Michael A. Klufas, MD

This is going to be a broad, overreaching question. I’ll start it off by asking Dave. What advice or practice pearls do you have for other ophthalmologists or optometrists in the management of diabetic macular edema [DME] and neovascular age-related degeneration [AMD]?

: For the general ophthalmologist or optometrist, it’s important to stress: take a moment to counsel your patients to maintain a healthy lifestyle. Do not underestimate the value of taking that moment to tell them: if it’s a diabetic patient, stop smoking, get control of your glycated hemoglobin A1C, keep your blood pressure down, exercise. The same goes exactly for our AMD population because there are a lot of natural history studies, observational studies, and population studies that have shown if our patients can maintain better control of their overall systemic health, it’s going to lead to better outcomes in the future for their retinal diseases than if they were not maintaining a healthy lifestyle. Take that extra minute to counsel your patients. I’d also say have a low threshold for referring your patients to a retina specialist. Every week referring providers in the community text me OCT [optical coherence tomography] images of their diabetic and AMD patients and ask what do you think about this? It doesn’t bother me at all because I am helping the patient and the physician make the correct choice about what to do with that patient as opposed to trying to manage something themselves and not having the expertise and thinking that everything is OK, and then the patient ends up in my office a few months later with a severe visual impairment that we could have done something about earlier on. So have a very low threshold to refer these patients to your friendly retina specialist.

: Blake, any comments, advice, or practice pearls to add?

: I think that communication is key. If we are communicating appropriately with our patients and our colleagues, then we are serving everyone, and it’s important for those who are seeing patients to communicate the idea and concept that there is hope, that there are treatment options, and those treatment options are evolving. The idea of intravitreal injection is frightening, and if they can set the stage that this is routine care, it’s going to serve our patients better when they are in front of us and we are having that conversation about intravitreal injection. It’s important for us as retina specialists to communicate back to the ophthalmologists and optometrists how our patients are doing, because oftentimes we get used to seeing patients on a regular basis, and if they are doing well, not communicating. But it is important for us to make sure that we are updating them so that they realize that they are still part of the patient’s care.

: Great. How about you, Mike? Any other words of wisdom?

: It’s a team approach. That patient with diabetic macular edema came into their optometrist’s to get new glasses. As a retina specialist you initiate anti-VEGF therapy, but they want the glasses at some point. After a couple of injections, let’s get them the glasses—get them seeing better, and stay up-to-date with the most recent treatment paradigms. Five or 10 years ago, we weren’t treating diabetic retinopathy without DME, but someone with severe NPDR [nonproliferative diabetic retinopathy] and uncontrolled A1C. In 2022, we have to discuss anti-VEGF as a treatment option. It may not be treating all our patients that way, but some of those patients do need to see retina a bit earlier—before things get worse. Staying up-to-date with all the treatment options as well can be a good practice for all of our eye care providers.

: I will add in 2 more things—2 more pearls of advice for our primary eye care providers. Number 1 is mention the importance of early detection, so if you have OCT at your disposal, anything that looks like it’s vision-affecting or vision-threatening complications of DME, or whether it might be neovascular AMD—early detection, early referral, early treatment have the best results. Have a low threshold to refer earlier. I find a lot of people underestimate the level or degree of diabetic retinopathy in particular and may miss early signs of wet AMD. The other is help us help our patients adhere to the treatments. Compliance—adherence to the regimens—is challenging, so having that reinforced by the primary eye care provider where the patient might go back and look for that new pair of glasses or help them manage their glaucoma—that can help us manage their wet AMD and their DME.

Thanks to all of you for this rich and informative discussion. Before we conclude I would like to get your final thoughts from each of you. Dr Klufas?

: 2022 has been an exciting year. Not only did we get the Port Delivery System but also faricimab, and we’re continuing to work hard with all the ongoing clinical trials. The future is bright, and I am looking forward to offering all these therapies to our patients.

: Goldilocks and the 3 bears sums it up: not 1 size fits all. We need to continue to personalize care for our patients and consider our patients’ preference when deciding how best to manage someone who lives with diabetes or macular degeneration.

: I agree with all, and I just add that the therapeutic pipeline is robust for both of these diseases. There is a lot in development for both diabetic disease and neovascular AMD, so the future, like Michael said, continues to look bright. We have a lot of more exciting therapies in the near future.

: I agree. Management and outcomes are definitely looking better, and we can do so much more for our patients now more than ever, and that’s going to continue to improve over time. Thank you for watching this 

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Retina specialists share advice and practice pearls regarding the management of DME and neovascular AMD, including counseling patients about the importance of healthy lifestyles. 

Practical Takeaways and Future Directions in DME and AMD

: Mike, we’re living in an exciting time in our space treating these common retinal disorders, neovascular age-related macular degeneration [AMD], and diabetic macular edema [DME], some exciting new therapeutics and approaches to treatment but the pipeline looks pretty rich. There are other things coming. Tell me about it.

: The future is bright, no pun intended, and it can’t be lost upon us that gene therapy is approved in the eye for 

-associated inherited retinal dystrophy. We are using the same technology to create an ocular biofactory to create anti-VEGF in patients with neovascular AMD and diabetic retinopathy and diabetic macular edema. These programs with pars plana vitrectomy and subretinal approach are probably coming to us in the next couple of years if they pan out. The holy grail for gene therapy is determining if we can administer this in-office via suprachoroidal or perhaps an intravitreal approach. That remains to be seen. If aflibercept is something we are comfortable with, there is a high-dose aflibercept trial which may give greater durability based on the preclinical data, and we are all eagerly awaiting those results. Tyrosine kinase inhibition is another pathway that is not a biologic that we can administer at very high levels in the eye without causing systemic adverse effects. I don’t think it is being touted as a replacement for anti-VEGF, but perhaps a maintenance therapy with a vehicle that will allow continuous release in the eye. We also have some other exciting things such as OPT-302, which inhibits not only VEGF-A but VEGF-C and -D. That could be a nice compliment to something like faricimab, which inhibits angiopoietin-2, and we will see if other types of VEGF isoform inhibition may allow us to have better outcomes in some of our patients as well.

: A lot of what’s in the future is directly or indirectly targeting VEGF-A, maybe other mechanisms of action—VEGF-C and D; perhaps that’s going to get us better efficacy. The other approach is TKIs [tyrosine kinase inhibitors]; maybe durability. Gene therapy—the ultimate durability; we say 1 and done, but in reality it’s not going to be a cure. It’s not going to control disease in everyone across the board. Even phase 1 or at least testing is indicating it can do that to some degree in some people, but not everyone. There is a lot that’s unknown there, and I am sure we are going to be closely following the safety profile of the gene therapy programs, but it’s exciting and it’s not far off, as you indicated.

Blake, given the recent approvals for DME and neovascular AMD with some exciting new therapeutics or therapeutic approaches, what unmet needs remain both in the research and clinical treatment of these patient populations?

: Carl, it’s an exciting time to be practicing retina. We have a lot of treatment options for our patients, but probably the biggest unmet need right now is going to be the recruitment and diversity and generalizability of our upcoming trials. I feel that as we have better treatment options, it’s going to be harder to enroll patients, and we want to make sure that we are enrolling patients that are within our community. Creating networks within underserved communities and a more diverse pool of not only investigators and staff will hopefully help us be able to have trials that are more representative of the general population. I also feel that it’s important for us to make sure that we’re establishing long-term relationships within our communities and encouraging patients if they haven’t thought about a clinical trial to consider 1, because it’s going to benefit not only hopefully them but other generations of people who live with diabetes or macular degeneration.

: It’s an interesting point you brought up about the research in the diversity of the patients recruited into clinical trials. It is known; we have seen some ethnic differences in response to treatments. It’s going to be important. We make sure we could encompass all patients potentially affected by these conditions DME and neovascular AMD. Neovascular AMD in a Caucasian population can be quite different in Asian populations, and so forth. We've seen some differences there. In fact, some of those countries want their own clinical trials because of those differences.

Carl D. Regillo, MD, FACS, leads a discussion with retina specialists about the future of care for AMD and DME, including tyrosine kinase inhibition and gene therapy.

What’s on the Horizon for DME and AMD

Mike, can you tell us your thoughts on how these newer therapeutic approaches—faricimab, the Port Delivery System—are going to affect patient outcomes?

: It’s great to have more treatment options. Seven years ago we had 2 or 3 treatment options. Now, for neovascular age-related macular degeneration [AMD] and diabetic macular edema, if you include clinical trials, you may have up to 10 treatment options to offer your patients. Faricimab (Vabysmo) and the Port Delivery System [PDS] or ranibizumab (Susvimo) are contributing to those options. Faricimab or Vabysmo and ranibizumab have come out around the same time, so it’s an interesting time to offer both to patients and see which option they may choose. In reality most of us are accustomed to the injection process, so integrating Vabysmo or faricimab into your clinical practice is quite easy. The Port Delivery System, or Susvimo—this is a paradigm shift and involves some training and a little bit of activation energy to offer this to our patients. For the right patient, it’s a great treatment option. I’ve heard many people say we’ll try faricimab first, and if that doesn’t work, we will go on to the Port Delivery System. In my mind, there are different types of patients, and I try to ascertain what patient may be an ideal candidate when discussing these options, because you can’t discuss everything with every single patient, and it could be quite confusing to our patient population as well. But all in all, if they are doing well on the current therapy, I will say, Hey, there is something new that may be coming out; I am considering this in the next couple of months. Here is some information, and we will make a decision in the future.

:Do you think we’re going to get better vision outcomes with these more durable approaches?

: A lot of these trials had a 1-year primary end point, and if we are thinking that we might have superiority of 1 to 3 letters per year, it’s going to take a couple of years to show that. In theory, especially with previous trials, they have shown more frequent treatment has yielded better outcomes by a couple of letters. If we follow these more continuous therapies over time, there is a potential to show that, and that would be a real advance for our patients. It’s something else to consider when offering these more durable or continuous therapies as well.

: I’m hopeful. I think it means less disease recurrence and better long-term maintenance of those vision gains we get up-front, rather than losing them as in the real world, which is typically what those studies show.

Blake, we have these new therapies. Have you encountered any apprehension or misunderstanding related to these new therapies as you’ve now started to think about them in practice or offer them to your patients?

: We can think about it as apprehension among physicians and then apprehension among our patients. If we drill down into some of the trial results, there is an apprehension for the risk of endophthalmitis, and it’s still a relatively low number of individuals that have had the Port Delivery System. When it comes to the risk for infection and the black box warning—at least within the retina community that I am exposed to—there is still a real concern for that risk of infection. As we continue to evolve techniques and more patients are undergoing the procedure, I think that we will be more comfortable, and I am hopeful that the endophthalmitis rate will be reduced. There is also concern about reimbursement. It’s difficult to have a surgery center or location where you can do the surgery and have reimbursement for it. Until those hurdles are lowered, we may not see the numbers that we are possibly expecting. I also think that among the patients that are currently doing well with standard of care, it’s often hard for them to want to change. I think they become dependent on coming in and seeing us and realizing that they are doing well. Oftentimes my patients are evaluating their images as much as I am, and they are discerning if they are having any increase in retinal edema. They get quite good at reading those images. They like the experience of knowing they are doing well and the reassurance of the current medications, because it is important to stress that the therapies we have are exceptionally good at helping stabilize disease processes and continue maintaining that visual improvement. As far as the next area of education, it’s important to be up-front with patients that it’s not just 1-and-done therapy. It’s important for those who have diabetes that we’re controlling their macular edema, and it is important on their end to continue to control their glucose levels. And for those with macular degeneration that we want to continue to monitor, if we're only treating 1 eye, you want to make sure that they realize that it could be a bilateral process. I really stress that.

: I’m glad you put it as apprehension broken down into among doctors versus among patients. That’s spot on. The doctor has different concerns sometimes compared with the patient. The patient as you said, is often hesitant to make a change if they are doing OK. But it’s probably going to be an easier transition to think about going from an older anti-VEGF to faricimab because that’s not as big of a change, but to go to the Port Delivery System, a patient might say, sign me up, but may not have a full understanding of all the issues involved in the potential new types of adverse events associated with them; the doctor may be perhaps a bit reluctant to offer that change. You’re right, it’s a combination of patients and doctors considering all the pros and cons, and we might have different ideas. You need to get on the same page and have a good understanding. It’s going to take a lot of effort and a lot of time in speaking to patients about making a change, especially if it means something truly different like PDS and going to the operating room.

Retina specialists discuss concerns and apprehensions that both physicians and patients may feel towards newer modalities and delivery mechanisms for the treatment of AMD and DME.

Practical and Clinical Implications for a Rapidly Changing Treatment Landscape in DME and AMD

 Blake, are you aware of any ongoing or expected data coming out within the next year or so with faricimab, with the port-delivery system for either disease state?

As you mentioned, Carl, our patients are living longer with their disease, so it’s important for us to continue to follow patients who were enrolled in clinical trials to see how their long-term visual outcomes are doing. Fortunately, for both faricimab and the port-delivery device, those enrolled in initial trials for FDA approval were able to continue in long-term safety and efficacy trials for both patients with diabetic macular edema [DME] as well as diabetic macular degeneration. Results will probably not be readily available for at least 1 to 2 years for the TENAYA and LUCERNE trials, which were the efficacy of faricimab in macular degeneration. The trials for YOSEMITE and RHINE will hopefully be within the next year or 2.

 We’re going to see extension data and some nice long-term data long beyond 2 years for these therapeutics, for these disease states, which is unique. With the previously studied drugs, we didn’t have clinical trial data beyond 2 years, or 3 for DME. We’re also going to have some global data from the port-delivery system with some tweaks in the way it’s refilled, comparing 24- to 36-week refill regimen; that’s going to be interesting. Everyone wants to know the long-term safety of the port-delivery system, and that extension trial is going to be particularly valuable.

Dave, what metrics or clinical diagnostics would you like to see included in some of these long-term extension trials of faricimab, port-delivery system, and so forth?

 We want to continue to follow both the safety and efficacy of the treatments. If we’re talking about the efficacy, we want to the see the best corrected visual acuity over the long term. Vision is quite important for patients. Patient-reported outcome measures over the long term are important as well. They’re also important for payers. How did these treatments do for the patient from the patient perspective over the long term? Looking at the anatomy, the OCT [optical coherence tomography], and looking at the fluid and the control of exudation in both of these diseases over the long term is going to be important. Because as previously mentioned, these diseases often require years of therapy, much longer than a 1- to 2-year clinical trial.

Some other things that would be interesting to see in patients with diabetic retinopathy and diabetic macular edema, specifically with port delivery, would be looking at correlating the hemoglobin A1C [glycated hemoglobin] to the control of the fluid over the long term. Monitoring hemoglobin A1C will be interesting to see whether that plays a role. For diabetic retinopathy, looking at peripheral nonperfusion and macular ischemia. We haven’t seen dramatic improvements in nonperfusion with our standard intravitreal anti-VEGF therapies, but maybe it will be different in the port-delivery system.

Another thing that would be interesting in diabetic retinopathy and edema would be looking at another functional measure, like microperimetry. I’m not sure if they’re following that in the trials, but there’s only a moderate correlation between fluid and visual acuity. That might be another functional test that gives us some more long-term understanding of how these therapies are doing from a functional standpoint for our patients.

 I’m going to also throw in analysis on geographic atrophy over the long run with the port-delivery system. There’s some suggestion that more frequent injections yield higher rates of atrophy in our patients with wet AMD [age-related macular degeneration]. We don’t think that’s a drug adverse effect. It may be the natural course of AMD, but we don’t know for sure. A̶behaves with true, sustained delivery more on the order of 0—order kinetics if you will, although not quite. It might give us something different, maybe something safer, maybe something not. Some additional analysis there would be useful.

 I’m also excited to see that there’s a clinical trial that’s incorporating use of continuous glucose monitors. Hopefully those data will give us a better understanding of disease progression for diabetic retinopathy. As we have more patients coming in with continuous glucose monitors, it’s important to watch their coefficient variance for glucose. It’s a pretty easy metric to get from their downloads that looks at the variability of glucose throughout the day. As we know, A1C is the average glucose level over a 3-months period, but it’s that time in range and the variability within that range that most likely could be worsening disease. We need to make sure their coefficient variance of glucose is below 36%. That’s an important variable.

Carl D. Regillo, MD, FACS; Blake Anthony Cooper, MD, MPH; Michael A. Klufas, MD; and David R. Lally, MD, talk about important data that has awaited for several newer and investigational therapies for DME and AMD.

Michael A. Klufas, MD

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