Good afternoon, everyone. Thank you for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the biotech analysts here, and, in this session, we are very pleased to have, Mr. Antony Mattessich. I hope I pronounced your last name right. CEO of Ocular Therapeutix for this fireside chat session. Welcome, Antony. Thanks for having me. Maybe before we get into details about the commercial products and the pipeline, could you first give us an overview of Ocular and, for the investors that are not super familiar with the story? Thank you. Great. Well, Ocular Therapeutix is a drug delivery company, I guess is to put it in broader terms, but specifically what we do is we make medicines that actually improve outcomes in the real world. So we typically take known APIs, we put them in our delivery technology, and through that delivery technology, we overcome issues of non-compliance, of misdosing, that actually help to make real-world outcomes, in essence, come in line with what we see at clinical trials. So we've started, as the name might sound, with the application of our technologies in the eye. We think we've developed better ways to get drug to the ocular surface, and in so doing, obviate the need for drop therapies, and we think, you know, our, our vision in the future is that, you know, in the future, when you go to ophthalmologists with, with an eye condition for an ocular surface issue, eye drops will no longer be prescribed because there are better ways to get drugs to the ocular surface. We get drugs to the trabecular meshwork to treat high, high intraocular pressure, that also obviate the need for drops, and we have better ways of getting drug to the retina in a sustained release manner so that you don't have to go, often for injections in the back of the eye. Okay, terrific. Maybe you can start with OTX-TKI in wet AMD, since this is a very attractive space and we have established the commercial market and also like we see the new drug keep coming. Where do you see the unmet needs there, and what are the opportunities for OTX-TKI in your view? Right. Well, it's now AXPAXLI. We've got it, we got it branded, so we're referring to it as AXPAXLI going forward. But yeah, OTX-TKI is the former product name, which is a combination of our polymer technology with a tyrosine kinase inhibitor called axitinib. And it's designed to give continuous drug delivery to the retina for nine to 12 months off a single injection. But as you mentioned, the opportunity is obvious. The key driver in the marketplace, we see Vabysmo's uptake, we see the high-dose Eylea uptake and with just a partial quarter. I keep—I think in some ways I'm the lone voice in the wilderness that says these drugs have not proven they're more durable, and from anecdotal reports that I hear from the field, they don't appear to be more durable than 2 mg Eylea. But even the impression that there is something that is longer durability seems to have a dramatic impact on the marketplace. You see that with Vabysmo, that is now a billion-dollar product, in a very short space of time, and it's done that, I said, without the proof, but with the hint of longer durability, because that is by far the key unmet need in the space. This is a classic area where clinical trial results, where people actually are required to come into the clinic and get regular doses, and then the real-world outcomes are vastly different. That the reduction in visual acuity, the gains are typically lost within a year or two after the patient leaves the clinical trial, which is an abysmal performance for drugs that have a great efficacy, but in a real-world setting, just do not maintain the vision gains that you get initially with treatment. Yeah. And we confirmed that we definitely see that market dynamic, as you mentioned. So earlier this year, you presented a 12-month topline data from a U.S.-based phase I trial in wet AMD. And, what are the highlights you would like to share, and what has been the physicians' feedback? I mean, the main highlight is the idea is that we need to reduce injection burden, and we, we reduced injection burden in that study by 90%. And at the same time, we maintained visual acuity outcomes, and we maintained central subfield thickness that was in line with what patients received when they got Eylea every eight weeks, according to label. So that, that reduction and the fact that we were able to get the, the majority of patients out to 12 months without the need for any injections other than a single TKI or single AXPAXLI. Here, now, I got to put money in the swear jar. Mm-hmm. But the single AXPAXLI is unlike any other data with an injection that's been shown to date. Okay, great. Switching to the pivotal trial in wet AMD, you recently announced the initiation of your first pivotal clinical trial, and also FDA agreement on the design. Mm-hmm. Maybe give us an overview of the trial details and the rationale. Right. I mean, traditionally, the way trials in this area have worked is it's non-inferiority. It is the comparator product goes against either Eylea or Lucentis, given according to label. What's been done recently with both Vabysmo and high-dose Eylea is that the high-dose Eylea and Vabysmo have allowed different cohorts to go longer than the once eight weekly that we see with Eylea. The problem is that they didn't allow the Eylea groups to go, the 2 mg Eylea group, to go longer if they were able to go longer. So the FDA is concerned that what's happening in the marketplace is that there is a level of misbranding that's going on that gives patients the impression and doctors the impression that these new products really do act longer than 2 mg Eylea and are subjecting patients to potential undertreatment. So the FDA has changed its guidance on how products with greater durability are meant to make it to the market. So we originally came to the FDA with a two-arm non-inferiority trial comparing our drug given once every nine months versus Eylea, given once every eight weeks. And that it would be masked by sham injections every eight on the eight -week cycle of Eylea. The FDA responded that sham injections were no longer acceptable, and that what we needed to do was actually, in order to demonstrate that we really did have greater durability, we needed to include a third arm that was dosed at exactly the same interval as AXPAXLI, or once every nine months. And furthermore, not only do we need to show non-inferiority to the Eylea every eight weekly, but we need to show superiority to the control arm that was dosed at the same interval as AXPAXLI. AXPAXLI. Looking at a trial like that, and the complexities of having to show non-inferiority versus eight -weekly Eylea, in addition to superiority over a control arm, is an incredibly complicated and incredibly expensive and difficult trial to do. The FDA also mentioned that, superiority alone, so in other words, that we didn't even need to have the non-inferiority line in that, that clinical trial, that we could just do a straight non-inferiority dose-to-dose comparison, and if we prove superiority, that that trial would be adequate for, for approval in the U.S. I think there was, there was some sort of, concern or, or, you know, unclarity or intransparency in the marketplace about whether that was actually something that the FDA would allow. It looks, on paper, something vastly different than what people have seen in the past, which actually required us to go and get a SPA, to go and get a special protocol assessment to make sure that the market understood, and certainly our strategic potential partners would understand that this actually was a legitimate pathway, a regulatory pathway, and that the feedback we've gotten from the FDA was a result of a change in the guidance that there is going forward with development of wet AMD products. So the trial that we've come up with is a trial that's essentially a dose-to-dose comparison of OTX-TKI or AXPAXLI versus one dose of 2 mg Eylea. We're looking for naive patients with confirmed Wet AMD with relatively good vision, and that those patients will be entered into the trial, and their vision will be optimized. So they'll have two monthly doses of 2 mg Eylea to get to day zero, where if they improve to 20/20, and once again, this is the current entry protocol that's in the SPA. If they improve to 20/20, they're then randomized to either a single dose of AXPAXLI or a single dose of 2 mg Eylea. And then the patients are managed PRN until a nine-month endpoint. The endpoint of the trial is a proportion of patients who lose vision in both arms, and that we believe that AXPAXLI will be statistically superior to 2 mg Eylea in terms of the proportion of patients that maintain vision over a nine-month period. Okay, great. Have you disclosed the statistical design details? Yes. I mean, we agreed with the FDA because obviously the SPA not only includes the trial design, but it also includes the statistical analysis plan. What we requested from the FDA in the statistical analysis plan is we said that what we will do, because it's the FDA requirement for superiority, there's only three ways to demonstrate superiority. You can either have a larger percentage of patients in your proportion of patients in the trial arm that gain 15 letters. You can have a smaller proportion of patients that lose 15 letters of vision, or you can have a mean change in baseline visual acuity of 15 letters. So you kinda have to pick your poison. If you're gonna be superior, you've got to pick one of those things. Based on the product we had, the data we had available for our product and the data we were able to glean from what we think the comparator arm would look like, we chose the proportion of 15-letter losers or the inverse of it, which is the proportion of patients who sustain vision over that nine-month period. Okay, great. And also, regarding the patient baseline for enrollment, is it consistent with the prior U.S. phase I trial? No, the prior trial- Yeah. We, we did a trial in naïves with monotherapy. Yeah. We did a trial in previously treated patients, where we maintained therapy. But what I didn't answer in your last question was the statistical analysis. Mm-hmm. So what we asked the FDA, we've gone for the endpoint of proportion of patients who maintain vision, or the inverse proportion of fewer patients that lose 15 letters. Mm-hmm. But we said that our intent to treat, our primary intent to treat analysis would include all patients who lose 15 letters at any point in the trial. So if you get out 12 weeks, you lose 15 letters, you can be rescued and rescued as often as necessary until the nine-month endpoint, and you're considered a 15-letter loser at the nine-month endpoint. We also said that any patient who drops out of the trial or any protocol violation also should be considered in the 15-letter loser proportion of patients, which means our primary intent to treat analysis includes 15-letter losers. Dropouts and also, the protocol violation, because this is a situation where you can imagine in a clinical trial, you have a patient who's had two straight visits of a 10-letter loss, their fluid has gone up 75 or 100 microns. You're getting nervous about the outcome of the patient, and so you either convince the patient to withdraw consent and drop out, or you go ahead and rescue the patient as a protocol violation. The FDA accepted that ITT analysis, but they did state underneath it that there would be—it would be a review issue that if patients drop out or protocol violate for reasons of efficacy, it's understandable to the request that we're making. If they drop out for other reasons, so if you move from Des Moines to Wichita, and you have to drop out of the trial, then presumably, that wouldn't be considered as an in the FDA analysis. In our ITT analysis, it would be considered a 15-letter loser. In the FDA look at the data, it would unlikely be considered that way. Regarding the enrollment target, is it considered overpowered? It is way overpowered for the difference that we expect to see. I mean, in all of the patients that we looked at in our two phase I/II trials, there was about 49 patients with AXPAXLI. We don't believe any of them would have, at a nine-month period, progressed to a 15-letter loss. There were patients who were rescued. They were typically rescued for fluid in a non-foveal environment. There was only one patient that actually did lose 15 letters, and that was because of a worsening cataract. So we believe that the proportion of patients that will lose 15 letters in the AXPAXLI arm will be well less than 10%. Now, in the Eylea arm, we've used a number of different databases. We used the PIER trial in the Lucentis registration trials, where there was an entry of patients, naive patients, into the trial, in a sham-only arm. 50% of those patients progressed to a 15-letter loss. Now, once again, this is from non-optimized vision. In our trial, we're optimizing vision, and the 15-letter loss is from optimized vision, not from study entry. Also, in the MARINA trial, which had some complications that confound the analysis a bit, but we think about 38%-40% of the patients in that trial who are analogous went on to a 15-letter loss. We've also looked at the IRIS database in the U.S., we've looked at the Aetna database in the U.K., and other databases in the U.K. For those of us, you know, now that we're in the U.K. and people here will remember this, when Lucentis launched in the U.K., the reimbursement pathway, the reimbursed product pathway was that you presented as a naïve patient, you got three monthly doses of Lucentis, and then essentially you were treated PRN thereafter, and you didn't get reimbursed until you got 20/40 or worse, which is exactly the patient population that we see in the comparator arm for AXPAXLI. So we're very, very confident that that arm, that 30%-50% of patients in that arm are going to proceed to a 15-letter loss. Mm-hmm. We have 300 evaluable subjects in the trial, and those of you who know statistics will know that that's way overpowered for this difference that we're expecting to show. The reason why we have 300 patients is not driven by what we expect the difference to be, it's driven for safety reasons, that we need 300 patients in the trial from a safety standpoint. Okay. For the subsequent pivotal trial, you... 'cause you mentioned the two, and are you thinking about a identical design? Yes, absolutely. I mean, one of the things that we've gotten feedback since we've had the SPA, we've been—it's nice to have a concrete, approved regulatory pathway. And we've talked to probably 100 different sites and investigators to get advice on the trial. I mean, after the initial shock of we're gonna have to manage a patient to 15 letters of loss, where we had the initial requirement that a patient get to 20/20 before being randomized, that the idea is that doctors would be comfortable going from 20/20 to 20/40 because that's not really life-changing vision. What we got from the sites is, after the initial sort of assimilation of the data was, "Wow, you could really open up this entry criteria. Mm-hmm. I'm okay with a 20/20 patient." There are others saying, "Hey, if a patient is at randomization, if they're 20/60 in one eye and they have a 20/20 eye on the other, I have no problem managing a 15-letter loss in that 20/60 eye because the patient's not even gonna notice that." So it's very clear to us is that we have the opportunity to open up that entry criteria. But because we have the SPA, it's very important that we do not violate the terms of that SPA. I mean, the FDA is gonna be very welcoming of the opening up of the entry criteria, but what we have to do is make sure that we don't violate the SPA. Anything we do that is not in accordance with the SPA actually invalidates the SPA, and that stuff's like gold. We do not want to lose that pathway. Great. How many study sites to be included first, for the first, the people who try, and what's your expectation on the enrollment pace and also the data readout? Well, we expect between 40 and 75 sites. Mm-hmm. And clearly, we expect to do two pivotal trials. A lot of these sites that we may not enroll in the first pivotal should enroll in the second pivotal. We're gonna do U.S. and ex-U.S. Mm-hmm. But the initial anecdotes from these sites are that they can fairly aggressively... particularly if we can open up the entry criteria, they can fairly aggressively recruit. A fast recruitment for this trial would be a six-month period, a slow recruitment would be a year or a little over. I would think that given the spare capacity that exists, particularly in the U.S. Mm-hmm There are very few late-stage wet AMD trials ongoing. We're looking for a patient population that no other clinical trial is targeting, patients with relatively good vision, naive patients with relatively good vision. Mm-hmm. So there's a tremendous pent-up demand and tremendous pool of patients that exists for the trial. Mm-hmm. We would expect to enroll it very quickly. Great. What, what is the cost associated with this pivotal program, and are you looking for partner given the substantial market opportunity for this asset? Yeah, we expect each of these pivotals to be between $40 million and $50 million, and a lot of that's gonna depend on where it enrolls. I mean, we will have ex-U.S. sites, and we'll have U.S. sites. U.S. sites are more expensive, tend to enroll faster. Ex-U.S., there are certain ex-U.S. sites where they will very aggressively enroll because the standard of care in these environments is difficult for patients to obtain treatment. So if it enrolls mostly ex-U.S., it's $40 million. If it enrolls mostly U.S., it's $50 million. Okay. And, diabetic retinopathy is another indication to pursue for this asset. And, what do you think about the focus, distributed across two assets at the moment? Well, this gets to the question that I didn't answer from your, your previous one. Yeah. You know, the SPA is hugely important for us. It's hugely important for sites. I think it's hugely important for the retina community to understand what it, the FDA wants and how it's looking at the development of these wet AMD drugs. It's also vitally important to strategic partners because anything that's new and different is always got antibodies kind of buzzing around, trying to kill it. So having a SPA, having something that the FDA has signed off on, and the detail that that SPA exists, is vitally important for our ability to bring on a strategic partner. We know we're not gonna sell this product globally. It is way too big a product for us to sell. There's way too much opportunity in the world for us to satisfy as a small company. But that also goes to indications. So right now, it's us, and we're funding it. We realize cash is hugely important, we're incredibly dilution sensitive. We have the cash to complete this first pivotal. Mm-hmm. We obviously are looking for opportunities to do the second. If we get a strategic partner with the level of strategic partners who we're discussing with, that would then allow a lot of other indications to come on as well. NPDR, DME, retinal vein occlusion, the opportunities in this product are immense. But as a small company that's dilution sensitive, we're gonna fund the wet AMD pivotals and nothing else, unless we have the cash to do so. Great. And then moving to commercial product, DEXTENZA. Among the approved indications, which indication do you see it being mostly used? And, do you have a plan to expand the indication, and how do you think about the growth trending to 2024? Yeah, I mean, we are 99% used in the cataract environment or the post-surgical environment. So we have indications in post-surgical pain and post-surgical inflammation. We also have an indication in allergic conjunctivitis. Mm-hmm. Now, the pain indication is where we have all of our focus because that's a concentrated market in the U.S. That is a consolidation of ambulatory surgery centers by private equity. We handle the private equity customers as strategic customers, and we work with them to help their individual ASCs implement DEXTENZA. But there's a real opportunity in ocular surface disease, which starts with allergic conjunctivitis and moves to dry eye. We have not funded the launch for that. That is probably a bigger opportunity from a sales standpoint. Mm-hmm. but it's more diffuse. And for a company that's acutely cash sensitive, we're not gonna invest in that launch until we have the capacity to do that. Yeah. 'Cause I think there'd be an element of DTC in that, that we'd have to do. Great. And you also have a glaucoma program ongoing. Maybe share with us why you're excited, and how do you think about the next step? Sure. We have completed enrollment in our phase II for our—an intracameral injection, an injection into the front of the eye, for a six to nine-month formulation for high intraocular pressure or glaucoma. That product is working its way to final completion. This is a sort of a strange situation where we are, you know, virtually certain the product's gonna work. It's going to meet its endpoints in terms of the IOP reductions. The pivot point for this product and the decision about whether we go into phase 3 or not is really on endothelial cell health. One of the benefits of our polymer is that it is not toxic to the endothelium. And obviously, if you're injecting into the front of the eye, you have a potential for your polymer to rest against the endothelium. So we're looking at pachymetry, we're looking at the endothelial cell count, both computerized and manual. And that's the key point. If we look at that, and the endothelial cells are unharmed by the injection, then this product is suitable for redosing and is ready for phase III. Terrific. And then maybe lastly, I want to ask, what do you think the investors are missing about the Ocular's story? It's interesting that as being in the evolution of where we are at the moment, TKIs, and I think in part, because I think there was a misinterpretation of what happened with Graybug, a while back, that the failure of Graybug had to do with their polymer and not with the mechanism of tyrosine kinase inhibitors, that it's taken the retina community a while to realize, hey, these things actually do work. You know, the results from EyePoint, from ourselves, and from Clearside demonstrate there's activity with these drugs. Mm-hmm. So the key opinion leaders are understanding now that, you know, maybe gene therapy is farther in the future than we thought. These drugs, these new drugs that are coming out really don't work longer, or at least certainly haven't proven that they work longer. So the new game in town, and the only game in town, really, are these extended delivery tyrosine kinase inhibitors. So the community gets it first. It's gonna take a while for investors to sort of understand the enthusiasm of the retina community. And certainly, the more data we pile on and the better we're funded to be able to get to NDA, I think is gonna make that change. Terrific. Looking forward to the next milestone, and thank you for a very insightful discussion, and thanks, everyone, for attending. Great. Thank you very much.