Ocular Therapeutix
The clinical trials industry talks constantly about regulatory strategy. Ocular Therapeutix actually built one from the ground up. The company’s lead asset, AXPAXLI™ (OTX-TKI), an investigational sustained-release tyrosine kinase inhibitor for wet age-related macular degeneration, is now the subject of an NDA supported by a single registrational trial, the SOL-1 study, conducted under a Special Protocol Assessment. At week 52, 65.9% of AXPAXLI patients maintained visual acuity compared to 44.2% for aflibercept. The treatment gap did not narrow over time. It widened. Peter K. Kaiser, MD, Chief Development Officer at Ocular Therapeutix, sat down with Vanguard to explain how FDA alignment became the architectural foundation of that program, not its finishing touch, and what sponsors designing retinal programs today would need to replicate it.
Moe: Why did FDA alignment have to come first in the development program, before the trial design was finalized?
Peter K. Kaiser: If you think about getting a drug approved in the United States, you really need to do it backwards from the way most people approach it. You need to be aligned with the FDA very early in your development program, because that’s how you avoid surprises when you get a trial result. If you decide to run the study without that alignment, you could be in for many surprises along the road. There are many drugs that do something we think would be very beneficial, but there is no way to get the FDA to say that this drug actually works. We are anchored by the agency’s guidelines, and the earlier you accept that, the better your program is designed.
Moe: How does the FDA’s Division of Ophthalmology’s unusual leadership stability change the risk calculus for retinal sponsors?
Peter: You're absolutely right that in many areas of the agency, the leadership is changing consistently, and the guidelines along with it. It is a moving target. In the Ophthalmic Division, however, we've been very lucky. There has been almost 35 years of consistency in leadership, first with Wiley Chambers and now with Bill Boyd, who worked with Wiley for many years. Because of that, the consistency of the rulings and guidelines coming out of the ophthalmics division is very different from other fields. It's almost like the Supreme Court: if Wiley handed down something 20 years ago, that's the way it works now.
That doesn't mean they don't change their thinking. A good example is optical coherence tomography. The FDA previously said you couldn't use it as a primary outcome, but we did get a drug approved using OCT as a primary outcome. That drug was called Jetrea (ocriplasmin). As long as you can give them the background and the evidence of why a primary outcome would work, they are flexible. Another example is using the ellipsoid zone for geographic atrophy studies, which was previously all based on fundus autofluorescence. The consistency is there, but they are also willing to listen to industry and move the field forward, as long as we can prove and validate the outcome measures we're using.
“There has been almost 35 years of consistency in leadership, first with Wiley Chambers and now with Bill Boyd, who worked with Wiley for many years.”
Moe: Why is the Special Protocol Assessment (SPA) so rarely used if it offers that kind of regulatory certainty?
Peter: Anybody can go to the FDA and get a Special Protocol Assessment. What it is, essentially, is an agreement, a contract that you are making with the agency. This is how we are going to run the clinical program, these are the patients we are going to enroll, and this, most importantly, is the statistical analysis plan we are going to follow and not change. The FDA's part of the agreement is that they say they agree with the study design and they agree that if it is positive, it shows what you said you were going to show.
Why don't more sponsors do it? Because a Special Protocol Assessment comes with its own rules. You cannot change it. If midway through the study you realize you need to make amendments, which is completely normal in a clinical study, it becomes very, very difficult to do that under a SPA. You really need to be almost perfect in your trial design upfront, because you cannot easily change it once you're running.
“A special protocol assessment is a formal agreement with the FDA that you are aligned regarding study design, endpoints, and statistical analysis. It doesn't mean it's an automatic approval, but approval is more likely if you have a positive clinical study behind it.”
Moe: Why did the treatment difference between AXPAXLI and aflibercept grow larger from week 36 to week 52, rather than narrowing?
Peter: Let me back up a little bit. In the SOL-1 clinical program, we took patients with wet age-related macular degeneration and treated them with either AXPAXLI or aflibercept, better known as Eylea, which is the gold standard control in clinical studies. The difference between aflibercept and AXPAXLI is that aflibercept works in the extracellular space and does not block all VEGF isoforms. AXPAXLI does two things: it blocks all VEGF isoforms because it blocks all three receptors, as well as other receptors that are important in macular degeneration.
What that widening result tells me is that the patients receiving AXPAXLI had a sustained release of the drug out to 52 weeks, whereas the effect of aflibercept was waning. So the delta increased with time. You would expect that if you continued to follow patients even longer without treatment, that effect would increase further. The whole rationale for AXPAXLI is to reduce the treatment burden in patients with wet age-related macular degeneration, by potentially giving them one injection per year, which would be incredible compared to what we currently do, which is injections every one to three months.
Moe: How did the SOL-R trial's role shift from second registrational study to confirmatory safety support, and what specifically changed in your conversations with the FDA?
Peter: Once we realized how positive the SOL-1 clinical study was, and the extent of confirmatory evidence we had to support it as a single study submission, we went to the FDA. We had what's called a Type C meeting, where we sit down, present our case, and they say yes or no to filing with a single study. We met with Bill Boyd and his team, and I do a lot of FDA meetings. It was genuinely nice to do it in person, because you can see the room's reaction to what you're presenting and you get real-time questions.
Once we knew we could file with a single study, we looked at SOL-R differently. The control group in SOL-R includes the two most common treatments for wet age-related macular degeneration right now: Eylea 2 milligrams and Eylea HD. We realized we could use this for our competitive advantage in the commercial marketplace. Physicians want to know how your drug performs against the current standards of care. When you are looking at superiority, the longer you wait to read out the primary outcome, the more likely you are to hit it. So, we moved that readout in SOL-R from around 52 weeks to two years. That gives us the best chance of demonstrating superiority to Eylea HD, which by the time AXPAXLI may be approved could well be one of the gold standard treatments. When we didn't need SOL-R for registration, we repositioned it for competitive advantage.
Moe: What does a sponsor designing a retinal program from scratch today actually need in place to earn that same kind of FDA alignment?
Peter: The use of a single trial submission is not new. We didn't invent this. If you look at FDA approvals in 2025, roughly half were based on a single trial. But if you are going to pursue a single trial approval, you need to be very careful not to commit to that at the outset without the appropriate safeguards.
If you go in saying your single trial will carry the approval and you later realize you did not meet the significance level or all the requirements, you would have to start a second program. That is why we had two programs running from the beginning. We were very optimistic that we would achieve a very high level of statistical significance, which is what a single trial approval requires. If you are going to design a program with only one study, you need to ensure your statistical power is correct, you need total alignment with the FDA, and you should probably secure a Special Protocol Assessment to confirm that.
Thus, a sham controlled study may not be submitted as a single trial, and two would be needed.
You also need to meet the safety requirements. We are using SOL-1 for both efficacy and safety, but we are supplementing that with safety data from SOL-R. So even though we are filing with one study, we are using confirmatory data from other sources. That is an important distinction.
“About 40% of patients stop their treatment within the first year, mainly just from getting tired of the injections. AXPAXLI was specifically designed to correct that problem.”
“The control group in SOL-R includes the two most common treatments for wet age-related macular degeneration right now: Eylea 2 milligrams and Eylea HD.”
Moe: Why does the two-thirds rescue-free rate at week 52 matter for actual patients, not just the clinical endpoint?
Peter: Wet age-related macular degeneration is a leading cause of blindness in older patients, and the anti-VEGF therapies have completely changed that. The incidence of legal blindness has been dramatically decreased. But that requires very frequent and very constant injections, which patients and their caregivers sometimes get tired of. About 40% of patients stop their treatment within the first year, mainly just from getting tired of the injections. That leads to long-term loss of visual acuity over time.
AXPAXLI was specifically designed to address this problem. It was designed to provide long-acting, sustained release of a Tyrosine Kinase Inhibitor (TKI). The results you mentioned, about two-thirds of patients going almost one year without needing another treatment, mean that instead of injections every one to three months, patients could potentially go nine to 12 months between treatments. That is much easier on a patient and much easier on a caregiver, and hopefully it will mean preservation of vision over the long term.
I will say that is an aspirational statement. We hope to prove it. We currently have a third study ongoing called the SOL-X study, in which we are following all patients from both SOL-1 and SOL-R out to five years, to demonstrate long-term stability in vision. That is our goal with that study.
Peter K. Kaiser, MD, is Chief Development Officer at Ocular Therapeutix.
Moe Alsumidaie, MBA, MSF, is founder and Chief Editor of Vanguard Publications, which publishes Clinical Trial Vanguard, Pharma Vanguard and BullScope, and Head of Research at CliniBiz. He has two decades in clinical trial operations and data science, with earlier roles at Genentech, Abbott Vascular and Stanford University Medical Center, and is a guest lecturer in clinical trial sciences at Rutgers University.
