Greg Nothstein:

Could TKIs be the game-changing therapy that makes wet AMD treatment less burdensome?

Scott Krzywonos:

I'm Scott Krzywonos with Greg Nothstein, and this is New Retina Radio from Retina Today and Bryn Mawr Communications. Dr. Dilsher Dhoot joins the show to examine the SOL-1 study, a superiority study assessing the safety, efficacy, and durability of axitinib for the treatment of wet AMD.

Greg Nothstein:

And Dr. Carl Danzig stops by to deliver four and a half year data from TRUCKEE, which tells us how real world patients with wet AMD perform when dosed with faricimab. How are patients doing after three, six, or even nine doses? Stick with us to find out.

Scott Krzywonos:

The SOL-1 data are some of the most compelling data in retina this year as they might represent a new wave of therapies that could meaningfully lengthen wet AMD treatment intervals.

Greg Nothstein:

Dr. Dilsher Dhoot had the privilege of sharing those data at ASRS in Montreal, and he's here with us today to do the same. Dr. Dhoot practices at California Retina Consultants in Santa Barbara, California. Dr. Dhoot, welcome back to New Retina Radio.

Dilsher Dhoot, MD, FASRS:

Hey, Scott and Greg, it's great to be with you guys.

Scott Krzywonos:

So we're looking at axitinib or OTX-TKI. Before we get to the SOL-1 study itself, just give our listeners a quick primer on TKIs in case they're just tuning in now that we're in phase three.

Dilsher Dhoot, MD, FASRS:

Sure, yeah. So current anti-VEGF therapies are selectively targeting only extracellular VEGF, and TKIs work in a different place. They're actually working at the intracellular level. If you take axitinib, for example, it binds all three VEGF receptors, one, two, and three in a pan-VEGF fashion. And by doing so, it acts independently of extracellular VEGF working at the intracellular level. That said, axitinib by itself is a small molecule, right? In order to stick around in the eye, you have to pair this with a sustained drug delivery mechanism. And in this case, they utilize a hydrogel. So combined with the hydrogel, axitinib, which is a potent TKI, the most potent currently being studied for any ophthalmic indication, can have up to 12 months of continuous and consistent delivery and has complete predictable bioresorption of the hydrogel prior to [inaudible 00:02:42].

Greg Nothstein:

Let's turn to SOL-1. How was that study designed and what were researchers trying to understand here?

Dilsher Dhoot, MD, FASRS:

This was a very bold design. This was a superiority trial. If you think back and look at your neovascular AMD trials, the vast, vast majority of them are all non-inferiority trials. If you go back all the way to ANCHOR, MARINA, those were superiority trials. But again, like those, this is a superiority trial. And in particular, looking at the efficacy and durability and safety of OTX-TKI and comparing it to aflibercept two milligrams. And so the trial design really starts off with treatment-naive patients, and it's a particular population. These are well-cited patients. You had to have vision better than 54 letters, which is 20/80, and a central subfield thickness less than 500 microns in order to be eligible to be screened. And then you received two aflibercept injections at minus eight and minus four weeks. And then you were eligible to be randomized if, and only if, you had a BCVA gain of 10 letters or you had visual acuity of 2020, along with central subfield thickness less than 350 microns.

If you met those criteria, you were randomized in a one-to-one fashion to either OTX-TKI or aflibercept at baseline day zero. And what's really interesting about this trial is that the visual acuity at baseline day zero was 80 letters. We've never seen a trial with such good vision, 2025 at randomization. Patients were then followed for 36 weeks, at which point the primary endpoint was a proportion of patients who maintained visual acuity, which is defined as less than 15 letter loss on the ETDRS chart.

Scott Krzywonos:

So this is a really straightforward study. It just feels like a sprint to the finish, right? One dose at baseline and then getting out to week 36. What did you and your colleagues find at weeks 36 and at 52?

Dilsher Dhoot, MD, FASRS:

52 was a key secondary endpoint. Week 36, the primary endpoint. And again, when it came to maintenance of visual acuity, we found that OTX-TKI met its primary endpoint maintaining visual acuity. And we saw that 74% of patients maintained vision in the OTX - TKI arm compared to 56% in the aflibercept arm. And this was highly statistically significant with a P value of 0.006. At week 52, the differences maintained, and we saw about 66% with maintenance of vision at week 52 in the OTX-TKI arm compared to 44.2% in the aflibercept arm. And again, highly statistically significant.

Scott Krzywonos:

You and your colleagues looked at time to rescue treatment, which I think is a pretty interesting real world approximation of how patients might perform and then re-present to a retina specialist. What did you find when you looked at time to rescue treatment?

Dilsher Dhoot, MD, FASRS:

Yeah, I presented at Kaplan-Meier showing the time to [inaudible 00:05:36] rescue. And you look at these Kaplan-Meiers and it's a time-to-event analysis. And so the event is rescue in 30% of patients at week 52 required rescue in the OTX-TKI arm. And then we look back at, well, when did that same proportion require rescue in the aflibercept arm? And it was around week 28, a whole 24 weeks or six months earlier. So really speaking to the durability of the OTX - TKI.

Greg Nothstein:

Dr. Dhoot, talk to us about the evidence pointing to sustained disease control in the study.

Dilsher Dhoot, MD, FASRS:

Yeah, there's a fair amount of evidence. Firstly, of course, you have visual acuity and central subfield thickness evidence that we're used to looking at. And when we look at disease control when it comes to these two outcomes, we saw that visual acuity remained stable. Now keep in mind, this is a super good vision population, so minimal drop-off, sustained vision through week 36. And with central subfield thickness, we saw the same. In fact, we looked at the mean change in retinal fluid volume, and that was about 30 nanoliters at week 36 compared to 60 nanoliters in the aflibercept group. So improved anatomic control also over the course of 36 weeks.

Greg Nothstein:

Let's chat a little bit more about that fluid volume. What else did you find?

Dilsher Dhoot, MD, FASRS:

We also looked at other outcomes when it came to fluid volume. And so, one of the other outcomes that we looked at was a proportion of patients that had central subfield thickness less than 350 microns. And this proportion was also greater at week 36, 68.8% in the OTX-TKI arm compared to 52.9% in the aflibercept arm. And this continued through week 52 where it was 64.7 versus 43.6 in the OTX-TKI versus aflibercept arms respectively. So each of these time points, we see the proportion of patients with drier retinas was greater in the OTX-TKI groups.

Greg Nothstein:

All right, let's chat safety here. Anything they'd be concerned about?

Dilsher Dhoot, MD, FASRS:

I'm happy to report that OTX-TKI was safe and generally well tolerated. When we consider these newer medications, we're always thinking about intraocular inflammation. There were nine events of IOI observed in seven subjects, and all cases were mild or moderate and resolved [inaudible 00:07:53] therapy. There were no cases of occlusive or non-occlusive retinal vasculitis or endophthalmitis. When you consider the common adverse reactions, those occurring greater than 2%. One of the ones that comes up is vitreous floaters. It was 12.4%. And we dug deeper into those patients and it turns out that population, all of these floaters were mild to moderate in severity, no evidence of IOI associated with the floaters. And the vitreous floaters coincided with the drug elution stage of the OTX-TKI hydrogel bioresorption, which occurs between 24 and 36 weeks. And so most importantly, the visual acuity was also not affected when comparing the onset of those floaters to the visit before the onset of the floaters.

Scott Krzywonos:

Dr. Dhoot, I'm curious where you envision a TKI existing in a treatment algorithm for wet AMD. To extend out this far, it almost feels to make a apples to oranges comparison, it almost feels like an Ozurdex and DME where you could reasonably give this to a patient in the real world and if it works, it's expected. They could last six months or so. Am I reading this right or do you plan on using this differently or do you see this fitting into the ecosystem in some other way?

Dilsher Dhoot, MD, FASRS:

Yeah, I think that this is going to have even longer durability than Ozurdex, which really typically in our hands is lasting three months or so. When it comes to this, I think we're going to see nine to 12-month durability. Certainly we have the results here of SOL-1, which is one trial. Well, we're going to look to SOL-R and SOL-X for more data to help guide us. But based on this trial and the phase one trials, I think that it has broader applicability. I think that you're going to see treatment naive or early on type patients will probably be treated with a couple of anti-VEGFs as they were in the trial. We'll look for nice response and then immediately treat them with OTX-TKI. And I think the vast majority of these patients will then go approximately nine months or so potentially without any further treatment. And this certainly will resonate with patients.

The other types of patients, there's patients currently that are being dosed every three to four months on a cruise control, I'd say. And those patients would love to be dosed at a longer duration. So those are the types of patients that could immediately be dosed at a nine to 12-month frequency. And then finally, there's the patients that are really high need, patients who are currently being dosed every four to six weeks and sometimes have persistent fluid no matter how frequent their dosing is. And that population will benefit also in my opinion. I think that that population we could potentially inject and maybe we'll need some supplement injections, but we'll ultimately have a reduced injection burden.

Scott Krzywonos:

Dr. Dhoot, thanks so much for coming on New Retina Radio and sharing these data then giving us some context for them.

Dilsher Dhoot, MD, FASRS:

Always a pleasure, Greg and Scott. Appreciate it.

Greg Nothstein:

We've had four and a half years of faricimab use in real-world wet AMD patients. How exactly are they doing?

Scott Krzywonos:

Dr. Carl Danzig answered that question for ASRS attendees at this year's ASRS annual meeting, and he's here to answer it again today for me and for Greg and for you, the listener. Dr. Danzig practices at the Advanced Retina Institute in Bonita Springs, Florida. Dr. Danzig, welcome back to New Retina Radio.

Carl Danzig, MD:

Thanks for having me.

Scott Krzywonos:

Today we're talking about the TRUCKEE study, which is the largest non-industry sponsored trial examining faricimab in the United States in wet AMD patients. Tell us how it was designed.

Carl Danzig, MD:

Great question here. So the TRUCKEE study is a real world study sponsored by physicians. There's no industry sponsorship. The CRO services were provided by Vial, but in the end, this was a physician-initiated trial. And we looked at safety and efficacy in the real world, and there were over 3,600 eyes and over 2,900 patients for a total of about 22,000 intravitreal injections. Now, when we look at those demographics of those patients, average age was about 81 years old, majority were female. And most patients were switch patients. And of those switch patients, the plurality of them were from aflibercept about 42%. And in the study, about 10% were treatment naive.

Greg Nothstein:

You broke down all 2,910 patients into three buckets, those with three, six, and nine injections. For the first part of this interview, we'll focus primarily on patients with anti-VEGF history who switched to faricimab. And let's look at the largest group first. Those with at least three injections in a real-world setting and anti-VEGF treatment history. What did you find there?

Carl Danzig, MD:

Right. So those three patients, amongst those switch patients, think about this. When the study started in 2022, who were we putting into the TRUCKEE study? Well, patients that were getting faricimab were the hardest to treat who are getting mostly aflibercept. But in general, any previously treated patient that was hard to treat was going to be switched, and that's who we included in the TRUCKEE study. So we saw a mean gain amongst all switch patients of about a little over nine days of treatment interval. No surprise the vision was stable. And we looked at the anatomic parameters like CST and PED height. They were actually reduced after just three injections. But if we actually start looking at those patients that switched from aflibercept, there was a mean gain of 6.1 days of treatment interval. And we start looking further in the parameter of IRF, SRF, and we see that all the treatment groups, faricimab showed better drying ability.

Greg Nothstein:

All right, so let's move now to the next group. What about patients who had at least six injections and had a treatment history?

Carl Danzig, MD:

So the trend continues. It went from a little over nine to 13 days of treatment interval increase. The vision remained stable. The CST and PED heights were still reduced. The intraretinal subretinal fluid was further reduced. It was dried out more. But amongst those aflibercept patients that were switched, so it's hard to treat ones, that went from six days of treatment increase to 12, almost two weeks after just six injections of faricimab.

Scott Krzywonos:

So we're seeing a lot of success among patients who were switched at all, but especially those that were switched from aflibercept. Let's look at the final group here of patients with treatment history. That's those with at least nine doses. So long-term faricimab patients switched from another anti-VEGF molecule. Tell us about those patients.

Carl Danzig, MD:

So amongst this treatment group now, nine injections over a longer period of time. There was a mean gain of just over two weeks, 14.6 days of treatment. The CST and PED heights continued to be reduced after nine injections. So continued treatment showed reduction and improvement in anatomy or reduction of CST height, improvement in anatomy, further drying. We did see that the vision kind of tapered off a little bit. There was actually compared to beginning about a little less than three letters difference. But amongst the switch patients with aflibercept, there was about that also minus 2.8 letters. Well, why did this happen? We started thinking about this. Well, this is a real world study. This is not a randomized control study where patients are super adherent. Those are the unicorns in our studies in our offices, the ones that go in our clinical trials. But here in the TRUCKEE study, it's the best available vision.

Patients get lost to follow-up. Patients then come back. They may have some atrophy. They get worse because they get lost to follow-up. So all of these factors looked into that. But what we did see was continued drying ability, especially with further reduction of IRF and SRF.

Scott Krzywonos:

So far we've looked at patients who switch from any other anti-VEGF agent. What about those patients who were treatment naive? You said it was about 10% of the patients on the TRUCKEE study. They obviously don't have a baseline to compare them with a previous agent, but I'm curious what you found that the faricimab perform as well as expected in wet AMD patients in the real world?

Carl Danzig, MD:

Well, in the real world, faricimab did perform quite well with treatment-naive patients. We have to then harken back to when the TRUCKEE study started in 2022 and how people were treating and extending their treatment-naive patients. Now in the clinical trials, those patients were extended by Q4 weeks. In the real world, that doesn't happen quite the same. And we saw that in the TRUCKEE study. So the treatment-naive patients had dramatic improvement in anatomy. Their vision increased, but over the course of four and a half years, it wasn't a huge increase like we saw in the clinical trial. It was about one line, but 3.5 letters. Now, why did the vision not increase as much as the trial? Well, you just didn't get the 10-letter gains in the real world because the same reasons why in the other groups, you have the loss of follow-up, you have atrophy, you have other life events get in the way.

Scott Krzywonos:

Life gets in the way sometimes.

Carl Danzig, MD:

Yeah, life gets in the way. So in the end, the treatment-naive patients had about a 72-day treatment interval, which is about a little more than 10 weeks. In the clinical trials, there were more than that. But in here, just 10 weeks, I think it goes back to how the physicians extended the treatment-naive patients.

Scott Krzywonos:

Yeah, that's pretty surprising. So in the trial, they were extended by four weeks. You're saying in the real world people are doing it by two weeks. Is this just force of habit that retina specialists in the US are you just extending by two weeks or so and doing treat-and-extend intervals rather than following a study protocol, maybe four weeks just instinctually feels a little bit too long? Or is there some other reason? What's your best guess here?

Carl Danzig, MD:

Well, it is interesting that you mentioned in the US. It was outside the US, some countries, the majority of physicians extend by four weeks. Here, commonly, I do see physicians doing by two weeks. Though in the treatment-naive population, for me, I try to extend by four weeks, much like the clinical trial. The faricimab and actually aflibercept eight milligram as well were designed to last longer. Their clinical trials showed that these patients, their intervals were increased by Q4 weeks. I like to give my patients the chance of going eight weeks after their last loading dose, provided they're completely dry.

Scott Krzywonos:

Oh, interesting. Okay.

Greg Nothstein:

Of course, real world safety is always of interest. Was there anything of note here?

Carl Danzig, MD:

There wasn't anything tremendously of note. There was demonstrated safety of faricimab in the real world. Now, there were a few cases of anterior uveitis, mild IOI that returned to baseline with topical therapy. There was one case of bilateral non-occlusive retina vasculitis. Now, this is a patient who had previous anterior inflammation with faricimab. Now, this patient's vision returned to baseline with no other sequelae. However, we did learn, and we do recommend, that if a patient has inflammation with faricimab, there's no need to re-challenge this patient again. Switch to a different medication. These patients may be sensitized and develop further or worse inflammation. Also, one of the patients, it was my patient, had mild anterior inflammation with faricimab. She had actually worse inflammation when she was on Brolucizumab prior to entering the TRUCKEE study. So who knows? But we do see that there are a few patients that have inflammation. It's generally very well controlled that they have it. Switch them to a different medication. Don't go back to faricimab.

Scott Krzywonos:

Let's zoom out a little bit. I just want some context for TRUCKEE. So I want to know the history of the study, where it started, who's involved, and then I want to know a little bit about the future. What can we expect next from TRUCKEE?

Carl Danzig, MD:

Okay, so the TRUCKEE study. Truckee. It's a town in Northern California by Lake Tahoe, and there's a Truckee River, and it flows through Reno, much like this study, and that's how the study got its name. Now, remember, in 2022, a lot of us had PTSD from the Brolucizumab rollout a few years prior. So physicians were a little skeptical of clinical trial data. We, at the time, weren't used to seeing that type of inflammation that we saw with Brolucizumab. And frankly, it scared a lot of us, and we never want to see that type of inflammation again. So it was important for us who believed in the clinical trial data of TENAYA and LUCERNE to demonstrate that faricimab in the real world was efficacious and safe. So we started this ourselves, and that's how we got three injections initially because, well, I presented it at the Javits Center in ASRS 2022 for the six-month data, and all our data cut was really just for three injections.

So we just started with three there. It's now four and a half years. It's still hard to get all of the data into the TRUCKEE study. Some of us, like myself, has switched practices. I don't have access to my old patient information. Other patients are lost to follow-up. Maybe they couldn't consistently get the same drug. Their insurance changed. The copay assistance isn't there anymore. So there's a lot of reasons why the numbers kind of tail off. I do expect the TRUCKEE study to go at least five years, but we're talking about even having up to possibly seven. We'll see. But at the bare minimum, I think you'll see at least five years.

Greg Nothstein:

Well, the story with TRUCKEE continues, and we're so glad that you brought us these updates. Dr. Danzig, thank you so much again for joining us here on New Retina Radio.

Carl Danzig, MD:

Thank you for having me.

Scott Krzywonos:

All right, that's it for this episode, but stay tuned. We have another episode coming up in your feed.

Greg Nothstein:

Be sure to download and subscribe to New Retina Radio on your podcast platform of choice to get more episodes from this meeting.