Longer-Acting DME Drugs Ease Burden, Not Vision: John Kitchens, MD

The patients with diabetic macular edema (DME) who stand to benefit most from new therapies are often the ones with the least access to them, particularly Medicaid patients required to fail off-label bevacizumab (Avastin; Genentech) before stepping up to newer, FDA-approved options, said John W. Kitchens, MD, a vitreoretinal surgeon at Retina Associates of Kentucky.

In part 1 of the interview with The American Journal of Managed Care^® (AJMC^®), Kitchens explained why he believes anti-VEGF therapy has hit its ceiling for DME and previewed emerging approaches that aim to restore the blood-retinal barrier rather than simply suppress fluid. In part 2, he discusses why treatment-resistant patients often serve as the field's testing ground for new drugs, why better delivery alone won't solve the DME burden problem, the stark access-to-care disparities he sees between his Louisville/Lexington and Eastern Kentucky patients, and how glucagon-like peptide 1 (GLP-1) receptor agonists are already changing outcomes for his toughest-to-control patients with diabetes.

This interview has been edited lightly for clarity.

AJMC: Patients who've failed or partially responded to anti-VEGF are often seen as the ones with the most to gain from new agents, but they're the hardest to study. How are you thinking about that population in the context of what's moving through the pipeline?

Kitchens: In reality, those aren't the patients who get into a study. They're patients who've had a lot of treatments—they might have had prior surgery or proliferative disease—so they're oftentimes excluded. What they are is canaries in a coal mine. When we get a new treatment approved, our tough-to-treat patients are the ones we try it on first because we want to know if it works better than what we're currently using. Those patients are also desperate. They're always waiting for something else to come around that could be better.

When a new treatment is released, you see those patients who are struggling, who you might have to treat every month, and you say, "We've got something new coming, and when it's available, I'd like to try it with you and see if we can get more vision, a drier retina, or extend you out longer between treatments." Those are the patients we judge whether one drug works better than another.

AJMC: Beyond the mechanism question, there's a whole parallel conversation happening around how drugs are delivered—sustained-release platforms, gene therapy, longer-acting formulations. How much of the DME burden problem is solvable on the delivery side alone, without changing the underlying mechanism?

Kitchens: I think there's going to be a benefit to patients from trying to deliver VEGF suppression more effectively in a variety of ways. Longer-duration therapies with fewer injections will benefit probably the majority of our patients, as long as the price point is right and the safety profile is there. For tough-to-treat patients, I don't know that giving them a more sustained or longer-acting drug is necessarily going to improve their overall outcomes. It might improve their compliance, since they don't have to come in as frequently for injections, and it might decrease their treatment burden. But if we're talking about improving visual acuity, we're maxed out on where we're going to get with VEGF suppression. We're going to have to look at a different mechanism—one that perhaps stabilizes the blood-retinal barrier, improves perfusion, and restores dying tissue.

AJMC: When you think about what's coming in the next 3 to 5 years, which patients in your practice do you think will benefit most, and which ones are you still worried about?

Kitchens: We've got a really interesting patient profile in Kentucky. In our Louisville and Lexington offices, we mostly see macular degeneration, but about 20% to 25% of the patients we see and treat are diabetic. They often don't have as much of an access-to-care issue as our patients in Eastern Kentucky. The patients in Eastern Kentucky really struggle. They have really bad diabetes, they often have trouble accessing health care, and their hemoglobin A_1C is in double digits—10, 11, 12—when they come in. They present late with a lot of proliferative disease or really bad diabetic macular edema. Really, the key for those patients is going to be having access.

Unfortunately, our toughest-to-treat patients are often our Medicaid population, and sadly, new therapies aren't often covered by Medicaid as easily as the traditional, cheaper therapies. You run into this discrepancy: the patients who need the new drugs the most can't get them because they're stuck in a Medicaid bevacizumab [Avastin; Genentech]-first cycle.

AJMC: What has to go right, both scientifically and in terms of how care is structured and delivered, to get to meaningfully better DME management in 5 years?

Kitchens: I think we're starting to move in the right direction in one major way, and that's GLP-1 drugs. I've seen fantastic improvements in blood sugar in some of my toughest patients, and that's very meaningful for them. Patients with A_1Cs of 10, 11, or 12 are able to lose weight, decrease their insulin, and get their sugars under better control on GLP-1s. The holy grail of this whole thing, and how we cure diabetic eye disease, is to cure diabetes. That's a very high bar, but I've seen a tangible difference in my patients on GLP-1s. The key is getting patients on GLP-1s and their sugars under better control before they start to have end-organ disease and show signs of diabetic retinopathy. I think we'll see that needle start to move.

On our end, from the retina side, what's potentially going to move the needle is longer-acting drugs, improved patient awareness, and it's all going to have to start with safety. If we don't have safe therapies, we're going to have trouble. Anything with an inflammatory signal of any significance is going to make us hesitant to use that drug. It's going to have to be simple, something we can understand. Complex combination therapy—where you have to start somebody on an anti-VEGF, bridge them with some other treatment, and then come back and treat recalcitrant cases with more anti-VEGF—that bouncing back and forth and switching drugs, especially if the newer treatments are more expensive because they're more durable in clinical trials, is going to cause a lot of havoc with insurance companies. We're going to need some predictability from these treatments and an algorithm we can use to set a course, trust that it's going to deliver the results we want, and not have to do this in such a hodgepodge fashion.

AJMC: Is there anything else that you feel our readers should know about?

Kitchens: I think it's an exciting time. We've had 20 years of anti-VEGF therapy, and it's been a game changer for our patients. It's nice to see, and the feeling really is that every study we've looked at—minus the DRCR Protocol T study—has been fairly consistent. Protocol T was an interesting one: they compared aflibercept [Eylea; Regeneron] and ranibizumab [Lucentis; Genentech] to bevacizumab, and what they showed was that in tough-to-treat patients, aflibercept was clearly better.¹ That's really when everybody wholesale said, “This is a better treatment for our patients.” We'd seen tough-to-treat patients over time where it looked like aflibercept might be more effective, but you'd have people show good ranibizumab cases and good aflibercept cases. In that one study, we finally saw which one worked best in the toughest patients, and everybody said, "If it's the best for the toughest patients, let's use it for everybody."

Now we're kind of settling back in with these next-generation therapies—faricimab [Vabysmo; Genentech] and aflibercept 2 mg—saying they look like they work about the same, but we need another kind of breakthrough, because when you look at all of these studies, what we're seeing is fewer treatments but not necessarily better visual outcomes. We still have half the patients at 6 months with persistent edema. Remember, the patients who get into studies are often not the sickest patients, so we need something that can capture all of those patients and improve their vision. If you can restore the blood-retinal barrier, that can do so many things for a diabetic patient—it can extend the effects of anti-VEGF therapy, improve perfusion, reverse disease, and if it's got greater durability, if it's a 3- to 4-month drug, it could well be exactly what we need.

Reference

1. Diabetic Retinopathy Clinical Research Network; Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-1203. doi:10.1056/NEJMoa1414264