Here. thanks for joining this session with, MeiraGTx. My name is Alec Stranahan. I'm Senior Biotech Analyst here at Bank of America, covering Meira. I have the pleasure of introducing Alexandria Forbes. welcoming her back to another Vegas conference. Alexandria Forbes is the Chief Executive Officer of MeiraGTx. thanks for being here, Alexandria Forbes. Thanks for inviting me. Yeah, great. Well, maybe just to start off, you know, at a high level, you've materially repositioned MeiraGTx over the past 12 months. You took back the bota-vec rights from J&J. You secured the Hologen collaboration to fully fund the Parkinson's program. You got BTD for xerostomia. I guess, what is sort of the single most important de-risking event that you think the market hasn't fully appreciated for the company over the next 12 months? I'm not sure what the one thing that the market has not fully appreciated could be. Could be many things. I would say that buying back RPGR from J&J has been the most de-risking thing we've ever done at the company. Getting it approved globally is a real focus for us. Since we did that, I don't know, 10 days ago, two weeks ago. Sure. We actually have some quite senior people from J&J who may have been working at other places, come and join us or speak to us, and it puts us in a really good position to move super fast. You know, that drug came from us, and the people who worked on it at J&J are very keen to get it approved, and it's really great to have their help. One of them, Penny Fleck, led development of the whole therapeutic area, and she's now working at MeiraGTx as of this week. That's, I think, the most transformative thing we've done this year. Kind of liberating now to be able to talk about the program how you want and push it forward how you want. Yeah. Yeah. Yeah. I mean, you were always gonna be the manufacturer of bota-vec. Maybe we can just talk at a high level. I think the commercial scale manufacturing is maybe something else that's underappreciated. You guys sort of have an industry-leading, vertically integrated manufacturing capabilities for gene therapy within the company. I guess, how central is that manufacturing capability to sort of the valuation and the, you know, the story that you're trying to build for MeiraGTx? We didn't necessarily build the breadth of our manufacturing infrastructure on purpose. We did it over 11 years because it was absolutely necessary to develop genetic medicine drugs in a timely fashion. It does two things. Number 1, we have a platform process, and that allows us to start an IND with essentially similar to commercial material. Super important in gene therapy and has been very important for us. Number 2 is that as our own manufacturer, everything from the process to the GMP facilities all the way through to QC, so every single assay, we have commercial license, and we cross-reference everything with the FDA. The FDA and we are very familiar with what's required in a CMC section. We did initially for J&J, now for ourselves, full PPQ for RPGR. We're also familiar with what's needed to file a CMC section of a BLA or MAA. Those are very valuable and really important from a time perspective and a regulatory perspective. I think that having manufacturing in-house is probably one of the number one de-risking things you can do for any IND. It's difficult, though, because you've got to build it over many years. For us, that's what it's done. We wouldn't have four late-stage programs that we could file with our own manufactured material unless we'd done it ourselves. We'd probably be three years later in each program. Right. That's, you know, fixed costs that have already been, you know, put in place. Yes. Yeah. You know, beyond, you know, hitting the clinical endpoints that you hope to in your clinical studies, and we can talk about xerostomia next, but when you do go to file with the FDA, you've already kinda checked a lot of the boxes on the non-data components around CMC, et cetera, right? Like, you're ready for commercial scale. Yes. Yes. Our programs, another reason I think we've been largely successful in all of our programs, getting them to late stage, is they are small doses and locally delivered. We never do large systemic doses. That means that we start essentially at commercial scale. Some things for really big indications like Parkinson's, we increase the bioreactor size, but we have single use, so we can use the same suite for a 100 liter or a 200 liter or a 1,000 liter bioreactor. We built manufacturing to be scalable within one space. I mean, we've got lots of suites, but it's that was under the guidance of regulatory agencies. We start with something that is a commercial, close to commercial-ready process at a commercial-ready scale. Again, that's extremely important because what is the biggest part of any BLA or MAA is the CMC section. It's not only the biggest part of the BLA or MAA, it's the biggest part of the IND, it's the biggest part of your phase II IND amendment, of your phase III meetings. Throughout the regulatory process, you are iteratively learning what's needed on the same process with the same manufacturing from the agencies. In fact, you just mentioned xerostomia. One of the reasons that's a pivotal program, it started as a phase II, is we obviously manufacture it ourselves, and it's really high yield, we don't have to go to massive scale. We manufactured ourselves and filed our CMC section with the phase II IND amendment and started, you know, no comments in 30 days. We started, and six to nine months later, the FDA wrote to us and essentially said that if we manufactured within the parameters that we'd written, they considered the study pivotal. Without us asking, because of the CMC that they reviewed, that is what made that study pivotal. We got an RMAT, then we got alignment, written alignment with the FDA on the clinical side, and then we got Breakthrough, and then we got three-year data. Yeah. Right. Maybe we can, you know, unpack that a little bit further. I know that the pivotal study, I think it completed enrollment recently. It's finishing now. Yep. Okay. BLA filing, I think you're targeting for the first half of next year. Yes. You aligned with the FDA on the primary endpoint as the XQ, PRO and saliva flow. The PRO, yeah. Yeah. Saliva flow is the key secondary. I guess, you know, when you think about what good looks like from the study, maybe you can just walk us through sort of the powering assumptions, and you know, how important this patient-reported outcome metric is? Xerostomia is a patient-reported disease condition. It is not correlated at all with actual saliva volume. It results from too little saliva produced in the mouth of whatever individual you're talking to. one individual could have xerostomia with 10 microliters, four, five, you know, a minute for five minutes, another with a mil. The actual volume of water doesn't correlate with the symptoms, i.e., the definition of xerostomia. The XQ is a xerostomia-specific, PRO. We also have other PROs in there, which we also had in our phase I, and this XQ is the one that is most focused on questions related to what are normally the symptoms of xerostomia, such as sleep, eating, swallowing, how dry is your mouth, those sorts of things. it's a pretty standard PRO for xerostomia, which is only possible to detect by a PRO. However, clearly, there is some need in the face of a PRO to have an endpoint or some measure of the actual mechanism of the drug. The actual mechanism of the drug is you create more saliva. The secondary endpoint is the actual volume of saliva that you produce per minute when you spit into a tube for five minutes. That's another very standard way of measuring saliva flow. Okay. You know, you're testing for, I think, active dose cohorts here. Do you expect or do you hope to see a dose response or, you know, is it more of a hedging strategy, and do you think the label could end up covering one dose or multiple? This started as a phase II, right? We were doing multiple doses because our phase I had cohorts of three people, and while there was some incredibly good response, there was some much smaller responses, and we showed that in the three-year data. We showed patient data at every time point, individual patient data at every time point over three years. There was no dose response that we were able to determine. There was no correlation with vector genome titer, with total vector genome, with volume of gland. We had a lot of patients with very good responses, but no way of predicting how that related to dose, if it does at all. Because you're simply making the gland cells permeable, there isn't that much of a dose response, even in the potency assay, because once a cell is permeable, because it's got aquaporin channels on both sides of it. You add twice as many aquaporin channels, it's permeable still. There's not that much of a dose response even on a monolayer in vitro. The phase II has four different doses against two placebo arms, separate placebo arms. The study is designed and powered that any single dose cohort, no particular one in no particular order that beats the pooled placebo is a win, and it's 95% powered to be successful with the current patient numbers. Okay. Do you have an expectation, you know, from the survey work that you've done or from the phase I, what the placebo arm could do? I mean, these patients, they obviously can't make saliva on their own. I imagine the level on the PRO is gonna be quite low, but any sort of quantitation you could provide for the placebo expectation. It's an excellent question, and it is the question that we have thought about a lot. These patients are patients who remain with xerostomia for the rest of their life and only get worse. It's the 30% of patients after radiation, three years after radiation that have not recovered. 70% recovered after radiation, their xerostomia. 30% do not. Of those 30% that are moderate to severe, 85% don't respond to sialogogues, right? Those sialogogues, by the way, have a 25% placebo rate. These patients aren't even responding placebo-wise, unless the 15% that supposedly do respond is a placebo response, right? you're looking at a population, the natural history is they only get worse. They don't respond to a drug that has a placebo response. However, you always worry about the placebo response and how much is of your massive efficacy is related to placebo. When we showed the three-year data, if you look at that, patients gave the same response each year for three years in a PRO, even though they were treated three years before and they did the questionnaires 12 months apart. It's super difficult to imagine that is placebo. In addition, that wasn't only the best responders, but similarly, the middle responders were a bit more variable, but the level of response was maintained over three years. Again, it's hard to see a mechanism that a PRO, which they tend not to work after like 12 to 24 months, gives the very similar data at three years from one year. Given that there's no known placebo, we had a very high effect size, and I say high because it was a massive decline in the XQ. In the cohort, which treated both sides, there was a -21 improvement. -10 is transformational. The bilateral and unilateral had a -17. We used -17 as our effect size, and we powered to have success. We powered for a nine-point difference between placebo. That leaves you, even with 17, a big placebo response. With 21, it's more than transformative, right? That's how we powered it, and it will nevertheless would be successful if the other assumptions are correct at a six-point change. We designed it as conservatively as we could. We gave the placebo a transformative improvement. We'll see, right? We did what we could to use that big effect size, which we think is real. Okay. Okay. You know, you mentioned the three-year durability data. This could, I guess, potentially be transformative with how prescribers perceive treatment of this disease, which is mostly symptomatic relief right now, with a one-time therapy. I guess from your latest work, you know, speaking with prescribers or payers, you know, how are they viewing kind of this durability piece? Is this maybe one of the key items for adoption? How does this sort of feed into your approach to pricing and coverage? When we've recently spoken to physicians and payers, it was one of the key elements which changed the view of this drug. It had been a drug that had a big improvement on xerostomia, and physicians were very keen on using it. However, when we presented the three-year data, it sort of changed in the minds of physicians to what was noted is really simple, safe, virtually painless procedure, one time and a durable disease-modifying impact on a condition that is otherwise lifelong. Those were the words that started coming back and payers also looking at that data. Durability data gave a considerably higher price. Now, we have not done payer negotiation work. Obviously, we don't have our phase III data, and we gave a conservative number in our presentation of $150,000. The range when we were asking with that target product profile was 100 to 250. We will wait for the phase III data and then have pricing negotiations. I will say that for both RPGR, for bota-vec and this product, we think that small sales forces that are really targeted are very much within what we can do. However, our focus right now is patient access. That from both in both of these diseases, particularly in Europe, is the key thing that we're focusing on seeking. There are incredibly good payer access groups that will go to the meetings with you and, you know, someone at Novartis got that pricing for Zolgensma, right? We want those people to help us. It's the most important thing to us is exactly that, the negotiation of pricing US and for bota-vec, obviously Europe. Right. Right. That makes sense. Maybe that's a good segue to talking about bota-vec. You mentioned kind of a sales force and a commercial approach that you can maybe wrap your arms around on your own. I guess, what was the rationale for, you know, regaining the rights and self-filing versus maybe finding a new partner there? Bota-vec was, you know, born in MeiraGTx and the founders of the company, some of the founders of the company actually developed that drug, and the people at UCL who developed those drugs now work for MeiraGTx. We have great familiarity with bota-vec from its birth. One of the reasons we initially did that deal with UCL is its close association with Moorfields Eye Hospital. One of their lead IRD physicians, called Michel Michaelides, is also one of the founders of this company, and he, as a consultant, guides us on clinical development. Why I say that is Moorfields is arguably the most important hospital in the world for inherited retinal diseases. Michel Michaelides alone himself, not including the other physicians there, sees 100 IRD patients, adults and children, each week. That is so some physicians see that number of patients in a year. It turns out that there are about between 30 and 50 individual physicians in Japan, Europe, U.K., and the U.S. who have under their care 80% of all IRD patients, and 32 of them were in our phase III study because Michel Michaelides called them and asked them to be. Michel and each of those physicians has the phone number of the other physicians. From a sales force perspective, we currently have, you know, we can call, Michel can call, or someone from Meira can get in touch with most of the physicians that have under their care most of the RPGR patients in U.S., Europe, U.K. and Japan. In this past year, as J&J has not moved this forward, there has been an escalating cry or outpouring from those physicians and those patients to get it approved. As I mentioned earlier, finding the patients is not the most important thing for the launch. The most important thing for a fast launch is to make sure it's paid for and the value of changing those patients' lives and actually improving their vision when that, before this drug, it wasn't thought to be possible, that value is recognized, and we want to do it fast. You know, there are some things we can do which is we have the patients and the physicians listening to us. We need to get payers to agree to pay for the drug. Right. Obviously, the FDA as well is another stakeholder. You know, we listened to the presentation for J&J on the LUMEOS study and, you know, I think the feedback at that presentation was very positive from the patients and the patient advocacy groups within XLRP. I guess, how are you sort of approaching the submission package in terms of the totality of evidence from the study? How do you sort of package that for the FDA? Is there precedents in rare genetic disease that supports this approach? There's number 1, there's precedent in many diseases of a trend in a primary and very strong secondaries being approved for full approval. Number 2, there is a precedent in the only gene therapy for a blindness that results in dim light vision failure, and that is Luxturna. There are precedents for both. Luxturna is the closest. Luxturna also failed its primary maze, and they spent about a year doing post-hoc analyses and were able to show in a 20-patient crossover, so only 10 placebo patients or untreated patients in quite a confounded maze. They were able to show a difference between treated and untreated, and they got approval. They did not have strong secondaries, so that's a good precedent. In addition, the FDA's job is to make sure the risk-benefit that is provided to patients makes sense. on the Luxturna label, there was an issue which is, degeneration of the central retina, and it was put on the label, and physicians were not supposed to treat the central retina. Now that LUXTURNA degeneration has been seen out in the community and is very well known as a side effect toxicity issue with LUXTURNA. Because it's so well known, every one of our 135 patients that have been treated were looked at at every appropriate time point with fluorescence, looking at structure to see if there was such a toxicity. When you ask about precedent, we have a precedent where a very similar disease, albeit fewer patients, got approval for a very similar type modality of therapy with way less data. We've done three studies with different controls, with not even a trend in the primary to start with, and not the very strong secondaries. Our two secondaries are now accepted by not just the Europeans, but the FDA subsequently has accepted LLVA as an endpoint and as a primary endpoint. What is also important is when you have an endpoint that doesn't meet significance as primary, it's useful to show that that's because the tool isn't sensitive, not because patients fail to see in the dark. For us, there is a very strong response, pre-specified as a quite highly ranked secondary in the low luminance domain of the extreme lighting PRO that met with incredibly high significance, and it measures how you function in the dark. When the questions were looked at separately, the P value for mobility in the dark was 0.001. That shows you that these very same patients who were treated have a big difference in their mobility in the dark, and it's the same domain as the maze. We also have a discussion that indeed this was highly variable and with this number of patients, wasn't sensitive enough to show the change in vision in the dark and mobility in the dark that was shown with this very well-validated, commonly used endpoint, which is a PRO, and that was all pre-specified. Okay. Okay, very, very helpful. Maybe the last question, just in the minute we have remaining. I think you guys have done a great job driving value from the pipeline through partnerships over the past 12 months. You have the Lilly collaboration with LCA4. You've got the Hologen collaboration for Parkinson's. I guess how do you see these the BD activities I guess progressing over the next 12 months? I guess when could we see maybe a partnership from Riboswitch or somewhere else? That's an interesting question. We are focused on getting Riboswitch enabled Ribo-Leptin into the clinic this year, and we have discussed with the FDA we can do both small molecule and Riboswitch in a first-in-man dose-finding study, which is great. The material is being made currently optimized, so it's commercial-like. When will we do a partnership in Riboswitch? I don't know. We speak to many companies all the time about all of our programs and, you know, there are some companies that are interested in multiple of our programs. As we move towards commercialization to potential launches in multi-billion-dollar markets in the next two years, you become interesting not only to investors but also other companies, larger companies. You know, we have many meetings, many discussions, and we get to know companies and we consider their offers and also talk to them about things we might like to do. BD goes on, but I can't say we're about to do a deal tomorrow. Okay. I guess we'll stay tuned. Yes. Stay tuned. Yeah. I guess we'll leave it there. Thank you, Alexandria Forbes, for the excellent discussion and thanks everyone for your attention. Thank you. Thank you very much, Alec.