Good afternoon, everyone. Thank you for joining the 24th Annual Needham Healthcare Conference. My name is Joey Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next company, Inozyme Pharma. Joining us today from Inozyme is Chairperson and CEO Doug Treco. For those of you joining us on the webcast, if you would like to ask a question, please do so at any time. You can submit a question using the chat box at the bottom of your screen. With that, we'll get started. Doug, thank you so much for joining us today. Thanks, Joey. Doug, can you give us a quick high-level overview of Inozyme and your main asset, INZ-701? Sure. Inozyme Pharma is developing an enzyme replacement therapy for a number of rare diseases. They're highlighted by a disease called ENPP1 deficiency, where you're missing an enzyme that catalyzes the conversion of ATP into pyrophosphate. Pyrophosphate is a key metabolite that regulates proper bone growth and proper mineralization of tissue. When pyrophosphate isn't present or at low levels, you get abnormal mineralization throughout the body. INZ-701 is simply designed to give the enzyme back to people who are missing or have mutated forms of the enzyme so that they can generate pyrophosphate to normal levels and reverse the effects of pathologic mineralization. The pathologic mineralization can have a number of effects. It can lead to arterial calcification, tendon and ligament calcification. It also leads to when blood vessels in the heart, for example, become calcified, they don't function properly. Infants born with this disease have a high rate of mortality and morbidity. Finally, when pyrophosphate is low, the normal process of calcification, the normal process by which calcium phosphate forms bone, does not occur normally. You have aberrant calcification throughout the body, and the calcification at the bone is not occurring normally. Our enzyme replacement therapy, we believe, can restore this normal blood vessel function and bone health. You've presented clinical data. You have a registrational program ongoing. I guess, what do you think investors are missing about the Inozyme story? What's the biggest disconnect for investors, in your view? I think the biggest disconnect is kind of what a lot of rare disease companies suffer from early on in the development of a drug. I think we've learned a long time ago that in a rare disease, some physicians may have never seen a patient. When a patient shows up in their clinic or in their office or at their hospital, they may not know exactly what the disease is. They may not know who to consult for that. They may not know how to get a genetic test done for it. Really, at this stage, before there's a drug out there and before there's great awareness, the diagnosis rate is extremely low. The visibility of patients is low. The awareness among physicians is low. I think at an early stage like this, people will question, well, are there enough patients out there? We've never heard of it. I don't know anybody who has that disease, so how could it be very important? As history has shown, a lot of rare genetic diseases that nobody's ever heard of end up being blockbuster drugs once there's education, awareness, and good diagnosis. I think that's probably the biggest thing that people miss, that there's a predictive genetic prevalence of this. We're finding patients and building a registry. Ultimately, you don't really know this market until you have a drug out there and there's good diagnosis and awareness. Let's start with your lead program, ENPP1 deficiency. In background epidemiology, what's the prevalence of ENPP1 deficiency? Can you talk about the differences between biallelic versus monoallelic? How does the disease manifest in different age groups? How are patients diagnosed, et cetera? Sure. The first thing to say is, classically, this is described as an autosomal recessive disease, so you need to have two mutant copies to have the full brunt of the disease. I won't say a lot more about heterozygotes, but we know there are many out there that have a variety of symptoms that range from serious ENPP1 deficiency to a more mild phenotype and some subphenotypes where the abnormal calcification is limited to specific tissue. We do know that there's a number of heterozygous patients out there that are really only kind of an upside for us in the long run. When talking about the patients who have two mutant copies, call them biallelic or homozygotes for mutations, they typically can also have a range of severity. The most severe forms are in infants where they're born with highly calcified coronary arteries that lead to poor cardiovascular function and drive a high mortality and morbidity rate in the infant population. The infants who survive that infantile period, and again, half of them will die before six months, those that survive or may have had a somewhat more mild phenotype will go on and generate almost uniformly rickets. Rickets, as you're probably aware, is kind of the bowed limbs that people have. They grow in a curved structure, knock knees. These children have physical disability. It's also accompanied by short stature, growth defects. Some of the bone abnormalities can be quite severe, leading to a great deal of stigma and pain for these children. Their parents are out looking hard to get them treated. The children who never get treated, they're going to live with that rickets for all their life. They're going to grow up to be adults with physical abnormalities, gait problems, mobility problems. They'll progress into joint and tendon pain and inflammation that further leads to mobility problems. It is a progressive disease with the infants probably having the most acute need. Overall, it's the children who are growing deformed where their parents are out looking to get them diagnosed and treated. That's where we see the biggest unmet need because I think if we can intervene, we can help these children lead a more normal life. Now, you asked about the prevalence. We estimate through fairly, I would say, modern and sophisticated technology being able to calculate the prevalence at about one in 64,000 pregnancies. Now, this is a pretty good estimate because we're now at the stage where we can actually look at huge bodies of sequencing data and count alleles in the population. Rather than just rely on literature or a database, now we can go to big sequencing programs, count alleles, and actually know how many alleles are in the population. You can use simple genetic calculations to determine the actual number based on allele frequencies. There we get to about one in 64,000. That's a lot of people in the whole world. If you just look at the areas where we believe there's good medical practice and ability to get reimbursed for these drugs, and those areas are North America, Brazil, Japan, and Europe, that's about 10,000 patients. With rare disease pricing, which ranges in several hundred thousand dollars a year for a serious rare disease, we believe that if you treat a few thousand patients, you can get to a blockbuster status. It is not hard for us to imagine how you can get this to a blockbuster, even though it would qualify as an ultra-rare disease. You mentioned the 10,000 or so number prevalence in addressable markets. I guess, what's the diagnosis rate? How many or what percentage of those do you think are diagnosed? Is it reasonable to assume that the vast majority of the diagnosed ENPP1 patients would seek treatment, or does this depend on age or a variety of factors? For example, are adults less likely than infants or vice versa to seek treatment? All right. The first thing I'll say is it's highly underdiagnosed. I would be surprised if in those geographies I mentioned, 10% of the patients were diagnosed, probably less than that. That is a huge challenge. That's something that we spend a lot of time and money on. It's kind of a people-intensive process. A lot of it is boots on the ground where we attend conferences and we meet physicians and convince them that maybe you have seen a patient. They go, "Yes, I have. In fact, I know their family. I'll connect you to the family." It's a lot of work, but it's kind of something you have to do because when this drug's ready to launch, we want to hit the ground running. Which age group do you plan to initially target if INZ-701 is approved in ENPP1? Would you seek a broad label, no age restrictions, and is this needed for you to succeed commercially? I think we have a good chance of getting a broad label to treat all ages, but the real focus is on the pediatric population. Those are the patients that are in our pivotal study now. We think those are the ones who can benefit the most from intervention and lead a normal life. However, every baby that we can treat, we will try to treat. I mean, there may be 100 of them born a year in the U.S. and maybe close to that number in Europe. I mean, we're going to treat as many of those as we can. The real goal is to treat the—I mean, they have to be treated. We can save their lives. The commercial market for us is all those children whose parents are out there trying to get them a good diagnosis. I should also point out that not every baby is born so sick that they're known to have the disease on day one. The most severe form of this disease actually has its own name. It's called GACI, generalized arterial calcification of infancy. The babies who are born really compromised, they get diagnosed pretty early. We can look at our database and you can see somebody, they'll have a GACI diagnosis at four years. Obviously, they're not an infant anymore. The physician looks at them and says, "Oh, I see what's wrong with you. I see your bowed limbs. I see your mineralization problem. I see your calcification throughout the body. You had GACI," but they didn't even know it till they were three or four years old. That's the challenge we face. Got it. For ENPP1, you have a pivotal phase 3 program in pediatrics ongoing. You've previously disclosed a completed phase 2 trial in adults, and you've disclosed some initial data in infants as well. I guess, can you walk us through what the clinical development plan is in ENPP1 and what's the roadmap and data required for potential approval here? We know that regulators generally want to see a randomized controlled study to show that a drug's working. We've been able to agree with the U.S. and European regulators that our pivotal study, which we call ENERGY-3, comparing INZ-701 in children age one to less than 13 years old, that we can have a positive effect on both pyrophosphate and on rickets. The rickets is measured by or determined by an improvement looking at before and after treatment X-rays where a panel of readers makes a decision on improvement or worsening. We want to show both of these. I mean, regulators believe pyrophosphate is very important. It's a bioactive molecule on its own. Its generation generates an active metabolite that is preventing abnormal calcification. Given that scientific background, regulators see it as important and have given it primary endpoint status. Now, they also want to see, as a co-primary in Europe and as a trend in the U.S., improvements in the rickets score. We think that we have a very good window to show an improvement in rickets. We don't need to hit it with a traditional p-value of 0.05. It can be hit with a p-value of 0.2 in Europe. We think we have a pretty good window for showing an improvement. To be honest with you, if the drug only increases pyrophosphate with no improvement in rickets, then probably shouldn't be marketing and selling the drug. We really do want to see that improvement. The core of our now, we're optimistic that we can see an improvement because we know of multiple other ways that these bowed limbs, these abnormally shaped bones can change over time because there's other forms of rickets where you can treat with biologic agents, things like Strensiq and Crysvita for HPP and XLH rickets respectively. Vitamin D also, deficiency leads to rickets. These are all changeable in the course of a year. That's because bone turns over very rapidly. If you stop it from growing the wrong way and just let it grow its normal right way, that fixes itself pretty rapidly in physiologic timeline. We're very optimistic that if we are going to have the intended effect, we'll be able to see it in this one-year study. Sorry, go ahead. I was going to add that we're going to supplement that package with data from infants where we're treating them in single-arm studies and adults where we collected data and released that already in a single-arm study there. We think that with a strong package for the pediatric population supplemented by safety and preliminary efficacy in adults and infants, that should be supportive of a broad label to allow us to treat all ages. It's very safe in all those populations. I think that's what regulators are going to look for if they want to see us extend the label outside of pediatric population. Now, you previously disclosed data in infants and adults as we talked about before in ENPP1. Can you just summarize the efficacy data there in particular on the PPi and the RGI-C endpoints? Yeah. In the adult population, those patients are mature. Their bones are not growing rapidly. We don't monitor RGI-C there. We've looked at pyrophosphate levels that went up into the normal range rapidly and stayed there. We also looked at outcome measures like six-minute walk test and patient-reported outcomes where the patients were showing better mobility and better overall feeling. That was also supported by a clinician-reported outcome where they believe their patients were doing better. They stayed doing better throughout the study. We don't think these were placebo effects. We have lots of anecdotes from the adults looking and feeling better. We're encouraged by that. The bone biomarkers in the adults also showed that they were trending towards bone formation rather than resorption. That's what we want to see when we put our drug into a patient. If we see that in an adult, we can be reasonably confident that it'll be exacerbated in a positive way in a child. That is, when bones are turning over more rapidly, these bone biomarkers should turn over more rapidly. The adults give us preliminary evidence of efficacy, excellent safety, helped us pick the dose, and showed us that bone biomarkers change as appropriate. The infants were a slightly different story because we saw something in the infants that we did not see in the adults. We did see we treated five infants. Four of them survived. We are very pleased that although we know that we are not going to save every baby, some of them are born extraordinarily compromised with highly calcified aorta. We are happy we could keep four of the five alive. We improved heart function in the most severe, two of the most severe. Phosphate levels are improving. If your phosphate goes up, then you're not going to get hypophosphatemic rickets, right? It is called that for a reason. You need to have low levels of phosphate. As we're showing in these babies, we're stabilizing or improving phosphate levels. We're reducing calcification throughout the body. The babies who are older are not developing rickets by X-ray, suggesting that stabilizing phosphate and allowing normal growth is keeping these kids from going into the rickets. We did say something else in these babies that we hadn't seen in adults. That was three of the five infants had fairly high antibody titers. One of them had antibodies that kind of looked like adults, very low level. They kind of went away over time. Three of the babies had high titers. We hadn't seen that before. It did not surprise us really because all enzyme replacement therapies have antibodies at some levels. A disease like Pompe has infants have a very significant antibody issue. It is dealt with. It is either dealt with by increasing the dose frequency or a well-established immunosuppression regimen. It is kind of a learning that we have always thought we would need to have with infants, how to treat them best. Not everyone is going to be treated with the same level of ease and simplicity. We believe it is something to learn. Like Pompe, we expect this to be overcome. Like Pompe that treats infants, children, and adults and generates well over $1.5 billion a year for multiple drugs, antibodies in infants are not going to lead to a commercial problem for us. We are going to learn how to deal with it. Ultimately, these kids will get treated. I do think some investors view it as a negative or an impediment. We see it as. The ADA issue. ADA issues as a small issue in our smallest population. I guess just to follow up on that, Doug, on the ADA issue, sorry if I missed this, but did you touch on whether or not they were neutralizing? I guess you are seeing it come up a little bit more in infants, but not so much the peds and the adults. I guess what you're trying to say is that it's certainly or it's manageable going forward, and it's not a significant concern for you guys. Yeah, I think it's fair to say that in every enzyme replacement therapy that's been developed so far, antibodies have not been a problem that's prevented the drugs from being commercial successes. I don't know the standard clinical guidance for a patient with antibodies for an ERT is keep dosing because you'll probably tolerize them, and they'll get benefit regardless. I don't know of any case where patients are taken off drugs or where they're not getting reimbursed because they have ERTs, I mean, ADA. We generally think that it's a solvable problem in a small fraction of our market. The adults were largely clean. You did ask if they're neutralizing. That was the difference between the low levels we saw in adults that went away over time and the much higher levels in the infants that are increasing the half-life of or decreasing the half-life of the drug. For all intents and purposes, they neutralize the benefit to some extent. We'll call them neutralizing for lack of a simpler word. They do impact exposure. To that end, what you'd typically do, our first try would be, if the half-life is shorter, let's just increase the frequency of dosing. The hope there, and already, we're starting to see the kind of effects that we want to see there. Again, if necessary, we could immunosuppress, which has been done very successfully in Pompe. Those babies have an excellent outcome. Where do you stand on the long-term safety exposure requirements needed for regulatory approval? I think regulators want to see multiple treatment years, patient treatment years of exposure. There's no hard and fast rule for the number of patients you have to treat. Regulators often like to say 100 patients for a year. We're in that ballpark. I don't think we're going to have a big problem with the safety database. The safety with this drug profile has been excellent. Every patient who's on the drug either does home injection themselves. I think one patient has a nurse because they have vision problems, but they get it at home. All the babies who are sent home with drug, their parents are injecting that in their own home. I can't think of a more positive thing to say about the safety of a drug than a parent can take the drug out of their fridge, dilute it, and inject it into their baby in their own home and not have any issues. We are very pleased with that. Yep. The phase III ENERGY-3 pediatric trial, data coming in 1Q 2026. Can you give us a quick walkthrough on trial design and endpoints for that one? Yeah. So it's a randomized study with a control arm of standard of care, which is typically phosphate and vitamin D supplementation. So the standard of care are compared to treated patients. It's a two-to-one randomization. So we have twice as many treated as untreated. It's a one-year study. We closed the enrollment in January of this year with 27 patients. We calculate that with the statistical requirements needed in Europe, we still have a greater than 90% chance of showing benefit. It's powered for that. So we're very confident that and that benefit is in the RGI-C. So the endpoint for the study in the U.S. is pyrophosphate rising above sorry, compared against the untreated and a trend in the rickets score. So the U.S. has given us primary endpoint status for PPi, pyrophosphate. They want to see a trend in the rickets. They want to show these patients more likely than not are getting better in their bone phenotype. In Europe, it's a co-primary between pyrophosphate and the rickets score. They only need to see the rickets improving with a p-value of 0.2. We think that's a fairly relaxed window for showing benefit. As I said, we kind of modeled this off of other rare disease drugs where they've been used to treat rickets in a similar time period. We're fairly confident that the basic biology of bone is similar. That is, the bone turns over. If you stop it from growing wrong in the wrong way, it'll just start growing in the right way. Other things do it in that time period. We don't see why we would not have as good a chance as any for seeing an improvement. For the PPi endpoint, is it changed from baseline or responder analysis? And how will that be assessed? Oh, there'll be all kinds of analysis. All we need to show is a significant change from baseline. We'll also show a comparison to the control group. We have multiple time points that we can do repeated measure analysis. Regulators, even though they want to see your endpoint being different from your baseline, they want to make sure it didn't all happen in the last week, right? They just want to see some consistency. We'll have multiple measures. In the adult study, PPi went up to the normal range within three weeks, stayed there with continued dosing. Again, we're giving patients back what they're missing. The mechanism of action and the therapeutic hypothesis is pretty simple. Doug, you alluded to it earlier, but anything else you can disclose on the stats plan for the ENERGY-3 trial? You mentioned powering, assume effect size, things like that on both primary and secondary endpoint, the RGI-C. Yeah. So the RGI-C is, it's an X-ray-mediated procedure where a panel of trained readers will hold up a before and after X-ray and ask, did it get worse, much worse, very much worse, or better, much better, very much better? So it's a seven or no change. So it's a seven-point scale. Interestingly, if you look at something like Crysvita, their difference between treated and untreated was a numerical value of about 1. So on that seven-point scale, it was improving by about 1. That does not sound like the highest bar. Statistically, we do not need to get that big a difference. In fact, we are powered to see a difference between treated and untreated of about 0.7 and still be significantly different with a 90% power at a p-value of 0.2. So we think we have picked a number that is reasonable to achieve. Yeah. Got it. In terms of the PPi, you talked about RGI-C, but what's the bar for success on the PPi primary endpoint? It only has to go statistically significantly above background. It's probably not, I mean, regulators want to see both, right? We're confident we can achieve that. We think it's an important thing to monitor and know can happen. We also know that the parents who are putting these kids in the trial want to see their kids getting better at the pathologic level. We're just expecting we have to see that. The one or two other things I'll say about this, though, are that because we can get PPi into the normal range, we think we want to be in the normal range because I earlier alluded to the fact that we know of a lot of heterozygotes who have lower PPi levels and have distinct pathology. Some of them aren't as bad as the patients we're treating. Some of them are. We've seen patients who we thought would get into the adult trial who ended up being heterozygotes. We were surprised because the textbooks say autosomal recessive. This was news to us. We generally think that getting PPi into the normal range is a good thing. Getting it into a half-normal range is probably very good also. I think that the drug gets you into the normal range, and we're probably expecting to see people normalize. If they don't, they're still going to see, I think, huge benefit from going from a very, very low even into a heterozygous range. Can you describe some of the key secondary endpoints such as RSS and growth Z-score? Measuring this both week 26 and I think week 52, is the analysis on those done at week 52? How important are these from a regulatory and commercial perspective? Yeah. Yeah, the primary analysis is week 52. I should also add, and I always forget to mention this, at the end of a year, the patients who were not treated, they get drug. We will follow both sets of patients at least for another year in this study. We will ultimately follow those treated patients for a longer time or the initial treated ones. The ones who cross over in a year will be followed. The other endpoints, RSS is another way of qualifying rickets. The RGI-C is a measure of improvement in rickets. The RSS is an absolute measure of severity of rickets. To get into our study, you needed to have a certain severity of rickets as measured by the RSS. Our trained reader looks at every patient and decides, do they have a score of 1, 1.5, 2, 2.5, 3, whatever. You have to have a score of 2 to get into our study. That was picked knowing that half of the patients, half of the patients that we think are ill that would come to us needing treatment, we still are going to exclude half of them because they need to have a certain level of rickets. We've continued to have arguments with some of the kids who didn't get in or their parents because the kids were in pretty bad shape, but they just didn't get to that point, that 2 level. We have, I think, a very good starting point that is a fairly high burden of disease to see a change from the RSS score. The RSS score will be then reevaluated later. Hopefully, they'll end up with an absolute rickets score, not an improvement score for the RGI-C, but an absolute score that's lower than where they started. Again, we really only need to see them supporting the primary endpoint. Yeah. The growth, I think most patients with bone deformities like this end up with Z-scores, meaning they're outside of normal growth for their age, usually significantly lower. We expect that to improve with these children. Again, kids who are starting out 10 or 11, later in the age range may show smaller improvements than a 2, 3-year-old. We have a pretty broad range of ages in here also. Again, we continue to follow infants, several of which have aged into toddler age now. Doug, last question from us. It's on cash runway. What's your current cash position and your expected cash runway? We have cash until first quarter of next year. As many of you know, we put out our earnings release in March of this year. That was a bit of a clearing event because we made some announcements on programs. In particular, we're pausing a couple of our key programs. Two other diseases we think INZ-701 will be very valuable for, another genetic disease, ABCC6 deficiency, and an acquired disease called calciphylaxis. We're pausing them. We're not going to spend anything on activities related to them. We're really going to focus all of our efforts on ENPP1 because getting one approval is more important than spreading out your resources and potentially getting no approval. We have money till we get data from this program. We have announced $113 million in the last earnings release. We're hoping that investors will see that the program focus, unfortunate headcount reductions, spending reductions really cleared the path for us to get to data and that they'll see that is important. I think I say we have, yeah, I said the cash we have in the bank, right? Yeah. No, that's great. That's very helpful. Doug, thanks so much for participating. It was a very useful discussion. Great. Joey, thank you. As usual, thank you and Needham for your support. Thanks, everyone, for joining us on the webcast. Have a good rest of your day and a good rest of the conference.