Great. We'll go ahead and get started here, and thank you everybody for for joining us here. Second day of Piper Sandler's Annual Healthcare Conference. I'm Joe Catanzaro, one of the Piper Biotech analysts. It's my pleasure to kick off this next session here with Ocular Therapeutix. Joining us, we have Antony Mattessich, CEO, and Peter Kaiser, their Chief Medical Advisor on the retina side. So a lot to run through. You guys have had a lot of recent updates around OTX-TKI, so plenty to talk about there. But maybe first, Antony, I could give you a couple of minutes. You could sort of give a quick overview of Ocular, what you guys have been up to, and what we have to look forward to.
Great. I mean, we're a company built on the idea that very often patients do much better when they're in clinical trials, and then when they get out into the real world, they tend not to do as well. A lot of reasons for that, but the primary reason is that medicines are delivered in very onerous ways that make it hard for people to maintain the kinds of treatments that they need to have in order to benefit themselves in the longer term. We develop a number of medications, all of which are designed to improve results in the real world. I mean, obviously, we need to do well in clinical programs, but the real goal is to narrow that gap between how patients do in clinical trials and how they do in the real world.
Perfect. So maybe with that, we could talk about OTX-TKI and maybe to help set kind of-
OTX-TKI. You mean AXPAXLI.
Don't ask me to say that. You, you scared me there. You thought-
Yeah, yeah. No, no, no.
You're wrong.
We have a swear jar at work, and if you say OTX-TKI, you have to put money in the swear jar.
Yeah, it's a little bit tricky transitioning from, like, the generic name to the branded name.
Mm-hmm.
So I'm going to stick with OTX-TKI.
All right, all right. I won't, I won't throw you off your game.
So maybe to set some foundation, we could just sort of level set the stage here around the data we've seen for TKI to date, and what sort of the knowns are about its profile and what the drug can do, and maybe what some remaining unknowns might be around the program.
Okay. Well, I brought my retina muscle with me today, so I'm pretty much going to defer most, AXPAXLI or OTX-TKI to Peter. So, Peter, you want to?
Yeah. So TKIs have been used in the oncology space successfully. And historically, in the ophthalmic space, the oncology companies would just take their drug, whether it's IV or PO, and put it into an ophthalmology study, and they essentially, either due to side effects or other reasons, didn't work. Only when we started to put it in the eye, or at least around the eye, in a ClearSide's case, do we start to see some really good results. And the results to date with AXPAXLI have been both in treatment-naive patients, as well as in previously treated patients, both in combination with anti-VEGF and not in combination. To me, the not in combination is the important ones, because then obviously it's only related to the TKI that we're seeing the result.
And so in both those subsets of patients, we've seen excellent results. When I as a KOL, not speaking for OTX, you know, when I look at a space and you look at a class of drugs, are we seeing a similar response among the different companies? And if you look at axitinib, which is the same drug we're using as in ClearSide's case, they're mirroring our results just with less durability. So to me, that validates the TKI, at least axitinib, in AMD.
So you guys have now formulated a sort of registrational strategy within Wet AMD. Maybe you could talk us through a little bit how you got to this point and this trial design. And we'd sort of love to know, like, the level of FDA feedback, where the major questions lay around this, this trial, design, and how you went about addressing that.
So I've designed many clinical studies in retina, and historically, we've always, you know... So when we designed the Lucentis studies, it was similar to here, where it was prevention of vision loss, was the Lucentis studies. But every subsequent study was in comparison to the previous drug in a non-inferiority study. And so when we went into this, we thought, well, we're just going to do a non-inferiority study like any other drug would do, and just show they were the same as Eylea every two months. But then the whole world got put on its head when the FDA released its guidelines earlier this year. And when you read those guidelines, at first we thought, you know, Wiley Chambers must be, you know, having a stroke. There's an issue here. There's no way he could be serious about this.
But as we started to go to him with study designs, we realized that doing a non-inferiority study was essentially impossible in the absence of doing a saline injection in the study group, which is just untenable. And then the reason it's untenable is because a saline injection has its own side effects: retinal detachment, endophthalmitis, retinal tears, vitreous hemorrhage, happens at about a 2% rate in any study where there's a saline injection. If you want to look that up, just look at the Jetrea studies, where they had a saline injection in that study. So you can see what the sort of complication rate of simply a saline injection for the hell of it is. So most clinical trial sites wouldn't accept it.
My IRB wouldn't allow us to do a study with a saline injection, unless the saline had a reason behind it, like it did in the Jetrea studies. So because of that, we then said: Well, what are some of the other options? And that's where we landed on a, a superiority study. And the big question marks for us, and the reason why, SPA was, was, done, was because we wanted to know the answers to those questions prior to enrolling, starting the study, because if the answers were not what we wanted, we actually couldn't win. What do I mean? So if you're doing a superiority study, one drug versus Eylea, and the Eylea arm gets rescued, then they're not going to lose any vision. So the specific question we asked-...
The agency and the SPA was, if a patient lost 15 letters of vision, or if the patient, you know, had a protocol violation, or if the patient dropped out of the study, they should all count as failing the primary outcome. We weren't sure what the agency would say to that, to that question, but it turns out when we asked the question, they said, "Well, yeah, if you have a 15-letter loss and then rescue them, that patient is considered failing the primary." Because, you know, what will happen? That patient will gain vision with that rescue. So if you just look at them at nine months, they'll have gained vision back, there won't be a difference. But by counting them as a failed and then keeping them in the study, that was one.
Two, let's say you're in the Eylea arm and you lost 10 letters of vision. That patient, Ms. McGillicuddy, goes to her principal investigator, says, "I noticed this loss of vision. What's going on?" And then principal investigator says, "You know, I can't treat you till 15 letters, but it's your prerogative to drop out of the study." They didn't meet the 15 letters, but by dropping out of the study, they will, in the SPA, be allowed to be counted as also failing, right? So to us, those are the two key considerations that we got the answers to in the SPA, which allowed us to move forward and say, "Yeah, this, this is a rational study design, this is enrollable, and this is what we're going to move forward with.
Great. Maybe I want to tick through a couple of things with regards to the trial's design. Maybe first is the patient population you're targeting and why it's maybe the ideal wet AMD population to truly demonstrate the durable benefit that TKI might provide.
So the patients we know how they're going to respond the best are treatment-naive patients, because we've seen all of the clinical studies, so we know how they're going to respond. What we can't predict is someone who's sort of a non-responder. How are they going to do? Are they simply anti-VEGF non-responsive? Is that why they're not responding? So in that case, a TKI wouldn't work either because they're anti-VEGFs, but pan-anti-VEGFs. So if you're not a VEGF responder, you're not a TKI responder either. So by using treatment-naive patients, but then making sure they're VEGF responsive by doing two injections before they're enrolled in the study, now we know they're responders, now we know we can put them into the study. So in a sense, it's de-risking it for us because we're not enrolling patients who are not VEGF responsive.
Where is that, I guess, window of responsiveness? I guess what I'm referring to is, it sounds like right now the strategy is you take a patient, give them two dose, they need to get to, like, 20/20 vision. I think there's been talks of maybe you could sort of loosen that a little bit and maybe presumably aids in, like, the screen failure rate. I guess, how are you guys thinking about that? Are there some tweaks there that could happen?
So the original idea, when we first brought the idea of a superiority study, you had to lose 15 letters to sites. They're like: Yeah, no, we're not doing that study, period. And that's before they really started to read the guidelines and understand the guidelines. So then we came back and said, "Well, if you improve to 20/20, a loss of 15 letters is 20/30 to 20/40. You know, most of us feel pretty comfortable letting a patient drop to that point and then rescuing them." So that's why we went with that first. But that was three, four months ago. Now, when we talk to the sites, they're like: Well, the more we think about this, you don't need to get to 20/20. Like, in other words, improve to 20/20 to get into this study.
We would feel very comfortable enrolling a patient who improved, but improved to, like, 20/25, 20/30, 20/40 even. And so what we've done is, because we didn't want to invalidate the spots, we've gone back to the FDA and said, "If we change the inclusion to just improvement in vision," and we didn't define it. So basically, as long as the investigator feels comfortable putting that patient in, it could be 20/60, for instance. What that's done is it will dramatically increase the number of patients we can enroll. It will reduce the screen fail rate, and the sites are now on board. You know, three, four months ago, when we first floated this, they were like, "Yeah, okay, we can do the 20/20." But now they're like, "Yeah, no, I get this.
I understand it." And so we're going to start the study once we get the feedback from the FDA that they're going to allow this change. To me, my guess is they're going to absolutely okay the change because it increases the population of patients. It's more consistent with what we see in real life. So I don't see them changing because we're not changing anything about rescue or primary or anything like that. The only thing that's changing is what is the vision to get in. So instead of 20/20 to get in, it'll be less than that even.
I want to follow up on this sort of level of comfort physicians have with allowing 15-letter loss. Sounds like three months ago, that may have been a challenge. Now, it's almost... It's there. I guess my question is, like, how much education is needed on your part? Have all the sites kind of been educated and brought awareness to this idea and notion, or is there more work to do?
Well, nobody likes this. You know, you'd speak to a retina specialist, "Do you feel good about letting a patient lose 15 letters?" The answer is no. But unfortunately, that's the only way we're going to get drugs approved in the future. So it's more of an acceptance. We don't like it, but we accept it. The sites obviously are on board because they wouldn't even say yes to being a site. The education still needs to be to the general retina community, that they need to understand we're doing this in the most ethical way that we can do this study in the guidelines the FDA has put around us. So that education still needs to occur and is occurring, and will continue to occur.
What about on a patient side, I guess, going back to Mrs. McGillicuddy, right?
Mm-hmm.
How do you get patients comfortable with that notion? Do you run the risk of, you know, a high rate of dropouts in the absence of 15-letter loss?
Sure. You know, I think the question is, you know, can you enroll the study? And the reason you can enroll a study is the discussion with the patient would be, okay, you're treatment-naive, so this is the first time you're being told you need injections. And one option is we have treatments that work just fine for this. We're going to give you monthly injections until you're dry, and then we're going to start to slowly extend the number, the interval between your injections. But you're going to continue to get injections. At no point are we stopping these injections. So on average, in the first year of treatment, we're going to do nine injections. That's the average.
Alternatively, we can put you into this study, and we're going to do a few injections at baseline, and then it's possible you don't need any more up to nine months, right? That's why patients would be willing to consider the study, because when you're first getting into treatment for wet AMD, you're terrified of injections. I mean, think about it. Would you like a shot in your eye? No, neither do they. And so, to say to them, "Hey, if you get in a study, maybe you'll be less than that nine," that's a reasonable carrot to get a patient into a study.
The other thing on this sort of similar topic is how physicians might handle a patient who has c`hanges in their OCT measures-
Mm-hmm.
In the absence of any letter loss or 10, you know, 15 letter loss. What are your expectations there?
We designed the ANCHOR and MARINA Lucentis studies in the absence of OCT. In fact, OCT came out because we didn't want to treat patients monthly in Lucentis studies. We learned that you could use OCT as a guide. But one of the reasons why the OCT has never been put in any label is there's no correlation between vision and OCT changes. And in fact, the best example of this is home OCT studies, where patients have massive fluctuations in their OCT fluid when you're monitoring them every day, yet they don't have a loss of vision. And sometimes that fluid increases, and then with no treatment, goes back to being dry again. You know, that notion, we're starting to understand that fluid doesn't correlate with visual acuity outcomes.
So that's one of the things that, again, it's going to be educating both the physicians in the study as well as the physician community at large as to what does fluid on an OCT really mean in AMD. It's different in DME.
Maybe now moving to the primary endpoint, first on the sort of control arm side of things. What are your expectations over a nine-month period for how many patients in the control arm will require and meet that 15-letter loss or more rescue criterion? What informs your assumptions there?
So, so the issue for us when we, we calculate this is there's never been a study to do that, right? So we can look at predicate studies, and the, the closest predicate study would be the CATT Study. So in the CATT Study, they had a PRN arm where they got a Lucentis injection at baseline or Avastin, and then were followed and then treated only as needed. And in that study, 90% of the patients needed a shot in the, in the 1 year. So we don't have the nine month data on that, but at 1 year it was 90%. So, so we cut that number to about 40%-50% is our, our guess for how many patients will need an injection.
But then you flip it and say, well, if you're going to do power calculations, you got to need to know how what your drug's going to do. And if you look at the roughly 50 patients in the studies to date that we've done with AXPAXLI, none of the patients have had a 15-letter loss. So we're not going to put zero as a number. We're going to put a conservative number, but our power calcs are based on a 15% delta between AXPAXLI and Eylea. We expect it to be considerably greater than that, quite frankly. But the power calcs to go to 300 patients is based on a 15% difference.
So this is, I think, something I've spoken with you, Antony, about, but I'd love to hear Peter's thoughts. I've always wondered. I've been thinking why you couldn't just run, like, Kaplan-Meier analysis and, like, reduction in risk, meaning rescue, and whether there's a specific percentage reduction in risk that's considered meaningful and look to target that.
Yeah. So for all of us, we conceptually understand this, but if you speak to Dr. Chambers, he goes, "I've got a great treatment that I tell you to do every month, and yet you don't do it." And so treatment burden reduction has never been an outcome that he accepts for that very reason, because he says: "You don't even do what I tell you to do." So a Kaplan-Meier curve would be nice, and certainly we like a futility analysis. So in other words, if all these Eylea patients are getting rescued, for instance, so falling out, couldn't you just stop the study, say, five months in? Because it's obvious everybody's been rescued.
Well, the requirement is nine months, and for the OTX-TKI AXPAXLI arm, you want to go to nine months because you want to prove how many patients in the Axpaxli arm can go to full nine months without a treatment. So at least in the first study, we're going to want to do the full nine months. Now, futility analysis in the second study certainly is something we could have a discussion with the FDA.
Great. Maybe a couple more questions, on this. One is redosing expectations, whether that's going to be allowed in the trial, whether that's an extension part of the study. So where does that stand?
So, we're not going to redose in the first study. However, we plan to have an extension study-
...So a lot of our secondary outcomes are at the 12-month time period. So we want to redose at 12 months in the extension study, and then likely again at 18 months, with a final readout at 24 months. And that theoretically would get us a label anywhere from 6-12 months with redosing.
Maybe, maybe one for you, Antony, on sort of the more recent disclosure around... I don't want to say change in formulation, because I think you've been clear that it's not a change, but maybe you could speak to some of the decision points that led you guys to make some of those changes.
Yeah, I mean, at every stage along the development of all of our products, we iterate. We're formulators. We get closer and closer to perfection, until the last pivotal. Essentially, the last pivotal is the product you have to go to market with. So what we saw in our phase 1 is we saw what we thought is the ideal release rate, which is on our 3 times 200. And we saw that in naïves, and that's really the best data we have to demonstrate the efficacy of monotherapy with axitinib. As we move forward, obviously, we didn't want three inserts, we wanted one. We formulated it into one. That moved the flux rate down.
So, it actually, in our, in those trials, we had less active being released on a daily basis, which meant we had more drug at the end of the life of the ELUTYX depot. So what we've done in this iteration is essentially we've kept the ELUTYX. The ELUTYX was performing perfectly. We want a nine-month formulation, so that we can redose between nine and 12 months without a depot being there. And what we did is we just maximized the elution rate so that we're, you know, slightly above, but in the neighborhood of 3x 200.
And so we have an amount of drug left at the end of life, which is the amount we want, which would be about, you know, 10%-15% of the total dose that's loaded into the depot.
So maybe a question on TKI, but also more sort of general. How do you fund this program through a potential registration? What are some options? I know you guys have long spoken about potential partnership opportunities. Wondering whether the SPA now in place kind of changes some discussions. Where does all that stand?
Yeah, I mean, obviously, we've signaled a very, very strong desire for non-dilutive means to fund these trials. And we feel we're tapped out from a debt standpoint. You never say never, but that... I think that door is likely closed. So if we're looking for non-dilutive sources of financing, it's really business development that would be the, that would be in that gap. Now, we have a great profitable commercial business that can receive new products as well as can work with other companies that are selling their products.
We have TIC, which we'll read out in April, which has a very sort of understandable phase I, phase II kind of setup that actually is attractive to a number of companies that probably couldn't afford an AXPAXLI. So this would be something that could fill our funding gap, but not do it with the crown jewels. I mean, we love all of our children, of course, but AXPAXLI is really an opportunity that if we are going to partner now with AXPAXLI, it will have to recognize what we see as the value and risk profile for AXPAXLI.
I mean, when we talk about AXPAXLI, if we can deliver on the target product profile, nobody debates the pot of gold at the end of the rainbow. This will change the standard of care in the treatment of wet AMD, without a doubt, and it's an $18 billion market. The only question is: What is the likelihood of success getting there? When you look at the trial that we have, and you look at the responses on the spot that Peter referenced, we're going to win that trial. It's very unlikely that we would not win that trial. The real question is: Can you enroll it? And it all depends on who you talk to, when.
If you talk to somebody who's never heard about the trial, the first response is going to be, "This is absurd, you're not going to enroll it." If somebody has been understanding the changes at the FDA and has moved through the seven stages of grief and starts to accept, say, "Yeah, you probably can enroll it." Or people who've been around it for even longer to say, "Not only can we enroll it, we can enroll it pretty fast, and we can enroll it with a wider group of people." So it's really the enrollment risk that's what's standing in between us and that pot of gold. If a strategic understands that, then it's possible to also partner with AXPAXLI.
If they don't, then we would much prefer to find those other sources of non-dilutive finance to be able to fund those pivotals going forward, because we have a very high degree of conviction that we can get there.
I was going to ask, but I guess maybe it's still too early, whether you have any expectations around how quickly this initial trial might enroll?
Well, so first of all, being a safety study, it's, it's a much smaller study. So historically, you look at non-inferiority studies, these are 1,000-patient studies. It takes a couple of years to, to enroll those studies. We would anticipate, you know, months as opposed to years. If the FDA accepts, which we fully expect that they will, the loosening of the inclusion criteria, we think it'll be even faster.
So it sounds like, enrollment ability and pace is kind of a de-risking factor for this program. Are there expectations to kind of keep us updated on how that's going?
Absolutely. I mean, it. We look at the things that we're going to disclose going forward, and obviously, DEXTENZA quarterly sales. We have a strong belief that those are going to ramp upward, and those will be good disclosures. The non-proliferative diabetic retinopathy trial will read out, the TIC will read out. But I think more than anything else, the really important readout is going to be the pace of enrollment. So, you know, we haven't decided whether it's the first 50 patients or first 75 patients or whatever it is we decide to disclose. But if that enrollment is going above expectation, I think that's the most sort of impactful disclosure that we can make going forward.
So one last quick one, we're out of time. You mentioned the diabetic retinopathy trial. I think we'll get some data early next year. Anything we should keep an eye out for? What will we learn new, outside of new indication, about TKI and its opportunities?
Well, so TKIs, by definition, are going to be pan-VEGF inhibitors. We know that diabetic retinopathy is an exquisitely VEGF-sensitive disease. We have two treatments that are FDA-approved. The only reason we don't do it is because nobody wants to get an injection in both their eyes every two to three months when you're a working-age patient. So really, sustained release, sustained delivery in diabetic retinopathy is really where we'll be very excited for. We fully expect it to work. The question is, you know, what type of improvement in retinopathy scores are you going to get? Are you going to get... Nobody get worse, which would be just as good. What is the reduction in vision-threatening complications? These are all things that are as important of, as getting an improvement in retinopathy.
You know, think about you if you had diabetes. If you just kept me right where I'm at with a shot every once a year, that's pretty good.
Yeah. Perfect. Well, with that, we're out of time. I know we spent a lot of time on AXPAXLI.
All right, you did it!
There we go.
Yeah, you did it.
Thanks, Antony and Peter, for your time.
Thanks.
Thanks, everybody, for tuning in. Take care. Enjoy the rest of your day.
Thank you.
Thanks. Great.