nAMD and DME Management: Figuring Out the Timing

Commentary
Podcast

This special edition of the Ophthalmology Times® EyePod recorded in conjunction with Physicians’ Education Resource features an international panel of ophthalmologists, including Arshad M. Khanani, MD, MA, FASRS; Carl J. Danzig, MD, FASRS; and Anat Loewenstein, MD, MHA, who will discuss unmet needs in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) — and opportunities for extended treatment intervals that newer agents might provide. This program is designed to help clinicians better appreciate limitations of traditional anti-VEGF agents and optimize the growing toolkit of available therapies.

Welcome to this special edition of the Ophthalmology Times® EyePod recorded in conjunction with PER [Physicians’ Education Resource]. This podcast features an international panel of ophthalmologists, including Arshad M. Khanani, MD, MA, FASRS; Carl J. Danzig, MD, FASRS; and Anat Loewenstein, MD, MHA, who will discuss unmet needs in the treatment of neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME) — and opportunities for extended treatment intervals that newer agents might provide. This program is designed to help clinicians better appreciate limitations of traditional anti-VEGF agents and optimize the growing toolkit of available therapies.

Faculty:

  • Arshad M. Khanani, MD, MA, FASRS
    University of Nevada, Reno School of Medicine
    Reno, Nevada
  • Carl J. Danzig, MD, FASRS
    Director of Vitreoretinal Services and Retina Clinical Research
    Florida Atlantic University
    Boca Raton, Florida
  • Anat Loewenstein, MD, MHA
    President, Israeli Ophthalmological Society
    Tel Aviv, Israel

Dr. Carl Danzig:

Carl J. Danzig, MD, FASRS

Carl J. Danzig, MD, FASRS

Clinical trial patients are quite different from the patients we see in everyday clinic on our regular schedules. Our patients in clinical trials are the true unicorns in our patient population. They're the most motivated. They want to have the most cutting edge therapy. They are altruistic, and they understand the role they play in helping advance science. These patients are truly generous and deserving of our praise.

Our regular clinic patients, they may not want to be in a clinical trial, though it's hard to be a patient these days. There is more and more pathology out there, and we are seeing that our patients are probably a little sicker than they used to be. Sometimes they're coming in a little bit later, especially after the pandemic, back to the office.

Our patients in the real world, in the real clinic, life gets in the way from them keeping their regular appointments. Maybe they have a medical problem, maybe they were laid off of work, maybe they have an issue with their house or whatever it may be. There's always some reason why patients cannot keep their regular appointments.

In a clinical trial, those patients come in like clockwork every four weeks. In the real world, we try different treatment modalities, treat and extend, and still the patients are not able to be treated adequately. In the real world, they are being undertreated. In the clinical trials, that is not the case. They're being more closely monitored, they're getting regular testing. In the regular clinic, not so much, or not as much I'll say.

Clinicians need to be able to focus on the whole patient, not just their eye pathology, because our patients have multiple medical problems and they may not be able to come in regularly for visits. When we first meet a patient, we tell them that you have neovascular AMD or you have diabetic macular edema and you are going to need treatments, long-term treatments and frequent treatments. It can be dismaying for the patient. They think about all the other things in their life and now they're committed to monthly injections and then maybe we stretch them out.

We need to be compassionate, but we also need to talk to patients about being realistic, and they need to be a partner in their own healthcare. We need to discuss with them that there are treatments out there that may allow them to have fewer injections over time, and that's exciting. Before, patients were relegated to monthly injections, and now we're able to have less frequent treatments and patients can maintain hopefully their quality of life and their vision.

Dr. Anat Loewenstein:

Anat Loewenstein, MD, MHA

Anat Loewenstein, MD, MHA

The way physicians need to address their patients when they start managing their retinal disease is to do it comprehensively and take into consideration the whole status of the patient regarding his supporting family members and caregivers.

There are many factors that found to be in various studies as important in predicting how compliant will the patient be. Not all of them are intuitive. For example, a distance from the clinic is a significant factor in compliance of the patients. I think this is something that is quite intuitive because the further a patient needs to go monthly, if he needs to go monthly, makes it more difficult for him.

Other parameters that have been found to be significant are less intuitive. For example, it was found that if the caregiver is a spouse, then the compliance is better than if the caregiver is a son or a daughter. I think that the reason is that a patient kind of expects his spouse to accompany him and take the burden of the treatment with him, whereas for his children, he feels that it might be too much of a burden. He might not want to pose any difficulties on his children, and the children might be also more busier, so to say.

There are a few factors that we know that need to be considered, such as distance from the clinic, the person who is the caregiver. But I think the most important thing, and this is basically what leads me in my treatment decisions, is how much the patient himself is committed to the treatment. I think that for me, if I need to give a patient a loading dose that is comprised of four monthly injections, for example, and I'm telling him you need to come monthly and to commit to that, and if I say it upfront, I have much higher chances to keep his compliance and make sure that it comes.

Host:

When initiating anti-VEGF treatment in patients with nAMD or DME, clinicians have a variety of options. Dr. Danzig and Dr. Arshad Khanani provide perspectives on treatment decisions.

Dr. Carl Danzig:

When we meet a patient for the first time, we really want to give them the best care possible. Now, all too often we are handcuffed with step therapy where we can't necessarily start with a branded product first, but that aside, starting with first-line treatment such as faricimab will allow patients to have greater benefit sooner. We see greater drying effects, improved macular leakage on fluorescein when you start with faricimab.

Furthermore, we know from previous studies and previous presentations at various conferences that stability of the retina is important. The fluctuations of subretinal fluid and especially intraretinal fluid is deleterious for the retina and portends a worse visual outcome long-term. We want to eliminate the rollercoaster of fluctuations of fluid within and under the retina in order to give the patient the best chance for optimal vision.

I like to think of the retina as a tissue that has some elasticity but not indefinite elasticity. Think of it like a rubber band that you can stretch a rubber band and it snaps back, and then you stretch it again, it snaps back, and maybe a third time it snaps back, but you keep stretching it out. It doesn't have that same snap back that recoil that it once had. It doesn't have that same form and shape and strength that it once had.

The retina is similar that when you start seeing fluid going in and out and from underneath the retina and then drawing and then coming back, that's not good for the photoreceptors. I liken that to a rubber band that you stretch out just a few too many times.

Dr. Arshad Khanani:

Arshad M. Khanani, MD, MA, FASRS

Arshad M. Khanani, MD, MA, FASRS

Whenever you have a new patient that comes in your clinic with neovascular AMD or DME, obviously you need to look at the OCT, look at the visual acuity, and then figure out what their treatment needs are. As we know that anti-VEGF agents work really well looking at all different options we have available, but now we have agents that can go beyond VEGF-A inhibition including faricimab where you block VEGF-A as well as Ang2.

I'm looking for rapid improvements in anatomy, which in most cases leads to improvement in visual acuity and then also looking to extend the treatment interval so patients have less treatment burden. Again, we're lucky to have multiple different options. My goal is to give my patients the most potent agent that's available.

Host:

Next, you'll hear thoughts on a different scenario, how to move to the next therapy for patients who are having an insufficient response to their current treatment. First, Dr. Khanani on making the switch followed by determining the most appropriate treatment intervals for patients in general.

Dr. Arshad Khanani:

Patients who are getting treated frequently with anti-VEGF every month or every four to six weeks or eight weeks, obviously we won't want to see improvement in anatomy, which is evaluated on OCT. We also pay attention to visual acuity, but in clinic sometimes visual acuity can vary because we are busy, patients don't want to put in the effort that they put in the clinical trials using ETDRS testing.

In a clinic, we're using Snellen visual acuity, so our VEGF meter or our disease activity meter is actually OCT. What we are doing is looking at the OCT for fluid status, intraretinal fluid, subretinal fluid, looking at central subfield thickness and macular thickness. I think we gauge disease activity based on OCT.

If a patient is getting frequent anti-VEGF and they are not responding or suboptimally responding where you have some improvement in fluid, but it's not dried completely, we usually try to make sure that we are giving maximum dosing, so giving every month injection. After three to six every month injection, if the patient still has active disease, then you consider switching.

Obviously in the past we had to switch between anti-VEGF agents, whether you go from bevacizumab to ranibizumab to Aflibercept, Aflibercept two milligrams being the most potent agent in the past. Now we have faricimab with additional mechanism of action on top of VEGF-A inhibition, blocking Ang2 and activating type 2 receptor. That is a good option for patients.

Now, the diseases are different. Neovascular AMD is not an inflammatory disease in most cases while DME is an inflammatory disease. Addressing inflammation is also important in patients with DME, whether that means introducing steroids or introducing additional mechanism of action like with faricimab with Ang2 inhibition. I think we need to go beyond VEGF-A inhibition to control disease.

I think the goal is to dry the retina, whether it's neovascular AMD or DME, and then extend the patients out. Initially patients get monthly injections, whether three or four loading doses or more or less. And then we extend the patients out. If a patient was previously treated, I usually am very careful in extending the treatment interval. I usually go one or two weeks at a time. If you have a naive patient that's completely dry after loading doses, the question is you go two or four weeks.

In the past with just VEGF-A inhibition, I was going two weeks at a time, but with the availability of faricimab and the data from TENAYA and LUCERNE gives me confidence that if I have a patient that is completely dry after loading doses, I will extend them by one month or four weeks at a time.

I think this is changing as we have better agents that are coming since approval of Aflibercept in the past. I think what we want to do as clinicians is to maximize the treatment interval without compromising on anatomy or visual acuity. We don't want to extend patients too far out if they have recurrent disease activity because what we know is that CST fluctuations over time can lead to vision loss. We want to stabilize anatomy and keep the vision stable as well as CST.

I really individualize approach, use that approach to extend patients. For naive patients with no fluid after loading, I'm comfortable going a month. For previously treated patients, I want to make sure that I don't go more than two weeks at a time.

PDS is a paradigm shift in that sense that it's a sustained delivery device. It's not peak and trough injections. I've had extensive experience with PDS in the clinical trials as well as in the commercial setting before it was voluntary recalled because of septum dislodgment. Once it's available in the future, PDS the refill was done every six months in the pivotal trials. But we know from the phase 2 ladder study that there's majority of patients can go more than six months, and the median time to refill was 15.8 months or so.

What I'm doing with my PDSS patients is that I am treating them surgery healed, then I'm watching them until six months. If they have no fluid, I will watch them to figure out when the fluid starts to accumulate. That gives me their refill timing. So yeah, we are doing treat and extend in a very different way because a sustained delivery device, you have baseline levels of anti-VEGF at all times, so it's much less risky than peak and trough injections because neovascular AMD can rapidly progress and get worse if you don't have anti-VEGF on board.

In terms of high dose Aflibercept eight milligram, we have to get the clinical experience to see how the drug is. We'll use it in high need patients to see if we can control the disease like we did with faricimab or even switch faricimab patients to high dose Eylea to see if we can extend them or not.

Host:

Finally, for patients with DME who may require corticosteroid therapy, Dr. Loewenstein shares considerations when making this decision.

Dr. Anat Loewenstein:

When a patient with diabetic macular edema is diagnosed with significant edema and decrease in vision and we decide to start treatment, most of the time we start with an anti-VEGF agent. Now of course, we have [inaudible 00:16:01] drugs that are bispecific and have both anti-VEGF and anti-Ang2 capabilities, but basically we do want the anti-VEGF to be on board with us when we start treatment of patients with diabetic macular edema.

However, not all patients are responsive to the anti-VEGF pathway, and we know from Protocol T and Protocol I of the DRCR.net that about 40% of the patients remain with persistent edema after three months, six months. This actually predicts also the status of their edema at the end of two and three years.

In my opinion, at least when we treat with anti-VEGF monotherapy, if we see that there isn't any response after three injections or maximum six injections, then it really depends if there isn't any response or there is a partial response. If there is a partial response, I might go more towards the six months and wait, maybe the response will enhance. But if there is no response, I think this is the time to switch to another mechanism such as to a steroid.

Another parameter that I want to emphasize is that if a patient tells me upfront that he cannot come from monthly injections during the loading dose, which we know that for the anti-VEGF monotherapy agents, it needs to be five injections and for the combination treatments with anti-Ang2, it still needs to be four loading doses. If the patient cannot commit or does not want to commit to monthly loading, then many times I can suggest to start with a steroid. And then we have the ability of giving him one injection and then following him up. Of course, he still needs to take the pressure, but he might not need to come for monthly injections.

When we decide to switch to a steroid, we have a few steroids at our armamentarium. We have dexamethasone implant that we know that the duration of effect is three months or maybe a little more than three months. We also have the fluocinolone implant that we know that lasts for many, many more months, two years even. We also have the lesser line, I would say, triamcinolone, that we also have now products that are produced for the eye.

I think that nowadays it does not make sense to go to a steroid that is not one of the registered ones for intraocular therapy, such as the dexamethasone implant or the fluocinolone implant. Basically the steroid that I'm using is only the dexamethasone implant. The dexamethasone implant does have a pretty good safety efficacy profile.

Yes, if you give a patient a few injections of the dexamethasone implant, he will end up having a cataract and you will need to remove it, but we know to cope with the cataract. Yes, there are about 16 or more, a little more percent of the patients that will develop increasing intraocular pressure, but most of it is amenable to treatment with topical treatment only.

I'm not saying that I will run to treat the patients with a clear lens and patient immediately with a steroid, but if the patient is not responsive enough to the anti-VEGF agents or if he's not willing to come for monthly injections, I would treat him with the dexamethasone implant most of the time.

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