Spyre Therapeutics, Inc. (SYRE) Earnings Call Transcript & Summary

Welcome, everyone, to the 39th annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by Tessa Romero and Matt Bannon from the team. The next presenting company is Aeglea. And presenting on behalf of the company, we have CEO, Anthony Quinn. Before I turn it over to Tony, I just wanted to highlight for those on the webcast would like to submit a question, please use the Ask a Question feature and the portal, and I'd be happy to ask the question on your behalf. With that, I'll turn it over to Tony.

Great. Thanks, Anupam. Thanks for the invitation. So good morning, everybody. I'm very pleased to join you virtually at this year's JPMorgan conference. So at Aeglea, we are thinking differently about the science of human enzymes. We're reimagining the potential of these natural catalysts to benefit people with rare and devastating metabolic diseases with limited treatment options. We've made substantial progress over the last 12 months despite the operational challenges due to COVID-19, and I'm very much looking forward to sharing the progress we've made and the upcoming milestones with you today. Please note, I may be making forward-looking statements. We are a clinical stage biotechnology company that specializes in rare metabolic disorders. Our mission is to deliver metabolic harmony so that patients and their families have a chance of a better life. So to deliver on this promise, we're focused on developing innovative medicines that can address the imbalances that drive these metabolic diseases. We believe that by engineering small changes in human enzymes, we can have a really big impact. We've made significant advances in pioneering new generations of human enzyme therapies, where enzyme approaches have not historically been considered possible. Our most advanced program, pegzilarginase, is currently in a Phase III pivotal trial. Our second clinical ready program, AGLE-177 is a novel recombinant enzyme that can lower homocystine levels. And our platform sets us up nicely for additional attractive opportunities, including our most advanced research program, which is a highly innovative enzyme-based solution for cystinuria. Slide 5 outlines how we're looking beyond the conventional to unlock the potential of human enzymes. We've got very specific expertise in rare genetic diseases with validated metabolite targets. The nature of the work that we're doing and the expected transformative impact allows for an efficient and agile development process with a transition into a targeted commercialization model. So I'd now like to get to our most advanced program, pegzilarginase. Arginase deficiency is a debilitating progressive disease with early mortality, high unmet medical need due to a genetic disorder of arginine metabolism. This is a rare condition with at least 2,500 patients in the major addressable markets. The hallmark of arginine deficiency is high arginine levels, and it's these high arginine levels which cause many of the severe disease manifestations, including the characteristic spasticity, which begins in early childhood. We often talk about the medical aspects of arginase deficiency, focusing on the clinical manifestations of the arginine levels. But what truly matters is the experience of the patient and the families who live with this disease. So what I'd like to do today is share with you a video of Izea and his mother, who're going to share their perspective on what they have to face every day as they navigate the challenges of living with arginase 1 deficiency. [Presentation]

So as you can see, Izea is still young, and he hasn't yet experienced the impact of some of the more devastating disease manifestations. You can sense Izea's mother's fear of what's going to come and the heavy burden in the family of knowing that the disease is going to progress. And every day, the family struggles to manage Izea's condition, and they're not alone. So on Slide 9, let's highlight the significant unmet medical needs that remain for these patients. So even with standard of care, patients are not able to control plasma arginine levels, which means that the disease continues to progress. And the standard of care itself is actually a challenge. The dietary restriction is so severe that patients often become malnourished and it's incredibly difficult for the patients to maintain such a strict diet on a long-term basis. We have already got substantial clinical experience with pegzilarginase in patients with arginase deficiency. You can see here the baseline and the safety data from our Phase I/II and open-label extension study. As you can see on the right, pegzilarginase has a favorable safety profile. As of September of last year, we've given over 1,350 doses, with approximately 500 via the intravenous route, giving us a very robust safety database. The majority of the adverse events that we've seen are mild and decreased over time. And the most common serious adverse events were hypersensitivity, which only occurred early in the treatment course were manageable, and hyperammonemia, which is an expected complication of the disease. So moving to the next slide, you can see that pegzilarginase markedly and consistently improves plasma arginine control over time. So beginning from week 8, we achieved plasma arginine goal levels of less than 200 micromolars, with many patients achieving plasma arginine levels in the normal range. This effect is sustained through the 56-week analysis, which demonstrates excellent long-term control of plasma arginine. So on Slide 12, you can see that this marked improvement in plasma arginine is accompanied by a high overall clinical responder rate of 79% at week 20, with durability of that high clinical responder rate through week 56. The striking clinical improvements that we've seen far exceeded what we expected when we started this work on this devastating progressive disease. And the insights on the component mobility scores and the overall clinical responder frequency in these studies give us the high confidence in the Phase III PEACE trial on our clinical trial endpoints. So moving to PEACE. This is a 6-month double-blind placebo-controlled study with 20 patients on pegzilarginase and 10 on placebo. The primary endpoint is plasma arginine reduction. The key secondary endpoint gives us the same type of mobility assessments that we've used to capture clinical benefit in the Phase I/II and the open-label extension study. So I'd like to give you an update on where we stand on enrollment for PEACE. The significant second COVID wave has really created a challenging limited access environment, which has been impacting our ability at some of the sites to schedule and complete those important initial screening visits. So despite this, we've made progress continuing enrolling the trial. And as of January, we're about 75% of our target enrollment. As we previously mentioned, we've got -- identified nearly twice as many patients at the clinical trial sites, and that's why we're confident in our ability to complete enrollment and once we can safely bring patients up to the clinic. We continue to build our understanding of the arginase 1 deficiency landscape. So we've used a genetic prevalence-based model. And using that model, we believe that there's at least 2,500 patients in the major addressable markets, with more than 250 patients in the U.S. and more than 260 patients in the EU4 plus the U.K. We've been able to continue our momentum with our patient finding activities, and we've actually now identified more than 300 patients. And of those 300 patients, approximately 160 are in the U.S. And that's important because that represents about 65% of the genetic prevalence-based estimate in the U.S. So patient identification is an important focus at Aeglea, and it will continue to be so. And we're going to continue to invest in this important activity, which represents one of the 3 pillars that underpin a successful launch. So we recognize that physicians and payers, our key stakeholders, they play a critical role in helping patients access new innovative therapies like pegzilarginase. We've built a scientific communication plan to ensure that physician specialists recognize the disease and the potential role of pegzilarginase in disease management. And that brings us to our third pillar. We must build the infrastructure the distribution network and the payer relationships that are required so that these patients who can benefit from this therapy have access to this therapy. Our commercial planning is underway, and that will basically help us not only successfully launch pegzilarginase, but it's going to serve as an important foundation for Aeglea's future rare disease portfolio. So just to recap, we're continuing to make great progress with pegzilarginase despite the challenges of COVID-19, and we're confident in the opportunity to benefit a patient community with clear high unmet medical need. We've generated compelling data in our Phase I/II open-label extension on both the arginine lowering effects and the clinical impact of pegzilarginase. Our Phase III PEACE trial is ongoing with data expected in Q4, and we continue to make progress with our patient finding efforts and are building a strong foundation for commercialization. Our second program, AGLE-177 is the product candidate from our homocystinuria program. Homocystinuria is another debilitating progressive chronic disease with early mortality. So in addition to the disease burden and the risk of sudden unpredictable thrombotic, current treatments such as the severe lifelong protein restriction, really adversely impacts the quality of life for both the patients and their families. So homocystinuria is a much more common rare metabolic disease. We estimate there's at least 15,000 to 18,000 patients with the B6 nonresponsive form of the disease, which is the most severe type in the major addressable markets. So one of the things about homocystinuria, it's actually difficult to simply look at a patient and tell that they have the disease. And this masks the significant challenge that these patients and their families face every day as well as the severe complications that's always at the back of these patients' minds that they can experience, including that risk of early death. So what I'd like to do is share with you a video of Elliot and his family who talk about their experience with homocystinuria. [Presentation]

So similar to arginase 1 deficiency, I think we can see through Elliot story the challenges that is families are facing, particularly around diet and medications that are needed to manage this disease. I think this highlights how current treatments are not adequate to control the disease and how they and themselves, in addition to the disease burden, introduced a significant burden to the patients and their families. We see key -- 3 key areas of unmet medical needs in patients with homocystinuria. Firstly, therapy resistant patients, patients at high-risk of noncompliance and patients who are intolerant of other current treatments. One of the great things about homocystinuria is that the natural history is well understood. And the natural history study that's been done is important for 2 reasons. Firstly, it demonstrates clearly the severity of the disease and the early mortality. And then the second thing is that there's a clear link established between the risk of death and the risk of serious complications and the plasma homocystine levels. So our therapeutic approach to treat homocystine is focused on controlling homocystine levels in the plasma. Now what's important in the plasma, homocystine exists in 2 forms. It exists as a monomer, and it exists as a dimer, which is called homocysteine. And that most of the homocystine in the plasma is in the form of the homocysteine 4. So what we did is we used our platform to design an enzyme that can metabolize both homocystine and the homocysteine which is the dominant form in the blood. So Slide 23, what you can see on the left, you can see that we're able to efficiently lower plasma homocystine levels in a mouse model of homocystinuria. And what we can also see on the right in the survival curve, you can see that without treatment, these mice die very quickly, and we looked at a low, medium and high dose, and you can see we saw a survival advantage with all of those 3 doses and related to the lowering of the homocystine levels. We also went on to look at the abnormalities in affected organs. And you can see this on Slide 24. So the liver is abnormal. It progressively gets worse. With treatment, which lowers the homocystine levels in the blood, we get correction of the disease-related abnormalities. And then we also have looked at the bone. So patients get osteoporosis, the mice get osteoporosis and lowering homocystine levels in the mice with 177 leads to an amelioration of the osteoporosis. So our focus now is to establish proof-of-concept for this program in our first-in-human study. So Slide 25 gives you a snapshot of the trial design. So Part one involves an initial IV dose, and then we're going to switch to part 2, which involves escalating subcutaneous doses. What we're going to see from this study is we're going to see safety and tolerability data, we're going to get pharmacokinetics data, and we're going to get those first insights in patients about the lowering of homocysteine levels with 177. And that's really important because that proof-of-concept in humans is going to set us up for discussions with the regulators about the path to registration for this important program. We're working closely with our sites and investigators. We've reached out to several patients to begin the process of scheduling appointments, pending COVID-19 restrictions. And one of the things that we've done in addition to the sites in the U.K., we're working to open sites in Australia, and this should help mitigate some of the COVID-19 outbreak and risk and restrictions that are currently in place in the United Kingdom. So in summary, we are very excited about the opportunity we have with this program. There is a significant unmet medical need, particularly with the patients that are nonresponsive or don't tolerate common therapies. We believe that we have an enzyme therapy that's designed to lower both homocystine and homocysteine. It's a differentiated approach to treat this difficult disease homocystinuria. So let's now move on to our broader human enzyme platform. So our belief is that there is a significant untapped potential in human enzyme therapeutics, and we are working to design solutions for a range of rare diseases through our active enzyme engineering platform. As an example, Slide 28 provides an overview of our most advanced research program, which is actually focused on lowering urine cystine levels in patients with cystinuria who get kidney stones. So cystinuria patients get recurrent kidney stones from an early age. They get frequent episodes of abdominal pain. There are multiple admissions to hospital and multiple subsequent interventions. In addition, they get high blood pressure, and they are a risk of chronic kidney disease. So in healthy people, cystine gets filtered into the urine, it gets then [ pulled ] back out in the urine, get back into the blood, that keeps a level of cystine low and that's when we don't give stones. In cystinuria patients, they can't pull the cystine back out of the urine. They have this high concentration of cystine in the urine, and that leads to stone formation. So moving to the next slide. This is an example of how we're taking an innovative approach to using human enzymes. There is no human enzyme that metabolizes cystine. So we took another enzyme that metabolizes chemicals similar to cystine. And by making some targeted changes in the enzyme, we've been able to create a human enzyme with novel cystine metabolizing activity. By lowering cystine levels in the blood, we can lower cystine levels in the urine and reduce stone formation. And you can see on the right-hand side of the slide, when we took our enzyme into a mouse model cystinuria, you can see that the end -- the lowering cystine levels in the urine with this enzyme is highly effective in preventing stone formation in this mouse model even when fluids are restricted. So we continue to unlock opportunities for innovative therapeutics with unique mechanisms. So you can see here, it's another metabolic disease. There's more than 5,000 patients in the major addressable markets that are high levels of a metabolite is considered to be important in disease pathogenesis. So we've designed an enzyme to lower levels of this metabolite. And you can see that when we dose the mouse model of the disease, we've seen these phenotypic improvements in the disease model due to the lowering of the metabolite. So we're really -- we're looking forward to be able to share more details with you about this over time. So let me leave you today with a few closing thoughts. 2021 will be a critical year as we expect data from our pivotal Phase III trial of pegzilarginase and arginase deficiency as well as progress our proof-of-concept Phase I/II study of 177 in homocystinuria. We've focused efforts in developing therapies that address high unmet medical needs in areas with limited or no competition. We're looking beyond the conventional to identify innovative therapeutics for patients with rare and devastating metabolic diseases as we pursue our vision to be the premier human enzyme company. So to do so, we've positioned Aeglea to redefine the potential of human enzymes deliver disruptive solutions and change the lives of patients and their families for generations to come. Thank you.

Okay. We'll get started with the Q&A here. Tony, if you want to introduce a broader team on the line, we can get started.

Yes. Thanks, Anupam. So I'm joined today by Charles York, who's our Chief Financial Officer and Head of Corporate Development.

Good. Maybe I'll start out the discussion here with, you noted, I think, last week that the PEACE trial was 75% enrolled. You mentioned it in your presentation today. The completion guidance was now adjusted to March 2021. And the goal post on enrollment has moved due to COVID a couple of times. Like what gives you the confidence? And what are the push-pull levers to meeting this guidance? You mentioned you've got 2x the number of patients identified at these sites. But what gives you the confidence here?

Yes. So in terms of push-pull levers, every push-pull lever that is in our control, our teams have been working on with the sites. So having the patients available, being able to make sure we can get them up to hospital and transport them to hospital, facilitating that process. However, it's important to understand that with COVID, it's a really unique situation because there are some other levers that we do not have direct control over. And so I think we are prepared with everything we can do, but we do have to recognize that COVID is a very unique situation and we don't have control of all the levers. And to be honest, it's been very frustrating is that we've got the patients at the sites, we know the physicians want to get the patients into the clinical trial, the patients want to get into the trial, but the access to the hospital is limited because of the current COVID situation. It's also very variable and I mean we've had examples of in hotspots of COVID where we've actually been able to get somebody up and get them into the study. So it's very variable and unpredictable. But based on all of the information we've got at the moment, we -- based on that information we have at the moment that we can have this trial enrollment completed by the end of March.

Got it. I don't know if I said this before, but if you want to ask it -- if you want me to ask a question on your behalf for all the folks on the webcast, please send your questions through the e-mail portal, and we actually have a couple here. The first one is given the fact there's been some allergic and anaphylactic reactions to COVID vaccines attributed to peg components, how are you thinking about the peg component of pegzilarginase and what's been observed?

Yes. So we did see transient and low-titer anti-peg antibodies early on, during -- when we started dosing. Those antibodies disappeared very quickly. And we -- as I say, we've been continuing to dose these patients and frequently -- once weekly, we've giving a huge number of injections now. So we think it's something that we need to be aware of. But we were already aware of that because we knew that there was -- there is significant peg exposure in the community, and it's something that you need to be aware of. But it's really not much -- hugely different from some of the other things. Some of the enzymes that have sialic acid groups on them, people have pre-existing antibodies to sialic acid groups and glycan groups like [indiscernible] groups, they have those as well. So it's one of those things that you need to manage, but it's not a concern.

Okay. The second e-mail question we have here is how well does diet address the clinical manifestations of both arginase 1 deficiency and homocystinuria? Maybe from a relative basis, how does it compare to PKU?

Yes. In terms of arginase deficiency and diet, it has a very limited impact. And the reason for that is -- so the goal of the diet is to try and limit the amount of arginine and arginine precursors that are in the diet. And the challenge is that a lot of the arginine in the body is not coming from the diet. It's actually coming from normal tissue turnover. And then in the patients, it comes because the liver actually manufactures a lot of arginine. So really, you do see a very small reduction of arginine levels with diet, but it's really has a very limited effectiveness, which is why the magnitude of the changes that we've seen are so impressive. Homocystinuria is more like phenylketonuria, and that the if you're really obsessive with the diet, there is -- you can clearly get levels down. However, that being said, some studies that have been done with people on diet and on medication, they're still running really high levels. And I want to remind you that the normal level of homocystine, I think up from a normal, it's round about 15%. So the thresholds that have been set at a 100 for B6 nonresponsive patients and 50 for B6 responsive patients. The only reason they're set in that 50 and 100 is that those are realistic targets because it's not realistic at the moment to think about getting a patient with B6 responses down to levels of 50 and even lower than that.

Got it.

And I think one thing just above all you can see in the video you can see that measuring out the protein and trying to control the protein. And I think we're all fortunate that when we were looked after, when we were younger by our parent, they would do these type of things. But you can imagine being a 24-year old off at college, trying to kind of juggle that with all of the other things in your life, it's very difficult.

Yes. Tony, maybe in the context of the prior question and given your statements just now, how are you thinking about sort of placebo response and PEACE? Are you expecting -- it doesn't sound like you're expecting significant changes in arginase 1 levels here?

Yes. The arginine levels are pretty -- they don't fluctuate much at all. And we also know that because when we designed the Phase I/II in open-label extension study, we actually had a period where they came off drug. And as after they've been off drug for 4 weeks, their arginine levels basically bounce back up to very high levels. So these patients have persistently high arginine levels, and we have a very marked impact on plasma arginine with pegzilarginase. So we're not expecting much movement of arginine in the placebo at all, and we are expecting a very big reduction similar to what we've seen in the open-label extension study. There hasn't been a placebo-controlled trial in arginase deficiency before. And unlike some other rare diseases, where there's been more activity like Duchenne muscular dystrophy and other diseases like that and cystic fibrosis. And so we've had to rely on talking to experts about what do these patients look like in the clinic on a week-to-week basis. And the bottom line is that their disease is the same or it progresses over time. They don't have periods where we certainly see marked improvements in their spasticity and in their ability to work and carry out tasks.

And on the Phase III PEACE study, is there a clinically meaningful reduction in plasma arginine levels that you're looking for? Or what's clinically meaningful there? Or would you present the data as the portion of patients that have normalized? And is there a clinical threshold there that would be meaningful?

Yes. So the primary endpoint is looking just statistically significant reduction in arginine levels between patients on placebo and patients on ACTIVE. We do -- and one of the secondary endpoints, the current clinical guidance is to get arginine levels less than 200 micromolars. It's a little bit like homocystinuria, and that's been set to a level that you might be able to achieve. Although reality, all of the patients in our study were bit above that and to start with. So that will be a secondary endpoint looking at the proportion of patients who are less than 200. And we'll also have that secondary endpoint looking at the proportion of patients who have arginine levels within the normal range. So just to remind you, in our open-label extension study, all of the patients on the week 56 analysis had arginine levels less than 200, same at the week 20, and a significant number actually within the normal range, which is unheard of for this disease.

We've got another portal question here, which is, have you done any preliminary payer analysis on what you could price pegzilarginase and maybe even homocystinuria? Is the question.

Yes. So we've got a very good understanding of the payer landscape and understanding of reimbursement of these innovative therapies that address high unmet medical need with a big effect. So this -- a few things are important, the first thing is, what's important is, is this a serious disease, severe disease? The answer is yes. The second thing is, is that progressive disease and does it progress to bad outcomes? The answer is yes. And then the third thing that's important is, what's the magnitude of the treatment effect that you're actually seeing? Are you seeing a small treatment effect? Or are you seeing a big treatment effect? And what we've seen from our open-label extension study is we are seeing clinical improvements that look like a big treatment effect. So as an example, one of the patients that we've seen could not walk up a flight of stairs at baseline and was able to walk up a flight of stairs with minimal assistance after having been on the drug for 20 doses. So I think we -- so we understand the landscape. We tick all the boxes. And obviously, that's going to be an important part of our work as we move forward through our Phase III study and towards registration.

Let me turn it over to Tess from the team. I think she has a couple of questions on homocystinuria.

Yes. Thanks, Anupam. Yes, I was just -- I think the homocystinuria Phase I/II study, I think that initiated, I think, in June last year. Can you remind us kind of what are the expectations on how quickly you can enroll that study? And sort of how you're thinking about maybe additional data? Would you need to move through what cohorts? Would you need to move through all cohorts before we see some data there? Can you just remind us there.

Yes. Okay. Good. Yes, we moved that program really quickly through preclinical development. We scaled out the manufacturing. We did the toxicology studies. And then the timing was less than perfect in terms of arriving in the U.K. in the middle of COVID. So we've been using the time in terms of raising awareness from the patient community, working with the investigators, making sure that these patients that we've identified are potential candidates for the trial. And as I say, it's the same problem elsewhere at the moment, which we've actually started -- we're reaching out schedule appointments. But it's -- the issue at the moment is Phase I/II study and there's limited access to hospital facilities for a variety of reasons, either there's a government lockdown, the hospitals are overwhelmed with managing COVID patients, which means -- and then the thing we've had recently is, which I don't think is a surprise, with the high infection rate of COVID in the community, sites are now saying that they actually have got to delay things because some of their staff are actually now down sadly with COVID-19. So what we plan to do is that we will announce when we dose the first patient. And once we dose the first patient, I think we feel at that stage that we'll have a better understanding of the cadence of how that's going to progress. In terms of data, we prefer to present data at scientific meetings, and we have to have a significant -- we have to have an adequate volume of data -- meaningful data to go to a scientific meeting and present. And again, we'll be looking at that as we kind of move forward. But you're right, it is an open-label study. So we will get important insights during the course of that study. But that's a plan. We'll dose the first patient. We'll announce that. Once we've announced the dosing, we'll give an outline of the cadence of the -- likely cadence of enrollment and also expectations about data presentation.

Okay. But it sounds like you're raising awareness of the study in the meantime.

Absolutely. We're engaging the physicians, engaging the patient community. And then as I say, the other thing I emphasize is when we started with this study, homocystinuria is a more common metabolic disease. We knew from talking to the sites with our arginase program that they had a number of patients. But obviously, with COVID, what we've done is we've recently gone to Australia to get regulated authorization and actually sites in Australia to actually mitigate some of that U.K. COVID risk that we're seeing at the moment.

We've got another question in the e-mail portal here, which is, can you discuss some of the gross motor function end points of GMFM-D, GMFM-E? How are those assessments done? Are they independent measurements?

Yes. So the GMFM is gross motor function, and there's a number of parts, but we are focused on Part D and Part E. So the background to these assessments is they were originally developed for patients with cerebral palsy to assess the severity of the disease and the impact of therapeutic interventions. So you might say, well, why would you use something that's developed a cerebral palsy? Well, the reason is those assessments are tailored to patients with spastic diplegia. So patients with cerebral palsy have spastic diplegia. Patient with arginase deficiency have spastic diplegia. And a natural fact, we know that patients with cerebral palsy sometimes -- arginase efficiency, sometimes get misdiagnosed as cerebral palsy. So what the tasks involve is -- it actually involve performing a standard set of tasks. The GMFM-D is mainly focused on standing and sitting. So just as an example, tasks like having your arms folded and been able to stand up from a chair. And then the Part E is more challenging. It involves running and jumping and walking up flights of stairs. flight -- I mean just as a -- flights of stairs is really difficult for somebody with spastic diplegia because of the height for extended legs. They tend to trip on the stairs. So the most of tasks have been specifically designed as tasks that test out the ability of things that have adversely impact by specificity responsive diplegia. And so that's the background. And as I say, we're really pleased with those tests about -- we've shown for the first time that a, they can capture [ clinic ] disease burden; and b, they're highly effective at actually being able to capture the improvements that we're seeing in these patients.

Okay. We don't have any e-mail questions here. But I'll ask you a quick final question, which is, Tony, in the presentation, the January 2020 update on arginase 1 deficiency patient counts up to 300 now. That's a global number. But I'm just wondering, what's being done internally to kind of help standardize the diagnosis process, both in the U.S., Europe globally? Because my understanding from talking to physicians is that people have different levels and different criteria for diagnosing this disease and it's heterogeneous. So it makes patient identification may be difficult.

Yes. So I think the disease itself is straightforward to diagnose. If you have -- but you have to do -- I mean if I -- [ water ] diseases. If you think of and don't think them and you don't do the test, you're not going to make the diagnosis. So from a point of view of somebody who's got spasticity, measuring arginine level, it's very clear-cut that the arginine levels are elevated and then they do confirmation with genetics. I think some of the things that you might be hearing is newborn screening is available in the U.S. in 34 to 50 states. And I think there is a little bit of controversy about the newborn screening because different states set different thresholds. So what that means is that -- I think California is actually one of the states the more -- states with a more sensitive threshold. If you look at some of the patients that were diagnosed in California and you looked at their levels and then you looked at the criteria used in other states, then they would not get picked up by newborn screening in the other states because of the threshold and threshold used. And there's always that tension between false positive and false negative. The other thing that's important is there is an inherent limitation of metabolite testing for arginase deficiency. And we see the same thing with homocystinuria. So about only less than half of the patients with homocystinuria get diagnosed based on the metabolite present above, okay? With arginase deficiency, you can miss cases. And the reason is twofold. One is when babies are born, their physiology is different and their arginine levels are not particularly high at birth, and then they increased markedly over the first 2 to 3 months. And then the second thing that can happen at birth is the mother's blood cells may get into the fetal circulation. Now it's unfortunate that mother's red cells are absolutely stuff full of arginase. So that actually can spuriously lower the levels of arginase. Yes, so I think where we are at the moment, the newborn screening is it's good to have it in 34 to 50 states, but it's also important to communicate about the limitations and people to understand that even if you had newborn screening, you can miss the diagnosis. But I think one of the other things that's happening in the background at the moment is the increasing interest in actually using DNA testing to actually identify patients. So we know that the panel has now been developed of genes and diseases that cause epilepsy. So if you've got a patient with epilepsy, now you don't have to think, you basically take do the panel, and it will test all the known mutations. So it's important to make sure we get arginase deficiency onto those panels. There's also a panel for hereditary spastic paraparesis. At the moment, pediatric neurologists don't know their arginase deficiency looks for HSP. We're educating them and they are -- once you tell them, they see it. And the importance of that is if we get arginase deficiency on that panel, it's going to help with the diagnosis. So just to summarize, newborn screening is a good place to start. It does have its limitations. And we've got a strategic effort beyond just metabolite testing to basically address those limitations.

Great. Tony, Charles, I want to thank you guys so much for a productive session this morning. Super informative. Really appreciate it. Hope you guys have a great rest of the day.

Thank you. Thanks, Anupam. Thanks, Tessa.

Thanks, Anupam. Thanks, Tessa.