On February 17, Ocular Therapeutix announced that its investigational agent Axpaxli (OTX-TKI) outperformed an FDA-approved anti-VEGF therapy in the phase 3 SOL-1 trial for neovascular (wet) age-related macular degeneration (nAMD). Axpaxli is a bioresorbable intravitreal hydrogel incorporating axitinib, a tyrosine kinase inhibitor (TKI) with antiangiogenic activity. On February 27, the company presented detailed SOL-1 results during a lunch symposium at the 49th annual meeting of the Macula Society, held in Coronado, California.

Prior to the meeting, Pravin U. Dugel, MD, executive chairman, president, and CEO of Ocular Therapeutix, spoke with Retinal Physician about the company’s SOL-1 and SOL-R trials, the regulatory pathway for Axpaxli, and what the results could mean for the future of wet AMD care.

The following transcript has been edited for clarity.  

Pravin U. Dugel, MD: My name is Pravin Dugel, MD. I'm the executive chair, CEO, and president of Ocular Therapeutics. Thank you for this opportunity.

Retinal Physician: SOL-1 met a superiority endpoint against aflibercept, which is a high bar in wet AMD. Is there one aspect of the data that best explains why Axpaxli outperformed an anti-VEGF agent?

Dr. Dugel: First of all, we're very, very happy with the data. At the end of the day, this is historic because there's no other drug that has ever outperformed an anti-VEGF. This is the first superiority trial that has ever succeeded in the history of our field. And it provides us a direct path for potentially having the first and only superiority label ever in our field. For all these reasons, this is a landmark trial.

I think what's really important is to say that this drug performed better than we expected. If you had ever told me that we were going to have a drug where you could reliably say that with a single injection, at week 52, two-thirds of patients would be rescue-free—that in itself really would be very impressive. Then, if you could say on top of that, that the same drug would provide an objective measure of disease control, which is measured by the OCT, that the OCT would be stable up to 30 µm with a single injection at week 36, to complement that as an objective barometer, that would be really a grand slam. That's what this drug has done. So, we're extremely happy with the data, both from a subjective point of view—which is the visual acuity—from an objective point of view—which is the OCT—and from a regulatory point of view—which is the outcome that we showed at 36 weeks. This drug has beaten Eylea (aflibercept 2 mg; Regeneron), which is a fantastic drug, and this is a landmark study for that reason.

RP: Why was visual acuity maintenance chosen as the primary endpoint in SOL-1, rather than mean letter gain?

Dr. Dugel: It's important to state that this study was really designed, if you will, by the US Food and Drug Administration (FDA). The FDA in February 2023 issued very clear guidelines as to what they wanted, at the least regulatory risk, as a superiority study and as a noninferiority study, and we followed their guidelines exactly. That's why we were rewarded with a special protocol agreement (SPA). This is the study that the FDA wanted. In many ways, it’s an absolutely pure study. It answers many, many questions that physicians and payers and patients will have. But the endpoint, as I've always said, is a fantastic regulatory endpoint. It’s what the FDA wanted in terms of a head-to-head study.

It’s not necessarily an endpoint that clinicians use, because clinicians don’t wait for a 15-letter loss. That's why it's so important that we have gone ahead and extracted the clinically relevant information from this study. And actually, the clinically relevant information, such as the OCT difference and the visual acuity difference, is even more impressive. But to answer your question: this is a study that is specifically designed by the FDA, validated with a SPA, as a study that is the least or no regulatory risk for approval. And that's exactly what we've done. We've followed their guidelines to a T.

RP: How do you envision the FDA review pathway, and why pursue an accelerated 505(b)(2) strategy?

Dr. Dugel: Axpaxli consists of 2 components, and both of the components are individually FDA approved. The first one is the TKI (axitinib), and the second one is the hydrogel, and both of them individually are already FDA approved. What that means is that on the front end, it allows us to save a lot of time in our filing, because we can file via the 505(b)2 pathway. That saves us at least 2 months on the front end. On the back end, we have a SPA, or special protocol agreement, which means that the FDA has already validated and studied all the statistical analysis plans (SAPs), the powering, the clinical trial design, everything else. That's already been approved. So, we believe the filing will be very efficient.

We also made a statement a few months ago that through our conversations with the FDA, and as per the directives from the leaders of the FDA, Vinay Prasad, MD, MPH, and Martin A. Makary, MD, MPH, that we believe that we would be able to file with a single study, with SOL-1 only, because it met all the guidelines that they had articulated. And what's really important to state is that on February 18, an editorial came out in the New England Journal of Medicine, written by Dr. Makary and Dr. Prasad, that validated everything that we said, and also confirmed the fact that everything that we have in our trial—which is a robust p-value, a trial that is well designed, with proper masking, proper powering—it simply checks all the boxes that's in that editorial for a single trial to be acceptable for approval. So, with that in mind, our goal and our intent is to file for approval with SOL-1 alone.

It's important to state that we will still run our second study, which is the noninferiority study, which is SOL-R. We're not going to stop that. That will provide additional information, but we're more confident now than ever that we'll be able to successfully get this drug approved with one study alone, the SOL-1 superiority study.

RP: How do SOL-1 and SOL-R complement each other in your overall regulatory and commercial strategy?

Dr. Dugel: With what I've said, we don't think that SOL-R is going to be necessary for approval. I’ll reiterate again, especially with the February 18 written editorial, that we will be able to successfully file for approval with SOL-1 alone. But SOL-R is complementary to SOL-1 from an informational point of view. SOL-R may be a more traditional noninferiority trial. It uses Eylea per label, and I think it will provide additional information that the clinicians, patients, and payers will want. We're happy to continue to keep that running. We're not slowing that down, we're not stopping that, so that will provide us with a lot of additional information.

But again, to be very clear, we don’t think that that's necessary for approval. We’re filing for approval based on 1 study, SOL-1.

RP: If approved, where do you see Axpaxli fitting into the wet AMD treatment paradigm?

Dr. Dugel: It's a great question. Look, what physicians want is a safe drug that is going to allow for a greater sustainability. We know this historically, over and over again. If you look at Lucentis (ranibizumab 0.5 mg; Genentech) and Eylea, for instance, Lucentis had a 7-year head start. Eylea, arguably, may last a week or so longer. If you look at Vabysmo (faricimab 6 mg; Genentech), this one may last a couple of weeks longer. And any incremental increase in durability has really dominated the market.

We’re in a different orbit altogether. We're not talking about an extra week or 2 weeks. We're talking about a drug that will allow patients, two-thirds of patients, to be rescue-free up to almost a year. That's pretty remarkable. Again, we're in a different orbit, with a superiority label, potentially, that will distinguish us from everybody else. And why is that important for clinicians? Well, what that means is that there's a potential with a superiority label not to be subject to things like step therapy, for instance. And that's going to be very important for physicians and patients.

So, where do I think this will fit in? I think this will fit in immediately for all patients that doctors are treating. The workflow doesn’t change. There’s not a single piece of new equipment to buy. The process is going to be very, very familiar and seamless to all clinicians. They’ll simply reach out and get a better drug. They’ll be happier, the payors will be happier, and the patients will be happier. RP