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

Good afternoon, and welcome to the Aeglea BioTherapeutics KOL & Patient Caregiver Webinar on Arginase 1 Deficiency. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Aeglea website following the conclusion of the event. I'd now like to turn the call over to your host, Anthony Quinn, President and Chief Executive Officer of Aeglea BioTherapeutics. Please go ahead, Anthony.

Yes. Thank you for joining us this afternoon for our KOL & Patient Caregiver Webinar on Arginase 1 Deficiency. I'm very excited about the speakers we have for you today who are experts in this rare disease as they are the ones that treat and live with arginase 1 deficiency. Next slide. Please note that this webinar may include forward-looking statements under the Private Securities Litigation Reform Act. Actual results might differ materially from those projected in the forward-looking statements. Additional information concerning factors that could cause actual results to materially differ includes, but is not limited to the types of statements identified as forward-looking in our periodic reports filed with the SEC and available on our website. These statements should not be relied on as predictions of future events. And please note the additional disclosures on the bottom of this slide. Next slide. So Aeglea, we're thinking differently about the science of human enzymes. We're reimagining the potential of enzyme therapies to address the imbalances that are found in rare metabolic diseases. We believe that by engineering small changes in a human enzyme that we can have a big impact, benefiting patients and their families who are living with rare and devastating metabolic diseases where there's limited treatment options. So our lead program is pegzilarginase for the treatment of arginase 1 deficiency. So please note that pegzilarginase is investigational and safety and efficacy have not been established. Arginase 1 deficiency is a rare debilitating progressive disease with early mortality and high unmet medical need due to a genetic disorder of arginine metabolism, leading to high argin levels. In December 2021, we announced positive top line data from our PEACE Phase III pivotal trial, and we expect to submit our BLA to the FDA in the first half of this year. We're really excited about this program and are pleased that we've been able to bring together experts in the disease who can share their experiences with you today. So while the focus of today's call is Arginase 1 Deficiency, I do want to take a moment to remind you of the other programs in our pipeline. We're currently enrolling patients and generating data for our second clinical program, AGLE-177 for the treatment of homocystinuria, and we expect to share clinical data this year. We're also advancing a third program, AGLE-325 for cystinuria through IND-enabling studies this year as well. Next slide. So to start off for us today, Dr. Barbara Burton will provide an overview of the disease, diagnosis and currently available treatment options. Dr. Burton's clinical and research interests are focused on inborn errors of metabolism and newborn screening. She is an investigator in numerous natural history studies and clinical trials of new therapies for various metabolic disorders. She is a past President of the Society for Inherited Metabolic Disorders and the Chicago Pediatric Society. We next have Dr. George Diaz, the Principal Investigator for PEACE, and he'll walk you through the approach to treating arginase deficiency with an enzyme therapy and the clinical data that we've generated to date. So Dr. Diaz serves as the Director of Mount Sinai's program for inherited metabolic diseases, which is one of the largest metabolic disease treatment programs in the country. So his clinical focus is urea cycle disorders and is a site principal investigator for the NIH-funded urea cycle disorder consortium. So I'm also really grateful to have Tanja Brandt join us today. So Tanja will share her story on what it's like to be a mother of an arginase 1 deficiency patient from the day-to-day lives to their experience participating in the PEACE study. It's because of patients and caregivers like Tanja, that we can be here today to talk about the progress we've made to address this devastating disease and its impact on people's lives. We've learned so much from our patient and caregiver community, and we're so thankful for their contributions that they've made over the last few years. So finally, we'll wrap up today's call with a Q&A session. So I'll now turn the call over to Dr. Barbara Burton.

Thanks so much, Tony. It's a pleasure to be joining you today, and I will focus for the next few minutes on an overview of arginase 1 deficiency and then share with you my experiences with a patient that I've had the pleasure of following now for many, many years. So I think really illustrates some of the issues related to diagnosis and arginase 1 deficiency and more importantly, the issues related to current management. Could we have the next slide, please? So just to review, I think Tony started to talk a little bit about what Arginase 1 Deficiency is, but this is a genetically determined disorder inherited in an autosomal recessive fashion. It's a defect in arginine metabolism and is in that family of disorders we refer to as urea cycle defects. We don't know the exact incidence or prevalence of the disorder, but recent data suggests there may be over 2,500 patients worldwide with 250 or more in the U.S. and more than 700 in Europe. This is a condition that typically presents with clinical manifestation somewhere in the neighborhood of 2 to 4 years of age, babies appear normal at birth but then begin to have symptoms later in those early years of life. But there are certainly examples where symptoms aren't noted and reported until later. And the classic things that we see are developmental delay with increasing intellectual disability as well as frequently failure to thrive for weight gain and short stature. There are also prominent and progressive neurologic manifestations associated with arginase 1 deficiency. And the classic finding is spastic diplegia, progressive spastic diplegia involving the lower extremities, which leads to impaired mobility. Seizures are also seen pretty commonly. And as was true in the case, I'm going to show you, this can very easily be initially misdiagnosed as cerebral palsy because of progressive spasticity of the lower extremities or as hereditary spastic paraplegia. Next slide. We do see some of the other abnormalities that we see in the urea cycle disorders in arginase 1 deficiency, particularly hyperammonemia, but it's much less prominent than in the more proximal urea cycle disorders like OTC deficiency, for example. There are patients who have recurrent episodes of hyperammonemia resulting in hospitalization, but there are also patients who never have a hyperammonemic episode that's significant. Perhaps you measure mildly elevated ammonia levels in the clinic but it may never really come to clinical attention unless you know the diagnosis and know to measure it. So certainly, there are patients who really just present in a much more chronic fashion with the intellectual disability and the progressive spasticity really without the acute episodes punctuating the course that we see as being so typical in the other urea cycle disorders. Patients can have some of the other findings we see in UCDs like protein aversion, appetite problems and self-restriction of protein, but again, less prominently. And I think that the rarity of the disorder, and of course, the fact that the symptoms are so nonspecific and can occur in quite a number of different conditions are what lead to delays in diagnosis. If we suspect the diagnosis of arginase deficiency, it can be made reliably and pretty quickly by measuring plasma arginine, which is typically greater than 300 micromolar. We can measure the enzyme in red blood cells and mutation testing, DNA-based testing is also available for confirmation. So to just kind of sum it up, what we see is persistently high plasma arginine, which is accompanied by progressive and debilitating neurologic manifestations and functional impairment. We know that reducing the plasma arginine level improves the manifestations even in patients with established disease. But of course, as is true of so many conditions, our best hope of really eliminating evidence of the disease is to start this very early. Next slide. So timely diagnosis as early as possible and initiation of treatment to reduce arginine levels is essential to improve patient outcomes. The current standard of care for treatment of arginase 1 deficiency involves dietary protein restriction to restrict the amount of arginine that the patient is ingesting. And then that is accompanied by essential amino acid supplementation without arginine to provide the remainder of the patient's protein requirement for growth without an excess of arginine intake. Many people use nitrogen scavengers as well to reduce the risk of hyperammonemia or to control the hyperammonemia. And these are oral medications, typically given 3 or 4 times a day. Now dietary protein restriction on the surface to a lot of people may not sell like it's all that onerous. But we're talking about more significant dietary protein restriction than most people really imagine. So the diet is certainly associated with a fair amount of difficulty and the management of the diet, the special formulas, the medications, of course, puts a large burden on caregivers as well. And then on top of that, even if we do the very best we can with all of these management strategies, we rarely achieve plasma arginine levels that are sufficiently low to really control the disease. We certainly never get those arginine levels into the normal range and rarely get them below 200 micromoles per liter. So patients continue to exhibit significant morbidity. And although we think our current treatment helps them, there certainly is a great unmet need for better therapies to reduce arginine levels more significantly and to improve the clinical manifestations of the disorder. Next slide. So let me share with you a little bit about a patient who illustrates many of the things that I just said. Next slide. This is a Hispanic woman, who was diagnosed with arginase 1 deficiency at 11 years of age and is now 26 years of age. I have the opportunity to make the diagnosis and have been following her since that time. This was a patient who was born in Ecuador, she did not have newborn screening for arginase deficiency, and she was thought to be a normal baby initially. All of this history is obtained from the family. So of course, we don't have extensive records, but what the family told us was that she was thought to be healthy and normal, but they noted at a little over a year of age that she wasn't developing words, her speech was delayed. And by 5 years of age, it was much more evident that she had not only global developmental delay, but she was also beginning to show some neuromuscular impairment and her growth was diminished. The family moved to the United States when the child was about 10 years of age, and I'll tell you what happened subsequently. Next slide. I think we have a time line here that shows patient was born, have the delayed speech early on by 5 years of age. She's having some neuromuscular symptoms, including toe walking, frequent falling. She was never able to run according to her parents and have poor tongue coordination and her growth rate had slowed. Over time, these findings continue to persist at the age of about 9.5 years. She had an unexplained episode of loss of consciousness and was hospitalized, she recovered, no explanation was identified. And then when she was a little over 10 years of age, the family came to the United States. They saw a pediatrician in our area who noted that the child was abnormally small, had short stature, only weighed 22 kilos and referred the patient to endocrinology. This doctor also noted that she had very tight hell cords, was toe walking has spasticity of the lower extremities and diagnose the patient with cerebral palsy. So she was diagnosed and sent to endocrinology because of the short stature, they recognized that this was not the only problem that the patient also had intellectual disability and these neurologic abnormalities. So in addition to their endocrine studies, bone age hormonal studies, they did obtain chemistry panel and saw that she had elevated liver enzymes. They obtained an ammonia, which was minimally elevated. I'll show you shortly. And they obtained plasma amino acids. They noted the elevated arginine and elevated glutamine at that point, suspected, this could be a urea cycle disorder and referred the patient to our clinic. Next slide. So as I mentioned, the fact that the patient had lower limb hyper reflects the tight heel cords along with these other neurologic manifestations and intellectual disability, were felt to be consistent with cerebral palsy, but a metabolic disorder was also considered by the consulting physicians in endocrinology and it was their biochemical testing that then led the patient to us. When I saw the patient, I already knew that her plasma arginine level was 6 times the upper limit of normal. So it wasn't really too hard figuring out what the diagnosis was. It was apparent that there was a likely diagnosis of arginase 1 deficiency. And as I mentioned, she also had mildly elevated glutamine and mild hyperammonemia. An enzyme assay was done, measuring red blood cell arginase, which was severely deficient and confirming the diagnosis. And then her genetic sequencing showed a homicides novel variant in the ARG1 gene. Next slide. And here, you can see her laboratory values a little bit better. Her arginine was 621 micromoles per liter. You can see her liver enzymes. This was prior to treatment in 2007. They were ALT, AST, alkaline phosphatase, all elevated. Over time on treatment, those have normalized or less visit before making these slides was in August of 2021, they were normal, and they've been normal for some time. We had several other pretreatment amino-acid panels. And you can see the arginine levels varied a little bit from 657 to 681 always very elevated. Glutamine was mildly elevated upper limit of normal 823. And you can see we had values up to 999. Glutamine is kind of like the hemoglobin A1c of hyperammonemia. It gives you a little suggestion that hyperammonemia is happening over time, ammonia levels change quickly, but glutamine levels don't. Plutonic acid soaks up ammonia and turns it into glutamine. So clearly, she was having some mild hyperammonemia and her ammonia level was elevated, upper limit of normal 35. It was 48 at that initial assessment and over the many years since has fluctuated somewhat, her last measure was actually 67. She's never had a hospitalization under our care for hyperammonemia. But the one that the family reported from Ecuador could have been associated with hyperammonemia. We have no documentation, but she did have a spell, as I mentioned, where there was loss of consciousness. Since we saw her, she's been on treatment with the standard therapy of protein restriction, essential amino acid supplementation and with nitrogen scavengers. Next slide. And here, you see her arginine levels over time from those initial high levels in the beginning. You can see that with therapy, there has been a lowering of the arginine level, and it's bounced around quite a bit, but mean levels have typically been in the high 300s or low 400s. We had a few low ones back here in 2010, which all of her amino acids were low because of inadequate protein intake. And I'll call your attention to this little blip right here in 2013, where her levels again went up as high as 514. And I remember very vividly seeing her in a clinic just for a routine visit in the CNA, the nursing assistant who puts the patients in the rooms and weighs and measure them. She came in and said, oh, my God, what is wrong with her. She looks terrible. Really different from all these previous visits. And we went in and sure enough, she -- her speech was slurred. She was moving much more slowly. Her gait was affected. She just seemed slower verbally. I mean she is intellectually disabled, but is verbal, and she had been really noncompliant with her dietary management. We tightened up her control and got her levels down again, and we saw her come back to her baseline neurologic status, basically. So that is something that impressed on me, the fact that there may be some reversibility with these findings. Clearly, there was in her case, and that control of arginine is really very important in terms of seeing optimal function in the patient. Next slide. So as I said, she's now 25, 26 years of age. She's generally been clinically stable, never hospitalized. She is ambulatory and she's verbal, but she's not able to care herself. She lives with her parents and will not ever be able to live independently. Her arginine level has remained high. Her cognitive impairment has progressed, I think, some over time and her neuromuscular involvement in the form of her toe walking and spasticity has persisted. It varies in severity somewhat because we have been pretty aggressive with using things like baclofen and botulinum toxin injections to treat this. She sees a physiatrist but she clearly has significant issues. As I mentioned, her biochemical status, her liver enzymes have normalized. Her arginine remains significantly elevated. Her ammonia levels are variable in that mild to moderately elevated range. And she remains ambulatory, but has the persistent gait abnormalities and spasticity. So she's doing pretty well. I think some patients at her age probably not doing as well. Most of them wind up in wheelchairs at some point. But nonetheless, I think she's pretty typical in terms of what the patient looks like. Next slide. So just to summarize, she presented with manifestations and medical history that is consistent with the diagnosis of cerebral palsy that was initially suspected. She also had short stature and this is really what initially prompted her further evaluation at which time she was quickly diagnosed with arginase 1 deficiency. We know that chronic high arginine leads to progression of cognitive and neuromuscular manifestations in ARG1 deficiency and the occurrence of acute clinical deterioration in this patient associated with the transient increase in her plasma arginine really further underscores the role of arginine as the driver of these manifestations. Early diagnosis and initiation of treatment to lower plasma arginine is critical for decreasing or delaying of the progressive worsening of manifestations. And we also see that the current standard of care does not adequately lower plasma arginine as shown by the persistently high levels and progression in this patient. So there is an urgent need for more effective interventions. Next slide. Again, arginine 1 deficiency is a progressive, debilitating metabolic disease associated with high levels of plasma arginine, the cardinal manifestations, beginning in early childhood, our spasticity seizures and intellectual disability, delays in diagnosis are common. We do have newborn screening in some states, although we don't know what fraction of cases are detected through newborn screening and certainly high arginine levels are not even called out in many states. So we still have a real need for diagnosis based on clinical manifestations. The burden on the patients and the caregivers is very high and our only current treatment is the severe dietary protein restriction with supplemental formulas, which, as you've seen, is really not adequate. Next, I think I'm going to just thank you for your attention and turn it back to the next speaker.

Thank you, Dr. Burton for sharing your experiences with us today. So now I'd like to turn the call over to Dr. George Diaz, who's going to walk through his experiences with Arginase 1 Deficiency as well as the clinical trial data for peglarginates.

Thanks very much, Anthony. Next slide, please. So Dr. Burton gave a very nice discussion of patient's clinical course with Arginase 1 Deficiency. This is clearly a very serious progressive disorder. And there is early mortality and a very high unmet need. We discuss the hyperammonemia as an event that is not so common in ARG1 deficiency, but there is data supporting mortality. The disorder is caused by mutation in the arginase 1 enzyme, resulting in high levels of arginine as we've discussed. The picture shown here is a patient with actually the same mutation as the patient discussed by Dr. Burton. This patient presented at age 1 with hyperammonemia. So she presented much earlier, was diagnosed earlier as a result of the presentation. And despite being on therapy, still develop severe extremity -- lower extremity spasticity, develop speech delay, has a significant intellectual disability. So again, the treatment was protein restriction, which is really just a few ounces of protein a day really, really hard to maintain over time, treatment with some essential amino acids and ammonia scavengers to control hyperammonemia. Despite all of this, she did progress to having spasticity diplegia and [ joining ] with arm crutches was really very, very stiff. Biochemical studies, we'll be able to see no enzyme activity. And in the table on the right, you can see that her arginine levels at baseline are quite elevated. So here her arginine level is 389 micromolar, and normally ranges up to 115. If we look at the 6-minute walk test, the normal reference interval is going to be 310 to 664 meters, and she's coming in at 174 meters. So I'm really quite impaired in her mobility. And the gross motor function measure Part E, which has a maximum score 72, she scored 27. So significant mobility deficits. Next slide, please. So I've been fortunate to be involved with the studies of pegzilarginase in the ARG1-D population since the Phase I/II studies. So pegzilarginase is a recombinant human enzyme that's been engineered to lower arginine levels. And as you can see here in the table, the arginine levels in the Phase I/II studies and the open-label extension studies show that in 13 patients who have been enrolled in these studies, arginine lowering by the pegzilarginase was really very, very effective. Within 1 week, we can see significant reductions from the baseline. You can see here on the table that 200 micromolar is highlighted. That is a therapeutic goal target to get below. And so over time, you can see that the study population stays persistently below that goal and the arginine levels remain in the normal range. So this is a very durable response. In addition to the Phase I/II study, we also had the pleasure of participating in the Phase III clinical trial, which is the first placebo-controlled trial that's ever been conducted in ARG1-D. The top line data were announced in December 2021. And there was a significant reduction in pegzilarginase in this study as well with normalization of arginine levels observed in 90% of patients. There were positive trends in mobility measures and the drug was quite well tolerated. There are currently 31 patients that are still enrolled in the long-term extension. Next slide, please. So I'll dig into some of the details of that Phase III study, the PEACE study. This was a double-blind study, and the inclusion criteria are given here. Patients have to be at least 2 years old and have an arginine that was elevated beyond 250 micromole. And patients have to have a baseline deficit in one of the clinical response assessments. The patient population is in randomized 2:1 to either receive pegzilarginase at 0.1 milligram per kilogram by IV were to receive a placebo IV infusion. And this was done over a 24-week time course at which time patients were enrolled into an open label long-term extension going up to 150 weeks. So the key endpoints here are going to be plasma arginine reduction as a primary endpoint. So here, we're looking at the reduction of plasma arginine as compared to placebo with secondary endpoints that are looking at mobility assessments. So that GMFM-E that we discussed in the previous slide and a 2-minute walk test. So the distance walked in 2 minutes. So here, there's going to be continuous analysis of the secondary endpoints as well as changes compared to placebo control. Next slide. So this is a slide describing to you what the functional assessments were that were used in the study. So patients were baseline with a gross motor function classification system or GMFCS which is going to give you an overall description of motor function based on a series of different movements for which the subjects could use any assist devices that they came into the study ways. And so you can see here that the mobility assessment range from GMFCS of Level 1, where someone is completely unimpaired to Level 4, where they're dependent on ambulation assist devices, wheelchair dependence. We're assessing changes in mobility, we want you to be looking at the GMFM Part E. So this is a series of assessments that are not using any assist devices. So this is unaided mobility assessments, using a series of tasks involving walking forward or backwards, running, jumping and so on. And the scores you are going to be ranging from 0 to 72. In addition, we'll be looking at a time to walk test assessment, the 2-minute walk test will be used. Next slide. So we'll start with the safety profile. So the results from the study, were really very positive with regards to safety. So you can see here that in comparison to placebo, pegzilarginase had a comparable level of treatment emergent adverse events. So everybody had an emergent event in the placebo arm, 85% of patients in the treated arm had an emergent event. None of these events were significant and led to study discontinuation. There were some serious adverse events in each of the arms. These included hyperammonemia and vomiting, which is kind of the background for the condition. 2 patients did have hypersensitivity reactions in the pegzilarginase arm, but these were not frequent and they were managed easily with routine medical care. There were still some hyperammonemic events observed in the study population, both enzyme treated and placebo treated and there were significant differences across those groups. So the safety data are really very good with regards to tolerance [ to was ] quite well tolerated. There were no discontinuations in this study. Next slide. So with regard to the primary endpoints, here, you can see that very similar to the open-label studies, the enzyme is quite effective at reducing plasma arginine. You can see here at baseline, both the treatment arm and the placebo arm, both patient cohorts have significantly elevated plasma arginines in the range of 300 to 400. And those changes or the arginine levels were significantly reduced by 12 weeks in the treatment arm. The placebo arm subjects remained highly elevated. And by 24 weeks, you can see that the entire cohort that is treated is now in the normal range for arginine. So this is really a quite striking finding that the placebo arm remains where they were. So you can see that in the 24-week analysis, there's an 80% reduction in mean plasma arginine treated with pegzilarginase. So this is a highly statistically significant finding. So I think, again, this is a result that is quite in line with the Phase I data. And this is something that is really very gratifying to us as investigators. Next slide, please. So one important aspect here is we were looking at kind of a cohort of arginine data. And what you're looking at here is the proportion of patients for whom arginine levels were significantly reduced into the normal range. So at baseline, everybody had an elevated arginine. By 6 weeks, approximately half of the treated cohort was now in the normal range. And that improves over time. So that by 24 weeks, you can see that 90% of the pegzilarginase patients achieved a normal plasma arginine level. The placebo arm does not have any significant change in their levels. So again, to remind you that 200 micromolar is kind of the therapeutic goal that we as clinicians try to hit with dietary protein restriction. This is an incredibly difficult thing to do, as Dr. Burton described even on maximal therapy, our patients rarely get down even into the 200-micromoltarget range. So to be in the normal range is really a significant achievement and suggests that this could be potentially a transformative therapy because although we all see patients, you saw Dr. Burton's patient did achieve normal levels for a short time. But for an entire cohort to have normal levels is really unheard of the current standard of care. Next slide. So this slide is showing you the mobility assessments. And you can see here on the left side that the mean changes in the GMFM-E are shown. So here, we're looking at units of change, and the dash lines are giving you the minimal clinically significant units. So in the spasticity cerebral palsy population. So the minimal changes are defined between 2.8 and 4 units. And so you can see that at 12 weeks, we've got a positive change 2.9. And by 24 weeks, we've got a change of 4.2 units, which is surpassing the 4-unit threshold. So this is really a very gratifying result, especially in comparison to placebo. You can see here that over time, 12 and 24 weeks, there is no improvement in the placebo-treated arm. So kind of going back to the natural history of the disorder, it is a progressive disorder. One expects that over time, patients will do worse. This is a very short time course. So we don't expect patients to necessarily demonstrate progressive deterioration over 24 weeks. But to show improvement, again, is really quite remarkable. So in comparing the pegzilarginase to placebo arms, you can see by 24 weeks, we had that 4.6 unit difference, which is not quite statistically significant, but really, the trend is very, very encouraging here. If we look at the 2-minute walk test on the right, you can see that at 12 and 24 weeks, again, we're seeing this improvement trend where the mean difference between the time point and the baseline is in the net positive direction for the treated patients. And there is no significant improvement in the placebo arm. So in some these data show a positive trend in the GMFM-E in the placebo-controlled study, suggesting the potential for improvements in mobility. And again, kind of coming back to the patient perspective, this is a significant quality of life issue for these families. The spasticity really is very, very detrimental to them, particularly as patients progress to be in real triband, I think we can all appreciate that, that really is something that's very difficult for the caregivers as well as the patients. Next slide. So one of the gratifying things again, having had an opportunity to participate in both studies is to see that the mobility measures have been sustained over time. So we have patients in the Phase I/II study, open-label extension, who've been participating out up to 4 years. And you can see that the GMFM-E here is a very durable response. And in fact, over time, the mean change becomes increasingly positive. So this, again, is very much in contrast to the expected progression that we see in our patient side, had the misfortune of observing patients over many years. And similar to the story that Dr. Burton told you, despite maximal therapy, as we've seen these patients get increasingly debilitated over time, progressing from needing creche to being real to dependent and so on. So again, seeing increasing improved mobility is really something that is quite important to us. Next slide. So summarizing then, the PEACE study is the first ever placebo-controlled trial in arginase 1 deficiency because this is quite an important data set for us in the urea cycle community. We've really been able to collect a very, very substantial data on these patients, and the study has confirmed that the arginine levels at baseline in this cohort are persistently elevated despite being on maximal standard of care, highlighting the unmet clinical need here. The normalization of arginine levels, which we observed in this population, again, really not achievable using the dietary therapy scavenger treatments that we have been employing for many years. And so the normalization, I think a really important finding as a clinician. This is really what we've been trying to do with limited success. The GMFM-E data is also, I think, quite important. It's highly suggestive of the mobility benefit, which improves over time. So I've shown you the data on the improvements beyond the 4 and 2.8 units of GMFCSs 1 and 2, which are kind of the thresholds for a clinically meaningful result. So these are very strong and consistent data supporting that pegzilarginase has the potential to be a life-changing therapy for patients with arginase 1 deficiency and for their families. Next slide. And with that, I thank you for your attention, and I'm happy to take any questions in the call.

Thank you, Dr. Diaz. Good afternoon. I'd like to introduce you to Tanja Brandt. She is the mother of Willow, her 10-year-old daughter, who was diagnosed with Arginase 1 Deficiency right before her fifth birthday. She is also an adviser and steering committee member of the arginase-1 deficiency Foundation, which was recently formed to provide support for patients and caregivers alike. Tanja will share a look into their lives from the unknown to Will's journey to diagnosis, life today as well as their involvement in the PEACE trial. Her story represents their unique experiences and it provides a glimpse into what life is like for them living with and caring for a child with a rare and progressive disease. Thank you, Tanja, for joining us today.

Hello. Thank you, Tricia. As you all just heard, my name is Tanja Brandt, and I'm the mother to Willow, who is a 10-year-old girl who has arginase 1 deficiency. Our journey has been a bumpy road, but it started off with ignorant list really. I had no idea was pregnant for the first half of the pregnancy, literally 20 weeks of it. I had IED inserted before it was far enough along to propose test to catch it. And as you may or may not know, IED symptoms are very similar to pregnancy symptoms. Little Willow was incredibly determined to be here and wasn't going to allow anything to get in her way. The remainder of my pregnancy was uneventful as was her delivery. She was a very serious but healthy baby. The was a baby that strangers with all kinds of face that or wayback until their face is cramped so she wouldn't budge. She would just dead hands there until they eventually gave us, it's pretty funny. There were [ novelas ] regarding Willows development until about 10 months. Her first allay milestone was point herself up, but the doctor told me it no big deal, just hold your baby so much, which was really annoying to hear as I was in the kind of mom that never put a baby down. From that point on, all of her milestones were delayed, but she would always catch up just on a little of time at on pace. She learned to crawl around the time other babies were walking and was cruising around by the time other babies were running around in on that. But by about 1.5 years, she still hadn't started walking. So they decided it was time to start on some physical therapy. She eventually started walking at around 22 months. She eventually got to the point where she can run and jump and kick a ball all those typical kid things. Around the age of 3, though, we started to notice a decline in her gross motor ability. All those milestones that she finally reached are becoming more and more challenging. I started off with her falling and stumbling more often. And as we would analyze for Gaitmore we notice to walking and were dragging her toes often, which caused her to have a gait where she picked her knees up higher, almost like she was Martini. Keep in mind, this is all a very slow progression over the course of the month. So it's hard to pick up on it. Finally, when we went in for a 4-year well child checkup, obedidicion decided that her date was unique enough that it warranted some further testing. We were sent off to our local Children's Hospital where they saw -- she saw lots of different doctors. And it was assumed initially that she had cerebral palsy. That and spinoff are rolled out by MRI. While we are waiting to -- waiting for these tests to take place, below is developmental decline progressed. She got weaker and weaker and was losing even more milestones she worked so hard to achieve. She was no longer able to jump without holding on to anything and her gait was very clumsy and kind of stiff. It was like we're bringing with told her to run or to turn quickly, but her feet wouldn't cooperate, and she would just trip over them often. She loves a lot of confidence during this time. It became and she became incredibly cautious and scared of anything that required priming or walking around hyatt species. As we were awaiting for the test, we started to notice the new at behavior. Will would occasionally check out and just kind of start off. We would also notice her breathing would change out of its regular rhythm during this time. It was so short, fast initially that I just thought she was concentrated on something in her mind. But eventually, these little checkouts turned into what were clearly some sort of a seizure. She would be in the middle of the sentence than just stop talking, her breathing would change, her body would go lax and she would sometimes it or sort of why at her nose with the back of her hand and then shoot it back like net ever happened. Eventually, these would happen more and more and more frequently, and they would last longer and longer. At the height of them, she was probably having about 15 a day and those are just the ones we were catching. We told our current neurologist about testing, and he immediately switched back to original metabolic disorder. We had to try a few different medications to get the seizures under control, but eventually found an okay fit one that at least manage symptoms. By this point, it was very clear that Willow also stopped growing. So remain the same height and wait for over a year. She was stuck at 32 pounds and 4-year-old. We couldn't really seem to get her over that point no matter what we did. Meanwhile, behind the scenes neurologists tested for a more common disorder called [ CAPP ] first, that one was ruled out and then we tested for arginase-1 deficiency. They initially submitted this test inaccurately and had to redo it, which meant we had to wait an additional 6 weeks on top of the already 11 months we've been waiting before we finally got our diagnosis. I remember the doctor calling me, and I was so relieved. I held it together during the call and then immediately called my mom to tell her and we balled on the phone together. We had an appointment with the geneticist just a few days later, where we were given further instructions. We'll look at each 7 to 10 grams of protein a day and had to drink a formula of essential amino acids to make up for the lower protein diet. This formula tastes disgusting. Trying to get a split fire of a 5-year-old during this disgusting drink was then here possible to be frank. Finally, we found a concoction that was palatable for her, but it would take about 2 hours every day for 1 dose, and she had to drink 2 a day. We would spend 4 hours a day sitting down watching TV, telling our daughter, can't you just pull out about every 30 seconds, but it meant that she got the formula that her body required. We would often have to choose between her drinking her formula or letting her play with her friends or doing other activities. We never really let her skip it for fear that she would think that was an okay thing to do. So we would opt her to miss those play dates or other fun activities with her friends. She would also have to wake up very early for school, so we would have enough time to drink it beforehand, leaving her sleepy before the day really began. Now let's talk about her protein. 7 grams of protein for the whole day give or take a gram, this is about 1 egg or one serving a cheese or 1 glass of milk, not per meal but for the entire day. I had to find a way to keep her at 7 grams of protein while still keeping her fed full of calories to grow. There are specialty foods out there that we can get shifting, but they aren't cheap. It's expensive, but we were lucky enough to be able to report it. Not only was it expensive, but it wasn't good either. We made it work though. But even with this kind of controlled diet, which we were very strict about, it still wasn't good enough. Normal range of arginine is around 30 to 130 and Willow's arginine levels were still around 400. This means that even with the best management that we had at the time, she was still accruing brain damage. Her system was still so irritated. Her movement had been stuck at the current delayed state. She was still not able to jump. She couldn't keep up with peers, but -- and she was now seriously cognitively delayed, meaning she was still not reading and counting beyond 20 was a challenge. When we heard initially about the enzyme therapy, and we were incredibly hesitant, and it won't make kids to be experimented on. But I did more research and was lucky enough to be in school at the time where I could discuss the matter with various professors. After doing some, I came to the conclusion that I felt it was safe enough. The risk was worth it if it meant that my daughter's brain could be free of this toxic level of arginine. Her movement getting better wasn't even a blip on my radar. Maybe she would get lower arginine range and maybe that would be enough to let her think clearly, learn to read and solve simple math problems that would allow her to deliver a relatively normal life. Because, at this point, it was hard to believe that would be possible. The trial was a very bumpy road for us. It required weekly IVs, which she hated. It was horrible initially, having to basically hold her down just to get the needle into her skin. She hated the sticky tape required to hold it in place so that even once we got the needle in and the treatment completed, she then had to remove this terrible skin ripping tape. We told her that we would basically buy her an entire toy store, if you just hold your arms still. We said you can scream whatever kind of the terrible screams you can muster, but just hold your arms still. And guess what? She did it. And she loved her trip to the toy store, too. We had kept that going long enough that now it's no big deal for her to get an IV and simple blood draws a cakewalk. She doesn't even baton. When the double-blind phase was over, we were able to see Willow's arginine levels. Willow, for the first time in her life had a normal arginine level. It was an incredibly emotional moment for myself and the rest of my family. Once again, we all balled over the phone together. Once all it was diagnosed and felt like a relief initially, we had an answer, but the low protein treatment, low-protein diet treatment that we had in place that couldn't stop the brain damage. It felt like I was supposed to be okay just watching my kid slowly fade away, slowly lose motor control and the ability to learn and be independent. I tend to be a very skeptical person, but even with that, Willow's recent progression is clear. I can say that she was clearly declining for years and then held steady for years, but now it's progressing in every way. I can say that my most important factor has been achieved. Willow no longer has access at the same chemical in her brain if it has caused her to lose mobility and cognitive capabilities. Willow is now able to walk up stairs without the use of a wheel. She can jump with 2 feet over and over and over again. She can hop on one foot without any kind of support. She can run and kick a ball. She can ride a horse without any support people by her side. She can read and does so every day and is progressing in her math class and can now complete more complex adding and subtracting problems. It almost feels like a fog has been removed from her brain. She just catches on to ideas much more quickly now. Her hospital visits are also even easier and shorter now due to subcutaneous injections. Willow's formula intake is greatly decreased and is only drinking 1 juice a day. It is such a small volume that she can drink it in about half an hour, while we settled down for the night while watching a TV show. This is reduced because her protein intake is about 30 grams, and she can basically eat whatever she wants now. Lastly, Willow is no longer taking any medications to control her seizures and is completely seizure-free. Thank you for the opportunity to tell our story, but please remember, it is just that, it is our story. Only one voice out of the arginase 1 deficiency community, and we all have a similar yet unique journey living with this disorder. Thank you.

Yes. Thank you, Tanja, for that very moving story that you walked us through. Thank you, Dr. Burton, Dr. Diaz for your presentations. I'd like to now turn the call over to Tara who's going to open up the Q&A.

[Operator Instructions] Also joining us for Q&A will be Eric Bradford, Chief Development Officer; and Tricia Sterling, Vice President of Patient Affairs. [Operator Instructions] Our first question comes from Soumit Roy from JonesTrading.

Thank you, Tanja, for sharing Willow's story. Certainly, put things into perspective and an incredible journey. And thanks for -- to Dr. Diaz and Dr. Burton also for sharing the presentation. My first question is about the clinical data from the PEACE trial. Knowing what we know now, looking at the data, would you have designed the trial a little differently? Or would it have been unethical to increase the placebo arm size, rather take the reading at 36 or 52 week as you have shown lagged time point continues to show GMFM-E improvement? Anything we could have done differently?

Eric, do you want to take that question?

I think when we look back and reflect on the PEACE study, we're very encouraged by the results we've seen in this patient population in terms of arginine control as well as the benefits we're seeing from a neuromotor standpoint. One of the challenges, I think, most people are aware, this is an ultra-rare disease, and there's always a balance between generating the evidence as well as the practicality of running these studies, particularly in a placebo-controlled setting with younger patients. So we believe we adequately designed it. We had some assumptions going in, which we believe bought fruit in terms of the magnitude of response and the consistency of what we see with the 1028 data. So we believe we designed the right study. Clearly, we're seeing benefit with continued therapy, which we believe is important. We're starting that in 1028, and we continue to look at that in terms of the [ 308 ] study.

Our next question comes from Sam Slutsky from LifeSci Capital.

A couple of questions for me. I guess, for all the speakers, as discussed, we recently presented data up to week 104 with Pegzilarginase, showing a sustained improvement during that time period. I guess, in your view, how impressive it seeing the sustained improvement up to week 104? And what would you typically expect for a patient not on treatment to do during that time frame? Would you expect notable progression? Just help us understand versus your experience.

Dr. Diaz, do you want to take that one? And then maybe Barbara could also comment as well but based on our experience, if you want to go first, Dr. Diaz?

So I think the reversibility that you saw in Dr. Burton study, I think it's definitely a feature of this condition. We do see some transient versability from acute intoxication levels. But over time, this is really not sustainable in the patient population. Tony's presentation look really eloquently to how difficult this is to achieve. So progression is to be expected over 104 weeks, I think it's likely that we would see some progression. Some followed patients over decades, and there was a slow and persistent deterioration over time. So to see improvement, I think, is really, really striking.

And Barbara, do you want to -- you'd like to say just about your experience with patients over the years with kind of deterioration over that kind of 2 to 4-year period?

Yes. I mean I think it is a progressive condition, but I do think that there are periods of time where the progression is more obvious. And we heard it Tanja talk about the time period and her daughter when this occurred. I think sometimes as the patients get older, it becomes less obvious because they're already quite handicapped. So I think that the age of the patient may make a difference in terms of how much progression you would see over 2 years. But you're certainly not going to see improvement. The best you might hope for is that you have relative stability with current therapy, but you're definitely not going to see improvement. So I think that what you've seen in the data that you've reported really speaks to the efficacy of the drug.

And then also for the physicians in the PEACE study, they showed a 4.2 unit improvement in GMFM-E from baseline up to week 24. I guess observationally, what would a 4.2 unit improvement functionally look like for a patient? And obviously, this showed greater improvement about 7.1 units in the Phase I/II. Just help us understand kind of what this looks like [ or it ] to patients.

So Dr. Diaz, maybe your patient that you had in the Phase I/II study, I mean you've got a feel for what the GMFM-E improvement was, and you also have a feel for what you saw clinically. So that might help with the question.

So as Dr. Burton suggested the age of the patient certainly impacts to what point they have progressed. And I think that's an important variable in terms of their improvement over time. The patients that was highlighted in my slides, came in with really very restricted ambulation. She was quite stiff. The last slide showed her crossing her legs. This is something that she was completely unable to do. She became able to put on her own shoes and walk around without her assist devices. And so it is important for the family. The patient became much more independent and this really enhanced quality of life. The things that we don't measure actually are the things that Tanja alluded to in terms of this fog being lifted. This patient also had a remarkable turnaround in terms of her ability to interact with the world around her, became very engaging, a really very funny, funny individual. And that just didn't happen prior to the initiation of therapy. So there are elements here that we can't capture well, but just focusing on mobility, that's certainly something that is impactful in a meaningful way for the patients and the families.

And then just last question. Tanja, if I heard you correctly, your daughter increased her protein intake substantially after the blinded portion is still seeing kind of continued noticeable improvement in your eyes?

She did increase after -- yes, after the blinded, double-blinded phase was over from 7 to 10 grams and then now is at 30 grams.

Okay. And you're seeing maintain kind of, I guess, improvement on seeing that with the higher protein intake?

Yes, she's still progressing.

Tanja, did you mean when you say progressing, is she doing better or...

Yes. Yes, she did. Good clarification to yours.

Right. I don't know, Eric, do you want to just comment on that? Because I think it's an important point because we did do the trial in the background of stable therapy. But Eric, do you want to just provide your perspective, it's important.

I think as Tanja alluded to, each patient has an individualized approach during the confines of PEACE study, particularly the blinded portion, we had a set protocol around maintaining some relative consistency around diet to enhance our ability to determine -- benefit during the double-blind period. So we haven't formally assessed the ability of the pegzilarginase to liberalize diet. And I think when we look forward to is bringing this therapy to patients because we recognize each patient, as Tanja alluded to, is different. Each patient is individualized and they have different needs. And so we believe pegzilarginase it has the opportunity to be a very effective therapy for these patients.

Our next question comes from Anupam Rama from JPMorgan.

Dr. Burton, I had a question for you. You've done a lot of work on newborn screening in Fabry disease and other lysosomal storage disorders. Can you talk about the current status of newborn screening here in the U.S. for Arginase 1 Deficiency? Are there arginine cutoff levels or a range? Is there anything being done for standardization? Because our understanding is not all states have newborn screening and the states vary in Arginase 1 deficiency level cutoff across the states?

That's true. Arginase deficiency is not on the recommended uniform screening panel. So although all newborns in every state get their plasma amino acids measured because there are a number of other amino acid disorders that are on the screening panel, PKU maplserburone disease and so on. In many states, the arginine levels are ignored. So if they have an elevated arginine level, it's not reported. I think there are about 20 states, and I think some of the representatives at Aeglea may know the exact number, but somewhere around 20 states that do say that they screen for arginase deficiency by reporting elevated plasma arginine levels. But yes, there's variability in the cutoffs. And I really don't think we have robust data on how rapidly the arginine levels rise following birth. Of course, they'd be normal in the cord blood because it's all controlled through the plasena and the mother, and we typically screen at 24 to 48 hours. So we're -- we typically don't see levels as is we're going to see a week or 2 weeks or a month later, that's to an old diseases PKU included. So the cutoff has to be set at such a point that it's appropriate for the age of the baby. And I don't know that we have robust data that tells us what fraction of cases we would detect at 24 to 48 hours at various cutoffs. So labs just have to kind of -- that are doing screening really have to look at the distribution in the normal population and try to set a cutoff that is not going to call in too many normal healthy infants for further testing. But really, without the data that tells us what fraction of arginase-deficient infants are going to be detected because we don't have control specimens. What we need are some specimens from arginase 1 deficient infants at 24 hours of age. And those are hard to get by the time you diagnose the patient, well, that specimen is not around, except if you diagnose one through newborn screening. So over time, we will see in the cases that are diagnosed by newborn screening what those levels were. But because of the rarity of the disease, it's a little bit tough. So I think right now, we just don't know a lot of the answers.

Our next question comes from Gil Blum from Needham.

And I'd like to also join my thanks to the physicians for providing a clear record of the disease and also for the mother of overall, to give a very human point of view about this indication is. So we a question for both physicians. And I just want to really make sure that this arginine levels widely recognized in the physician community as a key driver of pathology.

Dr. Burton, would you like to go first and then maybe Dr. Diaz can give his perspective as well.

Yes. I mean I think the answer is yes, arginine and potentially other compounds wanted compounds derived from arginine. I think the opinion is widely held across the medical community that these are key drivers of pathology.

Dr. Diaz, anything to add?

Nothing. I'm totally agreed with that.

And that also dictates the standard of care. I just want to make sure this is first of all clear to me.

Yes. Yes. I think yes, it does.

Okay. And we've kind of touched upon this topic earlier. But in the patient time line and that his or her progression, there are different periods of different inflammation in decline. Is there a period of time that you would say there's the most decline? Is there -- if you gave the treatment at that time, would it prevent most of the disease progression? Is there something like this?

I don't know who that's addressed to, but I would just say that there's probably not one moment in time. I think the earlier, the better, and of course, the idea would be newborn screening. But as judged by our experience with some other metabolic diseases where we have progressive impairment over time, the earlier, the better. And that doesn't preclude there being some reversibility even in a much older patient. You're not probably going to reverse IQ loss in a 25-year old, let's say, if you start therapy. But there could be improvements in motor function. There could be improvements in higher-level cognitive functions, executive functioning, for example, if these are directly related to concurrent arginine levels. So I think there are probably both irreversible things that happen over time as well as reversibility and how much of that you're going to see is going to vary depending on the patient's age and probably other factors as well. But I'd like to hear what George thinks about that also.

I think as one of the states where a newborn screening it does screen for arginase deficiency. We've been in the position to actually have patients come through and kind of watch the evolution of symptomatology. And absolutely, in patients who don't present early catastrophically as the patient have described at 1 year. This is something that if you can treat early in a couple of years, you can maintain these patients with essentially normal in total development for patients for whom that's not possible because they've got lessons on activity. Again, we've heard about the rigors of the diet and the treatment side. They start to manifest developmental delay pretty early on. So I think our window is in early childhood.

Yes. So Dr. Diaz, you talked about the dramatic improvement in spasticity in one of your patients. I don't know if you -- either you'd like to comment maybe, Barbara as well about the potential impact of reducing spasticity in terms of improving outcomes with regard to things like the tendon contractors and the heel core tightening that I think people think may be related to long-term spasticity.

Yes, absolutely. So again, we've had patients that we followed over decades of time. And because this is a progressive condition, they have required additional interventions for this spasticity which worsens and actually starts to spread from the lower extremity theorems, to start to get tight in the arms as they age. And so our patients have had court releases and required BOTOX injections. And so this is not a passive thing that is happening. People are actively trying to manage this. So to have the ability to reverse some of this damage is significant. One of the point that I actually wanted to make also about the mobility assessment. The patient that I followed in the long term was significantly looser and the physical therapists who worked with her said that she was solo, she had to basically relearn how to ambulate because she was ambulating in a very, very stiff hip fashion and actually have to relearn. So I think that actually impacted also these assessments. So I think we find it difficult to really kind of quantify the improvements for these reasons.

Maybe a follow-up for Dr. Burton. Just maybe help me understand how much of the pathology of the disease is the restricted protein itself? Is this part of the farm that's cost efficient or primarily pathology is associated with elevated marketing models?

No. I think the other potential contributor to the pathology in some patients could be hyperammonemia. We know that hyperammonemia is harmful to the brain as well. So that is the other potential contributor. It's not the diet. I mean we have many patients on similar diets where we're trying to reduce one amino acid or another, and they are very, very restricted in their natural protein intake, but they're not a protein deficient because they get the protein in these formulas. We heard that they're difficult to take and they are unpleasant and all of that. But these patients get very careful monitoring by metabolic dietitians, so we're making sure that they have adequate total protein intake, some of them intact protein, some of it in the form of amino acid mixtures that they have adequate protein intake. We routinely do lots of nutritional surveillance looking at nutritional markers really. So their diets are really carefully managed, and I don't think there's any evidence that the diet contributes to the intellectual deficit or to the motor dysfunction. Other urea cycle patients are on the same type of diet, but we don't see them this progressive spasticity. I mean there are unique features of arginase deficiency, this progressive spasticity. We can see intellectual deficiency in some patients who've had -- certainly who've had hyperammonemic episodes that can be damaging to the brain or even we think with more low-grade chronic hyperammonemia and George Diaz actually has done some really nice work on that with executive functioning measures, looking at that in the face of mild hyperammonemia. So that's the one other potential contributor, but I don't think the diet itself is one.

Our next question comes from Yanan Zhu from Wells Fargo.

So first of all, I'm curious whether you have evaluated ammonium levels in the blood, given that 90% of the patients are in a normal range in terms of arginine levels is what would be the findings for the ammonia levels or the glutamine levels? And I have a follow-up.

So I think I wonder if Eric, that might be best for you to start with that. I mean, obviously, at the moment, we haven't disclosed anything beyond top line. But Eric, do you want to give a little bit of color on that, what you can talk about?

I think you raised a good point in terms of the understanding of the other profiles of other metabolites or ammonia specifically, we did assess that during the studies on a routine basis. And I think the results are encouraging there. But at this point, we can't provide additional detail from the standpoint as Tony alluded to.

You want just to remind, Yanan, about the SCE's frequency in terms of that?

Yes, sure. I think when you look at the -- which Dr. Diaz has highlighted in terms of the safety profile for pegzilarginase, when you look at the current of SAEs, they're relatively balanced across the 2 treatment arms in terms of hyperammonemia. Actually, the pegzilarginase group had a lower frequency compared to the placebo group, which we find highly encouraging in terms of the overall profile of the drug.

Yes, I was wondering about that as well. So then I'm interested in hearing Dr. Diaz and Dr. Burton's view about the lack of statistical significance on the secondary endpoints, how you interpret that? And how as treating physicians, what would be your message to the regulators when they are considering the data set?

George, you want to start with that since you're closer to the data and we're participating in the studies.

Sure. Happy to. So I think part of the issue here is small numbers. And I alluded to the effective age and disease severity. And that's a mixed bag. I think it makes it very difficult to assess. The biochemical measures are pretty robust because everyone has essentially the same starting point, so that's easy to assess. But with some ability assessments, you're looking at a very, very mixed population. So hard to hit significance. So that's my top-level interpretation of that. But again, I think speaking to the assessments that we saw individually in our patients, we know that these can be really quite significant and difficult to capture.

And I think I would have said exactly the same thing that I suspect it's due to a combination of the small numbers and heterogeneity in terms of baseline characteristics of the patients, some being significantly more impaired at baseline and some a lot of variation in age. So I think, obviously, my expectation would be in using the drug that there is going to be variability in patient response, how much improvement you're going to get is probably going to vary from patient to patient and be impacted by the patient's age, how much disability they have at baseline and so forth. And I think that leads to what was seen in the clinical trial data.

This concludes the verbal portion of our question-and-answer session. I'll now pass it to Hans Vitzthum of LifeSci Advisors to read the remaining questions.

So our first question is really directed to Tanja. And the question is, can you speak a bit about the Arginase 1 Deficiency foundation? It seems like it's been recently founded. But if you could speak to its mission as well as how broadly it has reached the arginine 1 deficiency community?

So it's very new. We are just getting started. Our main goal is to make sure there's accurate information provided to the Arginase 1 Deficiency families because we -- with other foundations, it's not always as accurate and clear and consistent. So we're hoping to build it by that. And then also a place for families to connect and to meet other families who are going through the similar changes that they're going to be having to go through. It can be only -- we didn't have that one. We were looking for it when we were first diagnosed and it made it even more challenging. So that's our main goal is just to have accurate information and a gentle place to land.

The following question is really probably more directed to you, Eric, or you, Anthony, but there's a numerical improvement in the placebo group between weeks 12 and 24. Do you think that was an actual improvement in the patient's functional abilities? Or is there another explanation?

Eric, do you want to take that one?

Sure. I think stepping back when you look at the data, you do see these differences between 12 and 24, doubt it's improvement. I think there's some variability in the assessment at week 12, and we've looked at that in a little more detail and get a better understanding why. And overall, we look at the 24-week data at time point as being reflective of what the patients were doing. So in the end, we feel we have a good comparison of group between the placebo and the pegzilarginase arms at week 24 to understand the impact of pegzilarginase.

The next question, Tanja mentioned that administration was quite difficult for her daughter. And the question really is, do you see that as a challenge for acceptance of the therapy? And perhaps, Eric, you could start off with the company's perspective and then we could turn to Dr. Diaz and Burton to weigh in on their own experiences?

Sure. I mean, I think when you step back and look at the management of ARG1-D, and Tony alluded to some of the challenges associated with it. We believe that pegzilarginase offers a good solution to a number of those challenges. We acknowledge that the IV formulation, as Tanja alluded to, presented some additional challenges, particularly in the younger pediatric population. As you may be aware, we've included subcu formulation or administration in the long-term extension studies. We have extensive experience in 102A with that, in which we hope we'll be able to be provided as a solution to overcome some of the challenges associated with IV therapy for this product.

Barbara, I wonder if you maybe want to comment because I think you're probably familiar with once weekly IV therapies for some of the [indiscernible].

Yes, absolutely, very much so. And if it had to be IV forever, it wouldn't be a deal breaker. We have lots of diseases where we use once a week IV therapy. Sure, young kids, they're not excited about having IVs. Some more than others, there's difficulty in some cases. But it can be done. This is a serious disease. And so I don't think the fact that it is IV is in any way going to discourage utilization. The parents are going to be motivated to make sure their kids get treated. The older patients are going to be more accepting. I do think the subcu is a nice advantage because it's simpler and easier to do at home, not that we can't do weekly IV therapy at home, we do it all the time. But it's a nice advantage. But honestly, I don't think the once-a-week IV is a deterrent at all to utilization.

I have the same experience and opinion about that. And kind of go back to Tanja's point about her daughter, the patients that we had in the study had similar issues with IVs initially. And again, as they responded to therapy also became really quite comfortable with it. So really not an [ uptick ].

Great. And this is the last question and the time that we've got, but it's also appropriate for a closing question. And for both Doctors Burton and Diaz, what is your overall impression of the PEACE data? And how do you see this affecting or impacting your care for your patients?

Well, I'll just say as a nonparticipant that I'm extraordinarily impressed. I think it's incredible that the therapy is able to bring the patients back chemically into the normal range. I mean we rarely achieve that in any of the diseases that we treat. So this is an extraordinarily efficacious product, and I haven't seen anything that I'm personally concerned about with regard to the safety profile. So I think it looks incredibly impressive from my perspective.

Yes, I feel the same. I actually was not certain that there would be a reversibility. And that was -- I think that is most impressive to me to actually see improvements in patients has long-standing disease. My thoughts on how this works going forward is we prevent the development of these complications in patients. So we should have a population of patients who, if this is approved, we'll have a tremendous benefit.

Thank you very much for those responses. Anthony, that clears it from the field, and we're right on the hour.

Great. So just a couple of points. So I'd like to firstly thank all our speakers today for taking the time to join us and share their knowledge and experience with arginase deficiency. This is a rare disease. And given its [ rare ]tape, we feel it's incredibly important that we continue to shine light on the disease. And the challenge is that the physicians face, the patients face and the caregivers face with its management. So thank you, everybody.