Thank you for holding. Good morning, and welcome to the Passage Bio conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open up the call for your questions. Please be advised that this call is being recorded at the company's request. At this time, I'd like to turn it over to Stuart Henderson, Vice President of Corporate Development and Investor Relations. Stuart, please proceed. Thank you, operator. Good morning, everyone. Today we will review interim results from the global Imagine-1 phase I/phase II clinical trial of PBGM01 in infantile GM1 gangliosidosis. Please refer to the press release issued earlier and the slides that we will be using on today's call on the Investors and View section of the Passage Bio website. Before we begin, I'd like to remind you that our presentation this morning will contain forward-looking statements based on our current expectations and beliefs of future events as of today. These statements are subject to a number of risks and uncertainties, including those risk factors from our latest 10-Q, that could cause actual results to differ materially and adversely from those presented. It is now my pleasure to turn the call over to Chief Executive Officer, Dr. Will Chou. Will? Thank you, Stuart. Good morning, everyone. I'm excited to build on the encouraging data supporting our global Imagine-1 phase I/phase II trial of PBGM01 in infantile GM1 gangliosidosis as we now begin to generate data in early infantile patients and patients treated at a higher dose. On today's call, I will begin with a brief summary of what we will cover during the presentation. Dr. Mark Forman, Chief Medical Officer, will review the interim results, and we are also thrilled to be joined by GM1 gangliosidosis world expert and clinical researcher, Dr. Jeanine Jarnes, Assistant Professor at the University of Minnesota Department of Pediatrics, who will describe the natural history of this disease. I'll begin first by summarizing our approach and the findings from this interim analysis. Turning to slide five. Our program for GM1 gangliosidosis was designed to address the high degree of unmet clinical need for this underserved patient population. GM1 is a fatal pediatric lysosomal storage disorder caused by loss of function mutations in the GLB1 gene, leading to a deficiency in the enzyme beta-galactosidase. There are no approved disease-modifying therapies. PBGM01 utilizes a next generation proprietary AAVhu68 capsid to deliver a functional GLB1 transgene encoding beta-galactosidase to the brain and peripheral tissues via intra-cisterna magna or ICM delivery. In preclinical models, we observed a clear dose response effect and meaningful transduction of both CNS and peripheral organs. On slide six, we provide a summary of key interim findings from the first six patients treated with PBGM01, highlighting the promise of our therapy. First, we are excited to see that PBGM01 continues to be well-tolerated and has a favorable safety profile. There have been no treatment-related serious adverse events, no evidence of dorsal root ganglion or DRG toxicity, no evidence of cell-mediated immune response, and no complications related to ICM injection. Focusing next on two key biomarkers in the CSF. We have observed dose-dependent increases in beta- galactosidase activity, the enzyme of interest, and dose-dependent decrease in GM1 ganglioside, a key substrate of beta- galactosidase. Lastly, we are beginning to uncover important learnings about where PBGM01 may offer the greatest benefit to patients. When looking at the data from clinical assessments on the Vineland and Bayley Scales, we have observed meaningful developmental improvement for a subset of patients. This contrasts from what one would expect from the natural history of the disease, as Dr. Jarnes will discuss shortly. We are also beginning to understand that the stage of disease at the time of treatment may play an important role in treatment outcome. Mark will describe this in more detail later in the presentation. It's now my pleasure to turn the call over to Dr. Jeanine Jarnes to describe the natural history of this disease. Thank you, Will. I'm excited to participate in today's discussion. Let me begin on slide eight. As Will mentioned, GM1 gangliosidosis is a fatal pediatric lysosomal storage disorder caused by a mutation to the GLB1 gene, and this leads to a deficiency in the enzyme called beta-galactosidase. GM1 gangliosidosis is a disease that primarily affects the central nervous system. Children experience a continuous decline and do not show improvement when they have this disease. Children with this disease experience rapidly progressive neurological decline, resulting in a variety of symptoms, including reduced muscle tone, progressive central nervous system dysfunction. Some children have deafness or develop deafness. Some develop blindness. There are no disease-modifying therapies currently approved for GM1 gangliosidosis. The next slide describes that GM1 gangliosidosis presents along a continuum. This continuum affects patients at different ages and results in varying disease severity. In the case of a rare disease like GM1 gangliosidosis, the natural history studies can play an important role in offering controlled data for designing a clinical trial and conducting that trial. GM1 gangliosidosis is a progressive disease. It has a continuous decline, and the natural history study data shows that patients who lose milestones almost never regain them. Published data has shown that the more severe the disease in patients with GM1 gangliosidosis, the lower the beta-galactosidase enzyme activity level in the children's tissues. There's some degree of overlap between patient categories. The infantile form of the disease is the most severe form, however, and the Imagine-1 study focuses on patients with infantile forms of the disease, both early infantile and late infantile. On Slide 10, it is important to highlight the differences between the early and late infantile forms of the disease. Early infantile patients experience symptom onset prior to six months of age and have a very rapid disease progression. In most cases, early infantile patients experience a developmental plateau around three to six months of age and do not gain new developmental milestones after that point. Average survival for this form of the disease is less than two years, depending on the degree of palliative care available. Late infantile patients experience symptom onset between six months and two years of age. While still rapid, they experience a relatively slower disease progression when compared to the early infantile. In most cases, these patients experience a developmental plateau around 12 months-1 5 months of age, after which the child ceases to acquire any new milestones. The average survival for the late infantile patients is between five years and 10 years. As the disease progresses, they experience a regression where they lose milestones they have previously acquired. Motor and language domains are generally the most affected, with children reported to never walk independently or use more than single words. Reverting this process and gaining milestones is the ultimate objective of a potential therapy for GM1 gangliosidosis. On Slide 11, there is an illustration of how the disease causes a rapid decline in the infantile form, with survival at less than 20% when by the time the child is 24 months of age. This retrospective meta-analysis natural history study data is aiming to provide a better understanding of the progression of GM1 gangliosidosis disease and the timing of developmental milestone loss. The status shows that the average symptom onset is around 2.8 months of age, and the time of the first admission to hospital is at 6.3 months of age. We can see that the diagnosis occurs even later, at an average of 8.7 months of age. The average age of death is 18.9 months of age, meaning diagnostic times are high relative to the patient's survival. This analysis demonstrates the devastating clinical course of GM1 gangliosidosis, as almost all patients experienced significant multi-organ system dysfunction and neurodevelopmental regression, particularly in the six-month to 18-month age range. It's also important to note that while palliative care for these patients can impact overall survival time, we still see a rapid decline in the infantile GM1 gangliosidosis patients with less than 20% survival at 24 months. With that, I will turn the presentation over to Mark to describe the Imagine-1 trial and review the interim results. Thank you, Jeanine. On Slide 13, I'd like to begin by summarizing the global Imagine-1 trial. As depicted on this slide, our Imagine-1 study is evaluating two different doses in early and late infantile GM1 patients. As Will mentioned earlier, our approach utilizes a proprietary AAVhu68 capsid and ICM administration. For immunosuppression, we're using a low-dose steroid regimen for four weeks, followed by tapering. Imagine-1 is a two-year study with a rollover into a long-term follow-up study. The focus of the initial dose escalation phase of the trial is safety and tolerability, as well as biomarkers, to enable design of the second phase or expansion cohorts of the study. This includes, importantly, the selection of dose and the patient population that will most likely see benefit from PBGM01. To date, we've completed dosing of all patients in the dose-ascending portion of the study, with a total of eight patients now on study. Data shared on today's call will focus on the first three cohorts, each consisting of two patients. These include cohort 1, low dose late infantile, cohort 2, high dose late infantile, and cohort 3, low dose early infantile GM1. The baseline characteristics for each of the first six patients are summarized on Slide 14. Consistent with inclusion criteria, the late infantile patients have onset between 11 months and 14 months, while the early infantile patients have onset before six months of age. All patients have very low or undetectable beta-galactosidase activity. Lastly, there's a wide range of ages at gene transfer from 6 months- 31 months. First, let me discuss the safety and tolerability of the interim analysis. As shown on Slide 15, we continue to see that PBGM01 is well-tolerated and has a favorable safety profile. There were no treatment-related serious adverse events, and all treatment-related adverse events were mild to moderate in severity. There were no clinically significant changes in liver function requiring intervention and no evidence of DRG toxicity as measured by nerve conduction studies. Finally, there were no complications related to ICM administration. Turning to Slide 16, we summarize the favorable immunological profile. As you recall, our protocol calls for an abbreviated course of low-dose steroids. With this regimen, we saw a favorable immunological profile following ICM administration. Specifically, I'd like to highlight a few points. one, neutralizing antibodies to the capsid were detected at low levels in the CSF, but only after day 30. These are not expected to affect CNS gene transfer. Two, no antibodies against the transgene developed in the CSF or serum. Three, there were no T-cell responses against the capsid or transgene. Next, I'll review results from the two key biomarkers. On Slide 17, we show data to demonstrate dose-dependent increases in beta-galactosidase enzyme activity levels in the CSF following the administration of PBGM01. The top chart shows the available results for cohort 2, the two late infantile patients treated at the high dose. The bottom chart shows the available results for cohort 1 and cohort 3, two late infantile and two early infantile patients treated at the low dose. A few highlights I'd like to call out. First, we observed a dose-dependent increase in CSF beta-galactosidase activity, with the high dose resulting in an approximately five-fold increase over baseline for both patients at one month and a 3.6-fold increase over baseline for the first-treated cohort 2 patient at six months. These enzyme activity levels are well above those observed in patients enrolled in the prospective natural history study we are conducting with the University of Pennsylvania's Orphan Disease Center. In terms of durability, our longest follow-up is from patient one, where we see sustained increases in CSF beta-galactosidase activity out to 12 months. Lastly, while we're not showing graphs of these results here, we also observed sustained increases in beta-galactosidase enzyme activity in blood. On the next slide, we show the data for CSF GM1 gangliosides using a similar format. As mentioned previously, GM1 gangliosides are a key substrate for the beta-galactosidase enzyme, with higher levels associated with more severe disease. GM1 gangliosides are the beta-galactosidase substrate hypothesized to mediate the CNS manifestations of GM1 gangliosidosis. We see a dose-dependent response where the two patients treated with high dose exhibited substantial decreases in CSF GM1 ganglioside levels. For the first patient in cohort 2, levels decreased by 30% and 75% from baseline at one month and six months, respectively. For the second patient in cohort 2, levels decreased by 21% from baseline at 30 days. Decreases in GM1 gangliosides also correlated with the higher levels of beta-galactosidase enzyme activity observed in the CSF. Taken together, we're encouraged by the dose response observed in these biomarkers and look forward to additional longitudinal data from these cohorts, as well as initial data from cohort 4. Moving now to Slide 19. As Jeanine described in her comments, GM1 patients exist along a continuum and are a variable population. We've already mentioned the wide range of ages dosed in the trial, shown in row three. The patients treated also exhibited a broad range of developmental age at baseline, as shown in row four. The bottom row of this table shows the developmental delay at baseline, which is simply the patient's chronological age minus their developmental age in months. You can see there is a wide range in developmental delay among these six patients at baseline. Two patients, one and five, exhibited developmental delay of two months and 5.5 months, respectively, which we have characterized as mild to moderate delay. The remaining patients exhibited developmental delay ranging from 12 months-24 months, which we've characterized as marked delay. Keeping this in mind as we move to Slide 20, we observed that patients with a lower developmental delay at dosing experienced a better clinical response to treatment, even when only given a low dose. Beginning on the left, we plotted the overall developmental age over time on the Vineland scale. Recall that the Vineland scale is assessed by a caregiver or parent and measures a variety of motor, language, and social domains. As you can see, the two patients in green represent those with mild to moderate developmental delay at baseline. Both patients showed improvement in their developmental age over time, which contrasts with the plateau and subsequent regression you would expect based on the natural history. The blue lines represent the patients with marked developmental delay. In general, these patients show stabilization or limited improvement. On the right of the slide, you will see that these findings are similar when looking at results from the Bayley Scale, which is assessed by a trained clinician. We look forward to generating additional data over time from more patients to further evaluate the role of baseline developmental delay and treatment effect. Before handing it back to Will, I'd like to conclude on Slide 21 by summarizing these findings. First, we continue to be pleased by a favorable safety and tolerability profile of PBGM01 and the ICM procedure also appears to be safe. Second, we've observed a dose response in both CSF beta galactoside enzyme activity and GM1 ganglioside levels. Furthermore, responses in these biomarkers appear to be durable. Third, there appears to be an emerging trend that milder developmental delay at the time of treatment may be an important determinant of treatment outcomes. We look forward to further evaluating this trend as additional data become available and plan to incorporate the degree of developmental delay into our pivotal study design. With that, let me now pass the call over to Will for closing remarks. Thanks, Mark. Moving to Slide 23. We continue to be encouraged by the data emerging from our Imagine-1 study as we make significant progress against our key objectives for the program. First and foremost, in the initial phase of the Imagine-1 trial, we are focused on patient safety, and we're pleased by the favorable safety profile for PBGM01 so far. Our second key objective is to determine the optimal dose for therapeutic effect. We are excited that the data shared today showed a dose response in key biomarkers, coupled with a good safety profile at the higher dose. Given the strong dose response that we've seen clinically, and that our preclinical toxicity studies showed no safety signals at doses higher than the current high dose of 1.1E11 genome copies per gram brain weight, we are currently evaluating treating additional patients at doses higher than 1.1E11. Lastly, we are seeking to understand how PBGM01 can benefit patients across the infantile forms of this disease. These interim data suggest that PBGM01 may offer a benefit to both early and late infantile populations, and that early intervention in patients with lower developmental delay at baseline may be an important determinant of clinical effect. Moving on to Slide 24. Data from cohort 4 will be important to add to our understanding of dose and patient selection. This slide provides some baseline characteristics for the two patients in cohort 4. Both of these patients were diagnosed with early infantile GM1. When looking at their developmental delay at baseline, you can see that both patients exhibit mild to moderate developmental delay of two and four months. These patients both received the higher dose of PBGM01. Given the strong biomarker response we've seen with other patients receiving the dose and the early trend toward more favorable responses in patients with less developmental delay, we look forward to gathering data over the coming months from these most recently dosed patients. On S lide 25, we've shared anticipated next steps for this program. In 2023, we look forward to sharing additional data from the study as it matures. In February 2023, we plan to present additional data from cohort 1-cohort 3 during the 19th Annual WORLDSymposium. We also plan to present initial data from cohort 4, the early infantile high-dose cohort, by the middle of the year. As I mentioned, one of our key objectives for the phase of this program is to determine the optimal dose for the confirmatory study. The observed dose response and absence of safety signals are encouraging, and we plan to evaluate dosing additional patients at both the current high dose and an even higher dose than our current high dose. Our GLP toxicology studies support doses higher than 1.1E11 genome copies per gram brain weight, and these preclinical studies showed continued dose response at higher doses with no limiting toxicity. Second, while we are very pleased with the translation of dose-dependent biomarker response to the clinic, what we are seeing in the data are that high biomarker response may be necessary but not sufficient to drive a strong clinical response. Patient selection may also be a critical factor. Therefore, another key objective is to determine at an early stage in the program if some subsets of patients may be more likely to respond to treatment than others. We've seen some evidence of this in our trial, as it is possible that treating patients at an earlier time in their disease course could lead to better outcomes. As we consider our pivotal trial design and potential modifications to the ongoing trial. We will evaluate potential changes to inclusion criteria to maximize the benefit risk profile of PBGM01. As our clinical data matures, we are planning for continued interactions with regulatory agencies to align on the design of our confirmatory study and the appropriate pathway to a BLA submission. Before opening the call up for Q&A, I'd like to extend a sincere thank you to the patients, families, caregivers, and investigators in the GM1 community for their continued support. With that, I would now like to open up the call for Q&A. Operator? If you'd like to ask a question at this time, please press star one one on your telephone. Again, that is star one one to ask a question. Please stand by while we compile the Q&A roster. Our first question comes from the line of Yaron Werber with Cowen. Your line is now open. Hi, thanks very much. This is Brendan on for Yeron. Thanks for all the great input here. Just a couple of quick ones from us. First, I wanted to ask for potential phase III here. I know we're thinking a little bit ahead, really kind of looking at your take from this data so far. I mean, I'm assuming you'll probably continue to focus on the late infantile phase or excuse me, just the infantile patients in general. Do you think that would mean that for a potential label, you wouldn't really be able to address the juvenile form? Do you think you would need separate cohorts of patients, in a potential registrational trial? Do you think that the, you know, what you're seeing so far and what you know from natural history would support use of the gene therapy in those patients? Second, really just looking at the baseline characteristics here, are you guys considering in any way maybe looking to enroll or maybe just stratify patients based on developmental age at baseline? Do you think that or would you expect that or a lack of accounting for this to potentially impact the likelihood of hitting a cognitive endpoint, whether in a pool patient population or not, in a pivotal study? Thanks very much. Great. Thanks for the question. Why don't I answer the second part of your question first, and then I'll turn it over to Mark for the first part. In terms of what we would be thinking about for an inclusion criteria, it's a little early for that right now. We need to watch the data as it matures. We are certainly evaluating different methods of demarcating developmental delay at baseline. We wanna watch the data mature, particularly cohort four data, before we make any of those decisions. Mark, do you wanna answer the first question, first part of that question? Sure. The first question was around the, you know, the population that we're studying. Right now, yes, our trial is focused on the infantile population, both early and late infantile disease. Presumably, you know, if successful, the label would reflect the population that we studied. Certainly as part of our development program, we would look to, if our drug shows, proves to be successful, we would look to expand the populations that we would study at a future point in time that would potentially include a juvenile patients with juvenile form of the disease. That's, you know, that would be something that we would consider down the road. Right. Great. Thank you very much. Our next question comes from the line of Madhu Kumar with Goldman Sachs. Your line is now open. Hi, this is Omari on for Madhu. We have a few questions. First, what would you need to see from a given dose to move forward into a registrational study? Are there prospectively defined milder baseline characteristics you could see to select patients? Lastly, what would you go about going to higher doses? Do you think the existing doses are not getting sufficient transduction? Okay. The first part of your question was what would you need to see from a higher dose to move into a higher dose to go to registration? Yeah. I think a couple of things that we would be looking for. One is obviously a strong biomarker response. In our pre-clinical studies, what we've seen as we've gone up in doses, we've seen an even stronger biomarker response, both for beta- galactosidase and lysosomal function. We've also clinically in the pre-clinical. I think we would need to see something similar, right? We would need to see continued stronger biomarker responses, and we need to also see a strong clinical effect in terms of developmental improvement. Are existing doses not getting sufficient transduction? That was another part of your question. Absolutely not. In fact, we're seeing the opposite. We're seeing evidence that with higher doses, we are getting very strong transduction. That just strengthens the idea for us that biologically, the product is doing what it's supposed to be doing, and it's also reflecting what we saw pre-clinically in that there was a dose response with strong transduction. It's incumbent on us to bring the most effective possible product to patients with GM1 gangliosidosis. That is the most important thing we need to do. When we are seeing better, stronger transduction and a better biomarker response with a higher dose, and we have room to go to an even higher dose, that's why we're considering that next higher dose. Mark? Thanks. Well, I think you hit upon the points that I was gonna make as well, which is I think, you know, the one, you know, if you think about this initial phase of our, of this trial, of the Imagine-1 trial, it's really around, as Will discussed, one, safety and tolerability, and two, dose selection. The key is we really need to make sure that we get now the dose selection part before we initiate the confirmatory study. Since we're seeing a dose response, but we haven't we don't know yet whether we've maximized that response, that we're considering the possibility of going up higher to really sort of better understand, to make sure that we have that piece nailed down. You also asked about I think we, you know, asked about the baseline characteristics. I think as Will talked, discussed earlier, I think that's something that we're gonna be learning as we go and seeing, and to find that we haven't yet defined what those inclusion criteria are gonna look like. Really, you know, again, to reiterate the data is that the patients which have, had a more limited developmental delay look like they're deriving greater benefit from the drug. The goal might be, you know, the goal would be to sort of can we define a population that would most likely benefit, meaning less developmental delay at the time of enrollment in the trial. There are clear, discrete criteria that would do that. We just haven't made the decision on which ones we could use because we wanna watch the data mature a bit more before we do that. Thank you. Sure. Our next question comes from the line of Laura Chico with Wedbush. Your line is now open. Good morning. Thanks for taking the question. I have one for Dr. James if she's still available. Some of the commentary about achieving new milestones was helpful. I'm wondering, in your opinion, would achievement of new learned milestones be a valid assessment or tool to kind of consider in future studies or even this study? Secondarily, I guess related to the biomarker changes, any perspective in terms of kind of optimal beta- galactosidase levels that you would think would be necessary here? Then I have one follow-up for the company. Thank you for the question. I think you're asking, would achieving new milestones, developmental milestones be an adequate outcome to measure to show a meaningful efficacy? Is that what you're saying? Yes. Okay. Would that give you confidence that the drug is generating a meaningful clinical effect? Yes. The answer is yes, and that sounds a bit simplistic, but what we do know, which is so key to this, is in the patients that have this disease, the childhood form of the disease, infantile, late infantile, even the juvenile, even though this trial is not in the class of juvenile. Once they start showing prominent symptoms of the disease, which typically occurs well before a diagnosis is made at this point in our landscape for this disease. Once they start showing these clear signals that there's something wrong, and this leads to a diagnosis, after that point of symptom onset, we see nothing. I can confidently say this. We see nothing but continual decline. In a way, it is a very complicated natural history, but in a way, it's simple when you look at it this way. If we see a treatment producing a reversal of that, where patients are starting to gain milestones or regain milestones that they lost, in my opinion, as a natural history expert, my clinical and research opinion, this would be a clear signal of efficacy from the treatment. There are some other trials in rare disease in which they even try to just show a stabilization or even a reduction in the rate of decline in the disease in diseases such as this, where there's a continual decline. That is kind of setting a pretty low bar but definitely if we're seeing some gaining of skills that were lost or even gaining of new skills, this is a very clear signal of efficacy. In terms of the biomarkers, I think we don't, I would say, and I could turn the question back to Passage Bio also, but with what we know right now, it's really important to see an increase in tissue beta-galactosidase activity and also a reduction in the accumulation of the substrate that is occurring in this disease, which is the GM1 ganglioside. Just exactly quantitatively what level we need to see to declare efficacy, I think that is still something that is being explored. It's very encouraging to see that these numbers, if they're going in the right direction, is a very encouraging signal. I hope that answers your question. Yes, it does. Perhaps, thank you, Doctor. Perhaps a question for Passage. I guess I just wanted to tease into the dosing strategy. Have you disclosed kind of what would be a higher dose level that would be acceptable for exploring beyond the 1.1E11 dosing? I just wanted to verify, for all patients that have been treated to date, are they continuing to thrive? Survival is obviously an important tool here to assess in terms of progression, but I don't think I saw that in the press release. Thanks. You know, for the dosing strategy, I don't think we have specifically settled in on the dose. We have, based on the toxicology studies, we have room to go up to higher doses with ample safety coverage to support those doses. We think that coupled with the safety profile to date gives us some room. The actual dose that we haven't decided upon the specific dose that we're going, and that's sort of a topic of internal discussion, and obviously, will have to be vetted with health authorities as well. So far to date, all of, all 6, all 8... Well, there are now 8 patients on trial. All patients are, you know, are still, are doing or have, you know, are still, you know, alive and doing well. In fact, I think there's a bit of a dissociation sometimes between how the physicians see the child and what they see on the scale, where we have some child, you know, some individuals where the physicians think they're doing well, and the scales, the Bayley Scales don't necessarily reflect that. I think there's, I think time is gonna be important. One of the things that we've learned from other gene therapy trials in the past is you need time to see the clinical benefit. What we've seen now is the biomarker response, and we need to follow these patients over time to really better understand the clinical responses that we're gonna get. If I might come back, Jamie, to the question you asked about the biomarker strategy just briefly. you know, how much increase in beta-galactosidase activity, as Dr. Jarnes said, is clearly not known. I think just if we go back to our preclinical data, where we've shown that in knockout mice, relatively modest increases in beta-galactosidase activity were associated with clinical benefit. higher doses, though, we saw further increases in beta-galactosidase activity in both mice and primates, and these were associated with improved lysosomal function. There at least is preclinical rationale for continuing to push the dose to see if how that will translate to human. that's sort of the discussion and that's how we're trying to map out our strategy looking forward. Very helpful. Thank you. Our next question comes from the line of Whitney Ijem with Canaccord. Your line is now open. Hey, guys. Thanks for taking the questions. First, I guess just to clarify on the potential higher dose, is that something you're thinking about, like adding a cohort to the existing study, or is that more a discussion around exploring a higher dose potentially in a pivotal setting? Second question, for the Vineland and Bayley Scales, I guess can you speak to any of the granularity of the domains of the scales? I know there was discussion of language domain in particular as it relates to patient one in previous updates. I guess any update on that patient in particular and anything you can say on what you've seen in patient five. Sure. Sure. For the dose escalation, what we would be considering is an additional set of patients in the current trial. That is the fastest way for us to do this. We know there's many patients with GM1 who are waiting for more availability. It's incumbent on us to make this decision and get this out to patients as quickly as possible. Then I'll turn it over to Mark to comment on the subdomain. Right. I mean, I don't think that there is any with regards to the subdomains, I mean, this is something that will be, you know, the subject of a future data releases where we discuss, for instance, at, you know, at the WORLDSymposium, we'll have an opportunity to talk in a little bit more detail and granularity around the different subdomains and how they're doing. I think this is also, though, I would just sort of as a preview, there's, you know, that there's a lot of variability. Some patients we've seen have seen improvement in different domains, and there isn't a consistent trend across all our patients as to which domains we're seeing improvement in versus versus others. I think, I mean, just that, like I said, that'll be topic that we will disclose at, you know, during the course of next year as we have more opportunity to really dig into that data and look at the differential responses across subdomains. Got it. Thanks. Our next question comes from the line of Neena Bitritto-Garg with Citi. Your line is now open. Hey, guys. Thanks for taking the question. I just wanted to ask about the commentary on the developmental delay at baseline, potentially being a driver of a better clinical response. I'm just curious what your thoughts are on age at dosing as well, just because it seems like patient one and patient five were also the two youngest patients at the time that they were dosed. I guess just any thoughts on that. Sure. I can start and then turn things over to Mark. You know, age is one of the potential criteria that we could use, but there are multiple, and so it's still a small N. As you saw, we've got cohort four patients that we will be able to see what their development status looks like, and we'll be able to use that information to help us guide future inclusion criteria. Mark? Right. Thanks, Will. I think what's also embedded in there is the different populations. The late infantile populations have onset between six months and 18 months, and the early infantile patients have onset before six months of age. That's a little bit of some of the dichotomy. What we showed is the two patients with the milder delay, actually, one was an early onset, one was a late onset infantile patient. I mean, I'm not sure where, as Will just said, based on the small N, we can draw any firm conclusions. I think that's also why, you know, seeing these additional patients, that seven and eight that we have just, that we have recently enrolled, and as we generate data from that cohort, sort of in the middle of the, as we talked about in the middle of the year, that should really help address your question about some of the age characteristics versus the degree of developmental delay. Again, it's sort of, you know. It's hard to draw, again, base small N, it's hard to draw firm conclusions, but that's part of the reason for expanding the cohorts a little bit to, in order to, really better understand our, these parameters that we would wanna incorporate into a pivotal study design. Okay. Got it. Thank you. I guess just can you clarify, just on your last comment, are you planning on actually adding patients to any of the existing cohorts, or you're just planning to add additional cohorts testing higher doses as you've discussed? I think the answer is yes. I mean, we're considering. You know, we haven't made any firm decisions yet, but what we are considering is both adding additional patients to the high-dose cohorts that we have currently, the high dose that we're currently studying, 1.1E11, but also considering going up to higher doses. Both of those are on the table and as we, as those decisions get made internally, they'll be shared, you know, we will share them in the context of either, you know, presentations at meetings or quarterly reports. But we don't have a firm answer yet exactly what the strategy is looking like. It's a work in progress. Got it. Understood. Thank you. Our next question comes from the line of Yun Zhong with BTIG. Your line is now open. Hi. Good morning. Thank you very much for taking the question. This is actually a follow-up question to the previous one on the developmental delay. I just wonder, looking at patient one and patient five, the developmental delay, is that dependent on diagnosis or is not dependent on... Whenever you diagnose those patients, the developmental delay does not change? I have a follow question, please. Yeah. I'll jump in and start that and we'll see and Dr. Jarnes has any further comments, she's welcome to chime in. I mean, the challenge with, as Dr. Jarnes talked about in the natural history, if you looked on one of, on the slide that where the patient, the retrospective analysis of data, what you can see is that the most in the infantile population, they're generally presenting at two to three months of age, and they're not being diagnosed till they're, you know, close to nine months of age. There's a long gap for a very young population in terms of time of presentation to time of diagnosis. The developmental delay that we're characterizing in this, in our study is based on what is their chronological age at the time of dosing versus what is their developmental age at the time of dosing based on the Bayley. The developmental age evolves over time. As Dr. Jarnes talked about in the natural history, these children, not only do they start plateauing, but they're then declining. Their age, the chronological gauge is going up and their developmental age is actually decreasing. That, that gap actually increases with time following presentation. I mean, I mean, hopefully I didn't make a mess of that, but Dr. Jarnes can sort of, and may potentially add any further comments if she has anything, you know, if she would like. I would have to agree with Mark, and it looks. The data that was presented here is the developmental delay at baseline, but we do know that the natural history of the disease, and this is maybe just reinforcing what Mark just said, is a continual decline. What we have seen in the natural history is a very marked decline in what we call age equivalent scores. What we're looking at, the chronological age versus the developmental age, there is a continual decline, and we would expect in the natural history that. With no treatment, this number would continue to decline. Is that addressing your question? I think so. It looks like it is dependent on the timing of the diagnosis. Also related to dose, looks like development delay is more important in predicting, treatment outcome because both patient one and patient five actually got the low dose. How, how does that affect your dose selection? Also, you know, when comparing to natural history data, how confident are you given that those patients, received a low dose, how much of the performance is due to treatment benefit as compared to maybe better performance in this type of patient just, if they do naturally? Yeah. I think it's gonna be a combination of things, right? And we know particularly from our preclinical data that the stronger biomarker response you get, the better effect on lysosomal function and the better effect on overall function. Biologically, that makes sense. Higher biomarker response is definitely a goal. What it looks like is it could be a combination of both things. You need that a higher biomarker response in combination with the right set of patients gives us our best potential to show improvement. Okay. My last question. Mm-hmm. Sorry for the many questions. Actually related to biomarker. You didn't show the natural or sorry, the normal range for beta- galactosidase in the CSF. You only showed natural history patient range. I wonder, does the treatment bring the CSF level, the beta- galactosidase level back to the normal range? Also in the low dose patients, even after treatment, the beta-g alactosidase level seems to be still comparable to natural history range. Right. You've highlighted one of the challenges that we're facing with, which is how do we define the normal range of beta-galactosidase in the CSF? Most of the normative data that's out there is based on an adult population, and we know that that is not the same as what you observe in children. We have an explicit. It's part of an ongoing effort, is to really define that normal range in healthy children to provide a benchmark. Right now what we're using is we have from our natural history study, the range of beta-galactosidase activity in affected children. What we're, the gap that we're sort of looking to fill over time is how do we understand what the normal range is? Again, we have an adult, we understand what the adult normal range in the CSF is, to getting that data in children is very difficult. Okay, great. Thank you very much. As a reminder, if you'd like to ask a question at this time, that is star one one. Our next question comes from the line of Danielle Brill with Raymond James. Your line is now open. Hi, guys. Good morning. Thanks for the questions. I guess I'm just kind of curious how you're interpreting the developmental data at this point. It seems kind of premature for pretty much everyone except for maybe patient one. Like, I'm just curious, based on natural history and late onset, whether that patient's trajectory could just reflect normal, functional gains or developmental gains and which then subsequently begin to decline. Just to circle back a little bit on the expression over time. I guess, like, are you, is it possible that you are transducing cells that are glial cells that are turning over? How, like, are you thinking about the loss of expression over time? Thank you. Yep. Let me start on this. In terms of one of the parts of the questions was, is patient one, is this just normal? I think what you've heard from Dr. Jarnes is that continuing to improve is not normal. It's not what is generally seen in these patients. We in fact are encouraged by this. I think the other part of your question is it too early to interpret results? Well, truly it is early for some of these patients, right? Patient 5 we've only observed for a short period of time. What I can say is that seeing and understanding which patients might not respond to your therapy is a good thing to identify early on in a clinical program. I think we've seen examples even recently of clinical programs that have identified populations that don't respond, but much later on, in the program. We think, it is good to get a signal at an early point of who is a better, who might be a better and worse responder. Mark, Turn it over to you for the last part of that question. Well, I mean, yeah. Before I turn over to the second part around the biomarkers, the first I'd like to just. In terms of patient 1, actually, this individual has had affected siblings that this child has already outlived beyond. Suggesting that, you know, it's not definitive evidence, but it's sort of associate, you know, it sort of implies that our therapy is having an effect on survival in this patient based on their sibling data. The second thing regarding the durability of the biomarker response, I think there's a couple points I'd wanna make. Yes, we did observe a little bit of reduction from, in that 1 patient where in the high-dose patient from one to six months, there was from about a 5x increase to about a 3.5 fold increase. However, I'd also sort of point out that the CSF substrate, the GM1 gangliosides, over that time from one to six months actually continued to decline. I think it emphasizes the point that we're using the CSF beta-galactosidase levels and the CSF as a proxy for what's going on in the brain. It's not a, it's not an exact predictor of what's going on within the cells of the brain. The ganglioside data suggests that despite we're measuring a loss of beta-galactosidase, functionally, we're continuing to have an impact with further reduction in the substrates over time. Again, this is something that we're gonna have, you know, it's early, as you pointed out earlier, it's early days and we need, you know, part of what we need is, you know, part of what we've been talking about over the course of the call is we, you know, more time to let the data mature. Potentially, given the small sample size is only two in each of the cohorts, potentially expanding them to really have a better data set to make more informed decisions as we move forward. Great. Thank you. That concludes today's question and answer session. This concludes today's conference call. Thank you for participating. You may now disconnect.