my hands yet. But I’m thinking about when I do, this is exactly the type of person who may end up with both injections, or I will at least discuss the option with them.

It’s inevitable. The day is coming that we’ll treat GA that converts to wet AMD. That’s a given, as we discussed. But wet AMD eventually gets GA, and we all have these patients. Their wet AMD is under phenomenal control. They’ve had great vision, but now their vision is being threatened or affected by the GA. They’re telling us that, and I think they’re going to want treatment.

Expert retina specialists discuss recent developments in the treatment landscape for geographic atrophy (GA) and the future management of patients with coexisting neovascular AMD and GA.

Managing Concurrent Neovascular AMD and Geographic Atrophy (GA)

. Let’s discuss that. This is a paradigm shift for retina. We’ve watched dermatology, neurology, and oncology go through it, and now it’s at the forefront for us too. I’ll start with you, Dr Scott. First, have you delved into biosimilars? What are your thoughts overall on the whole paradigm?

I haven’t waded into the biosimilar pond. I will if forced to by the insurance payers. I feel a bit disappointed in the price points of biosimilars. If the whole point is to save on overall drug costs for our health care system, to my understanding biosimilars are 20% discounted from branded medications. If that’s the case, if a payer is mandating it, I’d be more comfortable starting with bevacizumab. You’ve got a lot of data based on the long track record of bevacizumab. I haven’t used biosimilars. I would, and I will when forced to. But I’d start with bevacizumab before that.

Those are good thoughts. How about over here? Biosimilars?

I’m in the same boat. The jury is still out. In the long term, they’re probably OK. But the data aren’t there. We have other agents where millions of patients have been treated vs hundreds and thousands with biosimilars. I’m similar to Dr Scott. If the insurance payer mandates it, then I’ll use it. But I’m in the wait-and-see category because safety is an important concern, especially with these other anti-VEGF agents that came out recently. I don’t want to put our patients at risk for something that might have an adverse effect that might not be shown in the clinical trials. I’ll go with the wait-and-see approach.

Slow it out there. That’s OK. Dr Regillo?

We’re all in the same boat with very little biosimilar utilization. It’s mainly because the step therapy mandates know that there’s much greater savings with bevacizumab off-label. Sometimes we’ll go to a biosimilar as the next step. But the best savings at this time is still with bevacizumab. That makes our space unique. Unlike our other medical colleagues, who use physician-administered biologics, I’m not aware of any bevacizumab-analogous story out there.

Right now we have ranibizumab as a biosimilar, but coming soon will be aflibercept as a biosimilar. Is that going to change the market even more? Will that twist your arm a little more?

It all depends on the cost savings. If it’s a 10%-to-20% decline, are we saving a lot for what we’re doing for the patients? It depends on that and the insurance mandates as well.

By that time, what’s going to be happening with high-dose aflibercept? What’s going to be happening with the faricimab market? It’s a fascinating time to be a retina specialist with all these choices. I’m going to have a wait-and-see approach.

You might be able to get the equivalent savings by using a second-generation newest agent, which has greater durability than faricimab or high-dose aflibercept. If it translates to 1 or 2 fewer treatments a year, you’ve already saved more money than you would have if you were using a biosimilar of the first-generation drug.

Drs Nathan Steinle, Adrienne Scott, Carl Regillo, and Prethy Rao share their perspectives on biosimilars in the treatment of neovascular AMD and DME, emphasizing how their cost will affect their uptake.

Role of Biosimilars in Neovascular AMD and DME Treatment 

We have all this great clinical science, and we have to get it to our patients. Sometimes what’s standing in the way of us applying it to the patients is the insurers. We all say yes. A lot of times in these protocols, whether it’s for DME [diabetic macular edema] or for AMD [age-related macular degeneration], we have to go through step therapies, specifically in the off-label use of bevacizumab. What are your thoughts about bevacizumab? How do you approach step therapy?

Protocol AC from the DRCR [Diabetic Retinopathy Clinical Research Network] shed a lot of light in terms of how we treat patients and requirements from insurers. I was very hopeful that Protocol AC demonstrated that. If you had to start with bevacizumab and ended up switching later, the outcomes in terms of vision were similar in both patient populations. I have that discussion with patients when we’re limited by their insurance to start with bevacizumab. That reassures patients that their vision outcome still can be very comparable if we end up starting with this vs a different agent.

It’s reassuring to have a well-designed prospective study. It says that, on average, we’re probably not harming our patients starting with bevacizumab, a drug that’s obviously very inexpensive to use, that’s aliquoted and off-label intravitreally. But Protocol T definitively demonstrates that bevacizumab is not as effective as aflibercept. The premise is, should we start with aflibercept first, or can we switch? That’s how Protocol AC was designed over a 2-year time frame.

Over 2 years, 70% of patients got switched from bevacizumab to aflibercept. That’s a high percentage. Plus, when you look at the numbers in that study, the patients who started with aflibercept vs the switch arm from bevacizumab to aflibercept, had almost 2 fewer treatments in the aflibercept arm. From the individual patient standpoint, getting drier faster with fewer injections is attractive. Patients need to know that if we’re forced to go with bevacizumab first, it may result in more treatment and may ultimately switch, but also more injections to get to the same end point of vision gains and retaining those gains.

I agree. That 70% switch definitely caught my eye too.

Yes, for sure. How about in Baltimore? You’re next to Washington, DC. Can you teach me about the step therapies you have to deal with there?

I lean heavily on the DRCR Protocol T to guide my DME treatment. But insurance payers have other things in mind. Everybody understands that. The patient understands that. I feel comfortable, with the results of Protocol AC, starting with bevacizumab. It’s OK. We’re not harming anyone. I agree with what Dr Regillo was explaining that bevacizumab is a fine drying agent. However, it has to be given frequently. It’s counterintuitive to what we’re trying to do for our patients, which is to decrease their treatment burden. It’s nice to know that you’re not harming the patient. I’m not worried if the payer is mandating me starting with the bevacizumab. But I feel a little more uncomfortable using it in patients with poorer vision at baseline. Knowing what I know based on Protocol T, they would likely benefit from a more powerful drying agent.

That’s changing because we’re getting better-drying drugs. Protocol AC was using aflibercept, the best-drying drug at the time. But faricimab looks better. Even brolucizumab, which is FDA approved for DME, is a better-drying drug. Maybe that would translate to even fewer injections. Time to dry again is faster with the better-drying drugs, so that could be less treatment. There’s some cost savings to that too. Of course, this is all done because of cost savings. It’s same thing with biosimilars and so forth.

Think about what are we’re saving. We’re saving the cost of the medication, but that’s a patient who has to take time away from their work, family, and job, and this has a high treatment burden. What are we saving and for whom? What does that equal in the long term?

Adrienne Scott, MD, and Prethy Rao, MD, MPH, discuss implementation of step therapy in neovascular age-related macular degeneration and diabetic macular edema without compromising vision outcomes.

Approaches to Step Therapy in Neovascular AMD and DME

How about if we switch over to gene therapy? I’ll open this to everyone. It’s really fascinating. We’re talking about all these injections but maybe we’re going to stop these injections someday. What are your thoughts in general about gene therapy and how the field is evolving over time?

I think in the era of treatment burden and with the dry-emerging therapies for dry AMD [age-related macular degeneration], being able to say, “OK, you can maybe get 1 or 2 a year,” will change the lifestyle of the patient in terms of being able to get to the appointment. So, I’m super excited about it. I’m a little hesitant in terms of more of the inflammatory effect from these injections. A lot of these trials are now adjusting and adding steroids on top of their injections, which I think makes me feel a little bit better about having the inflammation afterward.

Yes. I agree completely. I think gene therapy treatments are the game changers that we really want to be able to offer our patients. I think the jury is still out about the mechanism of administration. If it’s subretinal, is it suprachoroidal or is it intravitreal? Probably not. We don’t know. But I think that’s just going to be the game changer we’re all looking for.

Yes. It’s an attractive notion. I’m super keen on the notion of sustained delivery, getting good long-term vision outcomes with continuous delivery of a VEGF-A blocker. Because of all the gene therapy programs—there are 3 now, 2 of which are intravitreal, and the other product is either suprachoroidal or subretinal—are aiming to produce an anti-VEGF-A drug. And we know that works great and continuously. We know from the port delivery system approach long-term vision outcomes are fantastic for something that can give us adequate levels continuously of a VEGF-A blocker.

And so, proof of principles there with sustained delivery, gene therapy holds promise. I think it’s very attractive for our patients, especially if it’s easy to administer and inflammation doesn’t prove to be an issue. Because it is something that we have to contend with, address, treat, suppress, and so forth in at least most of the approaches. Maybe not subretinal but suprachoroidal and intravitreal, some degree of upfront corticosteroid use is necessary to suppress inflammation, which is to be expected with the administration of a viral vector. It is inflammatory in nature, at least upfront. But we also have the potential for another sustained delivery which are the TKI [tyrosine kinase inhibitor] programs and there’s 3 active ones there.

Drs Nathan Steinle, Adrienne Scott, Carl Regillo, and Prethy Rao highlight gene therapy as a future treatment of neovascular AMD and DME and how it will significantly reduce the burden on patients.

Gene Therapy in Neovascular AMD and DME

One of the clinical programs I’ve been involved with a lot is the OPT-302 trials. I was in the phase 1, phase 2, and phase 3 trials for it, so it’s one I know pretty well. So far we’ve been talking about anti-VEGF, and we say anti-VEGF, but you mentioned one time it’s anti-VEGF-A. With OPT-302, they’re looking at anti-VEGF-C and D.

And so, they’re doing 2 different injections. Mostly, it’s ranibizumab but now with some of the newer trials they’re looking at aflibercept and they’re adding on top of it a second injection. It’s not coformulated but 2 separate injections. And the second injection is a specific anti-VEGF-C and D inhibitor. And so, it’ll be really interesting to see how that plays out in the real-world A, to get 2 different injections and also have a different mechanism of action to go after. And their trials for wet AMD [age-related macular degeneration] are mostly enrolled now looking at their phase 3 program. So, it’ll be going forward.

I was going to say this is a high bar because we’ve gone down this road before because the primary objective here is not durability play, it’s to add on a drug that is combination therapy to get better vision gains. It’s a superiority study. We’ve been talking, everything has been compared to a prior approved drug in mostly anti-VEGF-A and noninferiority trials. So, superiority, we tried it before with anti-PDGF added on to anti-VEGF-A, and it didn’t work. But you’re right. This looks promising. Phase 2 looks pretty darn good for better vision gains, and increased BCVA [best-corrected visual acuity] from baseline compared to just monotherapy anti-VEGF-A. I’m pretty excited but I’m cautiously optimistic as I should probably say.

So, are we talking about 2 different injections for the same patient in the same setting?

How do we feel about that logistically and do you think that’s a tough sell to the patients?

I think it is a tough sell to the patients. And they are looking at 2 different injections separated by a half an hour time point. And I think it’s going to be difficult for our clinics just from a flow standpoint. I’m also worried about the pressure on that patient over time. What are your thoughts?

Our future is, I think the writing’s on the wall because we now have our first geographic atrophy injection. And those patients will get wet AMD over time, or we might treat our wet AMD patients that are developing atrophy. So, the notion of 2 injections of 2 different drugs is coming in our very near future and if this trial is successful, I think absolutely considering starting with patients, especially patients with more decreased vision to try to get better vision gains. And that’s exactly how the OPT-302 study is designed, patients with more decreased vision upfront with nuance at wet AMD.

Expert retina specialists discuss the OPT-302 study and the challenges presented when using 2 agents in tandem to treat diabetic macular edema.

New Therapies to Supplement Anti-VEGF Treatments in Neovascular AMD and DME

We’ll move on now to emerging therapies. One exciting thing that drew me to becoming a retina specialist, and I’m sure all of you too, is that our field just keeps changing. It’s amazing. On the horizon, Dr Regillo, regarding high-dose aflibercept, instead of the standard 2 mg dosing, they’re prescribing 8 mg dosing. Can you talk us through a little bit about the protocols going forward and what your thoughts are on high-dose aflibercept?

Sure. It should say changing for the better.

Getting better, longer lasting therapeutics for both neovascular AMD [age-related macular degeneration] and DME [diabetic macular edema] and that’s a lot of what’s in the pipeline. And that includes on the top of the list because in the very near future, the potential approval of high-dose or 8 mg of aflibercept, quadruple dose, 2 mg is what we’ve been using of course on the label in practice. The drug at this dose was tested for both neovascular AMD and DME in the PULSAR and PHOTON studies. These were phase 3 registration studies, and they met their primary end point, which was noninferiority. The noninferior visual acuity gains compared to a standard 2 mg dose of aflibercept on the label, which means after the load, every 8 weeks for both diseases. And in the high-dose arms of the 2 studies, we’re able to dose up to 12-week intervals or 16-week intervals. Every time we get a new drug and a new study, the study design is always a bit different. So it can get a little complicated.

But to make it rather simple, I’ll say successful studies met the primary end point of being noninferior. And in those extended-dosing high-dose arms we saw fairly impressive percentages of patients being treated at the primary end point every 12 weeks or 16 weeks. Again, suggesting greater durability compared to 2 mg. And in the wet AMD study it was about 80% of patients were 12 weeks or 16 weeks in that range. The DME was even better, around 90% or around the 12-week to 16-week range. And again, based on the study design of disease activity criteria being used—every study is slightly different—but nonetheless, it gives us the impression of a drug that doesn’t give you better vision gains but seems to last longer and with a good safety profile. That’s key as we’ve talked about earlier about anything new that gets introduced.

So intraocular inflammation rates and other adverse events were very comparable between the old-fashioned, standard 2 mg and the new aflibercept at 8 mg. Interestingly, this was tried with ranibizumab [Lucentis] in the HARBOR study’s quadruple dose. And there were hints that you got a little better durability in the PRN [pro re nata] arms but nothing, I would say, clinically meaningful enough to pursue that dose. But this is looking different. And so, this has the potential to be FDA-approved in our hands for both indications this year.

All right, we’ll move off-topic now. We’ll go to a different set of molecules. We were only small for a long time in retina and now we’re talking about these large conjugates, these 1000-kilodalton conjugates. One is KSI-301. Can you tell me a little bit about that platform and what your thoughts are?

Yes, it seems like this drug is a go big or a go home drug.

It’s interesting. It’s an ABC, an antibody biopolymer conjugate. And so basically, the molecule itself is an IgG [immunoglobulin G] antibody that’s large and that’s combined with a biopolymer. And the idea is to provide durability for 2 different reasons. One is with a high molecular weight, which is this drug is 950 kilodaltons compared to way less in the other medications that we were talking about earlier. And the second is, is a higher dose. So those combination of things is what this molecule is trying to achieve.

And so, the DAZZLE and DAYLIGHT studies, mainly the DAZZLE study initially was a phase 2/3 study that demonstrated 3 loading doses of this KSI-301 study followed by an extension to 3-, 4-, and 5-month marks compared to ranibizumab on its own label use. And the results were promising but the primary objective was to look at the mean change in visual acuity and they did not achieve a noninferior result. It’s a little disappointing from that standpoint, I think, for everyone because we were excited about this molecule.

But, if you look at the fine print, a lot of these patients, I think Dr Regillo you mentioned this in some prior talks, is about 60% of the patients still end up getting to the 5-month mark with this medication. So that is still a good number of patients that are being treated out to this 5-month mark. The other thing that they did mention though was about 3% of their patients did have IOI [intraocular inflammation] events. It’ll be interesting to see how that translates going forward. So the DAYLIGHT study in contrast is looking at monthly doses of this medication compared to the aflibercept on the label. So, it’d be interesting to see what those results show.

Retina specialists review new and emerging treatments in neovascular AMD and DME, highlighting high-dose aflibercept and KSI-301.

Emerging Therapies in Neovascular AMD and DME

Back to faricimab, we talked earlier about loading doses. I’m really curious, Dr Rao, the question is coming your way this time. In the trials, they had loading doses, and on-label you had to do 4 loading doses or 6 loading doses of faricimab, then move on to extended therapy. What do you do with your DME [diabetic macular edema] population? Do you load these patients?

The purist, I’m a bit afraid. Along with the disease state of these patients is the treatment burden and having a bunch of other appointments for them to get to. I stick with my previous approach of 3 doses in a row, and then I’ll start to extend them a bit further. But I think 6 might be a little harder in the diabetic population because you want to build trust with the patient as well, and you don’t want them to be on this injection train of, oh man, this is happening forever. That’s 6 months of treatment, and they have to get to their other appointments, so I stick with 3.

Although I agree with you, there’s no fixed induction. The unfortunate reality is DME is a slower responding condition, and you often do need monthly treatments for 4, 5, 6 injections, and so I don’t want to start extending until I think the macula is as good as it’s going to get. Unfortunately, DME is particularly treatment heavy in that first year. That slower response, it’s never 1 and done. Very rarely do you get the wow effect from a severely thickened edematous macula to a beautiful macula after just 1 or 2 injections.

Loading doses for DME, how do you approach it?

Similarly, I’m not as stringent with this population as I am with patients with wet AMD [age-related macular degeneration]. Some of that is logistical. These are patients who, again, benefit from, they are not retired like our patients with wet AMD often are. So, I try to, similar I think to what Dr Regillo was describing, treat until I feel like the macula is fairly fluid free, or as fluid free as we’re going to get them, and then I start extending them out. But I tell them, we’re going to put in the work together the first year or two of treatment, and then after that, we can enjoy some of the benefits of maybe less treatment interval. But part of bringing them back is how I’m learning about their eye, and I’m learning about their disease process, and who’s going to need more treatment, and who you can be a bit more lenient with the visit. I’m learning about them, and having them back is teaching me how their eye is responding.

Oh, that’s fantastic. It’s really good insight.

Let’s not forget the systemic aspect of this disease. Every visit, I often tell the patient, we’ll do our part, you’ve got to do your part in between the visits, which means getting your blood sugars under the best possible control. Because if their diabetes management is not on par and their A1C [glycated hemoglobin] is super high, it works against us for sure. And that will lead to DR [diabetic retinopathy] progression and other potential vision-threatening complications, proliferative disease, hemorrhaging, and all.

In the trials, they had this magical number of 325 μm, and you could extend once you got below 325 μm. I must admit, I hardly look at the numbers at my clinic. I look at morphology. How about you guys, do you look at numbers or do you look at…?

Yes, and I look at the percentage change.

I look at the numbers in terms of gauging their treatment. If I feel like after maybe 3 or 4 that we’re having less than 10% reduction or 10% to 15% reduction in fluid, then maybe that helps guide me in terms of switching them a lot faster. It’d be interesting to see what your thoughts are, but I tend to switch these patients faster when I don’t get a great response because I do want that durability effect. And so, for a lot of these patients, it’s difficult to make the appointment, so I would like to see an effect a bit sooner to be able to help them.

Yes, it’s a good question.Do you switch quicker?

Yes. I was thinking about the central subfield metrics, and I use them when I’m deciding whether to initiate treatment. Then I look at morphology as the treatment process goes on and how much you’re responding. But that threshold, to me says, OK we need to seriously think about treatment, and I will look at the central subfield. And the thickness map is, again, I think a great teaching tool for the patient and the family.

So, they have that buy-in. It makes sense.

Drs Nathan Steinle, Adrienne Scott, Carl Regillo, and Prethy Rao comment on loading dose recommendations for faricimab or other anti-VEGF therapies in the treatment of DME.

Faricimab Loading Dose Adherence in DME Therapy

We’ve talked a bit about how the DME [diabetic macular edema] population is an interesting population. They’re working age. We also talked about this PTI [personalized treatment interval] arm, or treat and extend arm. In the real world, Dr Scott, how do you apply these clinical data from the YOSEMITE and RHINE trials to your patient population in Baltimore?

I do use this treat and extend strategy quite a bit. To me what that means, and again, I try to explain it so a patient can understand it. You come in, there’s no fluid in the picture, your vision is stable, the OCT [optical coherence tomography] shows no fluid. Then we extend and that means to me 1- or 2-weeks additional frequency.

How about this question? We’ve talked about anti-VEGF therapy. There’s also a whole other paradigm of steroids. I’ll throw it back to you. When do you switch to steroids, and how do you incorporate steroids into your treatment for DME?

I’ve become a believer in steroids, that some patients are more steroid-responsive with their DME. As was mentioned earlier, it’s a very complex pathophysiology about why some people get DME and how significant their DME is. For me, I tend to ascribe to the swim lane rationale, meaning that I’ll do an anti-VEGF first line, and after the first 3 anti-VEGFs I’m looking, and even after the first 1 or 2, if I don’t see significant improvement in their intraretinal fluid, certainly subretinal fluid should respond. But if I’m not seeing as much of a decrease in their central subfield on OCT, I’m starting to think and maybe even have the discussion about switching agents.

So perhaps after the first 3 anti-VEGFs, which are my first line of go-tos, I’ll consider using a steroid. Of course, you want to consider is that person going to be a good candidate? Do you have considerations about cataracts or elevated intraocular pressure [IOP], which I have become a bit more comfortable treating and managing those things, and being able to figure out the patients in whom they will be an issue. But I would go to steroids a lot earlier in my treatment armamentarium than I used to.

Interesting. How about this side of the table?

Initially I was fearful of steroids because of that possible pressure spike. It’s interesting, you talk to our glaucoma colleagues, and they are like, “Yes, just go ahead and inject. We’ll take care of it.” I feel like I’m similar to Dr Scott in that I’ve been a bit more liberal with steroids. I would say I do try a couple of different anti-VEGF agents first before I do end up switching to the steroid. But I agree with Dr Scott in terms of it’s a very complex process, and so to be able to have that massive anti-inflammatory component really helps in these patients.

I also utilize intraocular steroids in DME. It’s proven to work, we’ve had that experience. In fact, our use of intraocular steroids for DME predates the anti-VEGF era, and studies have validated its use. Of course, with that benefit comes the adverse effects of intraocular pressure elevation in some proportion of our patients, depending on the product and the dose, and cataract progression is almost inevitable, especially with repeated dosing. I use it as the second line, exactly as described, and I think virtually everyone does. But the timeline might vary a bit in terms of when we think about switching. I certainly always try to get the patient to the best drying anti-VEGF drugs, give those a chance first, because of lack of adverse effects and so forth. If I’m using aflibercept or faricimab, the better-drying drugs in DME, and I’m not seeing a good benefit after several injections, I will then think about switching to an intraocular steroid.

Often, as Adrienne said, it does help. So, in patients who are inadequate or suboptimal responders to anti-VEGF, or patients who need anti-VEGF very frequently, sometimes there’s the added benefit of durability. You get about 3 months out of an intraocular steroid, whether that’s the dexamethasone implant or triamcinolone off-label. That is also a potential benefit for patients if you want a durability play to help ease the burden. But the reality is that the burden doesn’t necessarily get reduced all that much because you bring them back to get their pressure checks and so forth. The one big difference between DME and wet AMD [age-related macular degeneration] is that we do have another effective therapeutic. Then you could even throw in laser once in a while, though I have to say, I can count on 1 hand how many focal lasers for DME I’ve done in the recent past. It’s a pretty rare bird now.

The other benefit of using a longer-acting steroid in patients with DME is, I feel like if you’ve given a long-acting steroid, for example, a dexamethasone implant, and you bring the patient back in 1 month to check their IOP, I think it’s been shown that the people who do have an elevated IOP response will declare themselves pretty early. If they pretty much do not, then they typically will not throughout the duration of therapy. So again, I think we can figure out those individuals who would benefit from the longer-acting steroid, decreased treatment burden, little risk of glaucoma, [and] little risk of prior steroid-related IOP elevation.

Nathan, one other point I’d like to make is that we talked about neovascular AMD being a lifelong treatment process. However, that’s another big difference between wet AMD and DME. The DRCR [Diabetic Retinopathy Clinical Research] Network studies were the first to show, because they used a PRN as needed-like approach to treating DME, that each and every passing year, the annual treatment average was going way down. It dropped quite a bit. In fact, as Protocol I got into years 3 and 4, the mean number of treatments in our patients with DME was down to 0, or 1, and so forth, which meant that some patients needed ongoing treatment. Not everyone was able to come off treatment. But there were many patients who after a year or two of anti-VEGF therapy on a relatively frequent and regular basis could eventually come off.

So, in practice, I do deviate from the treat and extend approach in that I’ll utilize it to some degree, but I will test the waters and stop treatment. Therefore I go from regular frequent treatment, maybe a little treat and extend, and then transition to PRN to see if they can go without treatment. I think a lot of that is, you’re doing a lot of anti-VEGF therapy over the course of 6 or 12 months. You’re getting that added benefit of reducing the level of diabetic retinopathy [DR]. As the level of diabetic retinopathy goes down, they’re less likely to have DME and other vision-threatening complications. So, resetting the thermostat on the level of DR, and that may not be permanent, of course, you may still need ongoing anti-VEGF therapy to achieve the improved level of DR. But that is an added benefit. Sometimes I’ll keep a patient on anti-VEGF longer if they have a very high level of DR, like severe NPDR [nonproliferative diabetic retinopathy] or early PDR [proliferative diabetic retinopathy].

This is another area in which we can maybe now give our patients some more data. To turn it back to one of the original questions, what do you tell a patient about how many treatments will you require? I think we can look at the DRCR, for example, Protocol I, and you can say, maybe the first year you’ll get 6 or 7 injections, but then the second year there’ll be even less. Then by the years 3, 4, and 5, to your point, Dr Regillo, maybe 1 or 2 injections.

Retina experts discuss the benefits of using intraocular steroids to treat patients with DME as well as their approach to switching to steroids after a poor response to anti-VEGF therapy.

Wet AMD

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