Emerging Treatment Options for Diabetic Macular Edema

Nancy Holekamp, MD: 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?

Ehsan Rahimy, MD: 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.

Nancy Holekamp, MD: Thanks to all of you for this rich and informative discussion, and thank you for watching this HCPLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox.

Transcript edited for clarity.