Scott Krzywonos:

Gaining global consensus on DME needs will dictate the terms of future drug development. Can the findings from the DME AWARE Delphi study help?

Greg Nothstein:

I'm Greg Nothstein, he's Scott Krzywonos, and this is New Retina Radio from Retina Today and Bryn Mawr Communications. Dr. Baruch Kuppermann joins the show to review the findings from a 25 doctor panel of global experts. What did they conclude regarding the unmet needs in DME?

Scott Krzywonos:

And Dr. Moo Adam shares data from the RHONE-X study, an extension study tracking DME patients up to four years after they first enrolled in YOSEMITE and RHINE.

Greg Nothstein:

Did patients who switched from aflibercept 2 milligrams to faricimab for DME treatment experience changes that could affect your decision-making? Stick with us to find out.

Scott Krzywonos:

You might be surprised by the variability of thought in best practices for diagnosis, imaging and treatment around DME. That's where a Delphi study could become useful. Dr. Barry Kuppermann presented data from such a Delphi study at this year's ARVO annual meeting in Denver. Dr. Kuppermann is the chair of the Department of Ophthalmology and Visual Sciences at the University of California Irvine. He's also the director of the Gavin Herbert Eye Institute at UC Irvine. Dr. Kuppermann, welcome to New Retina Radio.

Dr. Kuppermann: Thank you, Scott. It's pleasure to be here.

Scott Krzywonos:

Let's start at the top for people who may not be familiar with a Delphi study. What is a Delphi study and how is it conducted?

Dr. Kuppermann:

So there's a lot of nuances to it, but basically a panel of experts is assembled, 20, 25 people and then a series of questions are asked. And each of us are to score it from, in the one to three category means we disagree strongly, seven, eight, nine, we agree strongly, and everything in between is the nuances of how much we disagree or how much we agree with the postulate, the question that was asked.

Scott Krzywonos: So that's a Likert scale, right?

Dr. Kuppermann:

Correct. That's a Likert scale. Exactly right. And then consensus is not, we don't try to achieve it necessarily. We look for where consensus lies. And consensus would be seven, eight, nine on the agreement side, or one, two, three on the disagreement side. And those are both very powerful statements that if you disagree very strongly with the statement, you're essentially agreeing to the opposite position. And if you agree with the statement, then that's where you are. And then statistics are run on that.

And then they go through different series of questions. So if there's a lot of consensus on a series of questions, then they move on to the ones that did not have consensus and then look to see if they could reframe those questions in a way that are achievable with consensus. And so there's a winnowing process trying to look whether we can go from the 30,000 foot view of where things had strong agreement or disagreement to the more nuanced questions and is there a way to frame it so that we can find where within that noise there is some consensus.

Scott Krzywonos: Did the participants in the Delphi surveys know who the other participants are?

Dr. Kuppermann:

Yes and no. I did not know when I was filling out the questions. I knew who the Delphi chairs were, that was announced to us. And at one point, we did have a Zoom meeting later. But as I was answering the questions, I did not know who else was in that except I was told it was peers of mine.

Scott Krzywonos:

Okay. Let's start then at the broadest scope. Where were some of the first areas of general consensus in this Delphi study looking at DME?

Dr. Kuppermann:

So the whole process, I'll be reporting on only a component of it, but the whole process involved things ranging from the patient journey, to what's involved in early detection diagnosis monitoring and management, and then the ideal attributes for current and future treatments across patient segments. And that's what essentially I'll be focusing on is that third level of the discussion that we had with all that. But again, there's this methodology that we went through on that. There was 284 total questions, statements essentially, because they're not really questions. It's not how do you do something? It's, here's a statement, what is your feeling about that statement? Is it you strongly agree? Do you strongly disagree? And you give that score, that Likert score from one to nine.

And so survey one had 207 statements, survey two had another 67 and survey three another 10 statements as we tried to narrow down and get through the sources of disagreement, and particularly when it came to management of patients and particular emphasis on unmet needs in the management of diabetic macular edema. The reason for that is for all that we're very grateful for anti-VEGF therapy, it's a hero, certainly for neovascular AMD, wet AMD, anti-VEGF therapy is unequivocal. It's the best there is and there's not even a second place really yet. So there are bispecific molecules and things like that that are add-ons, but they're all built around anti-VEGF.

When you get to diabetic macular edema, however, while it's still of the number one, it's certainly first line therapy, I view the response, certainly the response is not as robustly strong. And historically we've thought about two categories, the anti-VEGF responders and the so called suboptimal responders. But I don't think that that really captures the nuances. I view it really in three categories. There's the robust responders, the ones that get anti-VEGF injections with DME and their retinas dry out and we are happy as can be. We're not looking for anything different.

Scott Krzywonos: Knock it out of the park.

Dr. Kuppermann:

Correct. Then that's about a ballpark of about a third. Then the other third at the other end of the spectrum are the suboptimal responders and those, we don't know what to do with. Many people would persist in giving anti-VEGF injections. Others like me would maybe try a different one, going from aflibercept to faricimab for example. But ultimately we'd go to steroids and the DEX implant is the number one choice for that category by and large if you're going to go to a different class of drugs. And then there's the middle group, which are kind of the mediocre responders. They're not bad enough that we want to switch to a DEX implant with a side effect profile, so we sort of tolerate their mediocrity in a certain sense.

So that just gives you a flavor of the nuances. So how to manage each of those categories of patients was part of the discussion. And as a separate part of the discussion in the Delphi analysis or the statements was what about early treatment? There are patients that have early DME, early enough that you may not want to yet initiate anti-VEGF therapy.

So in a certain sense, there's a focus as we look at the unmet needs, is how to manage the patients in these questions, these statements that were presented to us and then we score them on the Likert scale one through nine? How would we manage early patients with one line loss versus two line losses? To what extent would we be willing to do non-invasive therapy or invasive therapy in the early treatment? And then there was discussion about, well, what about the ones that are more in the middle ground versus the more severely non-responders? So questions were asked surrounding all those and scores were given about that.

Scott Krzywonos:

Let's talk about some of those scores. So when it came to, for example, a patient losing at least one line from 20/20, it looks like there was a 70% consensus on prompting early intervention. Now is 70% really a consensus or is that sort of pointing towards something that needs more refinement?

Dr. Kuppermann:

70% is the lower threshold of consensus. That's the worst consensus that we'll abide on. That's seven, eight, nine, that's in that top category Likert scale. Conversely, 30% on the one, two, three scale would also be the weakest of the disagreement, the ones that we'd still accept as a consensus. So 70% is viewed as consensus. And what's interesting if there was a online loss, then 70% agreed that a non-invasive treatment would be desirable.

Scott Krzywonos: Such as?

Dr. Kuppermann:

Topical therapy, for example, would be a non-invasive form of treatment. Theoretically, systemic therapy, the invasive part is the needle in the eye. So when we think about all the, currently the main invasive treatment is the biologic injections that we're giving. There is under development, drug delivery systems, gene therapy, all these others, all those would also be considered invasive therapy. But for now, essentially the de-facto is anti-VEGF injections. There is also the steroid injections.

So there is a robust response, again, 70% agreement that with one line of vision loss, they would favor a non-invasive therapy, with only 5% saying that with one line vision loss, they would be prepared to give an anti-VEGF invasive injection.

But when you get to two lines of vision loss, then you see more emphatic responses. You get now in the 90% plus range of asking for a non-invasive one at two lines, which is interesting and that 5% invasive response went up to 40%. So still not ubiquitous, still not meeting the threshold of agreement. But again, there was an even more robust response when you got to two lines of vision loss for searching for some sort of treatment, but non-invasive would be preferred.

Again, as a reminder, that would mean they would be going from 20/20 to roughly 20/30, because there's 20/25 then 20/30. I think, which was not asked, once you get beyond 20/30, then I think people are going to want to start doing, that 20/40 range is when a lot of people would initiate therapy. There's been a lot of studies that have looked at even observation patients can do okay. So one of the noninvasive forms of therapy is observation. We're getting beyond the actual topical therapy versus just observational therapy, so to speak.

Scott Krzywonos:

And just to be clear, these non-invasive therapies that you're looking at are therapies that may not even be in existence yet, right? This is more of a theoretical, this is what I would do if given these options.

Dr. Kuppermann:

Correct with a caveat. There are no approved topical therapies for diabetic macular edema, but there is one under investigation from a company called Oculus. And with full disclosure, Oculus was the sponsor of this process, but was very hands off. We didn't even know who was actually the sponsor. We only discovered that after the fact. And I am a consultant to Oculus, so I want to acknowledge that as well. But again, I don't even know how it was funded and who paid for what. Again, we were all agnostic to that.

And they do have a product which is a topical steroid drop, dexamethasone based with cyclodextrin that's designed to penetrate the eye better and last better. It's had two large phase three trials with a total of 800 patients, 400 patients each. And we're going to hear that data soon in the next few months, maybe even sooner. But again, until that's proven, they have had phase one, phase two studies and those have been promising. They are the most likely non-invasive ones, but we weren't really focused on that when we were asked the questions. We weren't focused on whether it was a steroid-based therapy versus a non-steroid-based therapy, for example. It was more non-invasive therapy, would you sign up for it for these early patients?

So that was the nature of the questions or the statements again. Again, it's always awkward. It's a little bit like Jeopardy.

Scott Krzywonos: Right. What is?

Dr. Kuppermann:

Yes. If the response in Jeopardy is a question, here's the answer. It was never a question is being asked. It's a statement and do you agree with it or not?

Scott Krzywonos:

I can understand why a company like Oculus would be interested in conducting a Delphi study, again, doing it in a masked fashion like you described. But in a sense, it's a fact finding mission, right? Maybe they want to make sure that there's at least some interest in people or in providers allowing a non-invasive option, right? Because if this came back and we said, "Oh, with a two-line letter loss, only 30% of providers are interested in a non-invasive option," suddenly they're going, "Oh, we might have to change course here because there's not really an interest."

Dr. Kuppermann:

And in my experience, the bulk of the Delphi studies end up being sponsored by companies for that very purpose. It doesn't minimize their value. You always have to look at it with that lens of are the questions or the statements biased in some way. But we're all pretty independent minded specialists and our peers are the same and we all are more than happy to give our opinion. In fact, we're more than happy to give more than one opinion.

Scott Krzywonos: I've noticed.

Dr. Kuppermann: Yeah. So there's no hesitation there. It's not a shy crowd.

Scott Krzywonos:

Before we wrap up here, I want to touch on some findings on intraretinal fluid. It looks like there was some consensus around the importance of intraretinal fluid relative to say subretinal fluid when you're assessing DME.

Dr. Kuppermann:

Right. So again, there was a 7.5 response. Again, these numbers are usually whole integers, but this one was kind of, we had to split the [inaudible 00:13:20]. So somewhere between seven and eight, so a little bit stronger than seven in terms of the Likert scale, not as strong as eight. But there was this feeling that a suboptimal response to treatment would be less than 10% resolution of macular edema for those eyes that had thickness of greater or than or equal to 350 microns.

And again, so that's a pretty modest response. I mean, I argued for a much stronger one. To me, I personally, for example, the way that I evaluate patients and everybody has their own paradigm, I look at the OCT every single visit and I give an injection and I'm looking for reduction of at least 10% per injection, and maybe that's where we were. But certainly after three injections, if I still have more than 50% excess macular thickness, I'm thinking about an alternative strategy for treatment.

So I think it's all those nuances. But I am definitely looking at the edema and looking at a response. If it's dropping zero each time, that's no good. If I have to say conversely, if it drops by 10% with each injection, that implies it'll take 9, 10 injections to get there. But if the trend line is continuing, I'm happy to continue it.

Scott Krzywonos: Sure.

Dr. Kuppermann: It's when it plateaus and doesn't drop over multiple injections, I think that's when we felt more uncomfortable. And again, this is a manifestation of that. It was a way to find consensus around a number and that's why the 10% reduction in macular edema for those eyes that had 350 microns had fairly robust agreement.

Scott Krzywonos:

I understand what Oculus, like we discussed earlier, would do with these data, would do with the outcomes of a Delphi study, but what does somebody in clinical practice do with the outcomes of a Delphi study? Does it even apply to their day-to-day practice? Or is this something that is more like organized ophthalmology, organized retina societies seeking to come up with protocols might turn to these data?

Dr. Kuppermann:

I think it's a little bit of both. I think you could argue that this might help, for example, the DRCR Net design a study. But it also helps practice not about the non-invasive part because there aren't really options, but about thinking about what is the definition of suboptimal, what is the patient's journey that we didn't really discuss? All these other factors, the psychosocial, there's information that helps us understand how to best manage our patient. We want to make sure that we're good stewards of their care, that we're both conscious of what it's like.

Again, our diabetic patients, it's worth noting, are our most complicated patients. The 90-year-old with neovascular AMD, typically a 90-year-old woman, because there's way more 90-year-old women than men, speaking of as two men talking together, usually people show up with her 65 or 70-year-old daughter and the mom comes in and gets the injection and they go off for lunch and Chardonnay and they're going to show up next time. That 90-year-old lady is likely to outlive me and you, there's a good chance of that.

Scott Krzywonos: Sure.

Dr. Kuppermann:

But the diabetics, they're younger, have more disease, they have more complex lives, they have families, their working age, they have more doctor's visits. We want to make sure that we're managing these things in a way that are compatible with their lifestyle, because the worst case scenario is that they don't show up for their follow-up visits, they don't get the care they need. So these types of Delphi studies can help us understand better how to provide better care to our patients as well.

Scott Krzywonos: Dr. Kuppermann, thank you for coming on New Retina Radio.

Dr. Kuppermann: It's my pleasure, Scott. Thanks for having me.

Scott Krzywonos:

The RHONE-X extension study is the largest DME extension study to date. How could real world practice be influenced by its findings? Dr. (Murtaza) Moo Adam presented data on the RHONE-X study at this year's ARVO annual meeting and he has some ideas on what RHONE-X could mean for real world providers. Dr. Adam is the director of clinical research at Colorado Retina Associates. Dr. Adam, welcome to New Retina Radio.

Dr. Adam: Scott, thanks so much for having me.

Scott Krzywonos: Let's start at the top just for people who are unfamiliar with RHONE-X, the extension study. This was an extension study of the YOSEMITE and RHINE trials. Tell us all about it.

Dr. Adam:

Yeah. So RHONE-X is a two-year extension study of the pivotal phase three faricimab trials for DME, YOSEMITE and RHINE. After year two of YOSEMITE and RHINE, 91% of patients rolled over into the RHONE-X study. And all arms of the trial, so those that were treated with a fixed faricimab dosage frequency of Q8 weeks, those with a treat and extend interval of faricimab with flexible dosing that's individualized, and then those that had Q8 week aflibercept were all converted to a faricimab treat and extend paradigm shift in their treatment regimen. And those patients were then followed for two whole years.

The study in total had about 1,400 patients that rolled over. That's 91% of the patients from YOSEMITE and RHINE. And at completion at year four, so that's four years after the beginning of USANIRIN, 81% were retained, so 1,200 patients total. The largest DME extension trial that we have.

Scott Krzywonos:

Yeah, that is a lot of patients for DME extension trial. Let's talk about the treat and extend arm just for a second. Was this a treat and extend per protocol or was it up to the investigator discretion?

Dr. Adam:

It was per protocol. CST and visual acuity were the main drivers of treatment. So if patients were stable, they would extend by four-week intervals. If they were worsening, they would reduce by four or eight weeks, and they'd maintain if neither extension or reduction criteria were met.

Scott Krzywonos:

So just looking still very high concept at the RHONE-X study, it found that a lot of patients were able to go quite long with their intervals, right?

Dr. Adam:

Yeah. So for all patients, no matter what arm they started in for the YOSEMITE and RHINE trials, they generally could go 12 weeks or longer with about an 80% rate, depending on the arm of the study. So patients that were on aflibercept or faricimab before RHONE-X, then were switched to faricimab, 80% of them could go 12 weeks or longer with the treat and extend protocol.

Scott Krzywonos:

And then the RHONE-X study also looked at patients that were previously in the aflibercept arm and then switched over to the faricimab treat and extend arm. Tell me about some of the most important findings there.

Dr. Adam:

Well, one of the really interesting things about aflibercept patients is that the large majority of them did fairly well. We found that the faricimab was non-inferior to aflibercept 2 milligrams at a Q8-week dosing interval. But we did some post-hoc analyses looking at patients that were particularly hard to treat, those patients that had persistent CST of greater than 325 microns at the conclusion of the study. And we found that the sawtooth pattern of their CST was quite intense and showed a really, really limited improvement in their anatomy over that two-year period. When those patients were then converted and switched to receiving faricimab with a treat and extend protocol, those sawtooth smoothed out quite a bit, and the CSTs that were persistently elevated reduced to the levels of all the other arms of the trial.

Scott Krzywonos:

Talk to me about the sawtooth pattern? We hear about this a lot and I just want some clarity on why it's so bad to have the sawtooth pattern.

Dr. Adam:

Yeah, the retina is not an accordion. The macular cells that are in the back of the eye are incredibly fragile. And so we know that from post-hoc analysis of the CATT trial for AMD, we know from prior studies in DME that fluctuations in CST, variability in CST is a driver probably of long-term vision loss and disorganization of the retinal inter layers, DRIL. And so the less sawtoothing we see in CST, the better long-term outcomes we likely will have.

So what we saw for patients that had a high frequency of sawtoothing or fluctuations in CST, we didn't necessarily see a delta in their vision at the four-year mark. So patients that had a higher CST variability versus lower, they saw about the same. But I do believe in the real world, if you extend this pattern of sawtoothing out to three years, four years, five years, you're going to see a difference in visual outcomes for those patients that have higher variability in CST versus low variability.

And I think that plays into the fact that faricimab has a dual action, working both on the Ang-2 pathway and anti-VEGF pathway and stabilizing these eyes with DME.

Scott Krzywonos:

Is that because eyes with DME have both at play or only maybe in some eyes one is at play more than the other? I mean, what do you make of the dual mechanism of action in actual real world patients when we consider what's driving DME and so on?

Dr. Adam:

I think if we take a look at historical data from our OZURDEX trials, we know that DME can be largely ameliorated, but with steroid. And steroid works on the VEGF pathways as well as so many other pathways, including IL-6, which we know is inflammatory. And so DME is a multifactorial vascular disease. And so I do think there is an argument to make that the dual action of faricimab associated with a higher molar dose that faricimab supplies probably is why we see better outcomes in that post-hoc analysis in difficult to treat DME patients.

Scott Krzywonos:

Let's move over to patients with hard exudates. The researchers in the RHONE-X extension study looked at the proportion of eyes with the presence of hard exudates as measured on colors fundus photography and then assessed what they were like after four years. Again, two years of YOSEMITE and RHINE, two years of RHONE-X. What did you guys find there?

Dr. Adam:

Yeah. So at baseline, patients that had hard exudates on color fundus photos, regardless of the group, whether it was faricimab fixed dosing, treat and extend faricimab or fixed dosing aflibercept, 80% had hard exudates. But by week 96, year two, 53% of patients on aflibercept had hard exudates, whereas closer to 43, 45% of patients had hard exudates in the faricimab arms. Now what's interesting is when those 53% of patients were converted to faricimab, that hard exudate proportion reduced to 37% of patients, pretty much on par with what we saw at the end of year four for the both faricimab arms are converted to treat and extend with 35% of patients having hard exudates.

So really the hard exudates is a biomarker of disease activity and severity of diabetic retinopathy. And we know that hard exudates that precipitate out of vasculature, especially in the fovea, can lead to worse visual outcomes longer term.

Scott Krzywonos:

So let's just pretend that we live in a vacuum, there are no insurance considerations here. Would this suggest that maybe you'd want to start a DME patient on faricimab both for the structural reasons, like you were describing, less of a sawtooth pattern, the ability to eliminate hard exudates, which themselves are not necessarily bad, but an indication of disease activity? Or am I overthinking this? Should you stick to a pretty typical protocol that doesn't include faricimab until further down the line?

Dr. Adam:

Not at all. I think if you have a patient that's looking for returning to better driving vision, returning to better function at work, especially in DME patients that are working age, it makes so much more sense to not only have better anatomic outcomes, but having them quicker. That's one of the findings we found from YOSEMITE and RHINE that the delta between complete drawing of the macula came about 12 to 15 months earlier in the faricimab arms than it did in the aflibercept arms. That combined with superior anatomic and functional outcomes from a standpoint of visual acuity in the short term, I think makes a lot of sense to use these second generation agents sooner rather than later.

Scott Krzywonos:

I want to go back to the findings from RHONE-X when it came to intervals. It seemed like about half of patients, regardless of what arm they were in, at the end of four years were potentially able to go out to 20 weeks. I don't think they actually went out to 20 weeks in the study, is that right?

Dr. Adam:

That's correct. Yeah, 20 week intervals were not specifically tested. That'd take a long trial to design and map out and be quite expensive. But we looked at extension criteria of patients that were finishing the end of RHONE-X, so four years after the beginning of YOSEMITE and RHINE, and we found that about 50 to 55% of patients were so well controlled that they could have likely gone to 20 weeks. Now, I think that's great. For me personally, when a patient's doing that well, I might switch them to as needed treatment and bring them back in four to five months and see how they're doing. But again, I think it's a testament to what an improvement we've had from off-label bevacizumab to what we have today.

Scott Krzywonos:

In a pretty short period of time, relatively speaking, it's been a matter of years moving from off-label bevacizumab to what, potentially, 20 weeks, which now becomes as needed rather than treat and extend.

Dr. Adam:

Yeah. And the future is bright. We have so many other things coming with gene therapy TKIs to combine with these agents. So yeah, really excited for what's coming.

Scott Krzywonos:

Yeah, you might be seeing your patients less and less, which I think some of the retina specialists have said would break their patients' hearts because they love you so much, but it's best for them.

Dr. Adam: I don't know if my patients would say that, but I would hope so.

Scott Krzywonos:

Of course. No, of course they love you. Moo Adam is the director of clinical research at Colorado Retina Associates. Mo, thanks for coming on the show.

Dr. Adam: Scott, thanks so much for having me.

Scott Krzywonos:

Thank you listeners for sticking with us for our interviews with Dr. Adam and Dr. Kuppermann. We've got one more episode of ARVO coverage coming up soon.

Greg Nothstein: In order to get that episode, make sure you download and subscribe us from your favorite pod catcher of choice.