All right, I think we're going to get started now, guys. Hi, everyone. I'm Alex Kelly. I'm one of the biotech associates on Mark Pahn's team. It's my pleasure to introduce Inozyme in just a few moments here. Doug Treco, the CEO, will get up and deliver a presentation, which I'm sure will be fantastic, and that'll be followed up by some Q&A. First, just some brief background on the company. Inozyme's lead asset, INZ701, is a recombinant version of the ENPP1 enzyme, currently being evaluated in multiple diseases of abnormal calcification, including the rare genetic diseases ENPP1 deficiency and ABCC6 deficiency. An additional exploration is also planned in calciphylaxis in patients with chronic kidney disease. The company has produced compelling data to date across all clinical programs, and we have several exciting catalysts to look forward to in the next year and beyond, including the readout of the pivotal Energy 3 trial in pediatric ENPP1 deficiency, and Doug can fill us in on all of that. With that, I will hand it over to Doug. Thanks, Alex, and thanks, Cowen, for inviting us. Thanks, everybody, for attending. I've been assured there's multitudes online listening too now, so thank everybody online for listening. As Alex mentioned, we have a drug that we think we can use for a number of different diseases. We're going to talk mostly about ENPP1 today. This enzyme replacement therapy, INZ701, is a clinically validated mechanism of action for lead program ENPP1 deficiency. We've been able to see consistent biomarker responses in patients, adults, and infants, and our top-line data in a pivotal study in children with ENPP1 deficiency will be available in early 2026. ENPP1 deficiency represents a large market opportunity. We believe there's around 10,000 patients in the parts of the world where we think we can develop and get good pricing. That's North America, Brazil, Japan, and Europe, where we think there's, as I said, about 10,000 patients, and this is easily a blockbuster drug with rare disease pricing. We think we have a well-defined path to registration. We've got data in all age groups: infants, children, and adults. The disease has manifested itself differently in these populations, so they required somewhat different studies with different endpoints. We're in a good cash position right now. We have money, $113 million, in the bank at the end of last year. As Alex mentioned, we think we can use this drug not only for ENPP1 deficiency, but two other diseases: a genetic disease, ABCC6 deficiency, as well as a complication of end-stage renal disease called calciphylaxis. ENPP1 is a lifelong progressive disease. It causes pathology in multiple organ systems, and there's a lot of morbidity and mortality associated. The infants with this disease are called GACI infants or generalized arterial calcification of infancy, and they're called that because they have calcification throughout many of their major vessels, arteries, as well as soft tissue. This is accompanied by hypophosphatemia, which is going to lead to poor bone growth as these kids age. There's also, because of this calcification in the heart, there's severe heart function deficiency, and half of the children who are born with this disease die within six months. All the children who make it out of infancy end up getting something called rickets. These are bone deformities that you've heard a lot about, probably in the past: knock knees, bowed limbs, gait problems, short stature has accompanied this, and abnormal skeletal growth in general. The kids continue to have cardiovascular risk, and they start to lose hearing because the bones in their ears calcify. Adults with this disease will continue to have progressive bone disease. Typically, soft bones cause osteomalacia. They'll have a higher rate of fractures. They'll continue to have hearing loss and cardiovascular risk. The disease will spread. The calcification will spread into their soft tissues, joints, ligaments, and tendons, causing a lot of mobility and pain and inflammation that accompanies this disease. Many of the adults may not have even been diagnosed. This is a—I won't call it a new disease, but I'll call it a disease where there's still poor awareness and poor diagnosis, just like every other rare disease that's come before us. We have a lot of work to do in building awareness, diagnosis, and the market ultimately for this disease. How does our enzyme work? Our disease is characterized by low levels of a very important mediator called pyrophosphate, or PPi, as well as a second mediator called adenosine. Now, PPi is generated from ATP. Our enzyme, our enzyme shown right here, which is the enzyme itself attached to the Fc region of an antibody, gives it a long half-life, makes it easy to purify. It's a very common kind of design you might want to make. Our enzyme generates pyrophosphate from ATP, and then the AMP that's generated gets processed by another enzyme called CD73, which generates adenosine. Pyrophosphate is a bioactive potent inhibitor of mineralization. If you don't have enough of it, then you get mineralization occurring in the wrong places. We need to increase that. The other molecule, adenosine, prevents intimal proliferation. It prevents the growth of smooth muscle cells in the lumen of an artery, and that blocks an artery. If you have enough adenosine around, you can block that. You can get open vessels, and you can get vessels that lose calcification with treatment of our drug. The last thing I want to tell you is how do we make ATP? ATP is generated by this transporter called ABCC6. It shoots ATP to the outside of cells where our enzyme acts on it. If you do not have enough ATP around, you cannot make enough pyrophosphate and adenosine. That is when you get ABCC6 deficiency. The deficiency of ATP leads to deficiencies of pyrophosphate, and adenosine over here leads to ABCC6 deficiency. Just missing ENPP1 alone leads to, again, pyrophosphate and adenosine deficiency. We believe that we can use our enzyme for both of these rare diseases. We are only going to talk about ENPP1 now. We have a number of studies that were conducted for ENPP1 deficiency. The centerpiece of our plan is our Energy 3 study, which is a pivotal study in children age 1 to 13 years old. They are being randomized two-to-one treated to untreated. The study is fully enrolled, and it will read out in the first quarter of 2026. This is, again, agreed upon with regulators as the pivotal study that, if successful, should get us approval. We have a number of other studies that we are working on. I'll talk about—sorry. Wait, how did I go? Okay. Another number of other studies. The purple one on the far right, the 101 study, that is our adult study. We've shown some nice data there showing we can raise PPi up to normal levels within a couple of weeks. We can keep it there with continued dosing. Those patients have shown good benefits and patient-reported outcomes, as well as a six-minute walk test. Patients who completed that study could move to this ADAPT study to get long-term treatment. We included some of our ABCC6 patients in that. We have a number of adults in this ADAPT study that are getting long-term treatment, having completed either this study, a 48-week study, or a different study for ABCC6 deficiency, another 48-week study. Down here, we have three studies we're collecting data on infants. Energy 1 is being conducted all over the world. Energy 2 is being conducted at ex-U.S. We have some expanded access data from babies we just cannot treat at a center that is already an open site. We provide drug to those physicians to treat those infants and children. All of these infant studies will be combined for submission, along with our pivotal study and along with our adult study. The phase I-II study in adults, as I mentioned, had an excellent safety profile. All the patients who get this drug are administering it at home themselves. A few patients had low-level antibodies. These were typically low titer, had no impact in PK or PD. Most patients in this study had no antibodies by the end of the study. As I mentioned, PK—sorry, pyrophosphate—was elevated almost immediately with treatment. I will also say that in—oh, shoot. Sorry, I jumped ahead too. Sorry. The PK/PD that showed PPi rose immediately in those adults, and we had some favorable outcomes and patient-reported outcomes in six-minute walk tests. We also looked at a number of bone biomarkers that told us that the things that we want to happen in patients, that is, absorption markers, go down, formation markers go up. They all went in the right direction in the adults, supporting what we think should happen in children to make their bone growth more favorable. These are some of the data from that adult study. As you can see, PPi went up to the normal range. FGF23, which controls phosphate, you want that to go down, did go down. The serum phosphate went up. The serum phosphate went up in these patients, even in the absence of giving them regular phosphate supplementation. We're very encouraged by these data that they're having all the right effects on bone, or will have the right effects on bone. Now, to the infants that we talked about, we have a very favorable safety profile there also. These infants are getting the drug at home, being injected by their parents. It's a pretty good safety profile to be working with. We did see some ADAs, anti-drug antibodies in these infants that we hadn't seen in adults in the sense that they were a higher titer, and they did have an impact on PK and PD. We continue to dose those patients with the optimistic that we'll eventually tolerize those patients, as seen in multiple other enzyme replacement therapies. Finally, we've seen clinical improvements. I'll show you that in a second in multiple measures of the disease. Most importantly, as these infants have gone from being treated around six months of age through to beyond 18 months, we're not seeing any rickets developing in these kids. We think that's a really good sign for read-through to our pediatric study where we're trying to prevent rickets. As I said at the beginning, half of the babies with this disease that are born homozygous will die within six months. We're optimistic that 80% of our treated infants are still alive. We only had one death. We know we'll get deaths, but we're optimistic that we're improving survival. We've also had most of these babies had multiple ectopic calcification all over the body. We've seen substantial reduction or elimination, and we've seen improvements in heart function. Finally, 100% of these babies will ultimately develop rickets and hypophosphatemia. We haven't seen any evidence yet, and we're improving hypophosphatemia in these patients. Here's an example of that. The black line at the top is what happens in a normal child. As a child is growing, going from six months to young childhood, phosphate levels go down. That's because all the phosphate the baby and child consumes is going into bone, and the serum phosphate levels really never can quite catch up. In ENPP1 deficiency, they really drop down. Right? Here now, the phosphate is dropping dramatically, and that's why these kids are getting rickets. In these three infants, and this is shown for the duration of treatment across their chronological age, you can see in these three infants, two of them are showing clear improvements in hypophosphatemia, and one of them is somewhat stabilized and not with the same slope as what normally happens in ENPP1 patients. We're very optimistic that this hypophosphatemia is being stabilized and improved, and that that may be a good reason why rickets will not develop in these children. How do we want to get this approved? I talked briefly about the centerpiece of our plan, which is this pivotal study in children. We think that children are the real unmet need here. Yes, the babies are born severely affected. Yes, half of them die within six months, but they're pretty rare, and we're going to treat everyone that we can. The children are the ones who are living with disability right now. They're growing abnormally. They have gait problems. They have a lot of stigma associated with their deformities and their short stature. They are the ones who are out looking for treatment today. This is where we think the real unmet need is. This study has 27 patients randomized two-to-one treated versus untreated. It's a control arm. There's no placebo. They will be followed for 52 weeks, and then they'll enter into a long-term open-label study after that where everybody gets drug. The endpoint is the change in plasma PPi from baseline, and the secondary endpoint is the change in rickets score as measured by a radiographic hold-up to X-rays and asked, "Did this get worse or better or the same?" In the U.S., that's the way it's set up. In Europe, it's almost as good for us, but the Europeans wanted the rickets score to be a co-primary with the pyrophosphate, but they felt that it didn't need to be met with a traditional P-value of 0.05 and that a more relaxed P-value of 0.2 would be acceptable. This gives us really a great window for demonstrating benefit. All we have to show is PPi raises above the baseline level significantly, and we basically need a trend in the rickets score because all we need is a trend in the U.S., and the 0.2 P-value is essentially a trend in Europe. I think we have a really good window and opportunity to see benefit here. For approval, we think, as I said, the centerpiece will be the pediatric study. It'll be supplemented by infant data from Energy 1, Energy 2, and expanded access patients. It'll be supplemented by the adult data that we've already collected. We think that with a package that includes one randomized controlled study in children, supplemented by safety and preliminary efficacy data in infants and adults, will induce regulators to give us a broad label. Ultimately, we're doing a lot of work in the Middle East right now. We're starting to work in Japan and Brazil, and those will be the next places we'll go after Europe where we expect to file at the same time as in the US. Ultimately, we want to build this into a rare disease franchise built around INZ701, treating not only ENPP1 deficiency, but these other disorders, ABCC6 deficiency, and calciphylaxis. We're very pleased with how we're doing with patient identification. We've identified over 670 patients that are clinically or genetically diagnosed where we know where they are. We know their physician. We know how to get to them. We have another 860 patients we've identified by medical record searching where we built basically a profile of an ENPP1 patient and then pulled out matching medical records. Again, this is only in the US. These are US. These are worldwide. This adds up to about 1,500 patients. I don't think there's another rare disease drug that's had this many patients at a similar stage in development. We continue to work to build these data sets, but we have a great population to launch this drug anchored by the pediatric population. This is what I really want to point out about rare diseases because people seem to forget that we don't have diagnosis and you don't have awareness, and you've got to find KOLs who have actually seen these patients that you're going to think there's not that many of them out there. That was the case when they started to work on Gaucher disease and PNH at Alexion. When we started working on Hunter syndrome or Fabry syndrome—sorry, Hunter and Fabry—we thought there might be 5,000 Fabry patients in the world if we were lucky. There's 8,700 in the US alone now. These registries grow over time because there's a drug out there. If there's no drug out there, who's going to be looking for treatment? We know that people know the well-known story about Huntington's disease. You could get a test for it. Nobody wants to get tested because there's no treatment. This is what we're up against all the time with these rare disease drugs. These markets have to be built over time. This should show you that there's kind of a lot of room to grow when you start off with a few hundred patients. A few, 10 years down the road, you're at tens of thousands or thousands of patients in these databases. These rare disease prices, treating only a few thousand patients can get you to blockbuster status pretty quickly. We ultimately believe that all three of these diseases can reach this blockbuster status. ABCC6 deficiency is a little more prevalent than ENPP1. Calciphylaxis is probably about the same as ABCC6, but they're all ultra rare, and they all will require, or likely will require, one well-controlled randomized study for approval, and we're prepared to do that. We also have next-generation drug that has longer half-life that we think we can introduce down the road. Ultimately, gene therapy may be the ultimate solution for some of these patients for long-lasting, permanent care, and we have good IP for those approaches down the road. Again, that's pretty much the story. ENPP1 is our lead indication. It's clinically validated. There's a large market opportunity. We're in a pivotal study now that is set up for approval in both the US and Europe based on agreement from regulators. We have good capital reserves that can get ENPP1 to the finish line as long as we focus on it. We do ultimately plan to bring in these other indications over time. With that, I will take questions. I think Alex has some questions. Thanks again, Doug, for that great presentation. Yes, as far as questions, first, could you maybe comment on the specific aspects of the adult and infant ENPP1 data sets that really give you confidence that 701 will drive improvement not only on PPi, but also on the clinical endpoint of rickets in Energy 3? Yeah. One of the biomarkers that we wanted to look at was FGF23. FGF23 is responding to something going on in the body to now cause phosphate to be resorbed. These kids lack phosphate. When we looked in the adults, we saw that FGF23 was going down and phosphate was going up. We do not believe that biochemically or metabolically that should be different in children. We also looked at a couple of other biomarkers. One is called C-terminal collagen peptide, and the other is called bone-specific alkaline phosphatase. They both also changed in the direction you would expect for proper bone growth. We think in children where bone is turning over very, very rapidly, these biomarkers should just be exacerbated and see even a bigger effect in children. I think if you come at it from the other side, from the infants, again, you can see this hypophosphatemia improving. The reason you get rickets is because you're hypophosphatemic. As we see these children age and the phosphate continues to improve or is improving, we hope it continues to improve. This is a child. This is probably our oldest kid that we've treated so far. We started when he was around two and a half. You can see he's going up very nicely into the normal range. We think that these two bits of data kind of tell us that the metabolism that we want to affect in the children will happen. The other part is that rickets can be treated in a year. Now, you can think of a bowed limb. How can you treat that? You can treat that because the bone's turning over rapidly. It's being erased and reformed at such a rate that if you can stop the thing that causes the rickets from occurring, the bone will form normally. We know three ways you can treat rickets like this. One is with a drug called Strensiq to treat hereditary hypophosphatemia. That's what you use Strensiq for. Another is Crysvita, Burosumab, that you use to treat X-linked hypophosphatemia. Both of these form rickets. Similar are somewhat different. We have our own assessment protocol, which we took from those successful studies. Then you add on top of that vitamin D-dependent rickets. All forms of rickets, all three of these forms of rickets, can be treated with drugs in the course of a year. We don't think that our rickets is going to be any different, especially since we see the positive effects on hypophosphatemia and the bone biomarkers. I mean, it is surprising to think these deformities can change in a year, but they can. Thank you. That's very helpful. Can you comment on the likely size of the opportunity in ENPP1 deficiency? How many patients are currently identified, and what steps is Inozyme currently taking to increase diagnosis rates and to expand 701's addressable population? Yeah. A lot of the work we do is awareness and getting people to the right diagnostic pathway. One of the things we've learned early on is that there's almost no ability to get diagnosed in Japan. That's something we just started to build there. Whatever is happening in the U.S. and Europe is really because of us that we've put it in place. In the U.K., as I said, if there's no treatment available, then why diagnose? They said that to us in the U.K., and we convinced them that we were far enough along that they should start diagnosing. Genomics U.K., which is sequencing one out of 12 newborns as part of a big pilot program, is now including our two genes as two of the 200 genes they look at. It's quite an accomplishment. We were thrilled to have that. Now we have systemic newborn screening in the U.K., or at least a fraction of U.K. babies. All that said, we can count alleles from big genetic data sets that allow us to get a better handle on how many alleles are out there floating around. If you know how many alleles are out there floating around and how many people are out there, then you can calculate, well, how often do two of these mutant alleles come together, standard genetics, and you can make predictions on the frequency. With that data in hand, we were able to calculate a genetic—sorry, a prevalence of one in 64—sorry, an incidence of one in 64,000. That allows you to calculate how many people are in the developed world. That calculation got us to 10,000 people in Brazil, Japan, Europe, and North America. Some people say that you treat—I say you treat a few thousand people at rare disease prices. You have a blockbuster. You treat less than that at those prices. You still have several hundred million dollars of revenue, and that can still value a company at a billion dollars. We think the market is quite robust, and we're going to focus on the children because they're the most visible. We'll treat every baby we can. Like Crysvita and Strensiq, they start with the children, and they see their biggest growth in the adults as physicians see benefit and that there's more and more need. As they see benefit, they're going to start treating adults earlier and earlier. One question on the ground. How do you identify those patients? How do we identify patients at all? On the ground, you made a reference that I think it was in Japan that they're not well equipped to identify that particular disease. You made a point that you were able to identify 670 patients, I think. On the ground, how does that look like? I mean, this is not a disease that's tested commonly, or there are centers of excellence where? It can be a painful process. In Europe, there are centers of excellence. There's a few. If you're in the U.K., most of the patients end up at a Manchester hospital. In Japan, it's a lot different. In Japan, it's more isolated KOLs. You have to visit their hospital. You have to go on their ground rounds. You have to talk to them and get them to dig through their records and talk to their colleagues about patients with this phenotype that we then get tested. I mean, this is not any different than what was done in the early days of Hurler syndrome or anything else. It's just something that has to be done. But it's literally finding physicians, maybe an endocrinologist, maybe a pediatric cardiologist, find those patients, get them to start thinking about the phenotypes of their patients, and then they feed them into our diagnostic pathway, and then we come out with patients. Now, the other way to do it is sometimes patients will go—a kid will go and get a bone screen. Now, these genes are on some of the bone screens. So people will go and say, "If you're requesting this bone screen from Invitae, they will include ENPP1 and maybe ABCC6 in that." So we get some patients that way also. It is a ground war. It's like checking off physicians one by one and finding patients. I like to say this is the model that Genzyme invented that's worked extremely well for anybody who's kind of entered this. Find the patients. Sorry. Build awareness, b uild diagnosis, build up the patient database, build relationships with the patient organizations, and most importantly, the key to all of it is make sure everybody gets reimbursed. If you can do all of that, you can basically keep these very important drugs in the market at the prices they should command. Expecting data from Energy 3 in the first quarter of 2026, you said? Yes. When would you—I don't know if you've already said that, so I apologize if you did—but when would you complete enrollment on that trial? It is completed. That completed in January. That is why we think we can read out in the first quarter of next year. All right. Unfortunately, I think that's all the time we have today, but I'd just like to thank Doug and the Inozyme team again for the great presentation. Thank you.