MeiraGTx Holdings plc Stock

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.

Started here. Thanks for joining the session with MeiraGTx. My name is Alec Stranahan. I'm senior biotech analyst here at Bank of America covering Meira. And I have the pleasure of introducing Zandy Forbes. Welcoming her back to another Vegas conference. Zandy is the Chief Executive Officer of Meira. Thanks for being here, Zandy.

Thanks for inviting me.

Yes. Great. Well, maybe just to start off at a high level, you've materially repositioned Meira 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 derisking 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. It could be many things. But I would say that buying back RPGR from J&J has been the most derisking thing we've ever done in the company. And it's -- and getting it approved globally is a real focus for us. And since we did that, I don't know, 10 days ago, 2 weeks ago, 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 superfast and 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. Well, one of them, Penny Fleck led development of the whole therapeutic area, and she's now working at Meira as of this week. So that's, I think, the most transformative thing we've done this year.

And kind of liberating now to be able to talk about the program, how you want and push it forward, how you want.

Yes. Yes.

Yes. And I mean, you were always going to be the manufacturer of boto-vec. Maybe we can just talk at a high level, I think that 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 story that you're trying to build for Meira?

So 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. So it does 2 things. Number one, we have a platform process, and that allows us to start an IND with essentially similar to commercial material, super, super important in gene therapy and has been very important for us.

Number two 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. So the FDA and we are very familiar with what's required in a CMC section. And we did initially for J&J now for ourselves, full PPQ for RPGR.

So 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. And I think that having manufacturing in-house is probably one of the #1 derisking things you can do for any IND. It's difficult, though, because you've got to build it over many years. But for us, that's what it's done. We wouldn't have 4 late-stage programs that we could file with our own manufactured material unless we've done it ourselves. We'd probably be 3 years later in each program.

Right. And that's fixed costs that have already been put in place.

Yes.

Yes. And beyond 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 kind of checked a lot of the boxes on the non-data components around CMC, et cetera, right? Like you're ready for commercial scale.

Yes. So Yes. So 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. So 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 1,000-liter bioreactor. So 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. So we start with something that is a commercial -- close to commercial-ready process at a commercial ready scale. And again, that's extremely important because what is the biggest part of any BLA or MAA is the CMC section. And 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 meeting.

So throughout the regulatory process, you are iteratively learning what's needed on the same process with the same manufacturing from the agencies. And 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 ourselves, and it's really high yield. So we don't have to go to massive scale. But we manufactured ourselves and filed our CMC section with the Phase II IND amendment and started no comments in 30 days. So we started.

And 6 to 9 months later, the FDA wrote to us and essentially said that if we manufactured within the parameters that we've written, they considered the study pivotal. So without us asking because of the CMC that they reviewed, that is what made that study pivotal. Then 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 3-year data.

Yes. Right. Maybe we can unpack that a little bit further. And I know that the pivotal study, I think it completed enrollment recently in April.

It's finishing now. Yes.

Okay. BLA filing, I think you're targeting for the first half of next year. You aligned with the FDA on the primary endpoint as the XQ PRO and saliva flow...

Saliva flow rate. Yes.

Yes, yes. Saliva flow is the key secondary. I guess, when you think about what good looks like from the study, maybe you can just walk us through sort of the powering assumptions and how important this patient-reported outcome metric is?

So xerostomia is a patient-reported disease condition. It is not correlated at all with actual saliva volume. It is -- it results from too little saliva produced in the mouth of whatever individual you're talking to. But one individual could have xerostomia with 10 microliters for a minute -- for 5 minutes, another with a [ mL ]. So 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 have 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 drives your mouth, those sorts of things. So 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. And the actual mechanism of the drug is you create more saliva. So the secondary endpoint is the actual volume of saliva that you produce per minute when you spit into a tube for 5 minutes. And that's another very standard way of measuring saliva flow.

Okay. And you're testing 4, I think, active dose cohorts here. Do you expect or do you hope to see a dose response? Or is it more of a hedging strategy? And do you think the label could end up covering one dose or multiple?

So this started as a Phase II, right? And so we were doing multiple doses because our Phase I had cohorts of 3 people. And while there was some incredibly good response, there was some much smaller responses, and we showed that in the 3-year data. We showed patient data at every time point -- individual patient data at every time point over 3 years. So there was no dose response that we were able to determine. So there was no correlation with vector genome titer with total vector genome, with volume of gland.

And so 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 the 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. So there's not that much of a dose response even on a monolayer in vitro. So the Phase II has 4 different doses against 2 placebo arms, separate placebo arms. And 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 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. So I imagine the level on the PRO is going to be quite low, but any sort of quantitation you can provide for the placebo expectation?

So 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 is the 30% of patients after radiation, 3 years after radiation that have not recovered, 70% recovered after the radiation of xerostomia, 30% do not. And of those 30% that are moderate to severe, 85% don't respond to sialogogues, right?

So those sialogogues, by the way, have a 25% placebo rate. So these patients aren't even responding placebo-wise, unless the 15% that supposed to do respond is a placebo response, right? So 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 3-year data, if you look at that, patients gave the same response each year for 3 years in a PRO, even though they were treated 3 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 3 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 3 years from 1 year. However, we -- 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. So in the cohort, which treated both sides, there was a minus 21 improvement. Minus 10 is transformational.

And so the bilateral and unilateral had a minus 17. We used minus 17 as our effect size, and we powered to have success, we powered for a 9-point difference between placebo. So that leads you even with 17 a big placebo response. With 21, it's more than transformative, right? So that's how we powered it. And it will nevertheless would be successful if the other assumptions are correct at a 6% -- sorry, a 6-point change. So we designed it as conservatively as we could. We gave the placebo a transformative improvement. We'll see, right? But we did what we could to use that big effect size, which we think is real.

Okay. Okay. And you mentioned the 3-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 onetime therapy. I guess from your latest work speaking with prescribers or payers, how are they viewing kind of this durability piece? Is this maybe one of the key items for adoption? And how does this sort of feed into your approach to pricing and coverage?

So when we've recently spoken to physicians and payers, it was one of the key elements which changed the view of this drug. So we -- 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 3-year data, it sort of changed in the minds of physicians to what was noted is really simple, safe, virtually painless procedure, on time and a durable disease-modifying impact on a condition that is otherwise lifelong. So those were the words that started coming back.

And payers also looking at that 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 $100,000 to [ $250,000 ]. So we will wait for the Phase III data and then have pricing negotiations.

But 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 -- 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 someone got Novartis at pricing for Zolgensma, right? And we want those people to help us. It's the most important thing to us is exactly that the negotiation of pricing U.S. and for bota-vec, obviously, Europe.

Right, right. That makes sense. And 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 regaining the rights and self-filing versus maybe finding a new partner there?

So bota-vec was born in Meira 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 Meira. So we have great familiarity with bota-vec from its birth. Now one of the reasons we initially did that deal with UCL is its close association with the Moorfields Eye Hospital. And one of their lead IRD physicians called Mike (sic) [ Michel ] Michaelides is also one of the founders of this company. And he, as a consultant, guides us on clinical development.

Now why I say that is the Moorfields is arguably the most important hospital in the world for inherited retinal diseases. Mike Michaelides alone himself, not including the other physicians there, sees 100 IRD patients, adults and children each week. And that is -- some physicians see that number of patients in a year. And 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 Mike Michaelides called them and asked them to be. And Mike and each of those physicians has the phone number of the other physicians.

So from a sales force perspective, we currently have -- we can call, Mike 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. And 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.

So 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. So 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. And obviously, the FDA as well is another stakeholder. And we listened to the presentation for J&J on the LUMEOS study. And 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 a precedence in rare genetic disease that supports this approach?

There's number one, there's precedent in many diseases of a trend in a primary and very strong secondaries being approved for full approval. Number two, there is a precedent in the only gene therapy for a blindness that results in dim light vision failure, and that is Luxturna. So 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. And on the Luxturna label that was an issue, which is a 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 every appropriate time point with fluorescence looking at structure to see if there was such a toxicity.

So 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 3 studies with different controls with not even a trend in the primary to start with and not the very strong secondaries. Our 2 secondaries are now accepted by not just the Europeans, but the FDA subsequently has accepted LLVA as an endpoint and as a primary endpoint. And 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.

And for us, there is a very strong response, prespecified 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. But when the questions were looked at separately, the p-value for mobility in the dark was 0.001. So 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. So 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 prespecified.

Okay. Okay. 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? And 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 and Ribo-Leptin into the clinic this year. 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. So the material is being made currently optimized, so it's commercial like. So -- 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 there are some companies that are interested in multiple of our programs. And as we move towards commercialization to potential launches in multibillion-dollar markets in the next 2 years, you become interesting not only to investors, but also other companies, larger companies. And 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. So BD goes on, but I can't say we're about to do a deal tomorrow.

Okay. So I guess we'll stay tuned.

Yes, stay tuned.

Yes. But I guess we'll leave it there. Thank you, Zandy, for the excellent discussion, and thanks, everyone, for your attention. Thank you.

Thank you very much Alec.

Good morning, and welcome to the MeiraGTx program update. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the MeiraGTx website following the conclusion of the event.

I'd now like to turn the call over to Zandy Forbes, President and Chief Executive Officer of MeiraGTx. Please go ahead, Zandy.

Thank you, everyone, for joining us this morning. Today, we are presenting the full 3-year data from our Phase I study of AAV-AQP1 for the treatment of persistent, moderate-to-severe, radiation-induced xerostomia or RIX, following radiation treatment for head and neck cancer. We will also provide an update on the commercial opportunity for this potential therapy. Be aware that we're making forward-looking statements, so please read this slide.

On the agenda for today, I will first introduce the disease, go over the etiology of the condition and the mechanism of action of AAV-AQP1 therapy. I will give a quick recap of the Phase I 12-month data and then present the full 3-year data, which shows robust durability and within patient consistency over 3 years. We have 2 study investigators speaking today about the disease burden, the patient experience and importantly, their hands-on experience of delivering this therapy in our clinical trials. Following the physician's talks, I will be back to provide an update overview of the commercial opportunity, and then we will open the call for questions.

I thought we would start by considering how bad persistent radiation-induced xerostomia is. The answer is, it is very bad indeed. Persistent, moderate-to-severe RIX isn't simply dry mouth. It is a severe lifelong condition with devastating consequences and no effective treatment. Neither does it just affect a few patients as more than 30% of all patients who receive curative radiation treatment for head and neck cancer suffer for the rest of their life with this condition.

So what happens when you have persistent radiation-induced xerostomia? What are the symptoms? You have a very dry mouth. You can't swallow or chew and you lose a sense of taste. There are major diet restrictions. You may lose weight and you may even need a feeding tube. There are oral health complications and frequent oral infections and sores in the mouth. Constant pain, impaired speech, difficulty sleeping and inability to exercise because faster breathing may lead to choking. Difficulty eating and speaking lead to reluctance to interact with others and social isolation.

You can understand that poor nutrition, lack of sleep, inability to exercise, continual pain and limited social interactions have significant life-changing impact and can lead to frailty and even premature death. I'm not sure that people who haven't witnessed or experienced persistent radiation-induced xerostomia can truly understand how horrible it is. We will hear later from 2 physicians who care for many of these patients about the lifelong disease burden. As you can see from the quotes on this slide, some extremely unpleasant symptoms that can even lead to life-threatening consequences.

So how does this condition arise in patients cured of head and neck cancer. All patients treated with radiation for head and neck cancer get acute xerostomia at the time of treatment. However, in 60% to 70% of them, their xerostomia resolves or becomes manageable within about 12 to 18 months. However, in 30% to 40% whose xerostomia persists after 2 years, xerostomia then persists for life, only getting worse over time. 80% of these patients do not respond to any available therapies. So there are a lot of these patients with this severe untreatable lifelong condition whose trajectory is only further decline.

Currently, in the U.S., there are 165,000 of these patients with over 20,000 new patients each year. Globally, the number is large. 435,000 patients today and around 48,000 incident patients per year. This is a complete unmet need and a large commercial opportunity for an effective treatment. Salivary glands are very vulnerable to radiation, leading to acute loss of function and acute xerostomia in almost all patients at the time of radiation treatment. This disruption in salivary function can resolve over 12 or 18 months as the glands remodel and heal. However, often the damage is extensive and the salivary glands don't recover.

When salivary glands lose cells and structure, they lose the normal mechanism of saliva production. In normal glands, the polarity of the epithelial structure is critical for water flow as the water channel responsible for permeability, AQP5 requires polarity-dependent signals to function. Our approach is to deliver a onetime treatment with a viral vector that contains the human Aquaporin 1 gene, AQP1. The therapy is delivered by putting a little cannula through the opening of the parotid duct in the back of the mouth and instilling the appropriate volume directly into the lumen of the salivary duct.

AQP1 encodes a non-polar water channel normally found in red blood cells in kidney, expression of non-polar AQP1 in the remaining acinar cells and duct cells of the salivary gland results in these cells becoming permeable to water. This allows water to flow down the osmotic gradient across the cells from the interstitial fluid into the lumen of the salivary duct and into the mouth. Importantly, the delivery of AAV-AQP1 is quick and very easy. It involves virtually no pain, no anesthetic. It's a small dose locally delivered to the salivary gland and it's a low cost of goods. David Owens will talk more about this later in the call.

Now on to the Phase I study. First of all, let me remind you that xerostomia is entirely a patient-reported condition and severity of xerostomia is not correlated with the absolute amount of saliva. This is described in the ASCO Guidelines on xerostomia. Every person experiences a different degree of dry mouth, depending on their own threshold for saliva. For example, one patient may have xerostomia with 100 microliters of saliva and another will have xerostomia with a ml of saliva. The reason for this is that the shape and size of the mouth, the size of the teeth, the rate of breathing, all impact the amount of saliva that is effective in stopping dryness in the mouth. However, xerostomia does result from too little saliva, which causes dryness and all the features I told you about earlier.

So there's a relationship between xerostomia and saliva flow, but no correlation between the absolute values of either of these measures. In our clinical studies of AAV-AQP1, we look at measures of both xerostomia and water flow. First, the PROs, which is the patient-reported measure of the severity of xerostomia. In our pivotal study, the primary endpoint uses the xerostomia questionnaire PRO called the XQ, which is a standard tool to measure the severity of xerostomia. We also measure saliva flow, an objective endpoint that reflects the mechanism of action of the therapy. This measure is the Unstimulated Whole Saliva Flow Rate or UWSFR, which is the key secondary in our pivotal study.

The Phase I study design is as shown here. There are 2 dose escalating groups. The first set of cohorts were treated in one gland unilaterally. Having completed the unilateral dose escalation, we went on to complete a dose escalation treating both glands bilaterally. The primary in the Phase I was safety and the treatment in both unilateral and bilateral was remarkably safe with only a few mild treatment-emergent, treatment-related events, all of which resolved without sequelae.

The Phase I data at 12 months is very compelling with both XQ and Unstimulated Whole Saliva Flow Rate showing an unprecedented degree of improvement. Just as a reminder, here's the 12-month XQ data. In terms of XQ score, a decrease in XQ is a decrease in severity, which is good. On the graph to the right, the lower dotted line is the bilateral cohort. The same as in the primary in the pivotal study, in which all patients are bilaterally treated. The upper dotted line is the unilateral cohort and the green line is the average of all treated patients bilaterally and unilaterally.

The unilaterally treated patients do not have a stronger response as the bilateral. At 12 months, the bilateral patients had an average 21-point decline in the XQ. Consider this in the context of an 8-point decline being clinically meaningful and a 10-point decline transformative. In bilateral cohort, an impressive 75% of the patients responded with a transformative 10-point or more change in the XQ. While xerostomia score and salivary flow rate are not correlated, we did see a strong improvement in saliva production at 12 months. This is an objective measure of the mechanism action of the treatment and a key secondary in our pivotal study.

On this slide is biopsy data, 1 to 3 years after AAV-AQP1 treatment. You can see that in 6 out of 7 biopsies, DNA was detected with somewhat of a dose response. And in one patient, there was sufficient material for protein staining and AQP1 is clearly seen in the cells of the salivary gland.

Now moving on to the 3-year data. Here is the data for the XQ score over 3 years. When I saw this data, I must say I thought it looked remarkable. The 12-month time point, which we just looked at a little earlier is shown with the arrow, the 21-point decline in the XQ at 12 months. Then if you go straight out to the far right to the 36-month time point, the XQ score is virtually the same as 12 months. Even the difference between the unilateral and bilateral are maintained at 3 years. We think this demonstrates an extraordinary durability of benefit over 3 years, particularly as XQ is a PRO, which are sometimes considered potentially more variable than objective measures.

Even XQ measures collected at 12 months apart like 2 years and then 3 years are very similar. So from a population perspective, the effect of AAV-AQP1 treatment on the whole population is clearly maintained over 3 years. However, in order to understand that this average was not the result of some patients getting better and others getting worse, and this was not because of certain outliers or patients behaving strangely during those 3 years, we looked at the data for each individual patient at each time point.

First of all, let's look at the waterfall plots at 12 months. On the top left in dark red, you have the bilateral population which, remember, has a better XQ average score than the unilateral. And here, you can see a really nice waterfall plot where everyone gets at least a small bit better and some people get extraordinarily better. If you look across at the level of the 10-point decrease on the y-axis of the upper graph, you can see 75% of patients have a 10 or more XQ improvement.

At the far right of both graphs are the patients improving by over 40 points on the XQ in both bilateral and unilateral cohorts. To the right is that waterfall plot for the XQ change from baseline in the unilateral patients who responded on average a bit less well than the bilateral. And while there are a couple of very high responders to the far right, there are a few patients with no responses as you get to the far left. The graphs shown below show the percentage change from baseline, and they are very similar to the absolute XQ scores from baseline above.

When we looked over time and made little waterfall plots of the cohorts at each visit, the waterfall plots were very similar across time. There was some variability and at the 8-month time point had more missed visits. But on the whole, the patients making up the population remain consistently distributed over time. This gives us comfort that the durability of the mean changes in XQ score from baseline reflects durability of responses in the individual patients in the population.

Finally, we looked at the durability and consistency of the XQ scores in each patient at every time point. For this analysis, we put the patients in the order of magnitude of the 12-month waterfall plot for XQ data. For each patient, the score at each visit is shown. From the left to right for each patient, the darkest red is XQ score at 12 months. The slightly lighter red is at 18 months, the next 24 months and the bar on the right is at 36 months. What you can see at a glance is pretty good within patient consistency. The patients with the biggest improvements at 12 months to the right of each group remain strong responders over time. Those with the worst responses to the far left hovered around 0 over 3 years.

The good, but not shockingly good responders in the middle stay around that level and may be a bit more variable than the nonresponders to the left or the out of the ballpark responders at the far right of each group. One thing to note in unilateral patients who on average did not do as well at 12 months as the bilateral. While several of the nonresponders at 12 months remain nonresponders, 2 of them did respond at 18 months, patients 007 and 010 and then remain around that level of response out to 3 years.

When you look at the graphs of all treated patients, both unilateral and bilateral together, as is shown here, it is really striking how remarkable the consistency of the level of XQ responses over time is. We think this is indicative of real responses to treatment that are very durable. This increases our confidence in a positive outcome in our pivotal Phase II study.

In addition to the XQ, we also looked at water flow, Unstimulated Whole Saliva Flow Rate, the arrow points to the absolute change in Unstimulated Whole Saliva Flow Rate at 12 months. If you look to the far right, while there is variability and there are some missing data points, particularly 18 months, we do see a very durable improvement in water flow in this entire population over a 3-year period. When we look at the waterfall plot at 12 months, and then the consistency of water flow rates within patient over time, we see a very similar pattern to the XQ.

So on the far right, patients that respond extremely well with increased water flow at 12 months also respond well at 3 years. If you look to the far left, this is interesting because the patient that had the worst response, in fact, a negative response at 12 months, reduced water flow, that patient continued to reduce water flow further over time. The patients who did not respond or had minimal responses at 12 months remained the same over 3 years with some variability around baseline. And those middle responders remained middle responders with a bit more variability than the best responder.

Just one thing to note about the variability in water flow in these patients in the Phase I is that they all had different hydration levels. If you look at patient S016, that patient has a pretty good UWSFR at 12 months. but goes in completely the other direction, losing saliva production at 18 months. This was surprising and in fact, the only time this has been seen. And it was determined that on the way to the 18-month visit, this particular patient had driven for many hours to get there, drinking only coffee and when tested, they were found to be extremely dehydrated, explaining the inability to produce saliva.

Because of this case, we included in the pivotal study protocol a requirement that before each saliva collection, the patient is tested for hydration. If they're dehydrated, they're required to sit and drink water until they're fully hydrated. We think that this might, to some extent, reduce the variability in water flow rates in the pivotal study.

Based on the durability and the intra-patient consistency of this data in both XQ, the primary endpoint in our pivotal and in water flow, which is the objective measure of the drug function, we have increased confidence that the benefits we are seeing in response to AAV-AQP1 are real and higher expectation of a positive outcome of the pivotal study. We include the 3-year data in an application for breakthrough therapy, which we were awarded a couple of weeks ago. We also conducted a global physician and payer survey using the 3-year data in the target product profile, which further improved the view of AAV-AQP1 for the treatment of persistent RIX in the eyes of both physicians and payers, and I'll talk about this later.

Here is the design of the pivotal study. There are 4 escalating dose cohorts and 2 placebo cohorts. All patients are bilaterally treated. It is double-blind and randomized and conducted at 30 sites in the U.S., U.K. and Canada. The study started as a Phase II with 3 initial cohorts, 1:1:1 placebo to 2 different doses. In response to our IND amendment to open the Phase II, the FDA wrote to us and said that as the manufacturer, if we manufacture the material used in the study to the specifications outlined in our filings, they would consider this a pivotal study.

With this in hand, we filed for and were awarded RMAT status. And in response to the briefing book for our RMAT meeting, the FDA provided positive answers to all of the clinical questions we asked regarding the current Phase II being potentially the single pivotal study to support a BLA filing. With these written responses, we were able to cancel the FDA meeting, and we have clear written alignment with the agency on this pivotal study.

As we converted the Phase II into pivotal, in order to keep it double-blind and randomized and cover all the doses that we had seen responses in the Phase II, we completed the initial 1:1:1 placebo versus 2 different low doses and then carried out a second set of cohorts 1:1:1 placebo to 2 different higher doses. All patients are completely blinded until the last patient reaches the last 12-month visit. The study protocol has 276 patients randomized to 1 of 4 active doses or placebo. The primary endpoint is the change from baseline in the XQ score. The study is 95% powered for success with success being a difference in the change in XQ from baseline in any one of the treated arms versus the pooled placebo arms. The key secondary endpoint is changed from baseline in Unstimulated Whole Saliva Flow Rate.

With that, I will turn the call over to 2 physicians, both of whom have experience in treating RIX with AAV-AQP1 in our clinical studies. The first is David Owens, a consultant at the University Hospital of Wales in Cardiff. The second is Dr. Michael Brennan, Professor and Chair of the Department of Oral Medicine and Oral & Maxillofacial Surgery at Wake Forest University School of Medicine.

Dr. Owens, over to you.

Good morning. I'm Dave Owens, a consultant otolaryngologist at University Hospital of Wales in Cardiff and a Former President of the International Head and Neck Cancer Conference. Along with my team, I'm one of a number of consultants in the U.K. participating in the double-blind placebo-controlled AQUAx2 clinical trial of AAV-AQP1 in patients with persistent xerostomia following radiation treatment for head and neck cancer.

Today, I'll be talking about my experience of delivering this treatment to patients in the ongoing AQUAx2 trial. As consultant otolaryngologist, I look after cancer survivors with Grade II and Grade III radiation-induced xerostomia, which persists for many years after the cancer has been successfully treated. It is a genuinely miserable condition, a lifelong one for which we have no good solutions. And in many patients, it is considered the worst consequences of curative radiation therapy for head and neck cancer.

Anyone who has had treatment for head and neck cancer and suffer the consequences of dry mouth will know what an impact it has. Xerostomia is a social disability and can broadly affect the health and quality of the patient as well as their caregiver. These patients live with constant dryness, pain and sores in their mouth, swallowing is hard, taste is altered making it difficult to eat, which can result in unwanted weight loss and frailty. Difficulty in eating and talking means that social interactions may be limited. In addition, the loss of saliva's antimicrobial functions lead to dental deterioration, which can be very hard to control.

The reality is, we don't currently have treatment that works well for these patients. The drugs that can help in cases with less severe dry mouth are just not effective in this patient group. The only option may be gels and washes to reduce symptoms, which don't work well and provide minimal short-lived benefit at best. AAV2-AQP1 is different because its actions aim to restore salivary gland function, addressing the cause of xerostomia, not just the symptoms. The Phase I AQUAx data are really encouraging in terms of efficacy, safety and tolerability with transformative benefit observed in many of the treated patients, and the recently released long-term data from AQUAx demonstrate that this level of benefit lasts for more than 3 years.

The ongoing pivotal AQUAx2 trial, we mustn't forget is completely blinded with 1 in 3 patients receiving placebo. With that in mind, and not knowing who has received treatment and who has received placebo, some of our patients have reported very significant changes in symptom scores and saliva volumes. Importantly, the procedure of retrograde intraductal delivery of AAV2-AQP1 into the parotid gland is straightforward, minimally invasive and quick. From a patient's perspective, tolerability has been excellent. The procedure involves minimal pain with patients responding -- reporting that on a scale of 1 to 10, pain was somewhere between 0 and 1.

For a group that's already been through significant treatment, that matters. It makes acceptance of the procedure much easier. From a clinician's point of view, the procedure fits easily into existing practice. The skill set is familiar to those of us working in this area, ENT surgeons, oral medicine specialists, maxillofacial surgeons and interventional radiologists. With focused training, people can become competent quickly if they're not already so. It doesn't require a complex infrastructure or theater time, and I can do the procedure within my clinic in the clinic chair using the basic equipment I would expect to find in any standard outpatient clinic. It's also quick.

Bilateral treatment can be performed in under an hour, which means they can realistically be incorporated into a normal working day without disrupting clinical flow. I could likely complete 8 to 10 of these procedures in my clinic in a full day. Obviously, we need to wait for the unblinded results. AQUAx2 data is consistent with the Phase I AQUAx data demonstrating AAV2-AQP1 is as effective and as tolerable as we believe it is, the practicality of a simple onetime treatment and ease of use in real clinical setting is very compelling.

When you put all this together, a simple onetime treatment easily integrated in a practice with high tolerability and durable effectiveness, it becomes something that is genuinely practical, not just in theory, but in everyday clinical work and could become the standard of post-treatment care for survivors of head and neck cancer. Most importantly, this has the potential to make a real difference to the patients who are currently living with this severe condition and have very limited options. And for this group, as they will tell you themselves, that's long overdue.

Thank you, Dr. Owens. Good morning. I am Dr. Michael Brennan, Chair of Oral Medicine and Oral Maxillofacial Surgery at Atrium Health Carolinas Medical Center in Charlotte, North Carolina. I'm an investigator in both the Phase I AQUAx study as well as the pivotal AQUAx2 study. As a specialist in oral medicine, I care for individuals suffering from Grade II and Grade III radiation-induced xerostomia. During and shortly after radiation treatment for head and neck cancer, virtually all patients suffer from acute xerostomia, which is often severe. However, over the 12 to 18 months following radiation, xerostomia resolves to a manageable level in 60% to 70% of these patients. In the remaining 30% to 40%, xerostomia persists as a severe lifelong condition for which there are no effective or tolerable treatments.

This long-term persistent radiation-induced xerostomia is increasingly debilitating over time. Patients may suffer from mouth sores and continual pain, oral infections and uncontrolled dental caries. Difficulty swallowing and eating may cause weight loss and the potential need for a feeding tube. Dry mouth results in difficulty speaking, disruptive sleep and even the inability to exercise as faster breathing can lead to choking. Over time, these symptoms lead to nutritional challenges, frailty, social withdrawal and a meaningful decline in oral health and well-being.

For these 30% or more of head and neck cancer survivors, Grade II and Grade III radiation-induced persistent xerostomia is a lifelong, deeply burdensome consequence of curative radiation treatment. Yet despite its prevalence and its significant negative impact on so many areas of patients' overall health, there is no effective treatment, underscoring the severe unmet medical need. In the open-label Phase I study, I saw a truly extraordinary life-changing improvements in many of my patients who are treated with the AAV2-AQP1.

What makes this therapy particularly noteworthy is that it is designed to restore activity within the affected salivary gland epithelium to reestablish function at a biologic level. This represents a meaningful shift in therapeutic intent, one that aims to address the root cause of the condition rather than manage its downstream effects. The Phase I study results I have observed in both the patient reported outcome measures and the objective improvements of salivary flow are aligned with that ambition.

The durability of these transformative changes in PROs and salivary flow over at least 3 years in the Phase I patients is truly impressive. It reinforces my confidence and excitement of the pending data from the AQUAx2 pivotal study. In many of my patients who have shown a positive response to treatment with AAV-AQP1, the level of improvement has been dramatic and frankly unprecedented. They are regaining function that literally transforms their lives. They can eat comfortably, speak naturally and participate more fully in professional and social settings. They've shared that they feel a renewed sense of normalcy, something that had been lost following radiation treatment.

From a clinical perspective, this kind of functional recovery is both uncommon and profound. It is also important to highlight the degree of these responses. The improvements I have observed are clear, consistent and highly clinically meaningful. They are not subtle findings that require careful interpretation that benefits our evidence in both patient experience and objective measures. For example, in one of my patients who had been suffering with Grade II/III xerostomia for 7 years, the response was incredible. His overall xerostomia score showed a remarkable improvement in the first 3 months after treatment in many of the complications of xerostomia.

Importantly, he reported to me that he was able to exercise for the first time since undergoing radiation therapy. Another of my severely impacted patients had difficulty speaking and eating normally. In addition to the overall health impact of the xerostomia, she had become severely socially isolated. Following treatment with AAV-AQP1 in the AQUAx study, the impressive improvements in her xerostomia allowed her to regain more normalcy in her life for the first time since radiation treatment for her cancer, meaningfully reducing her social isolation and improving her quality of life and overall health.

I want to emphasize how important the 3-year durability data from the Phase I study are. A key consideration is the persistence of the transformative benefits demonstrated at 12 months following the onetime treatment with AAV-AQP1. In a severe lifelong condition where permanent dysfunction is expected, more than 3 years of durability is particularly notable. From my perspective, the durable effects of treatment results from changes to the underlying biology of the condition itself, that is disease modification.

The potential for an easy-to-administer onetime treatment to alter the course of radiation-induced xerostomia is especially compelling. Based on my first-hand clinical experience, treatment with AAV-AQP1 can have an unprecedented impact radically altering the patient's life and well-being. A simple onetime treatment can have a dramatic disease-modifying effect on this otherwise untreatable severe lifelong condition. It is wonderful to be part of the development of such a potentially transformative treatment for this population of patients and to witness its life-changing impact firsthand.

Thank you, Dr. Brennan. We conducted a global physician and payer survey using this 3-year data in the target product profile of the therapy, which meaningfully improved the view of AAV-AQP1 for the treatment of persistent RIX in the eyes of both physicians and payers compared to an earlier study using the 12-month Phase I data. We looked at physician preference, potential commercial opportunity, pricing, and we also looked at the concentration of the market in the U.S. as we start thinking about launching this product.

First of all, there was incredibly high physician preference. 70% to 80%, wherever they were in the world, said that they would use this treatment. This is very high preference share globally. What were physicians most compelled by? The endpoints which were used are convincing and exactly what physicians want to see. The effect sizes were unprecedented, very strong, and the durability to at least 3 years was very impressive, especially in the context of a onetime treatment with minimal safety concerns.

It was important that the onetime treatment is quick and minimally invasive and doctors can do it in their normal practice, as you heard from David Owens. You can see in some of the quotes from physicians here that long-lasting benefits of this single onetime treatment is very compelling. This therapy is now seen as a simple onetime treatment that results in a transformative disease-modifying effect on a severe otherwise untreatable lifelong condition.

So how does this convert into commercial opportunity? As we have seen, the physician preference is very high, around 78% globally based on the 3-year durability data and onetime treatment. However, we did not use that in our projections, rather the overstatement adjusted number of 52%, which has further decreased due to access and coverage and things like that. The number of prevalent patients today is large and importantly, for a onetime treatment, there is a significant annual incident population.

In the U.S., there are 165,000 patients existing today with around 20,000 new patients every year. Globally, it's a very big number, 435,000 with about 48,000 new patients a year. The 3-year durability data also impacted payers and what they're willing to pay for therapy in the U.S. Previously, with only 12 months data, we had 90% coverage of $100,000 for onetime treatment. Now we have a range of $100,000 to $250,000. Here, we're looking at $150,000, 15% to 20% gross to net with 90% coverage, and it's a medical benefit.

So with those numbers, you can get a global peak net revenue of $3.7 billion, reaching a steady state of about $3.2 billion because of that 480,000 (sic) [ 48,000 ] new patients each year. In the U.S., the numbers I've gone through result in about $2 billion peak sales with a steady state of $1.8 billion, which is very impressive for a onetime treatment. These projections didn't come from treating every RIX patient that exists. In these projections, around 32% to 37% of available patients have been treated after 10 years. So we think these are reasonable projections, and we're very excited to launch this product at the beginning of 2028 following, of course, positive clinical data.

We also learned something that was incredibly encouraging to us. We learned that over 60% of the U.S. population with this condition are within 3 hours drive of only 15 metropolitan areas. And within those areas, they're seen at 15 specific individual sites. These big centers are the usual suspects, and we had envisioned them being sites that we would go to anyway, but we didn't quite understand the concentration of these patients to these large sites that treat over 60% of head and neck cancer. So we feel confident that we can have a strong launch with little teams focused on each site that address every touch point for these patients.

This may be the oncologists, the radiation oncologists, the ENT, the dental division, the nurse practitioner. It is different at every center. But as there are only 15 of them, we feel that we can get to everyone who sees these patients. And finally, a summary of what I've shown today. AAV-AQP1 is a onetime therapy delivered via minimally invasive quick procedure, which can be done as part of normal ENT clinical practice. Unprecedented improvements have been demonstrated in the XQ PRO and objective endpoint of Unstimulated Whole Saliva Flow in patients treated in the Phase I study. Data from the long-term follow-up of all cohorts in the Phase I shows durable and consistent responses in both PROs and saliva production out to 3 years.

The consistency of the data over time gives us a lot of confidence in the outcome of our pivotal study, which uses as a primary XQ and as a secondary Unstimulated Whole Saliva Flow Rate. Not only does it give us additional confidence, but the durability data had a meaningful impact on how physicians and payers see the product. With the 3-year data, the view of this potential therapy has changed from one that had a meaningful impact on xerostomia at 12 months to a product that is disease-modifying, life-changing, onetime simple treatment that transforms the life of these patients who have been cured of head and neck cancer, but without this therapy are looking at the rest of their life suffering with persistent radiation-induced xerostomia and all of its debilitating consequences.

This is a big unmet need and a large commercial opportunity with a very concentrated initial market in the U.S. with a significant incident population leading to substantial ongoing annual revenue of up to $2 billion in the U.S. alone. AAV-AQP1 has been granted Orphan Drug, RMAT and Breakthrough therapy designations by the FDA. We have written an alignment with the FDA on clinical and CMC requirements for the BLA supported Phase II study. The data from the pivotal Phase II study and the subsequent BLA filing are expected in Q2 2027 targeting an early 2028 launch in the U.S.

With that, we will open the call up to questions.

[Operator Instructions] Our first question comes from Alec Stranahan at Bank of America.

Congrats on all the updates today. Really fantastic to see the progress across the pipeline. I guess 2 on xerostomia. You noted a consistent response with individual patients between the objective salivary flow and the subjective symptom scores. I guess how do these findings strengthen your confidence in using XQ as the primary endpoint in the Phase II? And then I've got a follow-up.

Thank you. Thank you for joining the call. The -- I think one of the things that gave us great confidence is that if you look at individual patients, you see that whatever the response at 12 months, it was maintained largely all the way to 3 years. And you can see that when you compare the 12-month waterfall plot to the plot that has each time point for each individual patient.

So if you think about an XQ and you consider what may be a placebo response in a PRO, right, which is one of the concerns. If you have the same scores coming out of that PRO that is targeted specifically at xerostomia and those scores are equivalent 12 months apart and over 3 years, it encourages you that those are real actual responses, real changes in xerostomia that are not the result of a simple placebo response.

Okay. That makes sense. And Zandy, I guess, my follow-up is just around sort of the expectations heading into the Phase II readout later this year, I guess. But based on the 12-month data you're seeing in Phase I, is sort of a 10-point or more mean change from baseline kind of the expectation in the Phase II as well? I appreciate, I guess, you're using slightly different doses in the Phase II.

Okay. So thank you again. And the method of dosing in the Phase II is slightly different. You're right. However, we did 4 different dosing arms so that all of the actual doses that patients saw in the Phase I are now covered in the Phase III. And we did that because we did not see a clear dose response to the way of dosing in the Phase I. So we wanted to cover everything that had given good responses in that Phase I. The -- sorry, I've forgotten the beginning of the question. Can you say it again, Alec.

Yes. Just around the, I guess, the change in XQ you expect to see...

So it was hard here because there's no evidence or understanding of what a placebo response would be in this treatment and in this sort of patient, right? There's very few studies and there's only one other drug approved. So we actually based the study, the Phase III study, on the data that we got from the Phase I. We used the average of minus 17 as our expected change in the XQ, that was all patients treated, not just bilateral. So bilateral was minus 21, so that was high. And then we powered the study to be successful if we powered it for a 9-point change compared to placebo. And it would be successful with a 6.5 change.

In that way, the placebo would have to be around or more than 10 points, and that would mean that the placebo alone would be transformative, right, in the XQ. So while we didn't know how to estimate the placebo, we use the data we have and our best understanding of the potential for the XQ to respond in powering the study.

Our next question comes from [ Yixin Zhang ] at Evercore.

This is [ Yixin Zhang ] on for Gavin. I have a question about market opportunities. So out of those 20,000 U.S. newly-diagnosed patients who are eligible to receiving the therapy. Just wondering what percentage do you believe is immediately addressable based on your current payer and the physician checks.

And secondly, I have a question about the saliva flow rate improvement. So just to help us contextualize this number, so what magnitude of those improvements is considered as clinical meaningful?

Okay. So first of all, I'll do your second question, okay, and then we go back to the first question, which -- can you repeat the first question?

Yes, first question about market opportunity, like what percentage is immediately addressable, yes.

Okay. So to the first of your questions about the water flow and the good increase that we saw in water flow at both 12 and -- 12 months and 36 months. This is one of the reasons I emphasize that there is no direct correlation between xerostomia, which is the clinical measure -- sorry, the XQ, which is the patient-reported clinical measure of xerostomia. It is only a patient-reported condition. There is no direct correlation between the absolute amount of saliva and xerostomia.

So one person, as I said, with 100 microliters can have xerostomia and another person with a ml can still have xerostomia. So there is no clinically meaningful change in an absolute water flow or a percentage water flow. However, xerostomia is caused by too little saliva to make the mouth wet. It's a different amount for every patient, so there's no correlation. However, it is related to water flow. And water flow is -- the increasing water flow is the mechanism of action of our drug. So the water flow data is not clinically meaningful. However, we are -- we have it as a key secondary because the FDA wanted us to show something that said that our drug was working by the mechanism that we suggested. Is that -- do you have anything more on that? Or is that okay?

I'll then go on to the market question. So you asked about the 20,000 new patients a year. And that 20,000 is the patients who are immediately available to the extent that they are all patients who have had radiation treatment in the previous or 3 or more years before and they all have moderate-to-severe Grade II/III xerostomia. They don't respond to pilocarpine or cevimeline or any other drug. And essentially, those are the people who are immediately available for treatment. And I would say probably more immediately available because they are more recently post radiation treatment, and they are more frequently arguably seeing their physicians at the oncology center in order to have -- in order to be screened for recurrence of their cancer. So that 20,000 is actually the number of patients for whom this drug is targeted.

Our next question comes from Christopher Raymond at Raymond James.

A couple of questions, I guess. First, Zandy, I just wanted to zero in on those 3 patients that seem to do worse at 36 months. Do you have any more color on -- I guess, I know you mentioned there's no dose effect, but anything that happened between months 24 and 36 that you could sort of talk about or any conjecture on what happened there? Or did they get a lower dose? And then I have a follow-up.

Okay. Do you mind going -- let me go back to the slide because I'm not sure that there were 3 patients that did worse. Sorry, let me get the slides and I will -- is this in the XQ?

Yes. So I think it was the bilateral patients. Yes, it was XQ.

Okay. Sorry, I don't have. Can you...

Zandy, what's the slide number? We can pull it up for you.

I think it's 31, maybe.

Okay. That would be great if you can get to the slide. Thank you.

Great. We'll pull it up.

Thank you. But I'll start by saying with respect to predicting who will respond and who won't respond or a dose response, we looked in the Phase I at many metrics such as gland size, such as the actual titer that the patients saw, the total viral vectors that the patient saw and we were unable to find the time since radiation, we were unable to find anything that predicted the response.

It was Slide 32, I think, actually. And yes, I guess -- well, and what I -- really the more important question was maybe my second one is you're going to have a variability, I guess, of sort of durability. And this might be -- maybe a cart before the horse question. But I know typically, AAV therapies are not redoseable, but this is a low-dose local delivery. Have you thought at all about the possibility for redosing?

Yes. So I'm just -- so this was -- sorry, can we just go back to your other question.

Yes, sure.

Okay. So this is at 12 months -- are you talking -- I don't have the -- it's 12 month waterfall and you're looking at the unilateral, the light pink population. Is that right from my memory, the unilateral?

No, I'm talking about bilateral.

Okay. The 12-month waterfall plot, everyone gets a little bit better at 12 months. And then later on, there's only one patient, which is the worst patient at 12 months, which is 009, who gets worse in the XQ.

Yes. So that's not the slide. It's the waterfall.

Okay. So the waterfall, you have 3 patients that get worse, on the right-hand side, right, as I'm remembering, and they're unilateral. And the one that is the worst remains a nonresponder. But then the patients after that are interesting because while they had a negative response at -- or they didn't get better or a negative response at 12 months, what you can see in the waterfall plot of the unilateral is those were the patients that didn't respond at 12 months, but then responded at 18 months. And after responding at 18 months, they kept that response until the end of treatment, right? Those ones that went up in the light pink waterfall plot.

Yes. So I'm actually asking, sorry, Zandy, I'm talking about the bilateral cohort of XQ, there were 3 patients that appeared to -- one was marked. The other 2 were only minimally worse between month 24 and month 36. And my original question was, was there anything that seems remarkable, right? If you see these patients doing better for 2 years. And my question is what might have happened at 3 years. That's it. And it's for bilateral.

Yes. Okay. So we're looking now at the entire population, and we're looking at the bilateral, right? And the patient -- the worst patient in the bilateral, right, did get worse at the light pink line, which is at 36. Then you've got another patient who was the second worst responder and they are basically flat or tiny bit worse. That is just within variability. Now I will say that the patients who didn't respond hovered up and down around baseline and tended to have the biggest variability, right? That was also true of middle responders. And you can see in patient 024, for example, they went in the other direction. They actually improved more at 12 months.

So there's definitely some variability, and we don't know why certain patients respond at certain times, there is variability in this score. But overall, for an open-label study and a 3-year PRO, I would say this is generally very, very consistent, particularly at both ends of response, right, really good and really bad.

Great. Okay. Good. So maybe just the other question that I thought was -- and this is kind of out of nowhere, but have you thought about possibly redosing just given the low-dose, local delivery, et cetera. I know that this is AAV gene therapy. There's the common wisdom that due to immune tolerance against the capsid, you can't redose but this is kind of a different thing. Any thoughts there? Or is that just not possible?

No. It's a really good question. And yes, we think you can redose. We obviously haven't done it. However, this is AAV2, and it is very local. It transduces just the cells that it touches. So this doesn't really get very systemic, right? In some cases, you don't even get antibodies to AAV2. And even where there are preexisting antibodies, it doesn't change the response. So this was also shown by the way for adeno in the first study ever of Aquaporin 1.

So patients who had already antibodies to the adenovirus, they were -- how they responded was not dependent on a preexisting antibodies in the serum. So it seems that the salivary gland is somewhat immune protected. And just I suppose, anecdotally, we developed this program with the NIH and at the NIH Dental Division, this was the work of [indiscernible], who is one of the original studiers of AAV, the discoverer of AAV5, et cetera, who has spent his career looking at AAV and response -- immunological response as well as clearing of the virus by the immune system. And he mentioned that when I asked him this question that all of the neutralizing antibodies he had ever seen are IgG and the antibodies that are secreted into the duct of the salivary gland are IgE.

So he doesn't know if that's one of the reasons there doesn't seem to be an effect of antibodies on transduction or function in the salivary gland. But it was his response to me when I asked that question. So given that there's no difference if a patient already has preexisting antibodies, we think we could redose.

Our next question comes from Ashleigh Acker at Piper Sandler.

I'm asking a question on behalf of Allison Bratzel. So first, congratulations on the data today, really impressive. So from us, just two questions. So we know that FDA has emphasized wanting to see a clinically meaningful PRO. And also wanted to see an objective measure, which would be the saliva flow. So we're just wondering if the Phase II trial hits statistical significance on the primary XQ, but misses on the secondary saliva flow rate. Is a BLA path still viable? Or would this change any regulatory interactions and just the impact there?

And then second from us, you've also highlighted potentially entering into Sjogren's and radioligand-induced xerostomia. Are there any gating steps and time lines to getting these expansion indications into the clinic? Or is the focus really on getting this into RIX first?

Okay. Thank you for those questions. First of all, on the Phase II pivotal study, right? So there was a discussion within the company of the potential need to do a combined primary, and that would mean that we would have to hit both the XQ and water flow. And I think that pilocarpine, they were supposed to hit a combined PRO, it wasn't XQ and water flow. I'm not sure if it could be either or, but they only hit the PRO and not water flow and they got approval.

Now in our case, we very clearly have advice that the primary is purely the XQ. And the secondary, a secondary, the key secondary we've made it is water flow. So yes, if we hit on the XQ and we have a change or something nonstatistical in water flow, this is still an approval supporting study. So is that okay for your question?

Yes. Yes. That's great.

And with regards to Sjogren's and PSMA radioligand. So yes, you're right. Both of these forms of xerostomia you can potentially treat with exactly the same product, AAV-AQP1, which obviously when this is approved, if this is approved, will be manufactured as a commercial product, so it would be a label expansion. Yes, the preclinical data for Sjogren's is very clear. And it seems to have a really good response in mouse models of Sjogren's in restoring salivary function and also actually having an impact on the systemic immune system.

So it is a really good second indication, and it is something we will continue to look at. And as we get further on in the RIX study and our efforts for approval there, we will probably look next at Sjogren's. And with respect to PSMA, this is very interesting because we did ask doctors about this in one of our surveys. And yes, xerostomia is one of the dose-limiting side effects in the use of PSMA radioligand and there was an interest from those physicians who obviously don't have the same degree of understanding of radiation-induced xerostomia as the traditional head and neck treaters who have used radiation for a long time. And there was a big interest in anything that could prevent the severity of xerostomia during treatment.

And we do have some data that is preclinical that suggests that pretreatment with AAV-AQP1 could prevent or reduce the later appearance of radiation-induced xerostomia and potentially reduce that dose-limiting side effect, which would be really helpful. That's, again, preclinical data, and it's a very interesting opportunity to think about, and we do have interest from that group of physicians in exactly that.

Our next question comes from Elemer Piros at Lucid Capital Markets.

Zandy, how do we know that these patients who entered this study are at their steady state, meaning they are not prone to spontaneous improvement?

Okay. Thank you for that, Elemer. So we are treating only persistent Grade II/III moderate-to-severe xerostomia. And something is defined as persistent if it's in our hands, if it's 2 to 3 years after radiation treatment. In our Phase II study, the pivotal study, we actually had a 3-year limit before patients could come into the study. Now when you have radiation, everyone who gets radiation therapy for head and neck gets xerostomia acutely and it can be very severe. And those patients -- of those patients, about 60% to 70% resolve their xerostomia over 12 to 18 months, right?

Once you get 18 months to 2 years and even to 3 years, xerostomia just becomes persistent. And we're treating those people with persistent xerostomia, which only goes down from, let's say, 2 years after radiation treatment. And it is persistent Grade II/III because they can't respond to any of the available therapies. So we only treat patients at a time when resolution just isn't part of the natural history. It just isn't seen. So that's why we don't think we'll have spontaneous resolution in these patients.

Yes. And I think previously, you also looked at another instrument, the McMaster Global Rating of Change Questionnaire. Have you looked at that? And have you seen any corroboration with the XQ? And will you also use this as a secondary endpoint in the pivotal study?

That and a single question are in the pivotal study. Now the McMaster is not xerostomia specific. It is -- do you have a disorder? Has your disorder changed? So it could be Parkinson's, it could be whatever it is. Has your disorder changed? If it has changed, is it better or worse by how many points, right? And so yes, we did that. I have actually -- I'm not sure about the 3-year data, but it's a PRO that doesn't, as reliably as XQ, demonstrate real actual xerostomia. It's general feelings of your symptoms of the disease, whatever that may be.

So yes, it is a secondary. Yes, it did correlate in the Phase I with the XQ as did the single question, I think the dry mouth question. And yes, I seem to remember that dry mouth was very closely correlated to xerostomia score, which makes sense.

Our next question comes from Daniil Gataulin at Chardan.

Congrats on all the progress announced this morning. I have a question with respect to durability for patients who underwent several biopsies. How did the vector copy number changed over time?

Okay. So no -- so the biopsies were in an NIH study that is still going on of the AAV-AQP1 vector. It's actually the same batch and a few patients agreed to one biopsy, right? So there are no serial biopsies over time. It's actually quite difficult to get xerostomia patients to have biopsies of their minimally existing salivary glands. So the data on biopsies is a onetime biopsy, and most of that is just looking for the DNA of the vector. And one of them, there was enough tissue to see protein, and that was between 1 and 3 years post AAV-AQP1 treatment.

With respect to durability of the, I suppose, the vector, these cells that are not dividing, the durability that we've shown as well as durability that has been shown for the original adeno study, which was out to 5 years functionally in very few patients, but the study was supposed to be 45 days, right, because it was so immunogenic. The functional durability seems to be a consequence of the DNA and the protein still being present in the gland. We don't -- it's very, very hard to get these patients to do more biopsies than they've done already.

Okay. Got it. That makes sense. And another question with respect to variability, you mentioned that hydration levels will play a role and you're accounting for it now. What are some of the other factors that could result in variability in response and how are you managing those?

So there are many factors that lead to people's variable responses to PROs and many factors that lead to variation in water flow over time, right, emotions, for example. And if we knew precisely what those were, we would try and control for them. However, other than everyone being trained in how to deliver a score, everyone being trained in how to collect saliva and hydration, from a practical point of view, it's very difficult to specifically address the variability in PRO or in water flow.

What I will say, because we haven't been able to identify, in general, a particular feature that can predict a good response or a bad response is a lot of the variability may be due to the structure of the gland. And this is something that we don't necessarily know. Remember, these patients' glands have all received side effect radiation, so they're each going to get a different amount of radiation and in some cases, different parts of the glands will be destroyed and they can be destroyed to different extents.

So I'm guessing and we think that the variability in the actual structure of the glands between different patients is just something that leads to the variability in response. And the long-term data we think showed us that the XQ if it does respond well at a particular time point, it will continue to respond well. So the inter-patient variability is something that we have seen is good in very good responders and also is probably true in those who don't respond.

So we've conducted the study powered in a way to take into account variability and conducted it with scores and training that we hope in any pivotal study will keep that variability in the range.

Our final question comes from Lisa Walter at RBC Capital Markets.

Congrats on the progress. Zandy, maybe just wondering if you can comment on patient discontinuations. It looks like patient 18 and patient 13 do not have data past 12 months. Just wondering if these patients discontinue due to an adverse event or another personal reason? Any color here would be helpful.

Okay. Thank you, Lisa. Well, number one, that we really didn't see any adverse events that were of particular clinical importance. As I mentioned in this study, there were 6 treatment-emergent, treatment-related mild AEs, and they all resolved without sequelae. So from the perspective of safety, this was very safe. And of course, it's a onetime treatment, so you don't have ongoing sort of toxicity that in some drugs can make the patient withdrawal after a certain amount of time when they just don't want that anymore. They have a onetime treatment. They now have that for the rest of their life in this case.

And we think probably people just didn't turn up for visits after the 12 months. It was in a long-term follow-up. And you can see that at 18 months, for some reason, there weren't as many people that came in. They -- many of them came back, right, at 24 months. So there can be personal reasons. There can just be motivation reasons for why people don't come to particular visits. But I don't think it's anything to do with a negative feeling about the treatment.

Got it. And maybe just one last one on your regulatory plans here. I know it's still early. And of course, we have to wait for the pivotal results to come out. But I'm just curious if your plan is to file a BLA for both the high and the low doses, or if you're thinking of just moving forward with the dose level that has the best benefit risk profile?

So with respect to dosing, as I've mentioned, we haven't seen any dose responses when we look at vector genome per patient, titer that the patient sees, gland size, anything like that. So that's the reason we did 4 doses in our pivotal study. We're powered such that the study is successful, if any one of those doses improves in the XQ compared to the placebo, right? It doesn't matter which dose that is.

Now we -- I personally think that they're most likely to all respond in a similar way based on previous data. If that happens in the pivotal study, what normally occurs is that you file the data and you get approval for the lowest dose that works. So in that case, that's what we would do. And I think it's normal practice when you have a multiple dose Phase III or pivotal.

Got it. Thanks, Zandy. And congrats again on the progress.

Thank you, Lisa.

Yes. Thank you for the questions, Lisa. This concludes our Q&A session for today and also our event. We thank everyone for joining. You may now disconnect.

Good morning, everyone. I'm Lisa Walter, biotech analyst here at RBC Capital Markets. Thanks for joining us at RBC's Ophthalmology Conference. This session, we have Alexandria Forbes, President and Chief Executive Officer of MeiraGTx. Zandy, thanks so much for joining us today. How are you doing?

Well, I'm doing very well. Thank you for inviting me to speak today.

Well, it's a pleasure to host you this morning. Zandy, maybe just to kick things off, can you give us a big picture overview of the company and give us a sense of where things stand with the ophthalmology programs at Meira?

Okay. That would be fine. We are quite a broad company in that we currently have 3 late-stage programs that have come through this company. Two are in the eye, which are both for inherited retinal diseases. And one is partnered with J&J, one is partnered with Lilly and both are awaiting filing with global regulatory agencies for approval.

We also have 2 late-stage programs, which are not in ophthalmology, but large indications and not inherited disease. One is in xerostomia, 2 years after patients have been treated with radiation. So this is severe long-term xerostomia and intractable and very unpleasant condition. And the second is in Parkinson's. Both of those are in a Phase II and a Phase III study that's in Parkinson's starting this year.

In addition to that, we support our programs with our own internal manufacturing, which gives us very good cost of goods and speed with regulatory agencies. We have highly advanced optimization technology from capsids, promoters and all sorts of different tools we can make to improve the potency of our vectors by up to 3 logs, again, reducing the dose that we need. And we have a platform which and is now a mechanism for delivering any protein that can be encoded by transgene using small molecule oral inducers.

So onetime delivery of a DNA template and daily oral pills that can deliver you any antibody, Herceptin, PCSK9, any peptide, EPO, GLP-1, GIP or combination of peptide, which is extremely powerful today as we're starting to find hosts of smaller proteins and peptides that could be used as therapeutics if they could be delivered in their native form or in a form that allows them to be dosed effectively in the body without having to be made synthetically and long-acting outside the body first. So that's the broad range of the company.

And one more thing I forgot to mention, which is the entire company was built using only locally delivered small doses of AAV. So that's how we got to our indications rather than large intravenous doses. The delivery of small local doses has an impact on safety, on the cost of goods and is really one of the reasons that all of our programs so far are now late stage and has been successful, we think.

Got it. Well, definitely a lot to unpack, a lot going on at Meira at the moment. But I -- this is an ophthalmology conference. So I'm going to focus on those programs first. Maybe just on an inherited retinal disease. Zandy, Meira has a lot of experience developing gene therapies for the IRDs. There's an XLRP program, LCA4, and you also recently launched a program for BBS10. Can you maybe tell us broadly why inherited retinal diseases are attractive areas for clinical development and maybe also why gene therapies are well positioned to succeed in these disease areas?

So inherited retinal diseases obviously result from mutated genes. And therefore, intuitively, one of the best ways to treat them like many inherited diseases is to replace the gene. And there is a long history of being able to safely deliver genes to the back of the eye using AAV. And when you -- when I mentioned that at Meira, we only use small doses locally delivered, the eye is clearly a place where you only require very small, very local gene delivery, and it has the benefit of being able to actually look into the treated eye and be able to see the effect of what has happened.

In addition, there are many, many different endpoint measures of vision, visual function, retinal function that allow you to have quite a detailed look at the effect of your gene therapy. So if you are focusing on small doses locally delivered and safety, then the eye is a great place for inherited and also larger indications. And that is one of the areas we focused on. It's the only area actually we actually look at inherited diseases. Our other areas of focus are outside inherited for large indications like Parkinson's, like xerostomia and like pain and ALS and all those programs that are preclinical for us.

One more thing about expertise in the eye. The inherited retinal disease space is a very small one. There are probably between 30 and I'm going to say, 50 leading sites in the world with KOLs who see probably over 80% of the known patients. And when we went into this area, ophthalmology, it was actually the foundation of the company. We did a partnership with UCL and the Moorfields Eye Hospital. And the Moorfields Eye Hospital is arguably the largest catchment hospital anywhere in the world for inherited retinal disease and one of the centers from which this expertise emanates.

So through that acquisition of the spinout from UCL and Moorfields, we gained relationships with those in the world who are most experienced with these diseases, both identifying them, genotyping them and understanding the endpoints that will really show how the drugs have worked if they have. So that has been key in our success is that relationship and our deep connections with those thought leaders.

Zandy, that's very helpful to know and understand. And I don't think I appreciated how small the IRD space is and how few KOLs that are out there. I think that's really helpful.

Well, and there's one other thing is that there are hundreds of IRDs, right? And the same doctor at the Moorfields will see patients with all of them. So you don't have a KOL for RP and a KOL -- a different KOL for LCA. Those physicians have seen -- all those leaders in those centers -- who run those centers have probably seen all of those IRDs. And we work with Mike Michaelides at the Moorfields. And I believe he probably sees, I think, it's around 70 IRD patients a year -- sorry, a week. It's a lot. And that's both children and adults. So those KOLs are very few relatively in the world with very concentrated knowledge of a vast array of these different diseases. Are they real experts, right?

So Zandy, there's kind of some synergy, I guess, if you're working on one IRD, it almost makes sense to look at other indications as well. Is that fair?

I think that's fair. And that's not only sort of academically, but also from a clinical trial perspective. The Phase III study with Johnson & Johnson was at 30 sites in Europe and the U.S. and that included those leaders through the relationships with Mike at the Moorfields. And those very same physicians will be the physicians that treat and prescribe these multiple gene therapies. So from an academic all the way through to development and commercialization, there is a lot of synergies between each of the different diseases.

Got it. That's really helpful. Zandy, I do want to talk about the XLRP program. I think many investors listening in are familiar with this. This is, of course, partnered with J&J. And we had the Phase III readout last year, and this really did show some promising trends. I'm just wondering if you can share any updates on this program?

We -- this is owned by Johnson & Johnson. We sold it back to them, and we are the commercial manufacturer. And we agree as do many of those KOLs, particularly the ones that were in the study, that the data that was presented was extremely promising and showed that in the eyes of these thought leaders and the FFB that this therapy was having a very positive impact on these patients' lives. And so we know that the data actually was meaningful, and we are waiting to hear J&J's strategy for getting that to patients.

Got it. Maybe more broadly, were there any learnings from the XLRP pivotal study that you are taking with you and applying to your other inherited retinal disease programs?

That's an interesting question. There were many, many learnings from all of the studies that we have done and many of those KOLs have done that led to the Phase III. And those are things like the surgery technique had been developed through multiple studies that we, the Moorfields [indiscernible] have done. That went into this Phase III.

The steroid regimen, and that was presented a few years ago when it went into the Phase III almost obliterated the inflammation that had previously been seen in some of these studies. So those sorts of logistical learnings actually supported the Phase III in RPGR as well as the surgical training. So I said there were 30 sites. There were 2 surgeons trained at each site. So we now have 60-plus surgeons fully trained who were involved in this study who are ready to deliver IRD therapies.

And as was presented, there were virtually no surgical issues, safety issues in this study. So I think we have, through the last decade, learned how to safely and effectively deliver inherited retinal disease therapies to the back of the eye. And that's applicable to any indication you might want to do. It was applicable to AIPL1 to the Specials programs that we're now doing and any Phase I, Phase III that may be done in the future.

Got it. Well, it certainly sounds like we've come a long way since LUXTURNA gained approval in 2017. So I do want to touch on your -- the LCA4 program with -- that has now been partnered with Lilly. Can you remind us where this program stands as well as the Lilly partnership?

Yes. So this is an ultrarare -- unlike [ RPTR ], which is one of the commonest RPs, this is one of the rarest LCAs. It is caused by a mutation in AIPL1. Infants are born blind. So they can hardly see a hand moving in front of their face. And through our Specials license, which allows physicians to deliver a potential therapy to children, 11 children were treated under the age of 4 with this viral vector replacing the AIPL1 gene and all 11 gained sight.

Lilly have licensed this to commercialize and get it to patients globally. That was $75 million upfront plus additional milestones, $135 million based on various global approvals and largely U.S. approval and a PRV. Now PRV has been extended. So we now know that approval in the U.S. will give a PRV even if it is in October and not September this year. So that is a decreased risk in one of those milestones. And we work with Lilly weekly and daily to help in supporting them as they file for various approvals with regulatory agencies globally. And they're very focused on patient access to this particular drug for a very aggressive disease. They've got a very strong, large team working on this.

Got it. And thanks for reminding us about the PRV. I think that's very helpful. Maybe let's talk about the BBS10 program. You just recently launched this. Can you share a little bit more background? Is this a subset of the Bardet-Biedl syndrome population? Can you share a little bit more detail maybe on the prevalence and what your approach is here?

Okay. So I mentioned the Specials license. A Specials license is actually a manufacturing license. And we have a commercial manufacturing facility in the U.K. with commercial license QC in Ireland. So in addition to the commercial licenses for our facility, we also have something called a Specials license, which allows us to manufacture for particular patients that a physician wants to treat because there's no other option, even if the drug has not been in patients before.

So the BBS10 program arose through a patient advocacy group through parents, a particular couple who had a BBS10 child who supported Meira to design and make a BBS10 viral vector to manufacture it and release it under our Specials license for children who had BBS10 to be treated by physicians in the U.K. if they thought it was suitable. So that's how the Specials come about. And indeed, we're looking -- currently, we have another request for Specials from, again, a charitable organization and the same path can be followed.

So it's how AIPL1 got its data. We have started treating the BBS10. All physicians have started BBS10. We can supply that. And we are looking into the design and manufacture of another IRD treatment for potentially supplying under Specials. So it's a very unusual and sort of license and process. And it's -- we're very willing to take on board some of these extremely rare damaging diseases and supply under these conditions, particularly when parents or philanthropic groups come and request that from us.

Zandy, is the Specials license just a program in the U.K.? Or is there an FDA equivalent as well?

So at the moment, there is no FDA equivalent. The Specials license is related to manufacturing, and it's related to the physician being willing to use a drug that has never been in people before, right? The system in the U.S. -- let's just take out plausible mechanism for the moment, allows patients to be treated without clinical data -- if they do not get to enroll, they're not appropriate for an ongoing clinical study. So the material has to be released to FDA requirements. It's slightly different, but there are mechanisms for getting material to patients in the U.S. who are not eligible for current studies, but it's a different situation. This is a U.K. license.

Got it. Got it. Understood.

But just one thing is in the AIPL1 case, the patients who were treated, these children who were blind came from 7 different countries. So you're not limited in who can be treated, but the physicians can only request material to be used in the U.K. that are manufactured de facto in the U.K. at our facility.

Got it. So patients could travel to the U.K. to be treated, but they don't have to be from the U.K. Is that how to think about it?

That was the case for the AIPL1, very rare and patients came from 7 different countries all over the world. Even the U.S., patients came from. Yes.

And data that's generated from the Specials license, you can use -- or can you use that to support a potential filing down the line with the FDA or EMA or other regulators?

An important question. So that data needs to be collected in a way that it can be presented appropriately to the FDA. And this is physician-led studies. And if you can present that data and verify that data, yes, it can be used to support global approvals.

Got it. Very, very helpful to understand that. Zandy, there's some other programs going on with Meira that are ophthalmology related. I see one for Stargardt, wet AMD, dry AMD. Can you share some additional background on these programs? Are they using similar approaches as the inherited retinal diseases? Or is this something a little bit different?

So we do have quite a deep pipeline that has been developed over the years of inherited retinal disease programs that are moving towards IND. And in that collaboration with Lilly, the deal with the AIPL1, they also took on 2 other gene therapies for other inherited retinal diseases, not as rare as AIPL1. One is literally ready for IND. So those documents are being transported to Lilly. One is pre-IND. We can manufacture and we do manufacture for AIPL1 in the near term for Lilly.

And so yes, we have IND-ready and pre-IND-ready programs. We have a very deep [indiscernible] and that involves use of organoids, retinal organoids, and this was actually the group that came from UCL who developed retinal organoids with the Japanese many years ago. And that allows us to do 2 things very effectively in our optimization. Number one, very, very good intravitreal capsids that came from a monkey screen and [Technical Difficulty] what happens in humans, but you have 2 ways of getting as close as possible. [Technical Difficulty] sorry, capsids that really do reflect what is needed in the human.

Secondly, also using retinal organoids, we have a very large promoter platform, which is very powerful in the eye because we use retinal organoids and AI, and we have been able to develop strong, small, very strong, very cell-specific promoters for different cells in the eye. Why I mentioned both of those things is because Eli Lilly, who obviously have seen all the ophthalmology companies out there also got the rights to use both our intravitreal capsids and our promoters in vectors addressing Lilly targets. That's 5 targets, and we don't know what they are. Lilly will move them forward using our capsids and our promoters from our big 200,000 promoter library. So we do have very strong technology all the way from the very building of a vector right out to Phase III development.

Zandy, very interesting work on the intravitreal capsids. Can you maybe give us an idea about how these might be different versus what other folks have developed?

Well, we have, for many years, been looking at intravitreal capsids as many people have, and we have tested head-to-head with 7m8, which is gold standard, right, many intravitreal capsids from many private and other companies. And meanwhile, we did our own screen where we -- first of all, it was a screen replacing different pieces of the capsid and screening in NHPs and then taking our best hits and testing them in human organoids as well.

And we did the same comparisons as we have done for other capsids, intravitreal capsids that we ended up not using and versus 7m8. So the data that we have, we selected capsids that were looking superior in those assays, so monkey and organoid to anything else that we've seen and our gold standard was 7m8. So we can infer only that these are very good intravitreal capsids, and we can use them in our larger indications, wet AMD, dry AMD, glaucoma, et cetera. We actually did a screen for glaucoma-specific capsids. It's a whole other story for the front of the eye and promoters as well. But we'll just go with the intravitreal for now.

Got it. Well, very interesting. It would be very interesting to see a glaucoma-specific capsid as well. That would be a very novel innovation.

Ciliary body.

Ciliary body. Got it. Got it. Maybe just in the couple of minutes we have left here, I do want to touch on some of the non--ye programs. So xerostomia, can you maybe just briefly remind us where this program is right now? And maybe what the opportunity is here in radiation-induced xerostomia?

Thank you. And radiation-induced xerostomia, this is not at the time of treatment. It is radiation-induced xerostomia, which is durable after 2 years post radiation treatment. It's very severe, and it's actually a rather large market. We have redone our market research, and this is a multibillion-dollar global and even U.S. opportunity. The coverage and the pricing is strong and the number of patients each year is high.

So this is actually a very large market opportunity with a very low cost of goods and a manageable price that we think we can get from -- we've got 90 to 90-plus percent coverage in our surveys at least. And the study is a pivotal Phase II that the FDA has agreed in writing is one that can support a BLA as a single study. It is completing enrollment as we speak. And we are targeting filing for approval in this quarter next year with the aim of actual approval by or around the end of next year to launch in 2028.

Got it. And we are almost out of time, Zandy, but is there anything you want to touch on with either the Parkinson's program that's partnered with Hologen AI or anything you want to flag with the riboswitch program?

Riboswitch is we are in multiple communications with the FDA to prepare for an IND filing later this year for a program in leptin that we have very long-term data on. We have 3 small molecules, GMP manufactured ready for the clinic, one of which is going to be used in the leptin. In addition, we've talked about using this for pain in the past, and we have increasingly strong preclinical data in neuropathic pain.

And as we are discovering more peptides, short-acting molecules that are involved in cardiovascular, metabolic blood pressure type systems in the body, all of which are responsive, we recognize that we have a mechanism for the first time for readily dosing the body with effective doses of peptides, proteins and hormones which can't be taken out synthetically manufactured to be long-acting and put back.

So we're very excited as AI discovers all of [Technical Difficulty] to be able to turn them into drugs very rapidly. So we'll be in the clinic with our first this year. Pain is looking really good. And the target generation through [Technical Difficulty]. This is at the moment, the only way that you can deliver many of these metabolic and longevity-related homeostatic proteins.

Got it. Thanks, Zandy. Well, I'm afraid we're officially out of time. Thanks so much for joining us today at our ophthalmology conference. It has truly been a pleasure to have you.

Well, thank you so much, and I will speak to you soon.

All right. Thanks so much.

Let's go ahead and get started here. So next up, really happy to be joined by Zandy Forbes, who is the President and CEO of MeiraGTx. Only 20 minutes, so we're going to dive right into it. So Zandy, over to you for a quick introduction of the company where things stand today? And then we'll go into some questions.

Okay. So Meira is a genetic medicines company. We founded the company to optimize the ability to use DNA as a therapeutic modality, and in doing that, we started with AAV, and we have capsids that we've developed, 250,000 promoters that we've developed with AI, and most importantly, the thing that we set the company up to do, is to control genes, trans-genes with pills.

So we are now in a position, and we have done this in-vivo with many targets, every large pharma's antibody, so like a bio-similar as well as PTH, EPO, growth hormone, GLP-1, GIP, leptin, any peptide, you can -- we can take the natural sequence of any biologic, put that into the muscle like a vaccine, you take a pill everyday. And every time you take a pill, you dose very specifically with that particular therapeutic. It's a very powerful technology. We didn't know if we'll be able to do it, but we've done it. So we were a genetic medicines are a genetic medicines technology company who've developed some of the most innovative technology in gene therapy. And we recently -- you can look at our various partnerships around all of those technologies. which I think if you look at who those partners are, Sanofi, Lilly and J&J, that's validation of the technology.

But in addition to that, we had a deep clinical program -- pipeline and all of the programs that we started early in the company used very small doses, locally delivered to avoid immune response, but also where we saw that there was really good proof-of-concept. And because of that, we now have 4 late-stage programs. They're not targeting only inherited diseases. We're a company that wanted to use DNA as a modality broadly. So our first two programs are in the eye in inherited diseases, awaiting filing. One is for an ultra-rare disease that is the most severe form of blindness in infants. 11 children were treated all under the age of 4, all 11 children went from completely blind to being able to see and function normally. So that we're filing globally with our partner, Lilly.

Second is a much, much bigger indication. It's called RPGR. We have Phase III data, which we believe is approvable for sure in Europe and with discussion in the U.S. as well. That is currently with our partner, Johnson & Johnson.

The two other programs are not for inherited disease. One is for Parkinson's, where we have two double-blind studies that have been statistically significant and positive. No one else has ever done that in Parkinson's disease with an intervention like gene or cell therapy, and we have a very interesting program in xerostomia, which is in a pivotal Phase II. Both of those have an RMAT and both of them, therefore, have Fast Track and breakthrough.

And we have our own internal manufacturing end-to-end as well as process development in a very valuable process that we've developed over the last 10 years to manufacture our products, which speeds everything up. It's allowed us to be in this position of having all these late-stage programs.

Perfect. All right. Let's go program by program. Xerostomia. You've been so active on the BD front. I guess one of the questions is, is xerostomia going to be the first program that you take to the market totally yourselves?

It can be, yes, but we actually also have interest from others in that. That is a really interesting market because that's one of the reasons we took on xerostomia. It's not necessarily well known, but it's a very, very severe and the most important consequence of radiation that cures head and neck cancer. 30% of people who are cured of their head and neck cancer after 2 or 3 years, so this isn't concurrent with radiation. It's afterwards, so you're otherwise healthy, have severe or Grade 2, 3 xerostomia, very severe.

To explain how severe it is, not only do you lose your teeth and can't sleep and can't eat, but for example, you can't exercise, because it turns out that if you have a dry mouth, you can't breathe any faster. So you literally sometimes can't run up the stairs. And so we have a treatment for xerostomia. We had really impressive Phase I data, Phase I/II data. And we started a Phase II. The FDA wrote to us after we filed our IND amendment and looked at our manufacturing and said, because this is manufactured by you, if your manufacturing does come within the parameters of your release specs that you've written, we consider this a pivotal, which is sort of extraordinary because manufacturing tends to be the issue for a lot of late-stage gene therapy programs. It is not with us.

We have done everything in-house, and we have cross-referenced every filing with the FDA. So many, many reviewers have seen our manufacturing. We have commercial licenses in the U.K., in Ireland, we manufacture plasmid. We do the whole lot. As a result, our Phase II turned into pivotal. We then filed for an RMAT. We then got an RMAT meeting. We got alignment with the FDA on the endpoints, the stats, the clinical outline of the program. So we are currently approaching -- finishing enrollment of the higher dose cohorts of that Phase II. Sometime around the end of this year with data most likely in the first quarter of 2027 with a 12-month endpoint with filing shortly thereafter. We're targeting approval in '27.

This is a sitting duck market. I know all markets require you to sell. But in this case, every patient is in the healthcare system. Every patient has been cured of their head and neck cancer. Every patient is going to their physician at least once a year, to have their tumor checked to see if it's come back, and this is their #1 complaint. One of the first people we spoke to about this was Dave Pfister, who's obviously oncologist, Head of head and neck at Sloan Kettering, and this was like his #1 problem outside even cured people with head and neck cancer, he could do nothing about this. So it actually is very severe. We have treated quite a few patients, as you can appreciate, and we have incredible feedback from physicians and patients about how this changes their life. So that's our first late-stage program.

Second is in Parkinson's, where we completely avoid the quagmire of dealing with dopamine replacement. Rather, we do something that allows you to physiologically change the circuitry of the brain and avoid the need for dopamine in later-stage Parkinson's, a very small dose of the enzyme that makes GABA, the inhibitory neurotransmitter is put into the subthalamic nucleus. This is via an intervention that doesn't require -- it doesn't require general anesthetic. It's almost the same as deep brain stimulation, but you don't leave anything in the brain. And again, we've had 2 sham-controlled studies, which have shown statistically significant benefit, which is unprecedented, going into Phase III in the next several months.

Perfect. Just on the xerostomia side, can you just remind...

So can we market it ourselves? Yes, we can because all of those patients are sitting there. And it's a rather small oncology sales force, and there's a huge patient advocacy movement.

Perfect. For the xerostomia study, can you just remind us how you powered it?

We -- well, this is interesting because there's no precedent for placebo. So what we actually did is we looked at what's significant with respect to -- what's clinically significant in the xerostomia score, which is the agreed primary and a 7-ish point to 8-point change is significant.

I think in our bilateral cohort, we saw a 21-point change against baseline and an average 17. So what our assumption was is that we allowed for a large placebo and we were looking for, I think it's 90 -- I can't remember the exact powering, a 7-point change between one of our arms and the placebo. There are two arms, which are pooled.

How much variability is there in this endpoint? Like is that something you monitor on a blinded basis and maybe it will be kind of more of a next year thing?

We absolutely -- we don't look at the data at all. It's -- it's now a Phase III. So it's super, super regulated.

Yes. What about pricing in this market?

So we did an L.E.K survey some years ago, and they went out to payers globally, and we had 95% coverage in the U.S. for 100,000 onetime treatment, which actually, if you look at the number of patients, currently, the patients eligible for this, not everyone treated with head and neck cancer is about 170,000 and 15,000 new patients a year, reach that 3-year time point when they're eligible for treatment. So that's just in the U.S., a really large market, complete unmet need because these patients have de facto failed any other possible treatment.

All right. Going over to the Parkinson's and the Hologen AI side for JD. When are you presenting the full data at a conference? I think you mentioned you're going into a Phase III in the next few months.

Yes, probably sometime next year.

Okay. That makes sense. What's your economic stake for Hologen AI also, it's maybe worthwhile to kind of introduce that.

We formed a joint venture. We own 30% of that joint venture. The joint venture is 100% paid-for all R&D, all clinical studies up to $230 million, which we felt was way -- well, was certainly sufficient to do the Phase III study.

Yes. That makes sense.

[ Almirall ] received $200 million to use for our...

Perfect. Let's go over to riboswitch actually. I think that's going to be an area of focus next year. Maybe you could just introduce the platform in a little more detail on why you chose Leptin as the first target?

Well, as I initially described, this allows you for the first time to deliver to the body a very accurate dose at a very accurate time of anything that can be encoded by DNA. So like Moderna used RNA, which you inject, makes the protein and then disappears. We use DNA.

And the power of that is the sequence that we choose can be the biosimilar if it's an antibody, right, Dupixent or Erbitux or whatever it may be, or the native form of any peptide or hormone. And we've shown over a year in animals for Leptin that you can stop the pill, you can start the pill. And this last -- the dynamics are completely the same, day 2, day 370. So this is really a way it can be used in any context. So you don't -- we deliver through -- into the muscle with AAV. We can deliver through our lentivirus. We can knock it in. So we've also controlled the CAR in CAR-T, and we increase efficacy.

This is most important when you're dealing with agonists like GLP-1. GLP-1 switches on its receptor. It's very well known that if it's long-acting, that receptor down-regulates, you need more GLP-1 and you control insulin less well. We deliver GLP-1 with a pill in the morning to the mice, and it works way, way, way better than long-acting GLP-1. So in the case of agonist biologics, this is the first time you can physiologically dose them, which changes what the amount of protein you need, but also the efficacy.

Coming to Leptin, where there is an injectable Leptin, Metreleptin. However, it's a synthetic Leptin that's manufactured outside the body and it's immunogenic. So 10% of those people make neutralizing antibodies to Leptin, which is one thing, and that has catastrophic effects because when you have no Leptin, every calorie you eat turns to fat, your whole metabolism goes kaput, it's literally lethal, right? So it can't be used in many, many contexts.

So we have made the natural Leptin sequence, inject it into the muscle of mice, and we can completely rescue in a dose response fashion the reduction or the absence of Leptin in mice. And this has been over a year, and that will be the first that we take into the clinic. We have this optimized sequence for injection. We have GMP material for the small molecules. We actually got two, which work really well. So full tox, everything has been done. The material is waiting for the clinic, and that will be our first in the clinic. And we'll probably be working with Sadaf Farooqi, who's the expert on genetic leptin deficiency.

Perfect. What's the status of the regulatory discussions and kind of time line for when its starting?

We're in interact. So we're working out how we do this as a filing with SEB A right, at the moment.

That makes sense. As you look towards the Phase I in humans, like how do you actually prove out the whole platform? Like are you doing continuous PK monitoring? How is that going to work?

In humans?

Yes.

We would. We would look at leptin levels as well as everything else, but yes.

And essentially, like as you think about what's a good outcome in humans, you're kind of replicating what you showed in the animal models. Is there any difference as we're thinking about translating?

Does it work? Normal differences, right? I mean we all look at mouse experiments, but this injectable leptin works. We have very, very precise dosing. Really super precise. One small molecule makes RNA and it's really precise, way better than injecting something. So we have very, very strong confidence that it works.

Yes. All right. Perfect. Maybe on the manufacturing side, you kind of alluded to this briefly, but are there any public comps out there for how to think about the value of this business on a stand-alone basis? Obviously, it's a little complicated since there's a lot of strategic value to what you guys are working on.

Yes. So with manufacturing for each of our partners, we're the manufacturer because in gene therapy, if you manufacture -- when we manufacture because of our FDA and global regulatory interactions, our manufacturing process, which has been built on 20, 30 different viral vectors, actually gives us a GMP process fit for commercial, right, which is very, very valuable.

Now there have been similar companies sold, who don't have commercial experience. We actually have commercial license and have not done as many runs or batches or assays as we have because we do QC. The whole of QC is validated and in-house, we've got commercial license. And I think it's sold for around GBP 600 million.

But from a strategic perspective, we really wouldn't be in this late-stage situation, particularly if we hadn't bought QC in-house. And that's quite difficult. We use our preclinical guys. They do our potency assays. We translate them to cell-based assays. And it's very hard to explain how valuable it is. But from a timing perspective, it allows us to have very clear quick conversations with regulatory agencies about what commercial looks like and not what a clinical batch looks like. And that's very -- we learned that with J&J, our first partner, who we do commercial manufacturing for.

Perfect. Well, right on time. So we'll wrap it up there. Thanks so much for joining us Zandy.

Thank you.