Good morning, and welcome to the Inozyme Pharma conference call. All participants will be in listen-only mode. Should you need assistance, please signal a conference specialist by pressing the star key followed by 0. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then 1 your touchtone phone. To withdraw from the question queue, please press star, then 2. Please note this event is being recorded. I will now like to turn the conference over to Stefan Riley, Director of Investor Relations. Please go ahead. Good morning, and thank you for joining us for the ENPP1 Deficiency Program update call. Before we begin our formal remarks, I would like to point you to our forward-looking statements disclaimer. I would like to remind you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined in the company's recent filings with the Securities and Exchange Commission, which we urge you to read. We undertake no obligation to update or revise any forward-looking statements to reflect new information or future events, except as required by law. Our actual results may differ materially from what is discussed on today's call. I would now like to turn the conference over to Douglas Treco, Chief Executive Officer and Chairman of the Board of Directors of Inozyme Pharma. Please go ahead. Thank you, Stefan. At Inozyme, we are developing transformative therapies for rare diseases of pathologic mineralization and intimate proliferation. Our lead program addresses abnormal calcification of tissue and bone due to extremely low plasma levels of inorganic pyrophosphate, or PPI, caused by a deficiency in the enzyme ENPP1. ENPP1 deficiency is a serious disease of the vasculature and skeletal systems that causes a range of debilitating symptoms in infants, children, and adults. There is no approved therapy. Available treatments for patients with ENPP1 deficiency do not address the underlying cause of the disease. With a prevalence of 1 in 64,000 pregnancies worldwide, we estimate there are around 10,000 patients in major addressable markets. We are addressing ENPP1 deficiency by enzyme replacement therapy with INZ-701, a biologic product candidate comprised of the extracellular domain of ENPP1 fused to an immunoglobulin FC domain. In our ongoing phase 1/2 study of ENPP1 Deficiency in adults, INZ-701 has demonstrated rapid, significant, and sustained increases in plasmic pyrophosphate levels and exhibited a favorable safety profile. We reported safety, pharmacokinetic, and pharmacodynamic data from this trial in February of this year and plan to provide an interim clinical update with respect to the first three cohorts in September of this year. In anticipation of initiating a pivotal trial in pediatric patients, Inozyme today would like to discuss the status of the program and some of the details of the trial itself. We believe that pediatric patients represent the population with the greatest unmet need. These are children with bone abnormalities characterized as rickets, mobility and gait problems, and who can suffer stigma due to their skeletal deformities. We are pleased to have finalized our pediatric pivotal trial design with change in plasma pyrophosphate, a well-characterized natural inhibitor of calcification, as a primary endpoint for assessing the efficacy of INZ-701 enzyme replacement therapy. In the U.S., PPI is a sole primary endpoint, supported by trends in appropriate secondary endpoints assessing rickets, which include the radiographic impression of change or RGIC, the Rickets Severity Score, RSS, as well as growth Z-scores. In the European Union, the Pediatric Committee of the EMA, or PDCO, approved our pediatric investigation plan for the pivotal study with co-primary endpoints of PPI and RGIC. The statistical P value is relaxed with a target of less than 0.2 for the RGIC endpoint. The same study, patients and data, will be collected for both the FDA and the EMA, with the only difference being the statistical analysis of the secondary endpoints. We are very pleased to be in a position where we have a clear path forward on our global development strategy. My colleagues will now tell you more about the disease, our planned pivotal trial and regulatory strategy, the outstanding efforts we're making in identifying patients, our strong cash position, and our anticipated data and study milestones that reflect our strong momentum executing on our timelines. To do this, I'll now turn the presentation over to Yves Sabbagh, our Chief Scientific Officer. Yves? Thank you, Doug. I want to take a moment to orient you on the importance of PPI, which is a potent inhibitor of mineralization. On the left side of the slide, you can see how this molecule functions in the normal state, where it physically blocks the interaction of calcium and phosphate. On the right, when you don't have enough PPI, calcium and phosphate can come together and form these crystals that get deposited in the wrong parts of the body, such as in the arteries, where they can cause cardiovascular complications, and in the bones, where they can cause skeletal complications. In third-party studies, plasma PPI levels have been shown to correlate with the skeletal phenotype severity, as shown in the three gram. As expected, heterozygous patients have 50% of healthy PPI levels, and homozygous patients have about 10% of healthy PPI levels. These levels translated into a dose-dependent effect on key bone parameters such as cortical and trabecular thickness. This highlights the importance of PPI in the pathogenesis of the disease. We move to the next slide, we show that ENPP1 deficiency is a lifelong disease. In infancy, ENPP1 deficiency is known as GACI, or generalized arterial calcification of infancy, which has an overall mortality estimated to be approximately 50% within the first 6 months of life. Children who survive GACI will develop multiple chronic complications that affect multiple systems and develop ARHR2, or autosomal dominant hypophosphatemic rickets type two, due to low phosphate levels via renal phosphate wasting, which impedes normal bone growth and maturity. These skeletal complications persist through adulthood and are known as osteomalacia, leading to bone and joint pain and stiffness. On the next slide, I will show you what are the main players in producing PPI and adenosine in the body. Extracellular adenosine triphosphate, or ATP, is metabolized by ENPP1 to produce PPI or pyrophosphate and AMP, which is a precursor of adenosine and is processed by CD73 downstream. On the next slide, what's shown is when you have mutations in ENPP1, you have low levels of PPI, and you can imagine those patients have lots of calcification in various tissues and skeletal abnormalities. To address this deficiency, if you go to the next slide, we designed an enzyme replacement therapy called INZ-701, where we generated a soluble form of extracellular domain of ENPP1, which was fused with an IgG-Fc fragment to circulate throughout the body and access ATP and restore the missing enzymatic process. Our therapeutic objective is to use INZ-701 to replace the missing ENPP1 activity, to restore PPI and adenosine levels back into the physiological range to prevent and halt further disease progression. In order to evaluate INZ-701 in the clinical setting, we needed a robust and sensitive assay to measure accurately plasma PPI. We therefore developed a validated assay using an ATP sulfurylase luminescence-based method to measure PPI in human plasma. This same assay was used to establish our healthy volunteer range of PPI in a study of healthy subjects. This is shown on the right side, where we obtained healthy volunteer samples under controlled conditions of overnight fasting in 10 healthy subjects. As shown, there is a low intersubject variability, but the data also highlights that there are some intersubject variabilities that exist. On the next slide, we show that with INZ-701 and our PPI assay, we initiated a phase 1/2 study in adult patients with ENPP1 deficiency. As shown in the graph, the patients had really low levels of PPI levels at baseline, as shown by the red symbol. INZ-701 increased plasma PPI within 6 hours after the initial dose, represented by the first black dot, and the plasma PPI levels rose into the healthy subject range and remained sustained through week 48, with twice-a-week dosing. These results demonstrate that INZ-701 rapidly increased plasma PPI into the healthy subject range in our ongoing phase 1/2 trial, which we're very pleased to see. I will now pass it on to Kurt Gunter, our Chief Medical Officer, who will give key regulatory updates on the ENPP1 program. Kurt? Thank you very much, Yves. At Inozyme, we have achieved important regulatory milestones. We have recently had important interactions with the FDA and the Pediatric Committee, or PDCO, of the EMA, regarding the design of our ENERGY-3 study, a pivotal trial of INZ-701 in pediatric patients with ENPP1 deficiency. We are pleased that we have finalized our pediatric pivotal trial design, with PPI as a primary endpoint in the U.S. and as a co-primary endpoint with radiographic global impression of change, or RGIC score, in the EU. On the clinical side, we continue to progress patients through our adult phase 1/2 study and have recently begun dosing in a fourth dose cohort at 1.2 milligrams per kilogram to evaluate once-weekly dosing. We look forward to providing additional interim data from cohorts 1 to 3 of this study in September. We are excited that we dosed the first infant in our ENERGY-1 study, a phase 1b clinical trial of INZ-701 in infants with ENPP1 Deficiency, and I will be providing more information about the design of this study later today. Finally, we are on track to initiate the ENERGY-3 pivotal study in October of this year. Let's discuss some of the details of the ENERGY-3 trial design. ENERGY-3 is a randomized, open-label, pivotal study in children from 1 to less than 13 years with ENPP1 Deficiency, and is designed to assess the impact of INZ-701 on PPI levels and rickets in these children. Patients will be treated at a dose level of 2.4 mg/kg once weekly in the active arm, and patients in the control arm will receive conventional therapy, consisting of oral phosphate and active vitamin D. Patients will be followed for 1 year in the randomized treatment period, and all patients will transition to INZ-701 after 1 year of ENERGY-3 is a single global clinical trial with differences in the statistical treatment of endpoints based on guidance from the FDA and PDCO. In the US, PPI will be the sole primary endpoint, and in the EU, the co-primary endpoints will be PPI and RGIC, with a relaxed P value of less than 0.2 for RGIC. I will be describing the RGIC scale on the next slide. The RGIC scale is an accepted quantitative score for rickets and skeletal abnormalities and has been used to support approval of other therapies to treat genetic forms of rickets. The RGIC measures worsening or healing from baseline in predefined skeletal abnormalities. As you can see from this example, RGIC is a sensitive method used to determine relative changes in skeletal abnormalities in XLH or X-linked hypophosphatemia. Because each form of rickets has disease-specific radiographic features, we are developing an RGIC system specific for ENPP1 deficiency, using our extensive library of radiographs from our natural history database. Let's move on to the design of ENERGY-1 study. As mentioned, we have now begun treating a patient in this clinical ENERGY-1 is a single-arm, open label clinical trial of INZ-701 in infants from 1 month to less than 12 months of age with ENPP1 ENERGY-1 is designed to assess the safety and tolerability of INZ-701 in infants and establish an optimal dose level for a pivotal study in infants. Patients will be treated at dose levels ranging from 0.2 milligrams per kilogram once weekly to 0.6 milligrams per kilogram twice weekly, with the option for intra and intrapatient dose escalation to higher dose levels based on recommendations of the Data Review Committee. Patients will also be followed for changes in plasma PPI, pharmacokinetics, survival, and other clinical outcome measures, as shown here. On the left side of this slide, you can see a high-level overview of our ongoing and planned clinical trials in ENPP1 deficiency. We have just discussed the ENERGY-1 and ENERGY-3 trial designs. ENERGY-2 is a planned single-arm pivotal trial of INZ-701 in infants to be conducted outside the U.S. We intend to leverage our natural history database to provide control data for the ENERGY-2 trial. ENERGY-004 is a planned randomized study of INZ-701 in adolescents and adults, initiation of which is subject to regulatory discussions and appropriate financial resources of the company. We will be providing more details on our ENERGY-002 and ENERGY-004 trial designs at a later date. Putting it all together, we anticipate that our regulatory application package will consist of full data from our ongoing adult phase I/II clinical trial and our planned ENERGY-003 clinical trial, as well as available data from our ongoing ENERGY-001 trial and planned ENERGY-002 clinical trial. In addition, we anticipate that our planned marketing applications will be further supported with additional comprehensive data demonstrating the clinically meaningful benefit of PPI. If these marketing applications are approved, we expect to commercially launch INZ-701 for infants and pediatric patients as early as the second half of 2026. We anticipate the ENERGY-004 study in adolescents and adults will be completed after the ongoing and planned infant and pediatric trials, and therefore, expect the data from ENERGY-004 will be filed as MAA and BLA supplements. Now, I would like to introduce Matt Winton, our Chief Operating Officer, who will provide an update on the commercial opportunity, as well as our ongoing patient identification efforts. Matt? Thank you, Kurt. It is fantastic to see the continued progress being made in our ENPP1 clinical program. Today, I'm excited to share the advancements that we are making in educating the medical community, improving time to diagnosis, and identifying patients. These efforts are critical as we strive to capture the significant opportunity of the ENPP deficiency market. The latest genetic prevalence estimate of ENPP1 deficiency is 1 in 64,000 pregnancies worldwide, which translates to over 10,000 expected patients in major addressable markets such as North America, Europe, Japan, Brazil, and the Middle East. We have boots on the ground in key geographies working to identify patients. We continue to believe that a significant number of people living with ENPP1 deficiency remain undiagnosed or misdiagnosed. At Inozyme, we recognize the importance of early and accurate diagnosis for patients with ENPP1 deficiency. Therefore, we are actively working to reduce existing barriers to diagnosis and are fortunate to have the support and engagement of the patient and physician communities, including our strong partnership with GACI Global, a ENPP1 patient advocacy group. Creating awareness among healthcare professionals is key to building a successful rare disease franchise. Our experienced medical team is actively engaging a growing number of HCPs through individual touch points and via meetings at key medical congresses. In addition to raising awareness and educating the patient and medical communities, we have launched several important initiatives to enhance access to and use of genetic testing. We are collaborating with PreventionGenetics, Centogene, and Rady Children's Hospital to supply free genetic testing to physicians treating suspected ENPP1 deficiency patients. We are a founding member of the BeginNGS program and are working with several genetic diagnostic companies to increase the inclusion of ENPP1 in their genetic and newborn screening panels. We are also in discussion with governments outside of the U.S. to increase the availability of newborn screening globally. Our ongoing patient identification efforts have yielded promising results, with over 750 identified patients with confirmed, known, or suspected ENPP1 deficiency as of the end of May 2023. This is approximately 50 additional patients since our last update. Among them, over 250 have both a clinical and genetic diagnosis, while over 300 have a clinical diagnosis only. Additionally, we have found over 200 patients that are suspected to have ENPP1 deficiency through claims database searches and innovative AI approaches. At present, our database is enriched for pediatric patients, with the majority being from the US, the four large European markets, and the UK. We are encouraged by the fact that the list of countries where we have identified patients continues to grow. In preparation for the start of the ENERGY-3 trial, we are leveraging our patient database to identify physicians that have eligible patients at or near trial sites. We have already flagged approximately 80 patients that we feel fall into this category and have earmarked an additional 100 patients for whom we will confirm their eligibility and interest through planned outreach in the coming weeks and months. We believe that this proactive approach will help with timely enrollment of ENERGY-3 pivotal trial. In summary, our ongoing engagement with the medical community and patient identification efforts, coupled with the sizable commercial opportunity and significant patient and caregiver burden, make ENPP1 deficiency an attractive market for Inozyme. We believe that our investigational product candidate, INZ-701, holds tremendous promise in addressing this unmet medical need and are confident in our ability to execute our strategy. With that, I will hand it over to Sanjay Subramanian, our CFO. Thank you, Matt, and good morning, everyone. I'm pleased to share that we estimate that we have cash equivalents, and short-term investments as of June 30, 2023, of $140.2 million. This enables us to extend our cash runway guidance. We expect that our cash equivalents, and short-term investments will enable us to fund our cash flow requirements into the first quarter of 2025. All of us at Inozyme are working tirelessly towards developing INZ-701 to help address diseases of abnormal mineralization. On this slide, you will see that we have a number of anticipated clinical milestones over the next 3 years towards our goal. I'd like to focus your attention on the nearest term anticipated milestones. This September, we plan to report interim data from the first 3 cohorts of our separate ongoing phase 1/2 clinical trials in adults with ENPP1 deficiency and ABCC6 deficiency. The following month, in October of this year, we plan to initiate our first pivotal trial of INZ-701 in pediatric patients with ENPP1 deficiency. Following today's regulatory update, the wind is in our sails to realize our mission of meaningfully improving the lives of patients with these rare diseases. With that, we can begin the question and answer session. Operator? We will now begin the question and answer session. To ask a question, you may press star, then 1 on your touch-tone phone. If you're using a speakerphone, please pick up the handset before pressing the keys. To withdraw from the question queue, please press star then 2. At this time, we will pause momentarily to assemble our roster. The first question will come from Tazeen Ahmad with Bank of America. You may now go ahead. Hi, good morning, and thank you for the very detailed update. A couple questions from me. As far as the process to get sorted on the trial designs, did you have to have a series of conversations with the regulators in the US and Europe? Did you try to kind of coordinate, you know, what would be the requirements and try to design a trial that would address both? Secondly, I was curious as to why separate trials, specifically by the age brackets, as opposed to maybe trying to do one study and potentially having, you know, different cohorts for each age group? Just curious as to what makes more sense and why you decided to do the separate studies. Thanks. Okay. Hi, this is Kurt Gunter. I think that one should be addressed by me. The first part of the question is, did we have multiple meetings with regulatory authorities, and did we try to coordinate our clinical trial program? The answer to that is yes and yes. To give you a little more detail, we've had scientific advice meetings in Europe with several different national regulatory authorities, as well as the EMA. We've had the typical pre-IND meetings with the FDA, and of course, we've had ongoing written correspondence with the FDA. We conducted a Type C meeting with the FDA earlier this year. Last year, we started a process with the EMA through their pediatric committee called PDCO to establish a pediatric investigational plan. After we got advice from the FDA at the Type C meeting, we submitted a modification to our pediatric investigational plan or PIP. We recently met with the Paediatric Committee to try to totally harmonize ENERGY-3. The most part, we succeeded, but as you see, we were left with minor differences in how the endpoints are analyzed. In our minds, it's not a big deal to overcome. Even though RGIC is a co-primary endpoint, it has a relaxed p-value of 0.2, and really, in our minds, that's similar to analyzing for trends, which is what the FDA asked us to do. Also, we have scientific advice pending with the EMA on our entire program, but we've heard from PDCO that they're talking to the CHMP at EMA, so we don't expect a lot of feedback from scientific advice that would change our overall plans. We're, you know, we'll have ongoing dialogue with regulatory authorities about the other studies, too. Your other question was has to do with why we have separate studies for the different age groups. I think that's a really good question. We debated that long and hard. In the end, we thought that it made more sense to have separate studies because as Yves and Doug explained, the phenotypes of these different age groups are quite different. We also thought that it would... pediatric patients would probably enroll more quickly than adult patients, and we wanted to be able to bring a product to market more quickly in the pediatric groups. I think that summarizes our thinking on that point. Okay. That's a lot of good color. Maybe just a quick follow-up: Any sense on how this could translate into a pivotal trial design for CC6 in the future? What was the question? Any thoughts? Just I want to make sure I understand the question. Any read-through. Any Any read-through from this trial design, for PP1, on how you think a pivotal would need to look like for CC6? Specifically, could you use, PPI as a primary for that population, do you think? I think there'll be limited read-through. We are seeing significant elevations in PPI in the ABCC6 adult study, as you know. The PFC is a different kind of disease, and I think that will be very clinically endpoint focused when we get to doing those studies. Okay. Thank you so much. Our next question will come from Marc Frahm with TD Cowen. You may now go ahead. Great. Thanks for taking my questions, and congrats on all the progress with the different regulatory agencies. Maybe just starting with ENERGY-3, the FDA, you know, kind of looking at trends, do you expect them to mostly focus on RGIC also, like the youth focused on it? Or, do you think they're gonna look more broadly across or be more focused on a different way of measuring kind of the bone dynamics? Right. Thank you for the question. You know, I think an important principle at a regulatory agency is that when you're faced with a small clinical trial, and we have to run small studies because this is a orphan disease, you want to take advantage of every datum in the database to analyze the safety and efficacy of the drug. I'm sure most regulatory agencies are gonna look at all the secondary endpoints. Okay. Then ENERGY-2, you know, get that it's gonna start initially outside the U.S. What still needs to be done to kind of bring that to the U.S. and finalize the design with the FDA? Is it just getting some more safety data ENERGY-1, or, you know, are there really design elements that are still under discussion? I think the answer to, again, another good question. Thank you for that. The answer is both, all of the above. We definitely are gonna be collecting survival data as we go ENERGY-1 and safety data as well. ENERGY-1 will determine the dose for ENERGY-2 study. We will plan to start ENERGY-2 ex-U.S. We did discuss ENERGY-2 design with the FDA previously in the Type C meeting. We plan to have ongoing discussions with them about the design of ENERGY-2. We'll start it in the U.S. once we reach agreement with FDA. Yeah, this is Doug. I'd just like to add to that, you know, I think the FDA has suggested that a randomized study would be appropriate in the infant population. We've found it difficult to find a randomized design that works well. In particular, you know, for a indication where there's about 50% mortality, neither investigators, patients, or their families, you know, really have much interest in participating in a randomized study. So you know, we continue to look, we will continue to have discussions with FDA, but we believe that having, 2 trials, designed to collect information without 20 patients in a single-arm study will be good support for a broad label. I'll also say that these studies were agreed upon with PDCO, and they felt that the single-arm study approach was appropriate. You know, we have good regulatory support for that in Europe, and we'll continue to see if we can come up with something that works with the FDA. But that said, we're prepared to go ahead with single-arm study and take the go with the totality of the data with the agency. Kurt? I'll just add that when you look, historically at a number of orphan diseases and enzyme replacement therapies, it's not unusual to see, single-arm studies performed in infants. Okay, that was very helpful commentary there. Maybe just finally on from Sanjay, just on the cash runway guidance, can you just confirm, does that include advancement of ABCC6 into the phase 2, or is that outside of it? Hey, Marc, hey, good to talk to you. It's a good question. So we see this, we have an ongoing trial in ABCC6, the phase 1/2 trial. We're gonna see that through, and as we indicated in the milestones, we will have top-line results on that one for the 3 cohorts in Q1 of next year. Results from that will kind of shape the design for a subsequent trial. So we will be, at that point in time, look at appropriate regulatory pathway as well as funding to kind of continue potential phase 2 trial for ABCC6. Okay, thank you. Congrats again on all the regulatory progress. Next question will come from Chris Raymond with Piper Sandler. You may now go ahead. Hey, thanks a lot, and congrats on the progress here. Just a couple questions. I guess, maybe first on the ENERGY- 4 and the adult program that you have going writ, maybe writ large on adults. I'm sorry if this was already talked about, but I don't see it in the press release. What is the timing for that fifty- fif- for that endpoint? Is it 52 weeks or is it longer? Maybe first on that. Then on ENERGY- 4, on the bone mineral density measure, can you maybe remind us how quickly we should expect to see changes in BMD in adult patients? I think, I remember you guys saying that, you know, the impact that you'd see, in BMD would be, you know, most markedly seen in younger patients. Just talk about the expectation in adults. Thanks. Sure. We, regarding the design ENERGY-4, we haven't released any details on that yet. We do anticipate it'll be a study of about one year. We will be measuring bone mineral content, bone mineral density. We know that patients with ENPP1 Deficiency, once they, their growth plates close, they develop osteomalacia, and we think DEXA is an excellent way to measure the density of bones and the mineral content of bones as well. We think that'll be a useful outcome measure in ENERGY-4. It won't be the only secondary endpoint ENERGY-4. we'll also have functional testing, measures of pain, and patient-reported outcomes, and we'll be doing bone biopsies as well. Maybe I should let Yves, our CSO, talk about the timing for anticipated changes in bone mineral content and bone mineral density in a clinical trial. Thanks, Kurt. Like you stated, you know, bone turnover is quicker in children, so we do anticipate changes to be quicker. Again, in adult trials, within 6-12 months, you should start seeing some changes in BMD. We also have bone biomarkers that follow and usually start changing before you start seeing some changes by DEXA. I think a reasonable time point would be, again, a 1 year trial for the adults to see BMD changes. Oh, thank you. Maybe just a quick follow-up. On ENERGY-3, in the co-primary endpoint of RGIC, just looking back at your data that you presented before, I think we've seen GIC data, but not radiographic GIC. Can you just confirm, is that correct? Just maybe help us understand, you know, the difference there and get comfortable with treatment, you know, the impact on RGIC. Right. Good question, and possibly some nomenclature that could be improved. I'll just say this, that we previously presented data from our adult phase I/II study on global impression of change, and that's a patient-reported outcome. It's also reported by physicians as well. As you may recall, in that phase I/II study, we saw improvements in the GIC score, as we call it. This is simply a patient-reported outcome, where either the patient or physician assesses overall, how is the patient feeling at that specific point in time compared to baseline. It has nothing to do with radiographs or X-rays. The radiographic global impression of change is a different beast. It is a quantitative way to assess changes in skeletal abnormalities. The way we'll do it is by collecting, images in a standardized manner through a centralized vendor, at baseline, and then at 6 months and 12 months in the study. Transferring those images to a central committee of expert radiologists who are blind as a treatment assignment, and they will assign a RGIC score. Despite the similarities in the name, these are quite different, outcome assessments. Yep. Thank you. I should add that we will have the global impression of change patient-reported outcome in all of our studies. Our next question will come from Joseph Stringer with Needham and Co. You may now go ahead. Hi, good morning. Thanks for taking our questions. A couple from us on the pediatric ENPP1 program. Just to clarify, for the primary endpoint, is it relative or absolute change in PPI? Just curious, given some of the healthy volunteer work that you've done, are there any requirements from either agency around PPI normalization or getting those levels within a certain range? Second question is, on the RGIC score, you mentioned that you're designing this or modifying it specific for ENPP1. Just curious, is that something that will ultimately be the same for both FDA and EMA endpoints? Are both of those agencies sort of on board with how you're going about designing this? I suppose follow-up would be any modifications that you'd have to make to the Rickets Severity Score or RSS? Thanks. Okay, those are all good questions. Thank you for those. I'm gonna address them backwards. The RSS, we're not gonna be modifying the RSS. We'll use the original RSS as described by Thatcher et al. The RGIC score, we're working with an academic group, an outside group who's extremely qualified with a lot of experience in RGIC, to develop our scoring system. It'll be the same across all regions, and we'll, you know, produce a report. I'm pretty sure the regulatory agencies will want to see how we did it and how we validated it, but we're feeling good about where we are with that, based on our extensive library of radiographs that we're using to construct it. Regarding PPI, we are not planning to set up the trials to in a responder, non-responder type of analysis. We're gonna be measuring the differences between the control group and the treatment group in overall PPI change. We'll be measuring PPI concentration over time, and so we'll be utilizing PPI changes at all time points, using a mixed model, repeated measures type of approach. All that said, we really don't expect to have too many issues with PPI. In our phase one study, we've shown that a single dose of INZ-701 takes PPI up into the normal range that's established by Eve and his colleagues. I hope I answered your question. Yes, that's great. Thanks so much for taking our questions. Next question will come from David Nierengarten with Wedbush Securities. You may now go ahead. Hey, thanks for taking the question, and two quick ones on the statistics, if you could. Is the statistical analysis in the U.S. the same p-value for Europe on the primary endpoint for pyrophosphate lowering? Then in September, when you release additional data, will we, will it be maturing enough to see any or have any statistical analysis on the PPI levels in those patients? Thanks. Okay. Thank you for the question. We anticipate that the statistical approach to PPI itself will be identical between Europe and the EU. In September, we're only gonna be providing updates from the adult phase I/II study, although there obviously will be a PPI update there. I should clarify or go on to explain that there will be differences in how the secondary endpoints are handled between the US and Europe. In US, the FDA has stated, we should analyze the secondary endpoints for trends supporting the primary. In the EU, what we plan to do is utilize a co-primary endpoint alongside PPI. That will be RGIC at a relaxed p-value of less than 0.2. Let me just add that we believe or we're under the assumption that we'll be success on PPI will be assessed at a traditional p-value of 0.05. So in the phase I/II data that we presented in February and what we'll continue to update, we are seeing p-value change from baseline with a much below 0.5. 0.05. Great, thanks. Yeah, 0. Yep, yep. Cool. That's what I wanted to know. Thanks. Our next question will come from Nalin Tejavibulya with Jefferies. You may now go ahead. Hi, thank you very much for taking my questions. First question is. For the PPI measurements, could you please discuss a little bit more in terms of what range of inter and intrasubject variability we can expect? For the second question, for currently approved ERTs across various indications, such as for Gaucher, Fabry, Pompe disease, HPP, ADA-SCID, for example, they're all approved based on, you know, clinical endpoints. I understand that PPI is a key inhibitor of calcification and, you know, can, as an approvable endpoint in pediatrics and adults with ENPP1 deficiency. Could you please provide some clarification on what data helps bridge the gap on, you know, how plasma PPI increases would improve bone mineral density and rickets symptoms, and why the regulators are now comfortable with permitting the use of a biomarker as a primary endpoint? Thank you very much. Hi. We... You know, I think regulators, you know, sort of accepted that, you know, the literature has shown, you know, going back 60 years or so, that pyrophosphate itself is a bioactive molecule. It is an inhibitor of calcification. You can add it to solutions of calcium phosphate, and it'll prevent precipitation. It's not a signal in the body that, you know, something happened and then this marker is changing. It is, in fact, an inhibitor of calcification. We believe that, you know, that information was important to regulators in deciding that changes in pyrophosphate are more than a biomarker. That have cover, a dynamic marker of efficacy. So, I think it's likely that the science itself led them support this idea. You know, I'll also add that we have a lot of data from animal studies showing that raising PPI correlates with clinical benefit. I think the data that Yves presented, looking at heterozygotes. Now, heterozygotes are typically either asymptomatic or much lower level of symptoms than homozygous patients. I think that does reflect the continuum of pyrophosphate's effects on the symptoms of these various diseases. I mean, there's a lot of data out there on the correlation. I think regulators kind of accepted that as being, you know, kind of rising above your typical biomarker. I'll turn it over to Yves now to talk about the variability that is expected in these patients. Yeah. Thanks, Doug. As you saw in the graph I showed on the healthy volunteers, there is a inter-subject variability. We've realized that different people could come in at a different set point of their PPI, and we expect to have the same in the patient. What I can say is, most of the patients that we have in our trial adults, and we have now some data with our assay in kids as well. Their PPIs are within 80%-90% lower than the mean of the healthy volunteer range. We have some that have PPIs in the low, below 100, the nanomolar, compared to the mean of 2,000 of healthy, and we have others about 200-300. There is a range between the patients, but what we've seen in the adult trials is that we do see a big response in the PPI, in the patients, across the doses. Sorry, could you enter an intra-subject variability in terms of the difference between, you know, the measurements taken at different time points as opposed to different population, please? We have published the data in the healthy subjects, where we did evaluate fasting, overnight fasting, meals, and exercise. What we realized is the time, overnight fasting with no exercise, first thing in the morning, was the best, the lowest intra-subject variability that we can see. This is what we have been doing in our phase 1, ongoing adult Phase I/II trials, as well as the infant trials that we've initiated, where they are first thing in the morning, PPI and fasting, if possible with the infants. This was the best time to have the lowest intra-subject variability. There's a lot of data in the literature on PPI in patients. However, they're not done with a validated assay. They're not done under controlled conditions, It's really hard to make conclusions on, you know, different papers, looking at pyrophosphate levels. Everything we do is done, you know, central labs, validated assay, controlled sampling conditions, to ensure that we have the lowest intrapatient variability. It's a big issue. But yeah, we had to develop our own clear assay for that. We do see it. There's, there is could be up to 20% or more differences in the PPI between the two different individuals. The responses we've seen in our trial are, they go on a mean of about 400% increase in PPI. It's beyond any standard deviations that we would see, where the inter-subject or intra-subject variability might influence data. We're not concerned about that at all. Thank you very much. Our next question will come from Ed White with H.C. Wainwright. You may now go ahead. Good morning. Thanks for taking my call, my question. You're developing the RGIC specific for ENPP1. I'm just wondering if that's going to be a gating factor for the timing of data? Thank you for the question, and the answer to that is no, it will not. Okay. And- We're progressing. We've engaged a group who's already almost completed the exercise. It has to be in place, before we dose patients. Yeah, so it should not be, a gating item for collecting data. Okay, thanks. Do you expect to release the PPI and RGIC top-line data at the same time, or do you expect that data to come in differently, and would you report it if the timing is different? I think that when we release top-line data for this study, which is anticipated mid-2025, that we will have the RGIC data at that point and all those secondary endpoints, as well as PPI available at that time. Great, thank you. Just a last question. As an update on the Phase 1b study that you're enrolling patients in the U.S., you reported that you enrolled your first patient at the end of June. I'm just wondering if there's any update there as to the number of patients that you have enrolled there? We are not updating the number at this time. We're pleased with the progress. Yeah, we're just excited to be able to be treating infants here now. Yeah, we'll update that in the future. Great. Thanks for taking my questions. Sure. This concludes our question and answer session. I would like to turn the conference back over to Douglas Treco for any closing remarks. Thank you. I'd like to thank you all for attending today's presentation. I'd also like to thank the patients and families who have been and will be participating in our studies, as well as our team members, which have been relentless in their efforts. We look forward to updating you all in the future. This call is now concluded. Conference is now concluded. Thank You for attending today's presentation. You may now disconnect.