Okay, why don't we go ahead and get started? My name is Chris Raymond. I'm one of the senior biotech analysts here at Piper Sandler. Thanks, everybody, for being here. Very pleased to have with us our next presenting company, which is Inozyme Pharmaceuticals. We have with us Matt Winton, who's the COO, and so tons to go into here on this name, but before we do that, just a little housekeeping. This is a fireside chat, so it's meant to be participative, informal. Anybody has any questions, please raise your hand. I'll make sure they get asked and answered. If you're listening in on the webcast and you want me to ask a question, just hit me an email. And I'll be monitoring that as we go through this talk. But before we dive into questions, maybe Matt, if you wouldn't mind, just for folks who might not be familiar with the story, just give us maybe the elevator pitch, if you will, and the setup, the premise, and sort of the value proposition. Yeah, sounds good. Thank you, Chris, for having us. And thank you all for your interest in Inozyme. Inozyme's a clinical stage rare disease company that's focused on rare disorders that impact bone health and vascular function. And so we're focused on three diseases right now, two of them genetic: ENPP1 deficiency, ABCC6 deficiency, and calciphylaxis. All of these diseases have sort of a common underlying pathology, which is imbalance or dysregulation in the PPi adenosine pathway, which causes abnormal or pathogenic calcification and intimal proliferation or stenosis in these patients, resulting in disease. We have one program now that's in pivotal studies, hopefully to have final phase 3 data by the end of next year. And our two other programs are shortly behind. Hopefully, we'll be launching pivotal studies into next year. Okay, so you mentioned you guys are focused on disorders of the PPi adenosine pathway. Maybe just to start off, orient us on what this pathway is, maybe in the body, and what actually happens. Sounds like you've got three programs around this pathway, but what happens when it's dysregulated? Sure. So let's start with sort of the two major metabolites: PPi, or inorganic pyrophosphate, and adenosine, which are kind of the outputs of this pathway. PPi has long been known to be a potent inhibitor of mineralization in the body. If you take calcium and phosphate and you put them in a tube with pyrophosphate, they'll precipitate out. If you remove the pyrophosphate, they'll form hydroxyapatite crystals, which are sort of the building blocks of your bones and teeth. So it's critical when we're having calcification in the body to have calcification and bone formation in the right time and the right place. When you have lower levels of pyrophosphate than needed, you get ectopic calcification in areas where you don't want it. Adenosine, on the other hand, is a potent inhibitor of intimal proliferation. So it maintains healthy blood vessels and prevents sort of the overgrowth of smooth muscle cells inside the blood vessels, which cause stenosis and can relate to disease. At the core of the PPi adenosine pathway are two receptors that we focus on: ABCC6 and ENPP1. ABCC6 is an ATP transporter, which brings ATP from inside the cell to outside the cell. And there's very little reason to have ATP outside the cell in the extracellular environment, except for to have ENPP1 process that to pyrophosphate and AMP. The AMP goes further downstream and gets cleaved by another enzyme, CD73, to create adenosine. So for the body to sort of be healthy in a normal state, you have regulated levels of PPi and regulated levels of adenosine. In the three diseases that we treat, these levels are dysregulated and are driving the disease. Okay, so you mentioned three discrete diseases: ENPP1, ABCC6, calciphylaxis. Very divergent, different diseases in terms of their manifestation and severity. Even ENPP1 has some variability. You see a significant amount of patients that die within the first six months of life. Maybe just touch on the mechanisms underlying the difference between patient phenotypes. Sure. Yeah, so ENPP1 is a progressive lifelong disease that affects multiple systems across the body. In the sort of most acute or most severe form, it occurs in sort of the infants, and these babies get calcification through their vascular system, calcification of their aorta, of sort of the medium and large size vessels. And unfortunately, have, as you mentioned, Chris, a mortality rate of about 50% at six months, primarily due to cardiovascular disease and heart attacks. Those patients that survive that six-month period, as they grow into childhood, the phenotype shifts more to a bone phenotype, so these kids end up having rickets, bone abnormalities, fractures, bone pain, and that's thought to be more of a protective mechanism sort of of the body. As you have too much calcium, as you grow, that shifts towards the bone, and the bone becomes undermineralized as the body tries to eliminate some of this calcium in the body. They can also get calcification of the bones in the ears, and so these kids often lose their hearing as well. In addition, they still maintain some of the legacy effects from the cardiovascular and calcifications within their vascular system. As they grow older, they get osteomalacia, joint pain, calcification of the ligaments and the soft tissue, and continued concern for fractures. So you get this kind of progressive disease that shows up across different systems and with different clinical phenotypes in these patients. Okay, and so ENPP1 and ABCC6 are also fairly different between the two of them. How do patients get diagnosed with either one of these? And treatment options are somewhat limited, but maybe just walk through what they are. Yeah, so what's interesting with ENPP1 and ABCC6, the phenotype in the infants and patients zero to one is almost identical. They show up in the same way. They both have calcifications in the vascular system of the heart. So clinically, they look the same. And we find out if it's an ABCC6 baby or an ENPP1 baby primarily through genetic testing. And so these are diagnosed by neonatologists, by NICU doctors. A good maternal-fetal medicine can actually detect calcifications by the second trimester through echo or sonogram. And so ultimately, these babies are born very sick, get kicked up to the NICU, and end up getting diagnosed there through genetic testing. As they move to childhood, for ENPP1, it's more of a pediatric endocrinologist. For ABCC6, it's probably pediatric cardiologist. And then those specialties follow these patients through into adulthood. Currently, there's no approved treatment for either disease. You get some symptomatic therapies to measure hypertension, to try to reduce some of the calcification. But all the studies that have been shown show very little efficacy in the disease and just sort of manage some of the symptoms. So you have data, and I would argue it's proof of concept data that's pretty convincing in ENPP1, showing a fairly remarkable increase in plasma PPi levels, which drug's doing essentially what it's supposed to do. But you also have some biomarker data that's pretty interesting: serum FGF23, serum Pi levels. Maybe talk about these biomarkers. What do they mean in the context of actually showing a clinical benefit? Yeah, no, it's a great question. So just to take a step back, so our therapeutic INZ-701 is the active domain of the ENPP1 enzyme attached to Fc fragment of an IgG antibody. So it is a soluble version of the typically membrane-bound ENPP1 enzyme. And so for ENPP1, it's a pure enzyme replacement therapy approach. And so as we talked about pyrophosphate and the importance of pyrophosphate, these patients with ENPP1 deficiency have about 10% normal levels of pyrophosphate. So as Chris mentioned, we've been able to show rapid and sustained increase in pyrophosphate as early as six hours after treatment in these patients. And we've shown some preliminary efficacy looking at in adults, looking at six-minute walk test, as well as some other functional endpoints. But I think what we're excited too about are some of these biomarkers, some of these bone turnover biomarkers that we're able to sort of normalize or show tracking in the right direction. This is an FGF23-mediated disease. And so we're able to see reduction in elevated FGF23. We're able to see normalization of phosphate levels, which are high in these patients. And we're also able to see bone turnover markers like bone-specific alkaline phosphatase, or CTX, track in the right direction. And why this is critical for us is our pivotal study is in the pediatric population. Now, the bone environment in the pediatrics is much more dynamic. It's turning over quickly. And so any effect that we see in the adults should be magnified in this pediatric population. So this sort of proof of concept drug activity that we're seeing in adults should carry through in a stronger, more clinically evident way in the pediatric population. So this is a question I get a lot. You've got ENERGY-1, 2, and 3, right? So ENERGY-1 is phase 1b in infants. ENERGY-2 is your pivotal trial in kids zero to 12 months. And then you've got your ENERGY-3, which is in a broader sort of pediatric trial or population. So a lot to sort of discuss here. But one of the questions I get is, what's the rationale? Why do you have to run all these different studies and not just run one pediatric study? Yeah, it's a good question, and I think it's the nature of the disease. I mean, we love to run one study to cover the whole basis. Because the disease presents so differently in the different ages, more of the cardiac phenotype in the babies and more of the bone phenotype in the pediatrics and adults, we've had to run multiple trials, and I think it also really depends on sort of the endpoint we're looking at. For our infant studies in the ENERGY-1 and ENERGY-2, it's more of a survival endpoint for the babies. For the pediatric population, it's based on rickets, which is by definition a disorder of the growth plate, and so in order to have rickets, you need to have open growth plates, so you're looking at sort of a younger population. In adults, it's more bone mineral density and demineralization of bone. So it's forced us to run multiple trials. But what I think that allows us is when we put our package together for regulators, it allows us to go for a broad label because we've been able to show, or hopefully will be able to show, benefit across all of these different populations. And there is some precedent in that and some other drugs that have shown sort of juvenile onset or early onset of diseases that allow them to treat sort of all populations, all ages. In ENPP1, you have data showing that you can get PPi levels into the normal range. Your ENERGY-3 phase 3, FDA has agreed to using PPi as the sole primary endpoint. Europe wants RGI-C, the Radiographic Global Impression of Change, as a co-primary endpoint. Maybe just talk a little bit about the differences, I guess, in regulatory requirements here. Yeah, I mean, we're real excited that we got PPi as our primary endpoint with the FDA. If you ask our chief medical officer, he said there was no way we were going to get it approved by the FDA. And now he's pleasantly surprised. I think the FDA appreciated the important role that PPi plays in this disease and that it's more than just a biomarker. It's really sort of driving this disease. And so for our ENERGY-3 study here in the U.S., primary endpoint is pyrophosphate. Our secondary endpoint is an endpoint for rickets called the RGI-C, which is a Radiographic Global Impression of Change score. So it just measures improvements in the bone pre-trial, post-trial, and is an endpoint that's been used in multiple rickets trials before. And the agency has told us that they're just looking for trends in the secondary endpoint. EMA took a little bit of a different approach, but by and large, it's the exact same trial. They wanted to see a clinical endpoint as the primary, so we have co-primary endpoints, PPi and RGI-C as co-primary. But they gave us a relaxed p-value of 0.2 for the RGI-C endpoint, so PPi as primary with trends and secondaries and co-primary with a 0.2 p-value for the RGI-C for us is almost an identical study. We're running the studies the same way. We'll just have different statistical plans, and the other thing I think to note, we sort of took the unusual approach of powering the study on the RGI-C endpoint, on the secondary endpoint. If we powered it on the sort of PPi, which we've been able to show, we'd only need a couple of patients, which we knew probably wouldn't fly with regulators. So we powered the study on the secondary endpoint at a 0.05 value, knowing we only need a 0.2 or trends. So we feel pretty good about the study design and are looking forward to finalizing enrollment and getting the year-long treatment period started. FDA is obviously arguably more flexible on that PPi endpoint. But in your infant program, ENERGY-2, zero to 12 months, again, you're only planning on recruiting ex-US co-primary endpoints of PPi and survival. But remind us why you're not recruiting in the US and the interactions with the FDA there. Yeah, so it's interesting. So they were more flexible with our pediatric trial. But when we had discussions with them on our infant trial, or at least our pivotal infant trial, they wanted a placebo-controlled trial in infants. And this was a little surprising to us. This is babies that have a high mortality rate of 50% with no other treatments. And so in our discussions with them, we brought in advocacy groups. We brought in sort of KOLs, which both sort of disagreed with this stance. We actually even got some feedback from some of the academic centers where we were going to run our study that ethics committees wouldn't necessarily approve a placebo-controlled trial in babies with such high mortality. But ultimately, the FDA wanted to see placebo-controlled. EMA was happy with open label single-arm study compared to sort of natural history. So the largest sort of natural history database is at the NIH, and they have about 80-85 patients, all babies who they've tracked. And so for ENERGY-2, which is going to be ex-US sites, we're going to do a propensity matching to the natural history control. For ENERGY-1, it's an open label study that's here in the U.S. But ultimately, when we kind of think about our regulatory package, we're going to combine ENERGY-1 and ENERGY-2 together with our pediatric and adult data and bring that to the regulators. Yeah, I mean, I guess it's all academic at this point. You'll have your data. But when you guys first announced this decision by FDA, my first reaction was, well, this is a mistake. Yeah. Surely, given the ethical considerations, they'll reverse themselves. But they haven't. They haven't. Yeah, it's interesting. We actually were surprised as well. I think there's been some changes in our division of the FDA recently, and I think we've seen a very collaborative approach from some of the new leadership in our division, which we're very excited about. And ultimately, think if we can generate this data, even if it's from sites in Europe, ex-US, sort of bring that back to the agency that we can continue the discussion and sort of align on an appropriate path to sort of approval. Okay. All right. So let's maybe switch to ABCC6. So you've run a phase 1/2 trial. Just in broad strokes, you've got data showing convincingly that you can increase PPi levels, not to the extent that maybe with ENPP1 seems to make sense since these patients do have, to some degree, functional ENPP1 already. What's your impression maybe of these data and how do they predict clinical benefit in this population? Yeah, so we announced the adult data earlier this year, I think back in April. The trial met all endpoints and really did a couple of things. One, sort of it proved our hypothesis that we had shown in animals prior that using an ENPP1 enzyme replacement, that we can show clinical benefit in an ABCC6 deficient population. And so it's not pure enzyme replacement. It's more sort of enzyme kinetics. With ABCC6, since it's the main ATP transporter in the body, if they don't have functional ABCC6, they have less ATP there to be processed by ENPP1. So what do you do if you have low substrate? You dump in a lot more enzyme. And since that enzyme is soluble, it can scavenge and cleave all of the ATP that's present to drive up PPi levels. And we had shown that in animal models. And so now we had shown that we're able to increase PPi in this model. So we have this unique therapy that's enzyme replacement, but it can treat multiple diseases. We also showed that the therapy continued to have a favorable safety immunogenicity profile in sort of a different disease state. And we continued to see PPi levels increase and sustain throughout the trial. We saw some preliminary signs of efficacy looking at two different systems in the body, the vascular system looking at carotid intima-media thickness, as well as in sort of the retina looking at choroid thickness, and saw positive changes there. We also saw positive changes in sort of the VFQ-25 scale, which is a visual improvement scale, as well as in some patients, we saw a reduction in calcium load in these patients over time, as well as positive PROs from both patients as well as physicians. So I think this gives us strong proof of concept that our drug does have potential efficacy in an ABCC6 population, and it's really helped us to think about our next study, our next pivot, which will be a pivotal study in this disease. And so, yeah, and you've got into 2025 starting that. Maybe talk about the timelines leading up to starting that trial. Obviously, you have to articulate the design, gain alignment with agencies. What are the pinch points, I guess? Yeah, so the team has been sort of working hard to put together our study design. We met with the agency recently, and we had a very positive interaction with them. Got some very collaborative feedback, which we're going to take back and help improve the study. And so we look forward to sort of announcing that study next year and then move forward in starting a study subject to some financing and regulatory approval. Okay. So we've got just a few minutes left. I want to touch on your third program, Calciphylaxis. Kind of a horse of a different color, if you will. You've got two genetically driven diseases. Calciphylaxis is something that impacts a more diverse patient population with end-stage kidney disease. Maybe just talk about what that disease burden sort of looks like, treatment options such as they are today, and sort of the setup and what you guys saw in two minutes. Sure. That made you feel like this is important enough to discuss. So calciphylaxis is a complication of end-stage kidney disease. But the cause of it is a result of calcification of the blood vessels in the skin, as well as stenosis and reduced blood flow to the skin. So these patients get painful lesions that end up becoming septic, end up becoming wheelchair or hospital bound, and have a high mortality rate with about 50% in the first six months. So it has a similar driven pathology. We also have a collaboration with the folks at MGH in Boston that have shown a correlation between PPi and disease severity in calciphylaxis, as well as lesion size. And there's some literature that suggests some polymorphisms in the PPi adenosine pathway that may lead to increase in calciphylaxis in end-stage kidney disease. There's currently no treatment. These patients take a lot of pain meds and a lot of sort of wound healing and dressing treatments, but other than that, nothing is available for them. Yeah. So the premise obviously is low PPi leads to calciphylaxis. You ran the CPORT study, right, which showed an increase in PPi levels. Maybe sort of talk about what other clinical data you need to sort of generate to. So this was an important study for us because this was the first study that we were able to show the ability to raise PPi in a non-genetic population. It's also these patients are undergoing dialysis. And so we give the drug once a week, but they're receiving dialysis three times a week. So we were able to increase PPi and maintain that increase through multiple dialysis sessions. We know our drug is too big to pass through the dialysis filter, but PPi can be eliminated through dialysis. So the fact that we're able to sustain PPi levels throughout dialysis is important. And so it's also a population that has high morbidity. And so the fact that we were able to show that same favorable safety profile in this population was a positive. I think we have the data we need to look forward to our next study, which we'll have the discussion if it can be a registration or pivotal study with the agency. Excellent. Okay. Well, lots going on. We have no more time, however, though. So thanks so much for the great presentation. Appreciate it. Thanks, Chris. Thank you.