I guess we'll get the ball rolling. Thanks, everyone, for joining us for the next half-hour session. My name is Dae Gon Ha, one of the biotech analysts at Stifel. With me for the next half hour, we have Inozyme Pharma, and from Inozyme, we have CEO Doug Treco. So, Doug, thanks very much for your time. This is obviously my first time hosting you at a Stifel fireside chat. So maybe we can just level set what Inozyme is all about, talk us through the INZ-701 programs, and then we can dive right into Q&A. Sure, so INZ-701 and Inozyme is all about enzyme replacement therapy. We have an enzyme that can do two things. It can raise the levels of two really important biological mediators, pyrophosphate and adenosine. And these are two important mediators that promote blood vessel health and bone formation. So we believe that with this one enzyme replacement therapy, we can increase the levels of these metabolites, PPi and adenosine. And actually, we believe that this drug can be used for three different diseases. One would be the enzyme replacement for which the people are missing the enzyme. That would be something called ENPP1 deficiency. Our enzyme is ENPP1. There are two other diseases, though, where we think PPi and adenosine are important and cause severe problems that all look the same. You've got these blood vessels that are calcified, so they're kind of crunchy on the outside, and they don't pump blood properly. In addition, these blood vessels have been overgrown with smooth muscle cells, a process called intimal proliferation, so they become blocked or stenotic. So you've got these crunchy, blocked blood vessels that just don't pump blood properly. In the case of two genetic diseases, these are very pronounced in infants, leads to a disease called Generalized Arterial Calcification of Infancy. There's one type 1, which is ENPP1 deficiency. And then there's another one called type 2 for ABCC6 deficiency. Both of these diseases look similar, and we think we can treat both of them with our enzyme. In addition, there's a third disease, calciphylaxis, which is an acquired disease for people on end-stage renal failure on dialysis. Those patients have similarly calcified, blocked blood vessels. They also have extremely low pyrophosphate levels that we've been able to demonstrate over a couple of years of collaboration with experts at Mass General Hospital in Boston. And we believe that that disease, calciphylaxis, is also amenable to treatment with our enzyme replacement therapy. So we have three very rare diseases: ENPP1 deficiency, ABCC6 deficiency, genetic diseases, and then calciphylaxis, all of which we believe can be treated with this one enzyme replacement therapy. Yep. Very concise and elaborate approach. Starting with the ENPP1 deficiency, this kind of reflects on your regulatory strategy, but can you briefly remind us, what are the different manifestations you see GACI-wise, adolescent-wise, and what is the unmet need when it comes to these patients? I focused initially on the blood vessels, but the other thing I mentioned early is bone health and proper bone formation. In ENPP1 deficiency, the infants are born with severe ectopic calcification. They've got calcified arteries, typically a calcified aorta that doesn't pump blood properly. They can die of heart failure. Now, when a baby's born, he's got an incomplete skeleton. And in fact, metabolically, he's not, he or she is not using a lot of the consumed phosphate and calcium to build bone. It's for metabolism. But shortly after birth, when the skeleton starts to form and take shape, all the calcium and phosphate of the body now go into bone formation. And so when the babies were born, they had all this ectopic calcification. Some of that kind of gets slowed down. The baby, the calcification is going to other places, in the right place, bone. There's less of a chance for these ectopic calcifications to occur, but because they have low PPi, the bone growth is abnormal. So you've switched from a very serious condition where you're calcifying arteries to now a situation where you're not calcifying your bone properly. You get kind of a reprieve from the severe cardiac issues, but you enter a new phase where the bone is growing abnormally. In addition to the bone growing abnormally, which affects limbs and joints, bones in your ears don't grow normally. So there's a hearing loss that goes along with this disease, so the children with this enzymatic deficiency, ENPP1 deficiency, almost uniformly get a disease called rickets as children. Rickets is a disease of bone growth where the bones don't grow properly. It's often most clearly manifested by like a bowed limb where a femur might be bowed in a certain way. But it's got a lot of other features around the abnormal bone growth that prevents the bones from forming properly. It's this condition that we want to treat in our pivotal pediatric study. One reason we want to treat it is because it's children, and they're the ones whose parents are looking for treatment the hardest. They're young, they're growing, they have a lot of stigma associated with their disease, they have abnormal limbs, and they want to get treated. Their parents want them treated. That's our target, our core population there. And the other reason we want to treat it is because it's pretty uniform within that population that pretty much every kid with homozygous ENPP1 deficiency will get rickets. So it's a homogeneous population with a pretty big unmet need in children. That's where we're focusing. Now, we've done a study in adults and shown some benefit there on some patient-reported outcomes, on mobility, on biomarkers. And we're also doing work in infants with this disease, and we hope to get some of that data out later this year. I think we'll have a full package that we've shown benefits in infants and children. And then the core of our program, though, is a randomized controlled study in children with rickets, which we think will be, which has already been approved by regulators in terms of if we meet our endpoints, it'll get approved. So we think we're in pretty good shape for completing that study. I think you're talking ENERGY-3, right? yeah, ENERGY-3. ENERGY-3. A lot to unpack there. Can we just go back to the phase 1/2 data? From a finding standpoint, I mean, you measured the biomarkers, you also had some other like FGF23, pyrophosphate, but also six-minute walk. What are the key findings there, and what are the dose levels that you've selected? And if I can maybe tack on to that, cohort four was something that you also included in that study. What learnings did you take away from that cohort four? Cohort four was kind of an add-on after we had initiated the first three dosing groups. The difference was the first three dosing groups were twice weekly. They were an escalating dose regimen of 0.2, 0.6, and 1.8 mg per kg given twice weekly. Once we saw the half-life of the drug in humans, which was 126 hours, we thought that was pretty long, and we thought it would be kind of appropriate to switch to a weekly dosing. Cohort four was added on just to test the validity of our model, really. We wanted to basically be able to say that the model that we had developed based on the PK data and twice weekly dosing, collected on three doses, we put together a model, and we wanted to show that it would meet, it would match what we did when we actually did once weekly dosing, and so that's why we did it. We were able to show that the model matched perfectly, that we were able to predict what would happen with the 1.2 mg per kg dose. I think in the end, it's not a dose that we'll use. It was really just a test to see how the model performed. Moving forward in that pediatric population, we're actually using 2.4 mg per kg weekly. So maybe at this point, we can just highlight what is the regulatory strategy for ENPP1 deficiency before we dive into the phase trials? Yeah. So the regulatory strategy is to get approval for all age groups, and that we believe will be accomplished by a data package that includes adults in a single-arm study, the one we just talked about, the phase 1/2 study. Infants in a number of different studies, one of which is a single-arm study conducted in the U.S., one is another one conducted outside the U.S., and then the third is some expanded access patients that we've begun treating in geographies where we just couldn't get these kids to a place where they could be treated properly, so we'll have a handful of infants from those studies, but we hope to have about 20 infants overall, all treated in single-arm studies compared against a natural history database. We also have adults that we've treated already and we've reported on. Those adults have been shown it was safe and well tolerated, and we believe evidence for biochemical and clinical improvement. Those are also single-arm studies. So the real core of our regulatory submission will be the pivotal randomized controlled study in children. We believe that that will be a definitive study, does this drug work compared against the control. But we believe regulators will look at the adults and children, and if they believe the drug has shown benefit, then we would get approval to treat all ages. And we think this is not that different from a situation like Strensiq. So Strensiq is being used to treat another kind of rickets, HPP. And in that regulatory filing, Alexion only did a single adult study. And they ended up with approval to treat all ages. Now, it's in the form of a label that says infantile or juvenile onset rickets. Sorry, infantile or onset HPP. But we believe that that would, that's the kind of label we'd like, infantile or juvenile onset ENPP1 deficiency. Is there any reason to believe the XLH, Crysvita precedent would also have an impact on your regulatory strategy versus Strensiq? You know, with Crysvita, they use a very similar readout as us, which is the radiographic impression of change. So that was very helpful to us in picking an endpoint that we thought was, well, first of all, acceptable to regulators. Second is something that could change over a one-year period. So I think the experience, the clinical experience and the clinical success of Crysvita was pretty helpful to us. Yeah. Okay. ENERGY-1, the U.S.-based single-arm study and the compassionate use or the expanded access patients, that's what we're expecting an update from in Q4 of this year. Yes. Yeah. It's getting really close, so to the extent that you can comment on it, how much of a data are we expecting? What kind of trend should we be observing? Is there any statistical significance involved in this analysis? Anything to kind of set the stage for that readout? So yeah, all I can say right now is that we hope to eventually have 20 babies in this data set. This will be a subset of that, a handful of babies treated for at least six months. I think with a handful of babies compared to a natural history database, we believe that one key element of the natural history that we're looking for is survival. And we know that half the babies born before or will die before six months of age. I don't think we'll be able to statistically tell you that, hey, here's a breakthrough here, but I do think you'll be able to see that there's enough benefit and enough survival that points us in the right direction. So presumably a compare contrast to the natural history, you're going to show us what the handful of babies did. Are we talking one hand or two hands? I think one hands are going to tell you. ENERGY-2, you mentioned that's an ex-US single-arm. What's the purpose of that given that in the US and you also have the expanded access? Yeah, it's a little convoluted, but the rationale for that is that when we went to the U.S. FDA and said we want to treat infants and we want to compare the treated group to a natural history control, they said, we think you need to do a placebo-controlled study. We did not feel that was appropriate. We talked to our physician KOLs, we talked to the families. This was not going to be a study that could be done or would be done. And I think we generally feel would be unethical. If this was ABCC6, for example, you had an ABCC6 and said, well, is it ethical to give them ENPP1, sorry, to deny them ENPP1? Well, maybe because we haven't proven it worked. But if the baby's missing that enzyme, to deny them enzyme replacement therapy with that enzyme, knowing that we have good safety and tolerability already, we did not think that was appropriate. So in the U.S., we went back to them twice. They were adamant about a placebo-controlled study, and in Europe, they were not, so to satisfy both sets of regulators, we were only ENERGY-1 in the U.S. We're ENERGY-1 all over, but it's only U.S. It's the only site. Sorry, we're not ENERGY-2 in the U.S. because the U.S. said this is not a pivotal ENERGY-2 was designed as a pivotal study with European buy-in, and so that's being conducted outside the U.S., so that's why they're different. They're identical studies. I would also say the difference ENERGY-1 ENERGY-2 is ENERGY-1 is adopting a dose titration approach where we're starting low and building up the dose to find the right dose. That data was used to pick a dose ENERGY-2, by nature of it being pivotal, is a fixed dose that we determine ENERGY-1. otherwise, we're collecting very similar data. Got it. ENERGY-3 you mentioned is kind of the core grounds upon which you're planning on filing that regulatory submission. Right. And the single-arm babies, single-arm adults will be supportive. Right. So can you just remind us of ENERGY-3 trial design and the dose that you've selected? What gives you confidence that's the right dose based on your phase I experience? The phase I told us go high, go with a high dose. It was not. The pyrophosphate levels rose to a similar range for all three doses. When we looked at the bone biomarkers, these are the things that we think are going to tell us how the bone's responding. FGF23, C-terminal collagen peptide, bone alkaline phosphatase, their trend was most pronounced at the highest dose. We knew we wanted to go to the highest dose. We wanted to try to mimic 1.8 twice weekly with a weekly dose. Our modeling got us to 2.4 weekly. It's not perfect, but we think it's close enough to push all patients in the right direction over time. The design of the study is 2.4 mg per kg weekly. We're looking to enroll 33 patients, randomized two to one, treatment to untreated. There's no placebo. The control group is getting standard of care, so we're comparing them against patients getting their standard of care, which is typically phosphate supplementation and active vitamin D compared to INZ-701. We're optimistic that trials of one year with biologic agents like Strensiq and Crysvita have successfully treated rickets. We think that part of that's due to the fact that children, their bone is turning over rapidly, and as bone turns over, you can correct mistakes if you put patients in the right metabolic state, so we think that we should fall into that category, so we picked a duration, a year where we know other biologics have been able to treat rickets. The study's been powered to show an improvement in the rickets score, even though the primary endpoint is either PPi or co-primary of PPi. So I should talk about the primary endpoint a little bit. Again, U.S. is a little different. In this case, it was more favorable to us. In both cases, both regulatory bodies viewed PPi as really important, not as a simple biomarker, but as a biologically active agent. Been well known for years that if you take pyrophosphate and throw it into a test tube with calcium phosphate, it prevents precipitation. So it's a biologically active molecule. And so regulators have viewed it appropriately. So the U.S. said, this is a primary endpoint. You just have to raise that a significant level. However, we'd like to see improvements in the Rickets, a trend in improvements in the rickets score. In Europe, they said it can be a co-primary endpoint. We want to see improvements in this rickets score, but you don't have to meet it with a traditional p-value of 0.05. 0.2 would be adequate. So we think in both cases, they're really looking for PPi to go up, but a trend in the right direction in most patients in the rickets score. Okay. Could you talk about how sufficiently powered this trial is? You said it's adequately powered, but are we talking like 80%, 90% based on assumptions you've made? We think it's 80% powered to meet the rickets score with a p-value of 0.05. So we don't have to get there, but we think it's powered for that. Okay. And the rickets, I think XLH, they did RGI-C and RSS. Which one are you particularly looking at? We're doing RGI-C. So the RGI-C is a comparison. It looks at a change. And the change is a trained cohort of readers will look at a baseline and a 12-month slide X-ray film and say, is this worse, very much worse, very, very much worse, or better, better, better? So there's a seven-point scale, no change or up to plus three or minus three. So it's really a seven-point scale. It's been used, as you mentioned, for both Strensiq and Crysvita. We kind of modeled it after that. Yeah. Okay. Okay. Let's talk about ABCC6. Just the biological rationale of reintroducing ENPP1 or INZ-701 in ABCC6. What are sort of the nuances there that INZ-701 should work, or what are we missing that it might not be as robust as an ENPP1 deficiency patient? Yeah. With ABCC6, the deficiency is not in the enzyme, but it's in the deficiency of the substrate for the enzyme. In ABCC6, rather than missing an enzyme to generate PPi, you don't have the substrate that generates PPi, which is ATP. ABCC6 is a transporter that moves ATP from the inside of a cell to the outside of the cell. Probably its main function is to generate PPi from the ATP that it shoots out of the cell. We have an animal model of ABCC6 deficiency that gets pathology. If you treat these animals with ENPP1, you can reverse the pathology. You can also raise PPi levels. You can also raise adenosine levels. You can also show that you start off with low ATP levels. The animal model kind of suggested that this would work in patients. In patients, rather than having very, very low PPi levels like 10% of normal, they're really about the lower limit of normal. Now, why do they have disease if PPi is important? Well, it's not 100% clear, even though this is well recognized as being driven by PPi. But what we think is happening is that ABCC6 is not the only transporter. It's mainly expressed in the liver. And that's the main source for systemic ATP that we need to act on. Another transporter, ANKH, is more specifically expressed in other different tissues where it generates adequate levels of ATP probably. And INZ-701 is adequate to generate PPi. But to raise the systemic levels up, you need to get INZ-701 in there on top of the wild-type ANKH. So we've shown in humans that only the highest level of drug raised PPi into the normal range. In that case, it made sense to us because you needed more enzyme to drive that substrate to PPi. And so everything kind of makes sense to us from that point of view. That said, what happened when we treated patients with ABCC6 deficiency? Well, we saw many improvements in patient-reported outcomes. They look better. They feel better. But we also saw improvements in some imaging metrics. We saw a thinning of the carotid intima-media thickness, which is something that we think is really important in this disease, that you get narrowing cerebral arteries, reduce blood flow, and lead to ischemic stroke. So a thinning of that was really important, especially since patients with the adult form of ABCC6 deficiency show a typical increase in the thickness. So we had a decrease when patients typically saw an increase. Similar phenomena were seen in the retina. There's a vascular layer of the eye that normally thins with age, thins with the adult form of ABCC6. We saw thickening. So both of those are minor, small changes, but we think they're really pointing us in the right direction that when we treat patients, we should over long term, we should see these kinds of changes. Okay. One of the key questions I get about this particular program is not only the difference in biology, but the regulatory path is somewhat less well defined. If I recall correctly, we're expecting a regulatory update from you. So I guess the quick question is, have you already had that regulatory discussion or is that ongoing? And as it pertains to where you stand today, what's kind of your leaning in terms of what that regulatory strategy might look like? Yeah. So with ENPP1, we've talked to regulators, where everybody's come to agreement. And those things are always challenging with a new disease, right? This is a brand new disease. They've never even heard of, let alone thought of approving. So you got a lot of work to do. And we were at a similar place with ABCC6. So those discussions are ongoing. I think in principle, we believe FDA and European regulators agree with this kind of design. The design would be looking at hard clinical endpoints, major adverse clinical events, composite of major adverse clinical events. It would be a randomized controlled study. And again, I can't say too much now, but we hope to get a more complete picture out. We generally believe that the kind of randomized controlled study with a composite of major adverse clinical events unique to this disease is going to be appropriate for approval with a duration and a size that we suggested. Again, more details to come. We believe in principle, both European and US regulators agree with that. Now it's just sort of working out the details and giving them a study that they can sign off on. We're very optimistic that we've found a real unmet need and a path forward. Here too, you have sort of the infant population that has a different kind of manifestation and risk profile versus children versus adolescent. So what are your leanings right now in terms of sort of the infant population versus a children population versus an adolescent? We look at it very similar to ENPP1. We already have the adult data, and we probably won't do any more there. And remember, the adults are a unique phenotype called PXE, pseudoxanthoma elasticum. They've got a specific skin phenotype. They've got a specific retinal phenotype. The patients we looked at in our adult study were pretty sick, probably sicker than your average patient. But we have that data already, and the patients were improving. We're also treating infants as part of our ENERGY-1 study with ABCC6, the GACI2 infants. So we're already treating them along with some IS investigator-sponsored studies and expanded access. So we're collecting the babies in a similar way. So we're going to have two data sets very similar to ENPP1, adults that we've treated and infants that we've treated. And so again, the core, the centerpiece of our regulatory strategy will be a randomized controlled study in children supplemented by adults and infants to get all ages. Very similar strategy. But we've got to get to that agreement with the FDA, and we hope we'll be there clearly in the first quarter. Okay. Okay. The calciphylaxis program, you had an update at ASN Kidney Week. Quickly, what were sort of the key take home from that indication, given that it's not as clear-cut biology compared to the other ones? Yeah. So we're building the biology story. And it's a story we hope to get published along with our collaborator, Dr. Sagar Nigwekar at Mass General, who's really probably the world's leader in this field. He's been providing us with samples over time with clinical data to support it. And we've been able to show that there's a pretty much inexorable progression from PPi going down when you go from healthy to dialysis to calciphylaxis to those who are unlucky enough to die from calciphylaxis. It really just drops precipitously. That's data that we put out in posters. And that's, I think, telling is the big piece of the story here. The other thing to remember is that pyrophosphate, phosphate, and calcium all in kind of a weird balance. And if they go out of balance, then that can flip the switch to calciphylaxis. When you go through dialysis, these things are all changing, right? And that's probably why you start with somebody with five different risk factors for calciphylaxis, maybe 20% of the dialysis population. You say, well, why do only a fraction of them get calciphylaxis? Well, somehow that dance of pyrophosphate, calcium, and phosphate all went out of whack, and that precipitated this precipitation throughout the body. We think that one of the key learnings for us is that you will diagnose calciphylaxis based on pyrophosphate over time and that we will be able to start diagnosing people very early on because they have low pyrophosphate, and we can start treating them early on. I strongly doubt that if somebody is deep into calciphylaxis, they've got an ischemic limb that might have been amputated, and they're very close to death, we're not going to save that person. But if we can treat the patients who have been diagnosed with calciphylaxis, who have pain and a couple of open wounds, that's the kind of population we're going to go after. But we need to know who to treat because there's a lot of patients out there who have risk factors. So we really got to find a way to identify among those with risk factors who should really get treated early. And we think pyrophosphate may be the answer to that. Okay. Just to round it out, let's touch briefly on your financial position, and you have three programs now. What are sort of your priorities given your current cash balance? The only priority given the current cash balance is ENPP1. We definitely want to get progress with the regulators with calciphylaxis and ABCC6. The key goal for us is to complete enrollment ENERGY-3, get the readout at the beginning of 2026, and get it approved. We want to have enough financial security that we can get there before we worry about too much else. We'll spend some money on getting ready for ABCC6 and calciphylaxis, but we can't pull the trigger on that until we've got everything lined up financially for ENPP1. Then we would consider budgeting and financing for those other two. We don't want to do that until regulators tell us exactly what the study is going to look like. We're optimistic that we can come up with agreeable studies and just budget them and finance them.