Good afternoon. Welcome back to the Bank of America Healthcare Conference. I'm Tiziana Mott. I'm one of the senior mid-cap biotech analysts here at the bank. It's my pleasure to have with me our next presenting company, Inozyme Pharma. Presenting for Inozyme and sitting next to me is Chief Executive Officer, Doug Treco. Doug, good afternoon, and thanks for joining us here. Thanks, Tizzy, and thanks for having us. Maybe we can just start with an introduction of the company, what Inozyme does, the platform, and a couple of the important updates that have happened, and then we can talk about upcoming catalysts. Great. So Inozyme is focused on classes disorders characterized by inappropriate mineralization and inappropriate stenosis of vessels. And so we're looking at three diseases, two genetic and one acquired disease, that all share the same general phenotype. Their arteries get calcified, so they get stiff and inelastic, so they can't function in pumping blood properly. And they also get overgrown by smooth muscle cells. That's called stenosis or intimal proliferation, that leads to stenosis or blockage of blood vessels. So you got these two things going on that lead to really pathological blood vessels. The enzyme that we're looking at, enzyme replacement therapy, to treat all three of these, functions in a pathway which we call the PPi adenosine pathway. PPi or pyrophosphate, is an important natural mediator and inhibitor of calcification. So it circulates in the body, it's found in the interstitial fluid, and it prevents small crystals of calcium phosphate from growing into big crystals and depositing in places they shouldn't deposit. The enzyme also. So the enzyme generates pyrophosphate by cleaving ATP into AMP and pyrophosphate. And so I mentioned pyrophosphate does something important. AMP then gets processed by cleavage by another enzyme called CD73. CD73 generates phosphate and adenosine, and adenosine is a potent inhibitor of this smooth muscle overgrowth of blood vessels. And so you've got these two mediators being produced through this enzymatic pathway of which ENPP1, our enzyme, is the central regulator. So I didn't talk about the enzyme deficiencies quite yet. So ENPP1 is an enzyme that cleaves ATP and generates pyrophosphate. The ATP comes from another transporter called ABCC6, which moves ATP from the inside of cells to the outside of cells, and that's where ENPP1 acts on it. Then, as I mentioned, the product of that AMP, CD73, acts on it. ATP moves to pyrophosphate, moves to adenosine, and these are the important mediators that we care about. Patients with ENPP1 deficiency, ABCC6 deficiency, and this acquired syndrome of end-stage renal disease called calciphylaxis, all share these properties of calcified blood vessels and stenotic blood vessels. We believe that our enzyme, ENPP1, that generates pyrophosphate, as well as adenosine, can treat all three of these. We think that they're all ultra-rare diseases. By ultra-rare, I mean on the order of 10,000-20,000 patients in the developed world, and we think these are great markets for us, but they're all treatable with this one enzyme, INZ-701, which is a fusion of an immunoglobulin Fc region to the enzyme ENPP1. Okay, thanks for that overview, Doug. Because these are ultra-rare indications, I think it would help folks to know, what is the quality of life impact for patients if left untreated? Right. So I'll start with the two genetic deficiencies. So both of these, the babies that are born, share a very similar phenotype. They have calcified blood vessels, they have calcified aortic, calcified aorta, and calcified valves. Thank you. Calcified valves. They and they have a high rate of mortality. They, the ENPP1 deficient babies die 50%, within the first six months. ABCC6 babies die at a lower rate, but still about 10% of them die within six months. The ones that survive can go on to have different kinds of phenotypes. ENPP1 babies develop into children who have bone deformity. So the other thing that ENPP1, sorry, that pyrophosphate does, is not only does it prevent abnormal calcification, but it promotes normal calcification, and that's what happens on the surfaces of bones. So as the children age, they go from this calcification of arteries to now bone defects. Now, as they age into adults, those bone defects remain because they were never treated. You know, your bone defects just don't change. You may have bowed limbs, you'll have rickets. These abnormalities will persist forever if they're untreated. And then the adults now have further problems. They're going to have continued cardiovascular problems because of calcification, but they're also going to have a lot of bone and joint problems. They're going to have osteoporosis, they're going to have osteomalacia or softening bones. They're going to have a high rate of fractures. They're going to have bone and joint pain, and they're going to have mobility pain. The tendons and ligaments and where they attach the bones, they get calcified, and they cause all kinds of mobility problems. So the progression is early death in infants, rickets in children, and progressive mobility and joint and bone problems as adults. That's ENPP1. ABCC6 is a little different. The infants look identical. They have this cardiovascular valve defects, heart failure. They now will progress as children into a population at a high risk of strokes because the blood vessels in their brain are becoming stenotic. You're getting poor blood flow. We looked at 11 of these patients who had early onset ABCC6 deficiency. Five of them had had strokes before four years old. Others had clear arteriolopathy in the CNS, others had had heart events. They will all lose their vision eventually because their retina calcifies. So it's a very bad condition for the children, and I will add that we're the first that's really classified these children into this population at high stroke risk, high risk of losing vision due to ABCC6 deficiency. There wasn't anybody in the world looking at this as a population other than some isolated patients. We put them all together and then found a lot more, and I think we've expanded the market quite a bit. And then the adults with this deficiency now go on to have further calcification of blood vessels. They have trouble walking. They get what's called claudication in their limbs, pain while walking because of stenotic vessels. They have a risk of stroke still, and they almost all have lost most or all of their vision. So very severe phenotypes throughout life. We want to focus on getting these infants and children treated as soon as possible so that they have a better adulthood, and we think those are really the unmet needs that parents are really looking for, for getting their children treated quickly. Okay, thanks for that. So in terms of your patient-finding efforts, because this is ultra-rare, and because there's limited to no options available right now to treat these, these patients, what's been the approach that you've taken? Maybe let's start with ENPP1 to finding patients and how many have you identified so far? So, you know, we do focus on the areas of the world where, you know, we think we can do studies, get reimbursement, have, you know, good functioning medical systems. These include, you know, North America, Brazil, Europe, Japan. There's a fair amount in the Middle East, so we have a fair amount going on there, in Turkey also. In those geographies, for ENPP1, we think there's about 10,000 patients. That's estimated prevalence. We know that if we can keep some of these babies alive, we'll increase the population, the addressable population. It's a hard business, though, because in Europe, we have a little. It's a little better in Europe because there's some centers of excellence where you'll have a physician who knows all the patients in the country. So, like in Manchester, in the U.K., they know all the ENPP1 patients there. There's nothing like that in the U.S. It's very, very fragmented, and it's one by one talking to patients. You know, a physician could be in a department where, you know, the chairman of the department will say, "Hey, we want to come in and give a talk about ENPP1." They'll go, "We don't have any patients, but you can come and talk." And then when we give the talk, one of the physicians raises their hands. "Yeah, I got two of those patients." Very, very poor recognition of this disease, and that's what we have to change. So we have a lot of people who've done this before, who worked at Alexion, particularly who have developed thing, the market for Strensiq, for example. I've worked in areas like Fabry and Gaucher, where I've had to develop these markets. So we have an understanding of what you have to do, and it's basically a ground game. You're talking to KOLs, you're talking to physicians, you're talking to patient advocacy groups, you're talking to patients, you're talking to genetic testing labs, you're talking to hospitals and saying: Will you put our genes in your newborn screening panel? One by one, we have to do that. In the U.K., we were very fortunate to have been asked to participate in their whole genome sequencing program. I think they're sequencing one in 12 newborns completely, and we went to them and said, "Well, we want our two genes in that mix that you look for." And they said, "Well, you don't have a therapy approved yet, so we don't do that." We convinced them we were far enough along, and so now two of the 200 genes that they look for are ABCC6 and ENPP1. But this is like work, and every country's, we got to do that, and in the U.S., different hospital networks, we're doing that. So it's getting awareness out there, getting diagnosis improved, and making sure that probably our biggest challenge is that whenever a baby is born in the world with ENPP1 or ABCC6 deficiency or suspected, that there's a physician there that knows to call us. We're making a lot of progress there, and I'm very proud of the fact that we're getting so many inbounds now because of what we call our patient and physician services team. That's really building awareness and making sure that we get calls, inbound calls now instead of us making all the outbound calls. Okay, so thanks for that, for that overview. For ENPP1, you're now already in a pivotal study. You had given us an update about what FDA would be looking for, and, you know, it was, I think a big accomplishment to get alignment with the FDA on what your primary endpoint is for the study, which is PPi. Can you talk about why that's an important accomplishment and what you're looking for as a result? ...Well, if, you know, to have a marker like that as your endpoint makes life a lot easier, especially since we know we can raise it very readily in these patients. It's a biomarker. Well, you know, we call it a biomarker, but it's actually a bioactive molecule, so it actually does the work that we want, you know, the drug to do. It's, it's the molecule that prevents calcification. You know, as an example, we were talking earlier today with somebody about Fabry disease. So the Fabry disease drugs have been approved on a biomarker, but that's a toxic metabolite that accumulates in the body. So you're, you're basically making a treatment decision on lowering this toxic metabolite that accumulates. But, you know, that's just a signal of bad disease that you're getting rid of. Here, we're, we're adding the molecule that's preventing bad disease. So I think regulators see that as different than a true bio-- than a biomarker, more of a functional molecule, more of a pharmacodynamic marker. So they've viewed that for the valuable bioactive molecule that it is and said, "Well, then we can make that a primary endpoint." Our, you know, it took work, and our CMO, when he came into the job, never thought we would get that as an endpoint because it was, you know, very challenging. But regulators bought into it, and I think it was because we convinced them that, you know, it does have function on its own. Now that the study is underway, can you talk about how it's enrolling and when we should expect to see data and what would be good data? So our biggest focus for the year and our biggest milestone is to complete enrollment for the ENPP1 study in children. That study, you know, we began enrolling last year. It's a 33-patient study. We expect to have enrollment completed by mid-year this year. It's a one-year study, so that would read out mid-year 2025. And, you know, if we can get data soon after that, our plan is to have a BLA submission in early 2026. The study is, as I said, PPi is its primary endpoint. We have a secondary endpoint in the U.S. or a co-primary endpoint in Europe, where we're looking at the change in a radiographic measure of rickets. In this measure, the reader will hold up a baseline radiograph, a week 52 radiograph. He'll know what to look for, for rickets scoring, and he'll give, assign a score of one, two, or three better, one, two, or three worse. That's the scoring system. It's very similar to the scoring system that was used for approval of Crysvita. So regulators have a lot of experience with it, and you know, we had to make it unique for the kind of rickets you see in ENPP1, but that's all been done with experts, and so we now have a training manual to complete those reads. How big is the pediatric population, did you say? The pediatric population in, around the world is probably, you know, a fraction of the 10,000 I mentioned, so on the order of 2,500-3,000 in that pediatric population. What age range is that? For that study, the age ranges are one year up to 13 years. Okay. So that's our pediatric population, yeah. Are you going to stratify at all by grouping of age in that one to 13? By? By age at all, are you going to stratify? Do you expect to see different results? Possibly. You know, the older patients get and the closer they get to their growth plates fusing on the bone, you know, then has reached close to its maximum length, we expect to see less effect, but we still expect to see an effect in those patients. And, you know, we expect to see effects in adults also. I don't know if we'll have a formal analysis, but we'll probably, you know, crunch the numbers depending on their age, for sure. Okay. What impact on PPi would you expect to see in a pediatric population versus an adult population? Well, you know, we don't have any reason to believe that we wouldn't normalize it rapidly. You know, because, you know, we understand the biochemistry. At the least, we understand the biochemistry, that we should be able to raise PPi in those patients with no problem. You know, the cha-- not the challenge, but the question is, is normalizing PPi over a year going to lead to clinically relevant changes- Mm-hmm in bone? You know, we're encouraged because we know there are at least three kinds of rickets, besides these rickets, that can be treated in a year period. You know, with XLH, with Crysvita, HPP with Strensiq, and then vitamin D-dependent rickets. So bone is very metabolically active. It's turning over very rapidly, especially in children. And so we think that knowing that bone biomarkers are turning over in our patients, that we should be able to see improvements in these patients, because we know that rickets can be treated, and it's all due to the fact that bone is just turning over very rapidly all the time. Okay. So as you think about that program moving forward and with the timelines that you talked about for top-line readout, how is that influencing, if at all, your plans for ABCC6? So, I mean, they're independent. You know, we're, you know, we're treating them as independent studies. Obviously, the data for ENPP1 will help support the safety- Mm-hmm. Data for ABCC6, and the ABCC6 data we've collected so far will support our BLA for ENPP1. But they are different, and, you know, the biology is a little bit different. With ENPP1, pyrophosphate levels go from, you know, either 10% of normal or undetectable up to normal, very rapidly. With ABCC6, even though we think PPi is the main culprit, those levels are going from the lower limit of normal to mid-level of normal. So they're increasing maybe 30%-50% instead of five- to 10-fold. It's not as clear to us that regulators would view that as, you know, an immediately approvable endpoint. So with ABCC6, we're more interested in some, you know, real clinical measures or measures that have more prediction on the clinical outcomes that we're expecting to see. Is it because the severity of the disease is not the same level as what you described for PP1, that FDA is still trying to decide on pyrophosphate, or is there another reason? Well, we haven't had the discussion on pyrophosphate with ABCC6, so I'm just sort of predicting- Mm-hmm. -that we're going to be looking at some more hard clinical endpoints. I... No, it's not the level and the severity, because the children and the babies are very severely affected, and the adults who have symptoms with the ENPP1 and ABCC6 are severely affected. No, it's probably more to do with the fact where ABCC6 is expressed in the body and where its impact is felt. So for example, you know, ABCC6 is not expressed in bone, whereas the ENPP1 is, and so you have a big bone phenotype- Mm-hmm. in ENPP1, which you don't have in ABCC6. So it's biology like that that probably explains the difference. But yeah, the severity is very high for- Okay. all three groups. Yeah. So if you're not going to, you know, if you have to look for another endpoint outside of pyrophosphate, you know, what do you think are reasonable options to be looking at right now? For those of you who were able to listen in on our data release, I guess in early April, where we went over the ABCC6 data. phase I, II. Population. The early phase I, II? Yeah, the early phase I, II. No, the later phase I, II. This April, this past April. Right, but it was still phase I, II. It was phase I, II. Yeah. Yeah, yeah, yeah. When we talked about the data, we said, "Well, here's what we think we might do moving forward." You know, one of the parameters that we have to deal with is we want to do a randomized controlled study, because regulators like that, and we want to show real benefit. And we want to do it in children, so we can't keep them on placebo or untreated for too long. So maybe you've got a year, a year and a half. So what can you see in a year or a year and a half? So there's two schools of thought that we're looking at here. One is, if, again, from the data we put out, we saw a trend in the thinning of what's called the carotid intima-media thickness. So this is the thickness of the carotid vessel wall. It's kind of a signal on if the vessel is narrowing or not. And so that's what we want to deal with in this cerebral vasculopathy. If these vessels narrow, you get poor blood flow, and you can have a stroke, and that's what's happening in these children. So when we look at that carotid, we saw it thinning, whereas we know in other patients with this disease, it thickens as they age. So we were encouraged by that. So an endpoint where you looked at by imaging for cerebrovascular narrowing, what we think would be reasonably predictive of stroke, and in a year to a year and a half period, if you could see a difference, maybe you could get an accelerated approval based on that, followed by monitoring patients for real events, cardiovascular events, stroke, ophthalmologic decay. That's one way to do it. The other way to do it would be to say, "Hey, we got a year, a year and a half. Let's bucket events together into a composite endpoint, where we're looking at anything comprising a composite comprised of a cerebrovascular, like a stroke or TIA, a cardiovascular event, like an MI, or some other AFib or ophthalmologic deterioration measured by retinal calcification. Come up with a score for that, and then ask the question: do we see enough events in this period to see a difference? We're modeling and doing simulations on that, simulations on this right now to determine if we can see enough real events, so that we don't do an accelerated approval, that we just do a study to get real, full approval based on a composite endpoint. Those are the two things we're looking at right now. We hope to get them in front of FDA, you know, early in the summer. I think we're close to done our work, and we hope that our plan is that in the fall, we would have a path forward with regulators, and we'd tell people what our plans are. Okay. And just to, like, level set expectations, would you be disappointed if it's not an accelerated path? No. In fact, I probably would prefer that. Right. I mean, I would prefer being done, you know, and having a full approval, based on real endpoints. So I think the accelerated path, while we may be happy with it because, you know, it's streamlined, there'll be a lot more questions. There'll be a lot more questions about the validity of the endpoint you chose. You know, even if we convince regulators, then investors will ask those questions- Mm-hmm. because they're not straightforward. So there'll be those questions, and there will be then two or three-year period where we're then comparing events to a control population, which, you know, if we don't have to do that, I'd rather be done with it early on. So we would love it if we can convince ourselves that there's enough events in this population that we can monitor them over a year-and-a-half period to see a difference, as a composite endpoint. What is the competitive landscape looking like? Is there anyone else trying to develop treatments for these indications? Not really. It's fragmented. There's calciphylaxis seems to be the most active. I'm not sure why, because I think, you know, it's pretty ultra-rare, and, you know, we think, you know, people say it's 1%-4% of dialysis patients. We typically say 1%, other people say 5%. So we think it's on the lower side. And a lot of that's due to, you know, talking to people, how many patients they see. So we think it's pretty rare. There was a drug that just failed. It was a bisphosphonate analog, being developed by a company, Vifor developed it, and then CSL acquired it, but the drug failed. Their endpoints were pain and wound healing. Those are notoriously difficult endpoints in placebo-controlled studies. But they did see a mortality benefit, and I think we would want to build on that and, and potentially, use mortality as an endpoint. Somebody's also looking at a vitamin K analog for this drug, for calciphylaxis. So calciphylaxis seems to get attention. ENPP1, nothing really. ABCC6, there's a little bit of work with a, you know, small molecule inhibitor of, of alkaline phosphatase to raise PPi levels, but we haven't seen much action there. So, you know, we generally think, A, we're the only game in town. Mm-hmm. B, the enzyme is doing two things. It's not just raising PPi, it's raising PPi and adenosine, and we think these are both essential to treat these conditions. And so everything else that's been out there is really only looking at the PPi part of it. Okay. The few minutes we have left, I did wanna talk about what you're planning to present for Calciphylaxis from your program. So, calciphylaxis, as I said, is the acquired syndrome associated with end-stage renal disease. We've done a lot of work with our collaborator at Mass General, showing that, you know, as you go from healthy to stage renal disease, to calciphylaxis, to death from calciphylaxis, your PPi levels just really precipitously drop. So our study is asking, in a population of end-stage renal disease patients, no calciphylaxis, but with low PPi levels, can we raise them with our enzyme? If we can raise them with the enzyme, then we'll plan a, you know, a full-blown study with patients with calciphylaxis, where we're looking at, hopefully, we'd be looking at patients who are at high risk and may have early symptoms. This disease progresses very rapidly. If you go too late, you're treating sepsis, which we don't wanna do. If you go too early, you know, you may, you may not be treating the patients who even have calciphylaxis. So we gotta hit it right. We have work to do on that, but if we can raise pyrophosphate, we think we'll be on our way. So the data that we'll put out later this year will be, it'll be 10 patients, four weekly doses of INZ-701, our enzyme replacement therapy, and simply asking safety, tolerability, PK, PD, can we raise pyrophosphate levels? And hopefully, if we can, then we'll move forward with a full study in calciphylaxis. Is there a minimum amount of pyrophosphate increase that you'd be looking for for clinical meaningfulness? You know, our endpoint for ENPP1 is significant change from baseline. Mm-hmm. Which sounds great, right? But, you know, we think we wanna normalize, and the reason we want to normalize is because... And significant change, we wouldn't have to normalize- Mm-hmm. Because it's really low. But the reason I say that is because in the ENPP1 Deficiency, we know there's heterozygotes out there. They have intermediate PPi. They have a range of intermediate symptoms. So if you have a low level of PPi, you're gonna have some symptoms. So we think normalizing is probably where we need to be. Okay. Yeah. Till we find that out by the end of this year? Yes. Yeah, we hope to have that data, you know, easily by the fourth quarter. Yeah. Okay, great. With that, we're just about out of time, so I'll say thank you, Doug, for joining us out here in Vegas, and thanks for speaking to me. Thanks, everybody, who sat in on this session, and hope everybody has a great rest of the session today. Thanks. Thanks, Tizzy.