Nancy Holekamp, MD

Dr Leng, what do you see for the future directions in treatments for patients with diabetic macular edema [DME]?

 Going back to a point made earlier about at-home monitoring, healthcare is becoming more distributed and more personalized in the patients’ homes, and care is going to meet the patients where they are eventually. Whether that’s going to a health center at a local pharmacy, or another retail chain and having monitoring done, or having the device on their tabletop and in their own homes where they have daily assessments to see if there is a need to treat based on visual acuity changes, that are based on structural changes on OCT [optical coherence tomography] devices. The durability question is an important one because patients can’t be expected to come in monthly forever, or even for the first year, as we’ve seen in real-world studies where the average number of treatments is 3 to 4, and we have optimal outcomes compared to the clinical trials. At this year’s American Society [American Society of Retina Specialists Annual Scientific Meeting], retina specialists met in San Antonio, Texas, in one of my sessions one of the colleagues presented a data analysis looking at their patients at their center and what percent of patients would qualify for a clinical trial. They found that 50% of the patients in their center met the inclusion and exclusion criteria for a clinical trial. That tells us that half of the patients that we see every day don’t meet entry criteria for these trials that we’re basing these results in our treatment modalities on. There is an unmet need in that half of the patients out there won’t be able to enter, and therefore shouldn’t be expected to have trial outcomes. What are we supposed to do for those patients? There are many different areas where there’s an innovation that’s needed. Fortunately, as a field, both on the physician side and the industry side, there’s many innovative people and new ideas being brought to the forefront. The gene therapies that they work on could potentially be lifelong treatments and essentially be a cure for many retinal vascular diseases. That’s an exciting area to focus on. This implant that Dr Rahimy mentioned earlier, the port delivery, has the potential to become a platform technology with which we could administer multiple different agents over time and be able to give combination therapy through this device. The future is bright and our patients will ultimately benefit from the innovation that’s going on in this field, whether that’s in our offices or in their homes.

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Dr Theodore Leng discusses what the future may hold for patients with diabetic macular edema.

The Future of Treatment for Diabetic Macular Edema

Recently, there were 2 large FDA [Food and Drug Administration] phase 3 clinical trials. These were global trials that looked safe and effective for treating patients with diabetic macular edema [DME] at treatment intervals that we have not seen with our current anti-VEGF [vascular endothelial growth factor] agents. Although faricimab is investigational, I think it will be under FDA review and could get FDA approval in the first quarter of 2022. This is an active area of research, and I’m going to turn to Dr Rahimy to discuss some of the other compounds in development. Dr Rahimy, what excites you about this space?

 One thing that was exciting about faricimab is that this is potentially a novel therapeutic target. Many of us view the ideal tomorrow as having multiple agents to choose from, to mix and match, and to get personalized treatment. We discuss personalized medicine and that’s what we’re aiming for our patients; to figure out what combinations of therapeutic targets we can match with therapy to get the best possible outcomes for the longest duration of time. It’s sobering and disappointing so far in retina, anytime a new therapeutic target has come close to getting to the market, we’ve been met with disappointing clinical trials. We hear our colleagues’, and sometimes I consider, “maybe this is as good as it gets. Maybe all we have really is VEGF and steroids, and maybe that’s what we need to consider.” You can see that reflected on the clinical trial. Faricimab targets Ang2 [angiopoietin-2], but many of these other, you could call them compounds or even surgical platforms, that are in development are not going after a new target per se. They’re trying to create a better, longer-lasting anti-VEGF. We have 1 that just got FDA approved, although not for diabetic macular edema was the port delivery system. That brand name on that is this female, that is essentially a surgical device that is implanted onto the eye, and it slowly micro releases ran up a vitreous mac into the vitreous cavity. It was just approved for AMD [age-related macular degeneration] and the clinical trials are ongoing for the treatment of DR [diabetic retinopathy] and DME. Other compounds in development, Kodiak Sciences have a drug KSI-301 that’s called an ABC, an antibody biopolymer conjugate. It’s basically an antibody fragment, and the concept is that there’s increased bioavailability and durability, it sticks around in the eye and works.

There are also our gene therapy platforms. Regenxbio has RGX-314, essentially you are transpecting cells with a virus and producing an internal factor, if you were to produce anti-VEGF continuously. The Regenx platform is to be administered via the suprachoroidal space, but it helps bring something like that into the office setting, whereas other gene therapies require us to take patients into the operating room. In previous iterations of this, when you look at what matters most in clinical trials it’s efficacy, durability, and safety. From an efficacy standpoint, even with faricimab, it’s important to note that nothing has been shown to be better in terms of visual acuity. We’re pretty much seeing the same type of acuity gains on average across the board. If something comes out that’s novel and has a visual benefit then we’ll go to that as a first line, assuming it’s safe for our patients. We want the best vision possible for patients, but thus far it’s been a difficult task to achieve because everything is coming out more or less around the same. Efforts have shifted towards this durability game. I say game because, and I think we’d all agree, there’s a lot of gamesmanship. Clinical trials and design often skew things slightly in favor of the investigational compound versus what’s readily available. As we’re playing this game of durability, these new agents must be compared to what’s called standard. What they’re doing is investigational. They’re allowing for longer treatment intervals beyond what we’re accustomed to, or what we’ve seen from our previous trial data, and it leaves us to wonder clinically, if what we have is applied to those same methods, would we have gotten something comparable? Retina specialists, in general, are wising up to this and a theme is, that there’s a growing disconnect between the clinical trial world and the real world. That’s reflected in real-world studies that show outcomes are nowhere near as good as the trials. Many of these different trial designs are coming out with longer durations, Q4, Q6 months. You’re left to wonder if this is inherent in your trial design. Maybe what we have out there can go that long. I have plenty of patients that can go for months, and six months on various therapies. I’m sure we all have it. That speaks to the heterogeneity of the disease.

Finally, safety, and I said that last because that is the most important thing. We saw this in our field over the course of the last year or so. There was a new entry to the market role, abciximab, which had safety signals, and in phase 3 clinical trials our field was eager to use it. Not everybody. Some of us had concerns and we were watching and waiting to see the approach. I usually do that whenever there’s anything new. On the other end, we saw unfortunate events of occlusive vasculitis. In some cases, patients didn’t get their vision back and that drug cannot be called a second line at this point. Nobody uses it anymore. On the heels of that, AbbVie had a compound. They submitted a pickup bar that got denied by the FDA, and that was supposed to be a longer duration anti-VEGF. The pendulum in society is swinging towards the extreme of safety. First, do no harm, that’s why we’re all doctors beyond this durability game. I’m not sure if it’s part of the discussion, but we are seeing biosimilars come out for the first FDA-approved biosimilar, Lucentis [ranibizumab]. I’m already hearing from colleagues in certain markets that insurances are mandating that they use that. That’s important because biosimilars are not subject to the same trial design in terms of rigorous phase 1, 2, 3 studies to prove safety and efficacy. These companies are basically reverse engineering what’s already out there, and when you’re dealing with monoclonal antibodies a lot of that protein purification processes are proprietary. They do not have to disclose that. It’ll be fascinating, and honestly, potentially concerning when we see what happens in the real world, because thus far most biosimilars have been infusions or subcutaneous injections. This is the first foray into the ophthalmic space, and we know that the eyes of very privileged. We’re already dealing with issues of safety and inflammation. I’m concerned that we’ll see that with some of these biosimilars, especially as our markets are mandated to use it before we’re allowed to do other drugs.

Dr. Ehsan Rahimy describes the emerging treatment options for diabetic macular edema.

Emerging Treatment Options for Diabetic Macular Edema

We have had a great discussion about anti-VEGF [vascular endothelial growth factor] agents and the standard of care. We’ve discussed how effective it is to preserve and improve vision in patients with diabetic macular edema [DME]. We discussed how anti-VEGF injections can prevent future complications of anti-VEGF agents; the ones we currently have can also reverse the diabetic retinopathy score. That sounds great, but we’re still not satisfied because an underlying theme is the treatment burden, as it’s hard to translate what we see in clinical trials with highly motivated patients into the real world where there are real-world challenges. For the last 15 minutes, we’ll discuss emerging treatment options that may help us reduce the treatment burden. Dr Coney, can you to talk about one in particular? Which we have 2 FDA [Food and Drug Administration] phase 3 clinical trials that say it’s effective and it appears safe for treating diabetic macular edema. This molecule is a bispecific monoclonal antibody called faricimab. Can tell us about it?

This is when good is not good enough. We have great therapies, but we still have an unmet need and unmet burden. We still have room to grow in this space. We discussed the multi-factorial pathophysiology of diabetes and diabetic retinopathy. Because we have this there is some potential for multi-targeted treatments that may affect different pathways to get better visual outcomes. There’s a molecule that we’ve been observing, it’s called faricimab, which is a single molecule with a dual mechanism of action, and it blocks this VEGFA [vascular endothelial growth factor A] that we’ve been discussing. We know that VEGF is elevated in individuals with both DME and diabetic retinopathy, but this antibody also has a different arm, which blocks Ang2 [angiopoietin-2], which has been shown to be regulated in the vitreous levels in individuals with diabetic retinopathy. Ang2 works through an inflammatory pathway called the Tie2 pathway. This is potentially important because it promotes vessels breakdown, which then leads to leakage and proliferation that we normally see in diabetes and elevated levels of Ang2. It’s also been associated with microvascular inflammation. For normal eyes there’s an Ang1 [angiopoietin-1] that promotes or activates the Ang2 pathway and this stabilizes vessels, but in disease or sick eyes, as we see in diabetes, diabetic macular edema, neovascular AMD [age-related macular degeneration], and even vein occlusions there’s this angiogenic switch where Ang2 levels in the eye cause an [INAUDIBLE] in the Tie2 receptor. This causes a lease to the destabilization, increased permeability, and increased inflammation in the eye. We have the ability now to block both VEGFA and Ang2. The goal is that this new molecule may provide more stability in the vessels, and more durability in terms of how long the drug lasts and the long-term outcome beyond using anti-VEGF.

Joseph M. Coney, MD, provides an overview of the drug faricimab for treating diabetic macular edema.

Diabetic Macular Edema: Faricimab

 Ehsan, can you discuss the diabetic retinopathy severity scale [DRSS] score and how these anti-VEGF agents had a surprise benefit? It was initially a secondary end point, but it’s becoming something attractive about anti-VEGF therapy.

 Back to the RISE and RIDE studies, 1 of the secondary end points from those studies is that they saw that patients’ DRSS was improving. There became this metric to look at 2-step progression, to go back in time by 2 steps of severity, so if you’re moderately severe, you go down to moderate and all the way to mild. This was an added benefit that was noted with anti-VEGF treatment in these clinical trials. Similarly, VISTA and VIVID were landmark studies looking at aflibercept, or Eylea, for treatment of DME [diabetic macular edema]. They saw the same thing in both studies: roughly 1 of 3 patients, 33% or so, would experience 2-step improvements. Those observations served as the launching pad to do the PANORAMA study and also Protocol W study through the DRCR [Diabetic Retinopathy Clinical Research Network], which is essentially the same protocol as PANORAMA. In this case, we’re cherry-picking those patients at highest risk for progression to PDR [proliferative diabetic retinopathy], which is that moderately severe to severe group with ETR scores of 47 and 53. We saw in PANORAMA, and again in Protocol W, is that a significantly higher proportion of patients experienced 2-step progression—upward of 60% to 70%, depending on which treatment group you were in, that aflibercept study and PANORAMA.

One way we can reconcile this big difference has to do with what I just said: there was a ceiling effect in place. When you look at the patients enrolled in RISE and RISE or VISTA and VIVID, they may have had mild NPDR [nonproliferative diabetic retinopathy] or moderate NPDR. There’s only so much they can improve. You can’t improve by 2 steps of DRSS, as opposed to these states looking at the treatment of severe NPDR. There’s a lot of potential for improvement, and that’s 1 reason we had such a big disparity in terms of that DRSS improvement. The second reason is that in PANORAMA, all those patients were treatment-naïve. That was a very difficult study to recruit for. Many patients had 20, 25 visits—how long do you want to give monthly injections? it was a difficult and challenging site to recruit for, but all the better for having it been done, because we got some very powerful information, not only from the treatment but also from the observation group.

To that end, our field is all about durability. Is there a permanent benefit or treatment effect from this 2-step progression? In other words, if we stop, do we lose it all? Was it all for nothing? Will it quickly regress back to where it was? We’re seeing mixed studies and mixed results from our peer literature. Some people have hypothesized and decided to study fluorescein angiograms. Are we seeing reperfusion of tissue from earlier treatment, anti-VEGF, and is that sustainable over a longer period of time? When I get to a point in a patient’s treatment course—every 3, 4, 6 months, and their DME has regressed, they want to give a trial coming off therapy—we must be very careful that we’re monitoring that their diabetic retinopathy doesn’t start to progress. I’m reminded of Charlie Wyckoff, who did an open-label extension study of VISTA with aflibercept that looked beyond the 3-year study period and at patients who were getting whatever treatment their clinician decided they should and fewer injections. At that point, there were 60 patients who I studied, but 10% progressed from NPDR to PDR [proliferative diabetic retinopathy]. I tell these patients that we’ll know each other for life in a lot of instances.

 In that study, they didn’t require many injections. They were randomized to either acute QA or Q16 at the loading dose. We know that if individuals don’t have diabetic macular edema, the number of injections they will require will not just save vision—there were people in that study who did not have diabetic edema; their vision improved. There’s something going on that we still don’t know, but there was a visual improvement. There was an OCT [optical coherence tomography], a drying effect, although you couldn’t clinically see any swelling. If you look at the composite of sight-threatening problems, it was 42% compared with 10%. That’s a drastic improvement in someone’s vision that could have potentially been lost vision and that you ordinarily wouldn’t have retained. The study was hard to recruit for. It’s the same reason why people are nervous about treating individuals without sight-threatening problems. To this day, I don’t think it’s caught on as much as it should have, because it’s hard to talk to someone about putting a needle in the eye that’s 20/20.

If we want to try to save an organ, with the eye we still have to find the right people to move the needle. It’s not an emergent thing you must do, but we need to start having the discussion, especially if it’s your patient—you saw the person 5 years ago, when they had moderate disease, and now they’re starting to get severe NPDR. You can see that progression. That may be the perfect person to have that discussion with. It’s difficult when a patient comes in for the first time and they’re healthy and vibrant, playing basketball, running. They didn’t know they had diabetes. They have a severe disease, but they’re not bothered by it. That’s a very hard person to have that discussion with. This is where our optometric colleagues can help us out, by facilitating those questions to the health care professionals to talk about multisystem organs. Once they have kidney, foot, eye, and heart problems, you start to build up a story. This patient’s journey over time is not going to be very good. You have to look at a patient as a composite. Let them know that the same thing going on in your heart, toes, and kidneys and is going on in your eyes, and if we don’t get this under control in the next 3 to 5 years, you can have severe blindness.

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Retina specialists review clinical trial data on the impact of anti-VEGF agents on diabetic retinopathy severity scores.

Nancy Holekamp, MD

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