Good afternoon, everyone, and welcome to the 2024 Global Healthcare Conference at Jefferies. Thank you for coming. It's my pleasure to now introduce Doug Treco, the CEO of Inozyme Pharma. And just as a reminder, it will be about 20 minutes of a presentation and five minutes of short Q&A at the end. Okay, thanks, Kenny. And I want to thank the organizers at Jefferies for inviting us. So at Inozyme Pharma, we are focused on enzyme replacement therapy. I'm supposed to do these, aren't I? Okay. We're focused on enzyme replacement therapy. Please heed our legal disclaimers here. So we are developing an enzyme replacement therapy for disorders of bone health and blood vessel health. We're working on an enzyme, ENPP1, that we think can be used to treat three different diseases: two genetic diseases, ENPP1 Deficiency and ABCC6 Deficiency, as well as a third disease, which is a complication of end-stage renal disease and dialysis called calciphylaxis. All three of these share dysfunction in the PPi-adenosine pathway. That's the pyrophosphate adenosine pathway. This is a pathway by which our enzyme, ENPP1, participates to generate levels of pyrophosphate to prevent ectopic calcification within blood vessels, as well as produce adenosine that prevents the overgrowth of smooth muscle cells in blood vessels. This leads to intimal proliferation and stenosis, so all three of the diseases, in the more severe forms, suffer from calcified blood vessels and blocked blood vessels, and we think ENPP1 is the enzyme that can treat all three of these. We have conducted Phase I studies in all three diseases, and we've already moved into a pivotal study in children with ENPP1 Deficiency that we expect to read out near the end of next year and early 2026. We focus on rare diseases because we have a group that's done it before. We know how to build a commercial market here. We know that rare disease patients are hard to find. We know that we need to work with patients. We need to work with advocacy groups. We need to work with physicians. We need to identify these patients and build the market. And to that end, we've opened a registry for ENPP1 deficient patients. We think these are very strong markets for us. Even though these are rare diseases, they fall into the typical sizes of most of the rare diseases we like to think about. The geographies we're focusing on right now, looking for patients, are places where we can do good medicine as well as get good reimbursement. And so we're focusing mostly on North America, Brazil, the EU, and Japan. And across these geographies, we believe there are nearly 9,500 patients with ENPP1 Deficiency, nearly 25,000 with each ABCC6 Deficiency and calciphylaxis. So these are strong markets. This is, again, only a very small segment of the world where we're looking at these patients or counting these patients. We're actually very busy in the Middle East, where we see a lot of patients. We're very busy in Turkey, where we see patients. And they will, of course, be part of our core commercial geographies. But again, the prevalence in these markets alone is significant. And we believe that if we can do even a fraction of these patients, you can have three blockbuster drugs on your hands. Our pipeline, as I mentioned, we're in Phase III with ENPP1 Deficiency. We've completed a Phase II trial in ABCC6 Deficiency. And we just reported data in our calciphylaxis program, which I'll talk about near the end. There's some other diseases we're looking at. There's a subphenotype of ENPP1 Deficiency called OPLL, which is very prevalent in certain parts of the world. This is an ossification of a ligament that holds your spine together, and it's very painful and debilitating. It turns out that there's a lot of heterozygous patients or it's characterized by heterozygosity in ENPP1 mutation, so it's a very prevalent disorder and a very serious disorder, and then we have a number of other diseases we're thinking of that involve calcification and mineralization disorders, along with gene therapy approaches and next-generation programs, so I'll talk a little bit about ENPP1 Deficiency now. It's fairly complicated as diseases go because the infants, children, and adults all have somewhat different phenotypes. They all share a phenotype of ectopic calcification, which is most pronounced in the infants and the adults. The children have a different kind of a phenotype where they have abnormal bone growth. So children, infants have serious ectopic calcification. Adults have ectopic calcification. Children have a very specific kind of a bone defect, which manifests as rickets. Throughout life, they all have cardiovascular complications. They're all going to have hearing loss because the bones in their ears don't form normally. And so that leads to hearing loss in children and adults. We're treating all three of these populations. We did a Phase I study in adults as our first foray into this disease. Just to summarize at a high level, we had a very good safety profile. The pharmacokinetics and pharmacodynamics allowed us to understand the metabolism, and it allowed us to develop a once-weekly dosing strategy. I mentioned this molecule PPi, which is very important and an inhibitor of calcification. One of the key endpoints in that study, this study I'm talking about, was to raise PPi from a very low level into the normal range, which we could do nicely in this study. Then we did some exploratory clinical work looking at endpoints here. We used some patient-reported outcomes. We looked at the six-minute walk test. We did a number of biomarkers to look at bone biomarkers to monitor the effects on bone proteins and enzymes. We'll show some of that data. This is, sorry, I'm not going to, I guess we're missing that slide here. We had a favorable response on the patient-reported outcomes, the six-minute walk test, as well as raising PPi into the normal range. The bone biomarkers told us that the enzymes that are responsible for bone resorption and bone formation were moving in the right direction. For example, FGF23 showed a substantial dose-dependent effect that allowed us to pick the highest dose because that was the place where we wanted to see the biggest effect on bone metabolism. Now, these effects in adults on bone metabolism are modest in terms of the bone itself because bone is not turning over rapidly in adults. When bone is growing in children, that's when it's turning over the most rapidly. That's a time when defects that occur in the bone during development can actually be reversed because bone gets resorbed and remodeled and rebuilt at a high rate in children. So defects in bone can be corrected if you treat them early enough. To that end, we've designed this study. It's called the ENERGY 3 study. This is our pivotal study in children with ENPP1 Deficiency. I should also say that ENPP1 Deficiency in children is also known as ARHR2, autosomal recessive hypophosphatemic rickets type 2. So by that name, you can imagine that the bone phenotype that we're looking at in these patients is rickets. This is fairly homogeneous within children. 100% of the children that we've looked at who have ENPP1 Deficiency have rickets. We felt this is a proper endpoint for our study. Now, I did mention PPi. Regulators have viewed PPi as a very important molecule. They understand that it is an inhibitor of calcification, and they have awarded it a primary endpoint status because it is so important. In the U.S., it's our primary endpoint. We need to raise pyrophosphate levels. However, in the U.S., they've also asked to show improvement in the rickets scoring. So they've only asked us to show a trend in rickets improvement along with an improvement in PPi. In Europe, they've asked us to use PPi as a co-primary endpoint with our rickets score. However, they said that you don't need to meet the rickets score with a p-value of 0.05. A p-value of 0.2 would be adequate. So we think that showing trends, that is, the rickets score moving in the right direction in both the U.S. and Europe, along with a significant improvement in PPi, will be adequate for approval. We've conducted studies in adults. We're conducting a study in infants right now. So we've got the infants and adults covered. And the study that I just described will be done in pediatric patients. Some of the other details that I glossed over, it's a one-year study, 33 patients enrolling two-to-one treatment to control. There's no placebo here. So we're comparing these patients to a cohort that's been randomized and controlled cohort who are getting conventional therapy, which consists of phosphate supplementation and active vitamin D. We're near completing enrollment in this study. And so the readout will be about a year from completion of enrollment, which we hope is very soon. So as I mentioned, we've got infants in one study or a couple of studies. We've got adults we've already done. So the centerpiece of our regulatory package will be this randomized controlled study in infants. But we believe the supporting data in infants and adults will give us a broad label to treat patients of all ages. I'll move a little bit on to ABCC6 Deficiency. Again, like ENPP1 Deficiency, it's fairly complicated in that adults, children, and infants have fairly different phenotypes. Now, the phenotype in infants is almost identical to that in ENPP1 Deficiency. They're the ones that have these calcified and stenotic blood vessels. They are the patients who have a high rate of death in infancy. It's about 50% in ENPP1. It's about 20% in ABCC6. But it's very severe, and the patients die of very similar causes: calcified aorta, stenotic aorta, and heart failure. I'll flip quickly to the adults. The adults have a disease that's also fairly well characterized called PXE, Pseudoxanthoma elasticum. You can imagine that's a skin named after a skin defect. The patients lose elasticity in their skin. They get papules on their body. They'll go to a dermatologist. A dermatologist will look at it. They'll do an eye exam, and they'll say, "You have PXE. You have the adult ABCC6 Deficiency. You have a calcified retina. “And you're starting to see damage there.” And so that's fairly well understood. And we're treating those patients. In the middle, however, we identified a population of patients that were kind of different from either side here. They're closer to the children. They're kind of an exaggerated form of what's happening in the children. They have a high risk of stroke. They have a high risk of cardiovascular disease. They will all eventually lose their vision. And this is the population that we want to focus on because they really haven't been well characterized before. They're poorly diagnosed. And they represent a severe unmet need of children who are at risk of severe major adverse events. We did the study in adults. And again, we're pleased that it pretty much got the same data we saw in ENPP1, a very similar study, three patients in each of three dose cohorts. Safety was very clean. We have a very favorable safety profile. We saw a rapid increase in pyrophosphate in these patients. They don't start as low as patients with ENPP1, but we were able to raise the levels of PPi to the normal range at our highest dose. And mechanistically, there's a reason why you need more enzyme to raise PPi in this population than ENPP1. We won't get into it right now. I'll also say that in both of these populations, we saw a low number of patients who had antibodies, most of which were transient. By the end of the study, by the end of the 48-week study, most of the patients were antibody-free. And those that did have any antibodies were not neutralizing. And then from a clinical point of view, we saw positive changes in multiple organ systems. Now, here we were looking specifically at some imaging metrics. We were looking at vascular health by ultrasound, by optical coherence tomography in the eye, and we're able to show improvements in the carotid arteries as well as the choroid layer of the eye. These are particularly important in children with this disease, and that's why we focused on them, and so we're pleased to see that the changes that we saw in those parameters in adults were relevant to the disease itself, and we think that they'll be very useful when we look at our pediatric population, and we did see some improvement in visual function as well as multiple patient-reported outcomes, so our planned path to approval here is focused on the pediatric population, as I mentioned. Like all rare diseases, we believe regulators view approval as requiring one well-controlled randomized clinical study. We believe that the study we're doing in ENPP1 satisfies that, and regulators have said so. Here, we want to do the same thing. We want to design one well-controlled randomized study to treat these children with ABCC6 Deficiency. We've done some market research. We've identified a substantial pediatric population that recognizes these children as at high risk of stroke, high risk of cardiovascular disease, and high risk of retinal deterioration. A little background: why do we think this is important? We did a natural history study in these patients. And there's 11 patients shown here. These are patients who would have been characterized as having the early onset form of ABCC6 Deficiency. Some of them were diagnosed as having the disease early on. Some of them were diagnosed later. When you diagnose kids like this who look like this, you put them all into the same bucket. It's called GACI, Generalized Arterial Calcification of Infancy, type 2, different from GACI1, which is ENPP1 Deficiency. Many of these patients go from physician to physician until they get a good diagnosis. They may have shown up at a stroke clinic and didn't get any clear diagnosis. We think they all fall into this ABCC6 Deficiency bucket, and as you can see here, five of the 11 had strokes before their fifth birthday. You can see others that have cerebral arteriopathy. You can see cardiac arrest. These kids are very, very sick. When we saw this data, when we were conducting the adult studies, we started to get calls from people saying, "Well, you're doing ABCC6, but I got these kids with ABCC6," and we were a little mystified because most people didn't think about the kids with this disease. It's kind of a black box between infancy and adulthood. We knew about the infants. We knew about the adults, but nobody really knew what happened in between. This is what happens in between with these kids, and I think we figured it out. We then started to do this. This is an example of a medical record search we did, where we asked questions among a big medical record database and looked for kids or under-18-year-olds who had either reported with a stroke, with angioid streak, which is an eye retinal disease, aberrations in retinal imaging, or cardiovascular abnormalities. We found evidence, and so you asked the question, "You want to be under 18. You want to have one of these phenotypes," and the physician thought this might be PXE or a phosphorus disorder. Okay, so physicians knew about PXE, and they knew that this was a retinal issue. They knew some of the other stuff. So they knew enough to say, "These might be PXE patients." We thought there might be about 1,700 of these in the US, which is a good number for a rare disease. We found about 1,300 by this medical record search, so we think we're on the right track. We think these patients are out there. We have lots of them lined up from the literature, from individual physicians, so we're really optimistic that this is kind of the right next step for us in this disease, and again, we have a very similar regulatory path planned. We're doing infants as part of our infant study. We've done the adults already. Even though it's a small number, we think it's significant, but the core of our submission will be the randomized controlled study in pediatric patients using major adverse clinical events as an endpoint. We're talking with regulators about this. We believe, in principle, this is the right kind of study to do and that they're endorsing it. Building a rare disease franchise, starting from a small number of patients and into a large number of patients in the commercial market, has been done many times in rare diseases. Many of us who work at Inozyme have done it before. And we know the drill. We know the playbook. We know how to interact with the patient advocacy groups. We know how to work with KOLs to find patients. And we know that a lot of this is just having boots on the ground, going to conferences, going to medical grand rounds, making sure that the message is out. Because the number one problem is most physicians have never seen a patient with this. And so you've got to convince you've got to show them how to recognize the patients, how to diagnose the patients, and how to get them into a clinical trial. It's been done many times before, and this is no bigger challenge than any of those other ones. So we're really excited about moving forward in all of these indications. As I said, we've already identified over 1,000 patients with ENPP1 Deficiency. More than half of those are known by name. Some of them are known to exist through medical record searches. But I would say at this stage of development is an example of where some of the rare disease franchises started when they were just sort of in the clinical stage: PNH, Gaucher, Fabry, Pompe. You can see that at an early stage when they were in the clinic, they had 500-1,000 patients. In fact, for some of them, like Fabry, we thought there were probably 1,500 patients in the U.S. Now people think there's 8,000 patients in the U.S. Prevalence numbers change over time. They change with education, with awareness. And now you know how to recognize the disease. So early prevalence numbers often change. And again, here's three great examples of starting at 1,500 patients. And with Gaucher, you have 7,000 patients in the registry. And if you can treat only a few thousand of those patients at typical rare disease pricing, you can easily end up with a blockbuster. So we think we have at least three of these rare diseases blockbusters on our hands. I'll talk very briefly about calciphylaxis. Now, this is an acquired disease. It's not an enzyme. Sorry, it's not a genetic disorder. Although we do understand that there are some genetic factors that do contribute to calciphylaxis risk, and we're sorting those out now. Interestingly, calciphylaxis gets a lot of interest because a lot more people have heard of it than ENPP1 or ABCC6 Deficiency, and so I think people follow it. It's also, from a nephrology point of view and a dialysis point of view, it's an enormous burden on the system, even though very few patients get it. A lot of patients are at risk. They get monitored extra to make sure that they're not developing calciphylaxis. As I mentioned, it's characterized by these calcified blood vessels, stenotic blood vessels shown on the lower left. Within a year of diagnosis, half the patients will die, and often very rapidly, half of them within a few months. Unlike ENPP1 and ABCC6 Deficiency, the blockage is so severe that the tissues get completely ischemic. Patients get sepsis, and that's how they die. It's extraordinarily painful. There's really no good treatment right now. There's a few things that people are trying. As I said, because people have heard of this, there's more things being tried. None of them really address the same issues as INZ-701, our enzyme replacement therapy. Some of the data that we've collected, and again, we're the only ones who are really working in this particular area, but we've been working with Massachusetts General Hospital, where we've been able to get a lot of samples from patients where we know their history. The first thing that we were able to show was that when you go from healthy to dialysis to calciphylaxis to death from calciphylaxis, PPi levels go inexorably down. When you look at the number of open wounds people have in calciphylaxis, they increase as your PPi levels go down. We also know some genetic risk factors with calciphylaxis, one of which is an enzyme that generates adenosine, which, as I told you before, is important in our pathway. Another genetic risk factor is patients with ENPP1 polymorphisms show higher aortic calcification during dialysis. So we think we're on the right track here, that our enzyme to raise PPi is going to be effective. And the PPi is important in the disease, as judged by both the data and the genetic associations. So we did a study, just wrapped this up, and it was reported at Kidney Week in San Diego at the end of October. This was a Phase I study. It was four weekly doses of INZ-701. And we monitored pyrophosphate in those patients and looked at. We wanted to confirm that the PK and the PD was as we had seen in other diseases. And I think the core data from this that we're really excited about is that we were able to raise average PPi from a low level of around 700 in these patients up into the normal range after four weekly doses. Now, this is a very rigorous test of raising PPi because at every dialysis cycle, you're going to lower PPi. And they're doing three cycles between doses of INZ-701. So that means we've had three washes out of PPi. The enzyme's still there, that we confirm that. So there's enough enzyme there that every cycle, you can generate PPi and get you back into the normal range. So we think this was a strong and rigorous test of the enzyme's activity. We believe that if PPi is critical, then we know that in dialysis patients, at least, we can raise it into the normal range. It had a very favorable safety profile. One thing I didn't mention is we screened 21 patients, and we're able to identify 11 in the lower range. We already knew that they were going to be lower, but we wanted to make sure in this population, we could find low PPi levels. Those were the patients we started with. We're going to move. We plan on moving this into a full study in calciphylaxis. Again, our next study will be designed as a pivotal study. Coming up, we have completion of enrollment in our ENERGY 3 study. We're also going to release a small amount of data, interim data from our infant study in ENPP1 Deficiency. We also hope by the end of this year to give an update on what our regulatory conversations have been on our next ABCC6 study. We expect the top-line data from ENERGY 3, the pivotal study in children, to come out at the beginning of 2026, having the last patient in at the end of 2025. We hope to start a pivotal study based on our regulatory discussions in ABCC6 in 2025. We hope to also be able to start a study in calciphylaxis next year. With that, I will thank you. I'm just, maybe you remind what the key drivers are for getting the data early 2026. The key drivers are finishing up enrollment this year. It's a one-year study. That means the last patient would be dosed a year from now or from the year from December. And then you got to clean up the data and analyze it. So soon after that, like months, weeks, we should know the answer. But it will be 2026 because the last patient isn't going to get dosed till the end of 2025. Yeah. For the ABCC6, the next study, getting that regulatory feedback, that can be something. Yeah. Yeah. We're waiting for the final details. We're pretty confident the FDA is on board with the kind of study, but there's some details that have to be wrapped up. All right. Thanks.