MeiraGTx Holdings plc ($MGTX)

Good afternoon, and welcome to the Jefferies Global Healthcare Conference in New York. My name is Michael Scharfenberger, with the Jefferies Investment Banking Team. It is my great pleasure to introduce Alexandria Forbes, CEO of MeiraGTx.

Thank you very much, and thanks for inviting me to talk at your conference. So I'm just going to go through 2 programs that Meira has at the moment. We're a company that was built on many different technologies. The main one we intended to do was to control any gene with oral small molecules, which we can now do, and it's called our riboswitch technology, and we're taking that into the clinic this year. And I'll just mention that program at the end, but we have our own manufacturing, which has helped us have four late-stage programs, two of which I'll talk to you today about and next-generation optimization, which is one of the reasons our programs have been successful to date. Quite a deep pipeline, but our four lead programs, two of them are awaiting filing and two of them are finishing pivotal or starting Phase III. So radiation-induced xerostomia, wholly owned in-house, and that is in a pivotal study data, 12-month data will be this time next year. And we have breakthrough and RMAT, and we're hoping to file and get approval at the end of 2027 with a launch in beginning of '28. X-linked RP. We just -- we partnered this with Johnson & Johnson. They bought it from us. And then we bought it back from them just recently. And so this is a program where we are intending to get this approved in Europe and the U.S. and launch it in 2027. AIPL1, another disease for the eye. We developed it for philanthropically and 11 babies who were blind were treated with this drug and all 11 grew into children that were able to see. And Eli Lilly acquired this from us last year, and they are working steadily to get global approval in multiple markets for these children. And we have a collaboration with an AI company in Parkinson's disease. This has 3 studies, 2 are sham-controlled positive Phase II studies with UPDRS second -- with UPDRS as the primary endpoint, and that is going into Phase III as we speak. We have 3 deals with the one I've mentioned with Lilly about AIPL1 for blind babies, Sanofi has invested in us a couple of times, and we have ROFNs around our riboswitch and xerostomia, which means they get to look at our data for a few weeks before we're allowed to show it or discuss it with others, and the Hologen deal with the AI company for Parkinson's. So the first program I'm going to talk about today is the Aquaporin program. And this is for a completely untreatable condition called late radiation-induced xerostomia. And this is actually extremely common. And anyone who knows that patients who've had head and neck cancer and being treated with radiation, all of them will have had xerostomia, and 30% of the people, who have been cured of head and neck cancer and treated with radiation, maintain xerostomia, moderate to severe, grade 2-3 for the rest of their life. Now that is very, very bad. So they have dry mouth, they can't eat, they can't swallow. They often lose weight. They go on feeding tubes. They have terrible tooth problems and infections in their mouth. They often, because they can't speak or eat, don't go out. And we even spoke to an investor whose family member had had xerostomia and eventually refuse to go out and eventually just died. So it -- so don't be under the impression that it's a dry mouth and it's not severe. It's very, very severe for the rest of your life, and it's completely untreatable because these patients are the patients that don't respond to any other treatment that makes saliva be produced. So during radiation, the salivary glands are very sensitive to radiation, and that's why everyone gets xerostomia, which is a dry mouth. In most cases, 60%, 70% of cases, the xerostomia resolves over about 12 to maybe 18 months as the gland heals. And it's only the patients when they get out to 2 or 3 years that we treat who have a completely irreversible, and, I suppose, it's untreatable condition. So what we do is we take the gene for Aquaporin 1, which is a nonpolar water channel found in kidney, found in blood cells, and we introduce it to the duct of the parotid gland. So patients open their mouth, and you just squirt the viral vector AAV2-hAQP1 into the remaining glands. And that water channel, when in the glands, makes those glands permeable to water and water flows down the concentration gradient into the ducts and into the mouth. And we have done a Phase II -- a Phase I study, a dose escalation study where the data was incredibly strong. And we just presented 3-year data where it was maintained from 12 months out to 3 years. So when you ask physicians about this condition, having shown them the 3-year data, we had huge response from physicians. And this actually is reflected also in the very strong end of enrollment for our pivotal study, which was extremely crowded, has just finished. And you'll see some of the comments from physicians. They're dealing with patients who really have no option and what they really liked about this treatment is that it is disease-modifying. So it's a onetime treatment that you can give in surgery. It doesn't hurt. It doesn't need anesthesia. It's obviously, you go, and you don't stay there. And it looks like it has these transformative effects that are durable. So from a physician position, when they saw this 3-year data, they considered this something that they would be highly likely to treat their patients with 78% is what they said. We actually used a much lower number when we were modeling this, but this is a very, very good physician buy-in and similar actually buy-in from payers when we did this survey. So the -- this is a very large market, clearly an unmet need. 30%, 40% of radiation-induced xerostomia patients, that is just those patients, there are 165,000 in the U.S. and 20,000 new patients a year. So you can appreciate that's a large market for any gene therapy, genetic medicine, but also a continuing market. And we think that we can have reasonable pricing that we've discussed with payers. And this should be a multibillion dollar global market with an ongoing almost $2 billion a year market just in the U.S. From a point of selling, we discovered that in the U.S., there are 15 centers that treat or have under their care, over 60% of these patients. And so with a very small focused sales force, we could launch this drug ourselves, and we think be really successful and have a very good launch. So the data that we have recently released is from a Phase I study, it had two separate groups. It had a set of cohorts, dose-escalating where one gland was treated, a set of cohorts where both glands were treated. And this is 3-year data. And you can see that blue arrow is the decline in the xerostomia score, Ideally, you want it to go down at 12 months. It was minus 21% in the bilateral, which is the dotted line, and that blue line is minus 17%. And why I say those numbers is a 8-point change is clinically meaningful. A 10-point change is transformative, and no one's ever seen a 21-point change before. So really, really strong data at our endpoint, which was the primary endpoint for our pivotal at 12 months. We recently released 3-year -- oh, sorry, I forgot to show you 3-year. So you can see, other than a little bit of a blip down, the data was really, really durable out to 3 years, right? When you look at individual patients because we wanted to understand if different patients were going up and down or the population was variable. But what we saw is when we did waterfall plots in every patient, so the bilaterals on the left and the unilateral on the right, we saw these waterfall plots maintained over 3 years. You can see at the far right, there are a couple of patients that don't respond. And so it's not perfect, but it's a Phase I dose-escalating study with 3 patients per cohort. So we thought this is pretty good. And then what we did is we looked at every single patient at every single time point, and we compared their XQ score over 3 years. And what you can see here is the lightest -- the darkest red line is the 12-month data and the lightest red line is the 3-year data. And there's remarkable consistency. If you responded well at the beginning, you continue to respond well. If you responded poorly at the beginning, you generally don't respond. The one who responded worst was the worst performing. You can see that. I don't have a pointer, but that guy on the left, the line goes up. So a bit more variability when you don't respond, and most patients respond. You can see, remember, a 10-point decline -- this is percent, so that doesn't. But -- the -- if you look at unilateral, very similar, so you respond well, you continue to respond well. And in the unilateral interestingly, patients that see 2 and 3, you can see they didn't respond at 12 months, but they start to respond at 18 months, and they continue to do so. So this was very consistent data. We looked at water flow similar. It's a bit more variable, but similar. You can see the 12-month similar out to 3 years. And when we did the same thing, look at individual patient data, you can again see that there was a lot of consistency. So bad responders on the left, they lost water flow, good ones on the right, gained water flow. We were able to do biopsies, well NIH did them, and were able to show between 1 and 2 years, the RNA was present, DNA and protein. So that was very encouraging. This is a design of our current pivotal Phase II that will read out its 12-month endpoint. This time next year, we've just finished the study now. And this has full alignment with the FDA on both CMC and clinical design to support a BLA filing and potential approval if possible. We also have RMAT breakthrough, so we're going to hopefully apply for priority review. I'm not going to go through the summary. But that's the program that is wholly owned, very large market, and we're starting to look at not only filing the BLA, but how do we commercialize it in the U.S. ourselves. X-linked RP. So we started the company only doing local delivery of small doses of gene therapy, which took us to the eye. And I've mentioned the drug for blind babies that we sell to Lilly. This is a very -- this is the opposite of that. It's a very common inherited retinal disease. So XLRP, x-linked retinitis pigmentosa, is one of the most common inherited retinal diseases, and the mutations caused by RPGR, the most aggressive and common of XLRP. And that's what this is for. Patients start to go blind as children. The peripheral vision disappears. They can't see in the dark, and eventually are legally blind in their third decade. So we had partnered this with Johnson & Johnson. They paid 100% of development. We were out a 20% royalty. They paid another royalty, and we manufactured the product, and they acquired it back from us, so they wouldn't -- they bought the royalties back from us a few years ago. However, they decided not to develop eye programs. They shut their eye programs down at the end of '24. And this product became available. And we were able to acquire it a few weeks ago for $25 million. Now in addition to acquiring this product, a number of leaders from J&J have joined us, which is extremely helpful in getting the team together, again, who worked on the development of this program to move it now towards commercialization. So we've done a large Phase III. That Phase III had a novel endpoint mandated by the FDA. That was a -- did not hit its primary, but it did hit a trend. And every other of the secondary endpoints, and another functional vision endpoint met with very strong significance, and so we are looking for approval in Europe. U.S. and Japan based on that data supported by the Phase I study. You'll see these are quite large studies. A lot of patients have been treated, very good safety. We are the manufacturer, and we've completed PPQ, and we -- there are no capacity constraints, and it's actually a very low cost of goods when we make it. So just to go through the Phase III data, this was a blinded study with 2 dosing arms and a nontreated arm. The endpoint was the primary -- well, all the endpoints were at 12 months. And everyone in the nontreated after that period of time went into the long-term follow-up, and most of those, I believe, have now been treated. So the primary endpoint was initially a maze, which we spent 2 years discussing with the FDA, and particularly -- in particular, a gentleman called Wiley Chambers. And they would not budge on us developing and using this novel endpoint and a very novel way of scoring this endpoint. So we kind of had to do this as a primary. However, not only was it novel, but we were concerned about its variability because we had to build mazes all over the world. It was a 32-site study in Canada, U.S., Europe, U.K. and everyone had to go to different mazes, had different adjudicators, had different people guiding them in the maze. So it was a concern. And it's in the domain of functional vision. It did not hit its primary, but there's a trend. It's 2.5 more -- 2.5x more likely to respond with this strange responder analysis. If you've been treated than not treated. Importantly, in the functional vision domain, which shows the same thing, can you function in dim conditions, what's your mobility like in dim conditions? The Pro LLQ is a very well-validated and well-known PRO that measures exactly the same thing. And in the case of that, if you look down here, that PRO was quite a high-ranking secondary. And if you look at the exploratory analysis of individual questions, the p-value for the question on mobility is very strong. So going back to this, we had good responses in functional vision, despite the primary. Retinal function. This was the endpoint that the Europeans actually wanted us to use. And retinal sensitivity, central 10 degrees is how sensitive is your retina when you shine different light on it. And the static perimetry responder is the thing you may have heard about, which is, can you get 5 points increasing by 7 decibels and the same 5 points over 2 different time points. And that was a very high bar. And in both cases, we saw very significant improvements in treated versus untreated. And then LLVA, that is visual acuity on an ETDRS, on a line chart. And this was very strong data. You can -- this is a -- these are the individual patients LLA. And you can see that 46% of patients had a two-or-more-line difference in the treated and only two in the untreated. And in fact, there was confounding issues in the baseline of those two untreated, which did not exist in any of the treated. But this is -- in Europe, this sort of data would get something like EYLEA approved. So this is very, very strong data. And of late, more recently, the FDA itself has said that LLVA can be a primary. So while we missed the primary and only saw a trend, we have unprecedented data across all three domains of vision, very strong. And when we look at responders who responded to two or more domains, efficient and endpoint in two or more domains of vision, 40% are treated and 0 of untreated had that response. And this isn't cherrypicking because you can cut, you can mix and match any of the endpoints, and this is them all mix and match. And the difference between treated and untreated ranges between about 25% to 40%. And that's pretty good as a responder with no cherrypicking. So this is a large indication, over 20,000 patients in EU and U.S. It's a small community of physicians, maybe 40-50 in Europe and U.S. who see 80% of the patients, 32 of them were in our study, and we know them all and over 60 surgeons have been trained. So we have a lot of KOL support. We have a lot of European regulatory support, actually. And we have several hundred patients waiting. We have drug that we've made out of PPQ, ready for commercial. So that's already been paid for by R&D. And we have the capacity to manufacture this drug as much as we need it. So the Phase II supported by Phase I in extension that treated 137 patients, 127 patients, I think, 138 patients, very good safety. We -- every patient at every time point was checked for any safety issue, and it was really good safety. We have very good leadership from Johnson & Johnson and the very team that developed this with Johnson & Johnson now working for approval. And the EMA has requested a number of times that we file for approval, and that will be happening as we get all the information from J&J. And as soon as we get that information, also we'll be filing for meetings and designations with the FDA. Likewise, in Japan, four patients were treated, which is the same as Luxturna got approved on. And the physician who treated them saw some of the best responses in Japan. One of his patients had a 40 letter improvement in visual acuity. And there is a lot of excitement in the regulatory folks and the physicians in Japan. So we will also be looking to hire a Japanese group for approval in Japan, which is actually good for pricing because they are keen on making these sorts of drugs available to the Japanese.

Now first, I'll just ask any questions.

Xerostomia product, does that administering the product that does not require cannulating the doctors on that and part 1 and part 2...

Okay. So this can be done by a dentist. This can be done by a surgeon, and you can be trained in about 2 hours. So the patient opens their mouth, and at the back of their mouth, you can see the opening of the parotid. Cannula is inserted into the opening and the fluids is injected in to the volume that, that gland holds. So patients, for example, patients are asked how inconvenient, how painful this is and when very stoic gentlemen from the north of England, who was a miner, was asked how painful is this from 0 to 10, he went well, somewhere between 0 and 1. So it really is an easy procedure and the physicians who are doing it says it -- say it fits really readily into their clinical practice. And the person, who actually administered that to the gentleman I mentioned, said he could do up to 8 a day in his clinic. So it really is easy. And that's one of the reasons you have such buy-in. Patients are very willing to do it and physicians, it fits into their practice. And it's just a onetime, and then you have a lifelong benefit. Well, you have a benefit in an otherwise lifelong untreatable disorder. So very -- yes, another question.

And just for the XLRP, has there been any turnover FDA [indiscernible].

We have not spoken to the FDA yet. So what we're doing is we're collecting all the documents from Johnson & Johnson. And we -- while we prepare for EMA, when the IND is transferred to us, we will immediately start filing meeting requests, designations, all those sorts of things. We have not started yet. Yes.

For xerostomia, that was secured collecting data on like a PRO. So the patients, I guess, [indiscernible] feel about it. And then also how much saliva they are producing, which one is the FDA submit, which one carries more weight?

So the XQ, the PRO.

Well, you mentioned that somebody, who's had dry mouth, let's say, 3 years ago, and got treated. I have a hard time to imagine that they can really recall what that was like.

So this PRO, that's a very interesting question, because there are some PROs that say, are you better, worse or the same, right, from pretreatment. This PRO defines xerostomia. So it's not how much better are you, but how bad is your dry math? How bad is your sleep? How bad is it when you speak? So you can appreciate that seeing the consistency we did when it is a PRO, which are more variable, indicates that maybe when the PRO is done at 2 years and 3 years, and they come out the same in the same patient, that's pretty compelling that you've had a real change. But you're absolutely right about having to remember what it was before. Most PROs wear out that kind of PRO in a couple of years. This is -- and xerostomia is only a patient-reported indication. So if you look at the ASCO guidelines, there is no correlation between absolute saliva and xerostomia symptoms. So you can only really improve xerostomia by looking at the xerostomia scales, and that's what we did. And that's the primary. And our clinical trial design, primary secondaries have been agreed by the FDA as has the statistical plan in writing, in response to briefing that we gave them. Riboswitch, a completely different topic, but supercool technology. We think one of the coolest technology in genetic medicines in the world. And what this allows us to do is control any gene, the production of any therapeutic protein from peptide, hormone, antibody, CAS9, CAR, anything that you can encode in a gene, we can control the expression of that in a person, well, it's mice at the moment, but in a person using a pill. And we can control it more accurately than you can control by injection. So how we do that is a splicing mechanism. Essentially, we put a toxic cassette into our DNA sequence. You put the vector, you can inject it into muscle, leptin, ecDNA, whatever you want to do, it can go into CAR-T. And that gene sits there and that toxic cassette is spliced in and the entire RNA degrades. If you add a small molecule that alternative splicing happens, the toxic cassette comes out and RNA is made. This can be used for vectorized antibodies to control antibodies. We've done it for every pharma's biggest antibodies, CAR-T, it improves CAR, longevity and make some 4x more potent. We can control editors, we can do hormones, peptides, CNS delivery, many, many things. These are some of the things we've done. This is an example of the dose responses that we do very tight dose responses. And the thing that we're taking into the clinic this year happens to be one of these hormones and peptides. It is leptin. There's an unmet need for leptin, injectable leptin is quite toxic and can be immunogenic, and is only used in leptin now. Kids -- on the left, this is in vitro leptin expression in dose response to our molecule. On the right is the serum level. These mice have a gene collecting that's off all the time in their muscle that we injected onetime injection. And this is in response to an oral dose. So you see that dose-response. This is leptin-minus mice given an oral pill every day on oral molecule every day. And you can see really clear dose-response in obesity. And then we have done this. So given those mice, the small molecule every day for 20 months. And you can see here the OB mice at the top, the middle mice are mice that have low level leptin. So they're like a hypofunction, they're not now. And then the purple line have the controlled leptin. Every time you add the small molecule, their weight is lost, you take the small molecule away, they gain weight. They lose weight when they get the small molecule back. They gain weight, lose weight. And finally, at 274 days, which is a long time after they've been injected and they've been getting the molecule on and off every day, we gave them the molecule for another 4 or 5 months, and every day, they produce the same amount of leptin and maintain that lost weight. So that's what we're taking into the clinic this year. We have had interact meetings with the FDA. We're currently going into manufacturing of the viral vector. And our GM -- our small molecule is ready for its GMP, and it's ready for the clinic. That's it. Question, yes.

Is leptin in partnership with Sanofi?

No. Sanofi has a ROFN on incretins. And they did actually ask after the fact, could they include leptin. No, it's only ROFN. So it's only to discuss based on data. But we pointed out leptin isn't an incretin.

Right. But just thinking about the leptins, do you have -- while you have a very tight dose response, you initially have to get the gene therapy, DNA, whatever RNA into also aware what is rotation, but that's where you have the variability.

I don't have the slide. That's super interesting thing. So we've done PK studies, right? And in fact, as you're alluding to, for example, in the liver, the -- if you dose a number of mice with a gene in the liver, right? You get about a half log variability between the expression of that gene in the liver between mice. When you express the regulated gene, only with a small molecule, every mass produces exactly the same amount because it's limited by the small molecule. So you look -- it's -- what our gene is? Is this -- it's almost like -- it's a sensitive measure of small molecules. So one small molecule makes one RNA. So it's very, very accurately covers the different tissue-buyer distributions.

I wanted to get a minimum amount of DNA transaction you should be able to express that.

We do. So we've actually -- so we haven't only been developing this, but what we've been doing is improving and optimizing our vectors, promoter all sorts we do promote, we've got AI-driven promoters and capsid, all sorts of things. And so we have very, very potent vectors. So -- and I mentioned at the beginning, we only do local delivery and somewhat immune-protecting doses. So that technology was really developed for this. So we give really small local doses into muscle, which we manufacture, and actually have low cost of goods, because it's so potent. And now we're in a position where with low-dose vector and a dose of us even more optimized small molecule, because we can use different small molecules, we have about a pill equivalent to Advil and a single injection into muscle of a relatively low-dose AAV. This is not IV large doses. This is something that costs in the thousands cost of goods. I can talk to you more, if you like.