All right, great. Hey, everyone. Good morning or good afternoon, and welcome to day one of the 2024 Bank of America Healthcare Conference. Thanks for joining this session with MeiraGTx. My name is Alec Stranahan, and I'm Vice President and Senior Biotech Analyst covering MeiraGTx here at B of A. And I'm pleased to be joined by Zandy Forbes, President and Chief Executive Officer of MeiraGTx. Essentially, this is a 30-minute fireside, so we'll have some time for questions. So Zandy, let's just jump right in. Thanks for being here, first of all. Thank you very much for inviting me. Yeah, great. So maybe just to start at a high level, you know, for those less familiar with the story, what is sort of most exciting to you, in the company right now, and sort of what's the cadence of next updates we should be expecting? Well, thank you. So we think we're in a very exciting stage of the company, in that of the clinical programs that we have, in each of the areas, of the eye, the salivary gland, and the CNS, we have now reached a stage where each of those different programs is in a late-stage study, pivotal or phase III. So our ophthalmology asset in inherited disease, we actually sold to our partner, Johnson & Johnson, last year, and we became the commercial supplier for that product. That phase III enrollment completed in the third quarter last year, so we're waiting for data from that final big phase III towards the end of this year. Our two wholly owned late-stage programs, one is in xerostomia, and that's very exciting to us because it's a really large indication. It's not inherited. It occurs in patients who've been treated with head and neck cancer. Last year, we presented initial data, and just a month ago, the final analyzed data was presented by PI. The data that we saw in our phase I is quite extraordinary. It really transforms the lives of these patients who have no other option. They can't produce saliva. We've moved into a phase II, which is ongoing, and the FDA has recently told us they'll consider that study a pivotal based on our in-house manufacturing. That's really exciting, and we're pushing forward to get this product to a BLA based on this single study as soon as we can. Then our third wholly owned asset, or second wholly owned asset, third phase III asset, is our Parkinson's. We completed a bridging study, again, of our in-house manufactured material, and we're preparing to go into a phase III with that program, which again, it's inherited. It's to all patients that are no longer responding to dopamine, and again, very differentiated program and data. So we've got excellent phase II data in a sham-controlled study, and we're really looking forward again to having this in a phase III and moving this towards this rather large patient population in need. So our clinical programs have reached an exciting late stage, and we have started focusing with our gene control platform on two areas where, somewhat surprisingly to us, but not surprising when you actually think about the mechanism, we found that in controlling genes in CAR-T, as well as in metabolic diseases, controlling the delivery of GLP-1, GIP, PYY, we actually are having really, really significant impact on efficacy. This isn't only about delivery. It seems that delivering things in a physiological timeframe when they're normally short acting, actually really impacts how they work in the body, and so we're prioritizing those two areas to take them into the clinic next year. So it's a very interesting time for the company, and we're refocusing what the company is doing in the future. Right, and certainly getting that, the milestone from Janssen will help, Absolutely, yes. So definitely a lot of exciting things going on. Maybe we can just go one by one. I want to start with xerostomia, since this, you know, you recently had sort of an end of phase I data update, I believe? Yeah. And it's kicking into phase II right now. So I guess maybe just to start at a high level, you know, how should we be thinking about the xerostomia market? And, you know, do you see this market as growing, particularly as more radiotherapies come to market as another hot area of development now? Yeah. So great question, and I mentioned the sort of shockingly strong data that we saw in our phase I. And yeah, we're proceeding with enrolling and treating in our phase II now, which is designed to answer all the questions that the FDA has talked to us about, about what they want to see in a BLA-supporting study, and the material has led us to be able to have this as a pivotal study. So the market is very interesting, particularly for genetic medicine. This is not gene replacement. It's more tissue engineering, where we use water channels to permeabilize the glands of these patients who have grade two, three, so quite severe xerostomia. What that means is they do not respond to any drugs, and these patients are all in the care of physicians. They're returning to make sure that their head and neck cancer is not come back, and this is their biggest problem... We have huge support from the physician community who don't want to hear. Once they've cured someone of head and neck cancer, they come back and they say, "But our life is destroyed because we have xerostomia." And about 30%-40% of those treated with radiation for head and neck cancer actually end up with this grade two, three xerostomia. So it's a large population currently addressable in the U.S., 170,000 patients. Let's say around 15,000 patients each year, very readily accessed. They all have health insurance through the oncology of small oncology sales force, and, and the cost of goods is very low because it's a small local delivery of a viral vector. Now, you asked about expansion, and what's really interesting about this product is it permeabilizes salivary glands, and in preclinical models, we've shown it works for Sjogren's disease. By permeabilizing damaged glands in Sjogren's, you can actually cause water flow that then has a positive impact on the immune system systemically. In addition to that, we're starting to see with some of the prostate drugs, that radioligand-bound prostate drug, xerostomia is arising as one of the key side effects. We imagine that as you get further out from treatment, there will be those patients, just like radiation-induced xerostomia, that haven't been able to recover, and this might be the same treatment for Sjogren's, the same treatment for RIX. The exact same product, which the FDA said we could use in a pivotal study, could be used for those patients to expand the label. In addition, we are going to be looking at, can you prevent xerostomia by treating earlier? And so this is almost like a pipeline in a single product, and the product is the AAV AQP1 water channel delivery. And so we're very excited to not only move forward with this phase II, but look at how you can expand into these multiple different markets, immune disease, as well as different sorts of xerostomia caused by different cancer treatments. Hmm, interesting. Interesting. Maybe we can just touch on the latest data from the xerostomia program. I think you recently presented an update at AAOM in April. Yes. Could you maybe walk us through what we saw in the update, sort of in the context of the totality of the data we've seen so far for the program? From a high level, this was the official PI-delivered analysis of the data from our phase I dose escalation study, where four cohorts of three patients were treated on one gland only, and four cohorts of three patients each were treated in both glands. We'd shown top-line data a year ago, and this really reinforced what we saw in that top-line data, which was multiple fold. First of all, xerostomia is a PRO-defined disorder. Clinical meaningfulness, which is what the FDA demands for a primary endpoint for any pivotal study, is shown in PROs. We showed, using two PROs, an improvement across the board to a very meaningful extent in those PROs, at the extent being the meaningful extent. I say that because these are well-defined PROs. There is a good understanding of what's clinically meaningful in this space, and we saw very meaningful changes in the two PROs we measured. In addition to that, the FDA requires an endpoint that reflects the mechanism, an objective measure of the mechanism, and in this case, it's water flow. In addition to the PROs, which show a change in the disorder, we showed a very clear improvement in water flow over time, which was maintained one-two years after treatment, and we saw a greater change when you treated two glands than one gland. So across the board, these endpoints had a much greater effect size than we expected, and from a clinical perspective, the changes that we were seeing were considered transformative by the physicians and the patients that were experiencing them. Hmm, great. So, you know, we've got a good leading indicator of how the phase II could look, given the data we've seen from the phase I and- Yes. There's regulatory alignment that that would be an approvable endpoint? The discussions with the FDA have been around what endpoint do they need to see for an approvable study. Until we have the data, we're not going to go back and say: Is this approvable? But in the discussions, the FDA was very clear we need two things: something clinically meaningful, and from our eye programs, from our other programs, this has to be the primary. That's why the PROs were the primary. In addition, the FDA said you need an objective measure of the treatment. Now, salivary flow is that objective measure, and there is no clinical correlate. Therefore, it could not be the primary. So we're presenting clinically meaningful as the primary. Key secondary is the objective, non-clinical, mechanistic endpoint. So we feel we're covering... all the bases that the FDA told us they wanted to see. Right. Right, that makes sense. And maybe in terms of how the phase II looks, you know, any other framing you can provide in terms of, you know, duration, follow-up, you know, sort of, when the study started, how accrual has been going, anything you can share? So, the design is, initially we have a placebo. It's double-blind, placebo-controlled, placebo, low dose, intermediate dose. And because we saw no dose response in the phase I, we actually are adding and have manufactured the material now to add a higher dose. So this will be a four-arm, double-blind, placebo-controlled study with the doses being escalating. We did that because we didn't want to get really great data and the FDA to say, "Well, we want to see a dose response. We want to see difference between arms. So to stay as close as possible to what we thought would be required for a pivotal study, we added that extra arm, and we see that we expect that by the end of this year, with the release of the higher dose material over the coming months, we still target the end of this year for enrollment in that study. We have opened multiple sites in the U.S. and Canada. We actually got early approval about six weeks ago to open in the U.K., so we're now opening sites in the U.K., and we're starting, particularly after the data last month- Mm-hmm. There's a lot of enthusiasm from both physicians as well as patients coming into this study. So we're really excited about it. The 12-month endpoint, so data, we complete enrollment at the end of this year, data at the end of next year, with subsequent filings, if that data supports the filing. Okay. Okay, great. And this is, you know, one of your wholly owned assets, but it's another asset with large pharma interests, with Sanofi retaining a right of first negotiation to move the program forward. You know, how should we be thinking about this in terms of economics to you guys and retained optionality to develop it either yourselves or, or, or with other partners? So Sanofi does have an interest in this program. It is a very large market, very low cost of goods, and easy to sell and then expand the market. So I think any pharma company can see that there's a lot of potential there. We've done pricing analysis, and we think that it, it's, you know, a really robust opportunity. Sanofi has the right to look at data at certain cuts, or I want to say certain, at certain times, and they can decide if they want to potentially partner with us in that program. We have no obligation to accept an offer from them, but they do have the right to look at data at the trigger points that they ask for. So we'll see what happens. But, you know, I think this is a very exciting program for us to commercialize ourselves, and it's pretty near term. It's not like 2035. It's potential data in two years that we could file with, and it's a really good market that we can, we think, expand over time. Right. Right, and like you said, it's, you know, you've got the manufacturing kind of already in place today to support- Yeah. ...that launch. It would require probably a smaller, more targeted commercial effort from an oncology sales force. So something that you guys could probably manage on your own, even though it's a 15,000, you know, incident population. Yeah. But one other thing I think is very important when we think about gene therapy and gene replacement, large systemic doses. We were very focused when we started the company on local delivery of small doses, for many reasons, but one of the reasons was we could manufacture those doses and the cost of goods was low. Therefore, you don't have to price high. Mm-hmm. So the cost of goods is low because the dose is low. It's even lower because we manufacture in-house, and when we've gone to payers, the price that they would be willing to pay gives you a very good margin based on that low cost of goods because of the low locally delivered dose. So there's a lot of thought that went into this product, from the cost of goods to the safety, to the market opportunity and the expansion, which, when we decided to take it on, was our most, sort of financially driven, I would say, program. And no competition, because there's no drugs, there's no other programs, there's, there's no one else that can actually treat this disorder where the salivary glands just aren't permeable. The only thing you can do is make them permeable. Right. We're the only people that are doing that at the moment. Right. Very good. I want to move on to Riboswitch, because- Yeah. ... this is maybe arguably one of the most exciting developments in your, in your pipeline. And, you know, we're looking out to the R&D day in the second half. You know, I guess what are you sort of working on? Obviously, there's a lot of different directions you could take this, but what's sort of getting you excited now on the preclinical side? And, you know, where can we sort of see things going over the next 12 months? So, then this, this technology allows one to very, very accurately and precisely control the amount of messenger RNA, and therefore protein, that is produced by any gene sequence that's delivered in any way. Whether it's lenti, whether it's AAV, whether it's CRISPRed in, whether it's naked DNA. And so we developed this, designed this technology in order to be able to deliver any biologic drug, from antibodies, to peptides, to hormones. So you wouldn't have to manufacture outside the body, and you could dose exactly like you dose a small molecule with a pill. So you give a pill at a certain PK, the protein is produced with that PK of the pill, and that's what we've achieved. And so we started looking at where this was best used. One of those areas, we thought was metabolic disease. Because in our mind, like in the mind of the world, we thought GLP-1, great, but we all know that GLP-1 plus GIP, plus PYY, or Amylin, or whatever, works better. And what we'll be able to do is, within two months, we'll be able to make the construct for GLP-1, Amylin, PYY, which I happened to see at Amylin's R&D day in 2004, and I know it works really well. So we did that, and we've made many combinations, and it's true, they do have different efficacy, and they do have different effects on the quality of weight loss and metabolism. So that was exciting. However, what we started to find is something that we all should have known, but it's one of those things that you don't realize is obvious until someone asks the question. And that is, when you deliver short-lived peptides, GLP-1, Amylin, GIP, they last half an hour in the body. And you compare the efficacy of delivering a short-lived peptide in the physiological timeframe with a pill, once-a-day pill, and you compare it to high levels of persistently active GLP-1 and GIP, there is a massive difference in efficacy. It seems that while you have these peptides on all the time, there are counteracting systems which are trying to turn them off, which we completely seem to circumvent when we activate with a pill. So when we have GLP-1, GIP, and the animals are dosed daily, and they get bursts of those peptides, bam! They lose weight and maintain at the level of a lean mouse. Head-to-head, if you have GLP-1, GIP on all the time or persistently active, they don't gain as much weight, but they don't even get close to lean. And we're seeing this with multiple combinations. We see it again with CAR. We know T-cells don't like having the CAR there all the time. There's tonic signaling, and the cells are trying to switch it off, and you get exhaustion, and you get failure, and you get disappearance of CAR T, and they don't work that well. When we head-to-head control the level and timing of CAR using oral pills, we're able to transform T-cells from the slightly weird CAR T today to totally normal, indistinguishable from an IE T-cell, which, when it goes into the body, is four times more potent than the approved anti-CD19. It seems that we're not just having a delivery impact, a manufacturing impact, a combination impact. This ability to deliver signals or, receptors in a physiological timeframe makes a massive difference on how well they work as a medicine in the body. Mm-hmm. And that's super exciting to us, 'cause we all should have known it, but the pharma industry is used to making inhibitors. They're used to making things that work really hard for really long times. When you're using agonists, you maybe don't want them on all the time because they switch themselves off. And that's one of the most exciting findings that we, we've got from literally looking at our data. We didn't expect it, but we're really moving forward in these areas where the body's responsive to food, in the case of metabolism, to the immune to cancer, to changing environment and immune system in the case of cell therapy. So we're focusing on those two areas with our regulation, even though it can be used for tons of other things. You know, that's what we're very excited about right now. Right, and obviously very large markets there as well. We've got about five minutes left. I did wanna ask about XLRP. Yes. So we're expecting, you know, a few more milestones, I mean, one major one. What's sort of the gating around when you could get that? And is there anything to read into the timing of the acquisition, or it was just sort of right from Janssen's perspective? ... I think it was right from Janssen's perspective and our perspective. We did a great deal with Janssen, where they paid basically 100% of development, 100% for us to learn how to manufacture the product, and that was really helpful for us as we built the infrastructure both for science as well as manufacturing in-house. And we received a rather high global royalty of 20%. And as it got closer to commercialization, as we completed with our partner, Janssen, the enrollment in a phase III, I think it just became good for both parties. We were able to monetize some of those future royalties. Janssen took over any obligations to UCL, so we really monetized the product, and we got a third upfront last year and the beginning of this year, and $285 million on first commercial sales, and that's it. In addition to that, we entered into an actual commercial supply agreement, so a real agreement where we manufacture commercial supply to Janssen, and they pay us X amount of dollars per batch. So we still have revenues on the launch, and we still benefit from the strength of the launch, but it's through manufacturing. Mm-hmm. That's how we retain the interest in the program as it launches. And at this time in capital markets, it was a very... It was a great deal for us. I think it was a great deal for J&J, and we were very happy to have done it, and hopefully, the data will be good. We think it will. We had very good phase II data, and that will be sometime towards the end of the year. Okay, great. And maybe one last question, sort of pulling back, in the last few minutes. You know, how, how did getting those economics, you know, that you may have gotten through the prior partnership over the next three-four years, getting those pulled forward to today, how does that set you guys up to drive value from the pipeline? And I guess, where are you most focused in terms of allocating that capital? Well, you have to be pretty focused in allocating capital these days, don't you? So we really have decided to focus. Well, we've got-- we're, we're not initiating any more INDs. I mean, I haven't talked about our, the incredible pipeline at preclinical waiting to come because that's not our focus with the money we have in hand. So our focus is really executing in xerostomia, which we think we can continue to expand over the years. It is to to make sure that everything happens as I've described in that program, that we can file in an expedited fashion, and that's really the focus of the clinical aspect of the company. From a manufacturing perspective, we are very strong in manufacturing as a commercial manufacturer, end-to-end. There's certain value that we get from that, the timing of our programs. Two to three years time, we tend to save in a clinical development program, and that is witnessed in xerostomia, and so we're really concentrating on maintaining and building that manufacturing. So we are going to be a commercial manufacturer, which is great. And in the arena of riboswitch, I think the data has really led us to focus on the area of delivering these agonists in a physiological timeframe with oral small molecule, which actually solves so many of the issues that are appearing in the metabolic disease space, which includes muscle wasting, you know, fat regain, manufacturing. We obviously don't have to, but we're focusing our research and our next IND as we go into next year in that area. And our CAR-T programs are really in a separate... We've put them into a separate company, where we are looking at partnering and some strategic opportunities in that space because we are not a, you know, CAR-T company right now. Mm-hmm. Great. Well, unfortunately, I think that's all the time we have, so we'll have to leave it there. But thanks, Andy, for joining the conference and looking forward to the updates over the course of the year. Thank you very much. Thank you for having me. Thank you.