Good afternoon, and thank you all for joining us. We are very pleased to announce positive top-line results from the phase 2 Helios clinical trial of AMX35 in Wolfram Syndrome. Before we begin, I'd like to point out that we will be making forward-looking statements today, which are based on our current expectations and beliefs. We have a number of important disclosures on this slide, which I urge you to read. Touching briefly on today's agenda, Dr. Camille Bedrosian, our Chief Medical Officer, will share an overview of Wolfram Syndrome and will review the data generated from the Helios clinical trial to date, as well as discuss next steps for the program. We're also thrilled to have Dr. Fumihiko Urano join us today. Dr. Urano is the principal investigator of Helios and the Samuel E. Schechter Professor of Medicine at Washington University School of Medicine in St. Louis. Also joining us for Q&A are Josh Cohen and Justin Klee, our co-CEOs, and Jim Frates, our Chief Financial Officer. Please feel free to enter questions into the chat box on your screen throughout the event. Before I turn it over to Camille, I would like you all to hear from Raquel, a person living with Wolfram Syndrome. My name's Raquel Gabel. I am 19 years old, and I am living with Wolfram Syndrome. My path to getting the diagnosis of Wolfram Syndrome started when I was about four years old, when I got diagnosed with diabetes, and then when I was about five, I started losing my vision. Her pediatrician noticed she had a wandering eye. We took her to the ophthalmologist, and he noticed she had a pale optic nerve. And I said to the ophthalmologist, "Well, could that be from diabetes? 'Cause she just was diagnosed with Type One." And he flung around on his chair, and he's like, "This is so bizarre," because he just sat on a board for this rare disease. And he said it presents itself as Type One diabetes, and then it leads into optic atrophy or hearing loss. And we had her genetically tested, and it was Wolfram Syndrome. I've lived with vision loss and had diabetes since I can remember, and then when I was about 10 years old, that's when my bladder stopped working, and I got diagnosed with a neurogenic bladder, and then when I was about 15, I started getting these muscle spasms in my throat. We call them choking episodes. What happens with those is a lot of times I can't really breathe that well. I believe the hardest thing with the progression of Wolfram Syndrome is the vision loss. It just was really difficult as a mom to know that she's not gonna be able to see the beautiful sunsets that I see. This disease is hard living with, but you need to take it day by day, not look in the future and wonder: What if I get this symptom? What if this happens to me? We want her to be independent. We want her to enjoy the other things that her siblings are enjoying and just to live her best life. This disease doesn't have to stop me from anything I wanna do. I can figure out ways to do what I want around it. There's so much going on for this disease, so much research going on, clinical trials. There's a lot more funding coming in, and it means more for me for the younger generation because then they wouldn't have to go through everything I have. Good morning, everyone. As we just heard from Raquel, Wolfram Syndrome initially presents as juvenile-onset diabetes mellitus. The diagnosis of Wolfram Syndrome then may be suspected when the disease manifestations expand to include progressive vision loss and then progressive hearing loss, ataxia, and difficulties in breathing and swallowing. Wolfram Syndrome impacts multiple organs and systems and ultimately leads to death in the early thirties. We estimate that there are approximately three thousand people living with Wolfram Syndrome in the U.S. Currently, there are no therapies specifically approved for Wolfram Syndrome. Wolfram Syndrome is a monogenic disease caused by mutations in the WFS1 gene. The WFS1 gene encodes a protein called wolframin that spans the endoplasmic reticulum, or ER membrane. Loss of wolframin function leads to ER stress and consequently impaired mitochondrial dynamics, two connected pathways that, when dysregulated, lead to multi-organ cell dysfunction and death, starting with beta cells in the pancreas and then neurons in the visual system, auditory system, and throughout the body. Because of the clear link between WFS1 mutations and ER stress, Wolfram Syndrome is considered a prototypical ER stress disorder. AMX35 is designed to slow or mitigate cell death, the fundamental cause of neurodegeneration, through reductions of ER stress and mitochondrial dysfunction. Thus, we believe there also is a clear link between the mechanism of disease and mechanism of AMX35. Our Wolfram Syndrome program started more than eight years ago. Years of research looking at cellular and animal model studies showed the therapeutic potential of AMX35. Specifically, AMX35 improved WFS1 protein expression, increased insulin secretion, and inhibited beta cell death in cells derived from people with Wolfram Syndrome. AMX35 also prevented cell death in neuronal cells derived from people with Wolfram Syndrome. Furthermore, AMX35 significantly delayed progression of the diabetes phenotype in a WFS1 knockout mouse model. These compelling results were published in the JCI Insight in 2022. Following these promising preclinical data, we initiated the phase 2 Helios clinical study and shared positive data in April from an interim analysis. Helios is an open-label, single-arm study in which all 12 participants receive AMX35 for up to 96 weeks at one site. The Helios trial was designed to assess key measures of pancreatic function, visual acuity, and overall symptom burden. The primary endpoint is evaluation of pancreatic beta cell function as measured by C-peptide response. That is, the change from baseline in C-peptide levels monitored during a mixed meal tolerance test, or MMTT, at 24 weeks. C-peptide levels were determined from the area under the concentration time curve, or AUC, over 120 minutes. Adults aged 17 years or older with a genetically confirmed diagnosis of Wolfram Syndrome, defined by documented pathogenic variants or mutations in the WFS1 gene, were eligible for the trial. Importantly, participants were required to have insulin-requiring diabetes at baseline due to Wolfram Syndrome, and also were required to have some residual pancreatic function at baseline so they could respond to an MMTT. Participants also were required to wear a continuous glucose monitor for the study duration. The use of GLP-1 agonist was not permitted during Helios. The data we are sharing today are as of when all 12 participants had completed their week 24 assessments. As of the cutoff date, ten participants had completed their week thirty-six assessments, and six participants had completed their week forty-eight assessments, and the trial continues ongoing for longer-term follow-up. To provide context on why we are encouraged by the top-line data, I will review the endpoints and the expected trends in Wolfram Syndrome as Wolfram Syndrome progresses based on the natural history studies of the disease. As I mentioned, the primary outcome of Helios is C-peptide AUC response, a well-established surrogate marker of pancreatic function and glycemic control. C-peptide levels measure the ability of the pancreatic beta cells to produce insulin, or put more simply, measure how well the pancreas is functioning in managing blood sugar levels. C-peptide levels are expected to progressively decline over time in Wolfram Syndrome, confirmed by the recent natural history study, data shown in the leftmost panel of this slide. Secondary endpoints that also measure glycemic control include hemoglobin A1C in plasma, a well-recognized measure of diabetes progression. The hemoglobin A1C measures glycosylated hemoglobin and provides a sense of glycemic control of diabetes during the previous two to three months. Whereas we look for C-peptide levels to be higher with improved pancreatic function, we look for A1C levels to stabilize or decrease if blood glucose is well controlled with exogenous insulin and diet. Another frequently used measure of glycemic control is time in target glucose range. For both A1C and target glucose range over time, in Wolfram Syndrome, it may become more difficult for these measures to remain stable as the disease progresses. Moving now to measures of visual acuity, which can be assessed using the Snellen eye chart. In Wolfram Syndrome, visual acuity is expected to worsen over time. As shown on the right, from a recent 10-year analysis of 38 individuals with Wolfram Syndrome, visual acuity declined over time in nearly all participants, with a mean slope of 0.059 LogMAR per year. Some had faster declines than others, but nearly all declined. Moving to baseline characteristics. Participants in Helios at baseline range in age from 18 to 39 years, with a median age of 25 years. 83% of participants are female. The median time since diagnosis was 5 years, and median age at diagnosis was 21 years. The age of onset of Wolfram Syndrome manifestations aligned to natural history, with diabetes occurring first, followed by vision loss. For the 12 participants enrolled in Helios and receiving AMX35, we later determined that one participant did not meet the inclusion criteria for the trial based on genetic evaluation of the WFS1 mutations present. This participant had a pathogenic variant or mutation on just one of the two alleles. The other allele had a variant of uncertain significance in the WFS1 gene. Since this participant was enrolled in the trial and receiving treatment, we will present data, including this individual, as well as data from the 11 genetically confirmed participants with Wolfram Syndrome, which we define as a per-protocol cohort. Now onto the Helios efficacy and safety results. The a priori hypothesis was that AMX35 may slow progression of disease manifestations. As we had shared, the data presented in April improvement or stabilization on key outcomes, measuring the progression of diabetes, visual decline, and overall disease burden in adult participants living with Wolfram Syndrome.... Today, we are pleased to share positive top-line data from Helios for all twelve participants who completed twenty-four weeks of treatment, as well as longer-term data on participants who completed thirty-six and forty-eight weeks of treatment, respectively. Here we have a summary of the expected progression of Wolfram Syndrome as compared with the trend seen in Helios. This snapshot demonstrates why we are encouraged with the results presented today. The data indicate that all disease measures are moving in the same direction toward improvement or stabilization. Let's start by looking at the primary endpoint, C-peptide response during an MMTT at week twenty-four. We also included weeks thirty-six and forty-eight. Here we show the mean change from baseline in C-peptide AUC over one hundred and twenty minutes at the specified study time points. As a reminder, the expectation is for C-peptide response to decrease over time in Wolfram Syndrome, since it is a progressive disease with progressive decline in beta cell function. Instead, we are seeing an improvement in C-peptide response across all weeks shown compared to screening. While only a subset of participants have completed 36 and 48 weeks of treatment, we are encouraged to see the sustained improvement in C-peptide response at those time points as well. Moving to the secondary endpoints, we observed improvements or stabilization across all measures. The improvement in C-peptide response we saw with the primary endpoint was associated with lower hemoglobin A1C values. Shown on the left are the overall findings among the participants that reached each specified time point. The individual results are shown on the right. As a reminder, the expectation is for hemoglobin A1C to stay stable if blood glucose is well controlled. It may become more difficult for levels to remain stable as the disease progresses. Contrary to the natural history of the disease, here we are seeing an improvement in glycemic control across all weeks shown compared to screening. When we look at the individual results shown on the right, nine of 11 participants demonstrated reduced or stable hemoglobin A1C levels from screening to the latest available time point in the per-protocol cohort. We are encouraged by these results, as most participants demonstrated an improvement in the control of blood glucose, as measured by hemoglobin A1C, and these improvements were sustained over time. We also assessed changes in the degree of glycemic control through continuous glucose monitoring. Specifically, we evaluated the change from baseline in the overall time in target glucose range. This parameter is defined as a percentage of time glucose values are between 70 and 180 milligrams per deciliter, another well-recognized way of assessing changes in glucose metabolism. Shown on the left are the overall findings among participants that had reached each specified time point. On the right are the individual results. Consistent with the hemoglobin A1C findings and contrary to the natural history of the disease, here we are also seeing improvement in glycemic control across all weeks shown compared to screening. 9 of 11 participants in the per-protocol cohort demonstrated stable or increased time in target glucose range from screening to the latest available time point. Overall, this increased time in target glucose range was sustained over all weeks. As we heard from Raquel, vision loss represents significant morbidity in Wolfram Syndrome. There are no proven effective medical treatments for vision loss due to optic nerve atrophy in Wolfram Syndrome, and visual acuity is expected to decline over time in nearly all people living with Wolfram Syndrome. We evaluated the effects of AMX35 on best-corrected visual acuity on participants that reached weeks twenty-four and forty-eight. As shown on the left, we saw a trend toward potential visual acuity improvement compared to screening. On the right, when looking at individual data, eight of eleven participants in the per-protocol cohort demonstrated improved or stable visual acuity in their best eye. This is a particularly encouraging data set against a recent ten-year analysis of thirty-eight individuals with Wolfram Syndrome, in whom visual acuity declined over time in nearly all participants, with a mean slope of 0.059 LogMAR per year. Given the many manifestations of Wolfram Syndrome that go beyond diabetic and visual acuity measures, we wanted to understand symptom burden on a more global, holistic scale. We included the patient and clinician-reported global impression of change. A general approach uses an overall impact of a potential treatment. Both use a seven-point scale to evaluate the change in Wolfram Syndrome-related symptoms since initiating drug. Because, again, Wolfram Syndrome is progressive and declines are expected, Helios defines a responder on both scales as no change or improvement. Shown on the left is the patient-reported global impression of change, and the same is shown on the right from the clinician perspective. At week 24, 82%, or 9 of 11 participants, reported an improvement in symptom burden on AMX0035, and clinicians reported 73%, or 8 of 11 participants, improving. As a reminder, given the progressive nature of Wolfram Syndrome, even no change in symptom burden is considered different from the usual course of the disease. Therefore, all participants in the per-protocol cohort met responder criteria at week twenty-four, and the self and clinician-reported responders were sustained for participants who reached weeks thirty-six and forty-eight. Turning to safety and tolerability, safety findings in Helios were consistent with previous AMX35 clinical trial data. Namely, AMX35 was generally well-tolerated, and no new safety signals were identified. Diarrhea was the most common treatment-emergent adverse event. All cases were of mild intensity. It is important to note that while nearly all participants reported at least one treatment-emergent adverse event, none led to discontinuation. Now I'll turn over the call to Dr. Fumihiko Urano to provide his views on the data and their clinical relevance. Dr. Urano? Thank you, Dr. Bedrosian. Good afternoon, everyone, or good evening, depending on where you are. So the data Dr. Bedrosian has just shown is quite encouraging to me because of several reasons. So I'd like to tell you a little more about the scientific basis supporting my impression. First, the data from our natural history study indicates that C-peptide levels progressively decline in patients with Wolfram Syndrome, so C-peptide level is supposed to decline. The clinical trial data indicates that participants experienced improvements in both C-peptide and also hemoglobin A1C levels, suggesting that reduced beta cell endoplasmic reticulum stress and improved beta cell function. And that implies that AMX35 reduced endoplasmic reticulum stress in different organ systems or tissues, such as retinal ganglion cells in the eyes and some brain cells. Impact on diabetes-related measures and visual acuity support this concept and idea. AMX35 may be impacting multiple organ systems, not only beta cells, but also eye cells and the brain cells. The pace, direction of change, and the clinical of change, improvement seem to surpass a placebo effect. The reason is patients and the clinicians often have specific reasons for reporting improvements. So I did talk to all the patients and all the clinicians who have examined them. So, for example, some patients have mentioned improvements in bladder functions, needing to catheterize less often. As Raquel mentioned in her video, bladder problems are pretty common in patients with Wolfram Syndrome, so this is quite significant. Others have reported better tolerance to heat and cold. Heat intolerance and cold intolerance are also common in patients with Wolfram Syndrome. One patient also told me that her headaches have become less frequent. Sharp, stabbing headaches are common in patients with Wolfram Syndrome, so that's also quite significant. Understanding these individual experiences important because it helps us assess the beneficial effects of AMX35 more accurately in the ongoing trial and in the next phase. Thank you. Thank you, Dr. Urano, for your insights on the data. While this is an open-label, single-arm study in 12 participants, we are encouraged by the data we presented today. As I described at the start of today's call, Wolfram Syndrome is a progressive, fatal monogenic disease caused by mutations in WFS1 that result in endoplasmic reticulum stress and impaired mitochondrial dynamics, leading to cell death. We believe there is a clear link between the mechanism of AMX35 and the pathophysiology of Wolfram Syndrome. In the data shared today, AMX35 demonstrated improvement or stabilization across measures of different organ systems, including pancreatic function, glycemic control, vision, and overall disease burden. From the perspective of diabetic measures, we could expect to see progressively declining pancreatic beta cell function and worsening glycemic control based on the natural history of the disease. In contrast, in Helios, the results indicate improvement following treatment with AMX35. In addition, results indicate some improvement in visual acuity with AMX35. Finally, importantly, from the perspective of the investigating clinician and the participants in the trial, results again indicate an improvement or stabilization in perceived symptom burden with AMX35. These results were sustained in the participants that reached 36 and 48 weeks of treatment. We have been engaging with stakeholders, including the FDA, with these 24-week and longer-term data in hand. We plan to meet with the FDA and other stakeholders to inform a phase III program. We recognize that Wolfram Syndrome has clear, urgent, and unaddressed needs... and we are committed to working expeditiously on behalf of people living with Wolfram Syndrome and their families around the world. We are encouraged about the potential impact of AMX35 for people living with Wolfram Syndrome. I will now turn over the call to Jim. Jim? Thanks, Camille. Before we open it up for questions, I'd like to quickly walk through the key upcoming anticipated milestones across our entire pipeline. These include the interim readout from our PSP study in mid-2025, interim clinical data from our AMX114 program, and the readout of top-line data from the Avexitide phase 3 program, anticipated in 2026. We believe our cash will take us into 2026, and we'll work to manage the company through these meaningful clinical data readouts. I'll now turn the call over to Lindsay, who will moderate the Q&A. Thanks, Jim. As a reminder, you can submit your questions in the Q&A panel on your browser. To get us started, Dr. Urano, will you just walk us through the current treatment paradigm for people with Wolfram Syndrome and the rationale behind AMX35's use in Wolfram? Yes. So currently, patients with Wolfram Syndrome are getting only symptomatic treatments. So as Dr. Behrosian just mentioned, Wolfram Syndrome is characterized by juvenile-onset diabetes, optic neuropathy, and neurodegeneration. And there are some treatments for diabetes, for sure, and also, there are some treatments for managing ways to manage the condition by physical therapy for some symptoms related to neurodegeneration. However, there is currently no treatment that can delay, halt, or reverse the progression of Wolfram Syndrome. So that's quite important. So that's why it's so quite important develop a therapy that can stop the progression, halt the progression of Wolfram Syndrome, and AMX35 has such a potential. Thanks, Dr. Urano. Our first set of questions comes from Corinne Jenkins from Goldman Sachs. Just to start out, what's on your wish list as you approach regulators regarding the phase 3 trial design? How many patients do you think are necessary to demonstrate clinical benefit in this population? Great. Well, thank you, Corinne, for the question. First of all, as you heard from the data today, we are very encouraged by the data of all 12 participants through 24 weeks, including, and importantly, the longer-term data as well. So we plan to share those data with the agency. And as well, if we think about the plan for the phase 3 study, to conduct a study that has the possibility to lead us toward an approval, and hence, have AMX35 available to participants or people really living with Wolfram Syndrome as soon as possible. There's a tremendous unmet need, as you heard from Raquel earlier. Yeah, and maybe just adding to Camille's comments as well. You know, given the nature of the disease, our goal is, of course, to move as quickly as we can, you know, to help people in need. You know, we think we're looking at important and meaningful outcomes, you know, outcomes like C-peptide, hemoglobin A1C, visual acuity, et cetera. And, you know, the ultimate size of a trial will be defined by, you know, the number of patients we need to, you know, observe a meaningful difference on those. But those kind of conversations that work with FDA is ongoing. But, you know, we hope to present in twenty twenty-five, you know, the further details there. Yeah, and I'll just add one other thing is that, you know, one of the things I think you hear is that, in Wolfram Syndrome, we expect progression, and certainly in C-peptide, we're seeing increases. And to our knowledge, this is the first time there's been an increase in C-peptide across any diabetic trial. So, it's very exciting, but it's new. And so I think that, you know, that's another critical discussion to have as we proceed with the phase 3 trial. Corinne also asked: Can you clarify whether the patient excluded in the ITT population is also excluded in the 38, or excuse me, 36 and 48-week data points? Why do you think that patient experienced some benefit? So first part of your question, Corinne, that participant has not reached week thirty-six or forty-eight in the study, so not in either of those datasets. And that participant actually had normal values in all the measures, essentially, that we are looking at. And so normal to normal, if you will. And to the extent that C-peptide is the primary registrational endpoint, what would regulators want to see in terms of changes over time to support an approval? Right, so two parts to that, really. Again, reminding that Wolfram Syndrome is a progressive disease, and the natural history is for C-peptide levels to deteriorate or decline over time. And a happy outcome that we're seeing, unexpected, because our hypothesis was AMX35 would slow progression, we actually, as Justin just mentioned, are seeing improvements in C-peptide levels. So, and sustained over 36 and 48 weeks, which is also very encouraging for us as a measure of beta cell function. So. We need to discuss with the agency these findings, as it is an unusual finding in people with diabetes, of any ilk. So, we'll discuss with them, identify together with them what is most appropriate from a clinical trial perspective. Maybe if I can, you know, Dr. Urano, interested maybe to hear from you as well, what you view as kind of a meaningful, you know, difference in Wolfram as well. 'Cause I think, you know, especially as regulators think about these, a big question is, you know, what is clinically meaningful? Right. So what is clinically meaningful is probably the improvement in visual acuity. However, change in visual acuity is pretty slow. So if we can stabilize the visual acuity during the duration of the trial, that's clearly pretty meaningful. I also would like to emphasize the importance of C-peptide or diabetes-related outcome measures, because AMX35 is not a diabetes drug, for sure. So AMX35 was originally developed for the treatment of neurodegenerative conditions. So if the data, like our current data shows that AMX improves beta cell functions and also diabetes-related outcome measures, strongly suggesting that AMX targets the root cause of the mechanism of the disease, which is endoplasmic reticulum stress. So the data, our clinical trial data indicates that AMX is good for beta cells, suggesting that it's also impacting other organ systems, including eye cells and brain cells. Thanks so much, Dr. Urano. And the last question from Corinne Johnson at Goldman Sachs was: Can you help us understand how C-peptide changes evolve over the course of a patient's disease? Does it matter how long from diagnosis they are in terms of what you'd expect to see over twelve, twenty-four, thirty-six, and forty-eight-week time points? Sure. So the decline in C-peptide, as the natural history data suggests, is somewhat more rapid the first year after diagnosis, and then with a continuous, somewhat shallower slope of decline over time. I actually am going to turn to Dr. Urano in a moment to get his perspective on what he sees as he studies and manages his patients with Wolfram Syndrome over the years. I again will underscore that the people we're studying are adults who've had this condition for decades, if you will, and so their beta cells already have undergone quite a bit of degeneration and death, cell loss, and yet, we're seeing some improvement, but Dr. Urano, I'd be very interested to understand what your perspective is on the changes in C-peptide in the natural history of Wolfram at the time points Corinne suggested. I'd like to point out two things related to the data on C-peptide levels. We see an increase in C-peptide levels in general. In general, the participants who started on AMX0035 twenty-four weeks ago or thirty-six weeks ago, or it depends on their patient. That's quite encouraging because in most of our patients, C-peptide levels decrease over time, so the increase in C-peptide levels is unexpected. In addition, we need to see the pattern of C-peptide production. In patients with Wolfram Syndrome, there is a delay in C-peptide production. In non-diabetic individuals, their pancreas should secrete C-peptide, which is insulin, should secrete insulin right away. In sixty minutes, we see a peak in C-peptide levels. In Wolfram Syndrome patients, we see a delayed peak in C-peptide production. So we see a peak around 180 minutes, sometimes even points. And what's interesting is that during this clinical trial, C-peptide production, the peak of C-peptide production, moves to the earlier time points in most of our clinical trial participants, suggesting that their remaining pancreatic beta cells started working better. Also, most likely, the endoplasmic reticulum stress levels in their beta cells are reduced. That's probably good for other cell types too. So these two things are quite actually impressive to me. So the production, higher production of C-peptide levels, and also very interestingly, the peak C-peptide production moved to the earlier time points. Thank you. That's very helpful and important too. The body is responding as it should to help with the glucose from a meal, for example. Right. Only marginal comment, too. We also included a publication, if helpful, in the presentation that shows kind of the natural history for C-peptide in Wolfram, if that's helpful to review further as well. Thank you. Our next question comes from Charlie Yang from Bank of America. He asked: Can you discuss why there's one participant not fitting the trial inclusion/exclusion criteria? ... Sure. Thank you, Charlie, for the question. Wolfram Syndrome is a monogenic disease, autosomal recessive in general. So both alleles need to have a pathogenic variant or mutation in each allele to be de facto Wolfram Syndrome. And that was actually the requirement, inclusion criterion, or one of them, for the clinical trial, Helios. As we were reviewing the genetic results from the participants, we noted that one of the participants had a pathogenic variant or mutation on one allele, and a variant of uncertain significance per allele in the WFS1 gene. So that participant does not meet our inclusion criteria, hence is part of the intent-to-treat population, but not part of the per-protocol cohort. I'll just add, you know, taking learnings from it as well, you know, we'll certainly have a kind of genetic review in trials as we go forward, you know, to prevent this. But looking at the participant as well, they were normal across, you know, the measures, you know, C-peptide, you know, HbA1c, visual acuity, throughout the trial. So you know, they kind of came in normal, and the data we have on them today, you know, remains, you know, normal on those metrics. Our next question- I'd like to comment on this participant. So it's important to realize that Wolfram Syndrome is a spectrum of disorder. Some patients have milder manifestations, and some patients have more severe manifestations. The severity of the disease is mainly determined by the types of their mutations in the WFS1 gene. The participant who has been excluded from the data analysis had so-called milder genetic mutations. The participant still had both optic nerve atrophy and diabetes mellitus. Clinically, she had Wolfram Syndrome. However, genetically, she does not have the severe form of Wolfram Syndrome, as I say. Thank you. Thank you. Our next set of questions comes from Michael DiFiore at Evercore ISI. It seems that C-peptide response fluctuates over time. The interim data showed greater response at 12 weeks, which diminished at 24 weeks. Now, the full cohort data shows it increasing at 36 and 48 weeks. Any early thoughts you could share on the primary endpoint time point for the upcoming phase 3 trial? How much temporal variability is acceptable by the FDA? Right. Good question. Thank you very much, Mike. Again, we have ongoing discussions with the FDA, so the final duration of the study will be determined as we gain concurrence. It certainly is due to variability, as you point out, between 12 and 24 weeks. What is important, as you noted also, is a sustained response from 36 to 48, which is not a priori anticipated in a disease with progressive cell degeneration and death. So, we're quite encouraged by that and believe it's quite meaningful. And so we are working hard to move to the next steps with the agency, so we can finalize our agreement on the phase 3 program and move forward for people with Wolfram Syndrome. And then Mike also had a follow-up. Mm-hmm. That one outlier patient seemed to have an outsized deterioration on C-peptide response, which is based on the fact that their C-peptide levels were in normal range throughout the study, implies that this patient had significantly elevated C-peptide levels at baseline relative to the other patients. Is that correct? That is correct. Anywhere from, you know, three- to tenfold higher levels. It was well within normal range, in particular, the stimulated C-peptide level peak. But it stayed within normal, but the variation was there, as you note. And then Mike also asked: "How realistic is it to expect BCVA improvements in every patient? The analysis showed that one patient improved from legally blind to legally sighted. Did this patient maintain their vision at later time points? Yes. So, the BCVA is particularly challenging in individuals who are adults. They've had decades of progressive loss of optic nerve or retinal ganglion cell loss. So, the fact that there is even stabilization or, and some improvement that we saw in Helios is very encouraging. So it is unusual, to be sure. And we believe that as, we study younger individuals, this will, you know, we'll be able to potentially see other, indications and other manifestations and other consequences, I should say, of AMX35. With regard to the individual, in the interim analysis, that individual continues to maintain, better vision, and there is one other individual also, as you can see from the curves, who also gained some vision back. Yeah, and so, you know, Mike, to your question, just to sort of underscore what Camille was saying, you know, I think, again, it's a good surprise to see- Mm-hmm ... now not just one, but two people go from legally blind to legally sighted. You know, should we expect that in late-stage participants? You know, this is the first time I think we've seen that in Wolfram Syndrome, so it's exciting, but it's new. Our next set of questions comes from Graig Suvannavejh at Mizuho: Regarding the primary endpoint of change from baseline in C-peptide, why were data measured at 90 minutes in the interim readout and 120 minutes in today's readout? Yes. So thank you, Graig. We actually measured the area under the curve out to 240 minutes in the interim, and we have noticed through the diabetes literature and the diabetes world that 120 minutes is the generally accepted timeframe for the area under the curve of a C-peptide response to a mixed meal, so we are choosing the 120 minutes. Also, that is the time point after which the body tends to, you know, stabilize or go back to baseline, if you will, after the mixed meal challenge, so that's the reason. Greg also asked: What could the development path forward look like, considerations for a pivotal trial design, and when should we expect to find out more about the phase 3 trial design? Sure, sure. So we are working very diligently and as expeditiously as possible to finalize our phase III program. We are engaging with stakeholders, and importantly, also plan to meet with the FDA to gain concurrence on that program. When we do so, we certainly will share the details with all of you. And you asked when? We anticipate in twenty twenty-five. And then Joel Beatty, from Baird asked: Could you characterize the regulatory feedback you've received so far and what you see as the path from here to approval? Sure. So Joel, as you know, as we have ongoing discussions with the FDA, we don't really share the back and forth. So we do ask that you give us continued time to meet with the agency and finalize the program. We are working expeditiously because we are so acutely aware of the unmet need. You heard that from Raquel earlier. And we do because of the data we shared today, not only at week 24, but the longer-term data, particularly encouraged, as well as feel the responsibility to move as promptly as possible to advance AMX0035 through a pivotal study and onward as the data, when and if and as the data, you know, support. And there might have been another part to that question, Lindsay? No, that was- Okay. All right. Thank you for the question. And Joel also did ask, though, about the use of insulin. So could changes in the use of insulin or changes in lifestyle during the trial explain the results from Helios presented today? So insulin certainly is exogenous insulin, certainly is a consideration, and the better controlled, the overall better response. Having said that, we did look carefully at the insulin use over time in the study, and there was actually no change in insulin use. So that really, and C-peptide, as you know, is separate and distinct from insulin in the sense that it is a measure of the insulin produced by the liver and not exogenous insulin. Yeah, and I'll just to underscore the last point that Camille said, I think the reason that Dr. Urano and his colleagues have moved to using C-peptide as a meaningful measure in diabetic indications is because it's a measure of endogenous insulin production and secretion. So the fact that we see increases in that, and then as well, the concomitant changes in other measures of glycemic control is, you know, what one would want to see in a positive response. And we do see improvement in hemoglobin A1C levels over time. So the patients produce more C-peptide. Hemoglobin A1C levels decreased over time. And I think it's important to monitor their hemoglobin A1C levels, as well as their insulin use for a longer period of time. Because what I have seen so far is that the C-peptide levels start increasing pretty fast. You know, even after three or six months time point, we see an increase in C-peptide levels. And decrease in hemoglobin A1C levels occur more slowly. So I think it's important to monitor hemoglobin A1C levels and insulin use, the dose of insulin our participants take, for a longer period of time. That's quite important information. Yeah, that's very helpful, Dr. Urano. Thank you. Yes. Yes, thank you. And Marc Goodman from Leerink asked: Do you expect accelerated approval using the C-peptide as a biomarker, or are you planning to design a trial that meets a regular approval requirement based on an alignment with the FDA? Those are important questions, ones that we are discussing actively with the FDA, so please stay tuned. One follow-up from Mark is: Are you focused only on the U.S. regulatory feedback? Any plans to run a global trial, if possible? So... Oh, Dr. Urano, did you want to comment? ... Sure. So, regarding the, you know, the clinical trial sites, I think that's also related to the clinical trial sites. And because Wolfram Syndrome is a rare disorder, there are not many medical centers that have expertise in conducting a clinical trial. And so in the United States, I can only think of Washington University Medical Center, because we have multiple specialists who are familiar with the Wolfram Syndrome. And in Europe, actually, there are multiple potential sites, and so such as United Kingdom and Spain, Poland. There are medical centers that have expertise in conducting clinical trial in Wolfram Syndrome. And we do have potential sites in Israel, Saudi Arabia, and also Brazil. So I think, in my personal opinion, it's possible to do the clinical trials in Europe, Israel, Saudi Arabia, and potentially South America. Thank you very much. That's very helpful. As you heard from Dr. Urano, we certainly are considering a clinical study that goes beyond the U.S., and in concert, then, also seeking further regulatory guidance beyond the U.S. also. Our next set of questions comes from Ananda Ghosh at H.C. Wainwright: "What is the diagnosis rate of Wolfram Syndrome? Where do you find these patients mostly? That is, are they enriched in academic centers or more spread out? How frequent is genetic testing done in Wolfram Syndrome patients, and is there a plan to partner with any companies developing such tests? So, Wolfram patients with Wolfram Syndrome are everywhere and not always recognized because... But now, with the potential of a treatment, with raising awareness, that certainly may change. The population where individuals with Wolfram may be identified are those with Type 1 diabetes, but not due to autoimmunity, and so-called monogenic diabetes. And in fact, in terms of diagnosis, there are at least two companies that have a diabetes panel, and WFS1 gene is among the panel of genes that are known to cause insulin-requiring diabetes, not due to autoimmunity. So that's very helpful. Now, and we are in the early stages of doing our further work to identify the patient population, the landscape, et cetera. So, we'll have more information as we proceed with those aspects as well. And Ananda, also- So I'd like. Yeah. Go ahead. I'd like to point out two things about the diagnosis of Wolfram Syndrome. We find more and more patients with Wolfram Syndrome, and I think Wolfram is an underdiagnosed disorder. Ten years ago, I probably saw referrals maybe ten per year, and most of the referrals came from neuro-ophthalmologists. If you remember, Wolfram Syndrome patients develop diabetes first, then they start developing optic nerve atrophy and vision problems. Ten years ago, most of the referrals came from neuro-ophthalmologists, and now referrals come from pediatric endocrinologists. The reason is so-called monogenic diabetes testing. Genetic testing for patients with early-onset diabetes is more common in a clinical practice. Clearly, these monogenic diabetes tests are usually conducted at academic medical centers. So still, the patient referrals came from academic medical centers, but now it's shifting to a pediatric endocrinologist referrals, and also that means patients are diagnosed earlier, which is quite important. Yeah. Very helpful. Thank you, Dr. Urano. Dr. Urano, can you also comment, have you seen the referral rate increase with the use of those tests as well? Yes. So referrals have increased significantly. And also, the clinical trial, the Amylyx clinical trial, potential success has been attracting more patients for sure. The reason is, in the past few months, I have seen 27 new patients with Wolfram Syndrome in my clinic, and 27 in few months is quite significant because Wolfram Syndrome is such a rare disease. And most of these patients were referred from different states and different countries, and that means more patients actually contacted us. So I think the diagnosis rate is improving, and but still a long way to go. We need to increase awareness of Wolfram Syndrome, and we need to increase awareness of setting up monogenic diabetes genetic testing in children who have been diagnosed with atypical type 1 diabetes, which means, antibody negative, and also, they produce more C-peptide, and also they are lean. There is some criteria for setting up monogenic diabetes. It's important to raise awareness, and Amylyx has been helping us raise awareness together with patient organizations. ... Thank you so much, Dr. Urano. It underscores the unmet need around the world, doesn't it? For sure. Charlie Yang from Bank of America had a few follow-up questions. Can you discuss patient feedback on the bitter taste of AMX35? This seems to be an issue for ALS patients, which drove some discontinuations, but we're not seeing that. Yeah. Maybe I'll start to say that, actually, in ALS, that was very, very rare that that was a cause for discontinuation. So while it is a facet of the drug, we actually did a survey, and for the vast majority of people, it was not bothersome, and certainly not to the point where they would discontinue the study treatment. But Dr. Urano, particularly for people with Wolfram Syndrome in the trial, I'll pass to you. Sure. I did talk to all the 12 participants about the taste of the AMX35. First of all, no one stopped taking the medication due to the taste of the AMX. Some patients told me that they got used to it. They got used to the taste. Also, Wolfram Syndrome affects their ability to smell and taste. Some patients actually cannot taste the AMX35. It's a little complicated, but my point is, no one stopped taking the medication due to the taste, and some patients told me that they got used to it. Well, that's very helpful. Thank you. Charlie also asked: What would the potential impact of GLP-1 across these in Wolfram Syndrome, and for phase three trial, would GLP-1 be allowed in phase three? So for our phase two, GLP-1s are not permitted during the study, and I expect, given the cardinal rule of not changing too much in phase three, we would not be including them in the phase three. Now, subsequent evaluation, you know, different, but not in the phase three. Yeah, and I underscore to say that, you know, I think GLP-1 agonists have been around for a long time. So it's not uncommon for people with Wolfram Syndrome to even try GLP-1 agonists. Despite that, there's a huge unmet need, as Dr. Urano was saying. Our next question comes from Julianne Harrison at BTIG. How early do you ideally want to initiate treatment? Has the FDA conveyed any expectations for clinical development in patients less than 17 years old? So as you heard from Dr. Urano, and it's quite logical for a monogenic disease, the sooner one initiates treatment of a drug that has a positive effect, the better. And we are discussing the age ranges for our phase three program and going beyond that as well. So for sure. The next question comes from an investor: Do you have plans to measure an endpoint related to neurological function, as this is the leading cause to mortality in these patients? I'm sorry, could you repeat, an endpoint? Yep, related to neurological function. So we are, in the sense that we're measuring the optic nerve function through visual acuity. And there may be some other measures, the ataxia, the swallowing, and other measures that we actually capture overall in the global impressions of change. So we're working through an understanding of how best to capture those features as well. Neurogenic bladder is another that Dr. Urano mentioned. So we're working through all of those aspects because we do appreciate that there are, you know, a significant burden of the disease for individuals and, you know, we want to address as much as possible the unmet needs. In terms of risk, maybe Dr. Urano, I think my understanding is it tends to be the choking episodes that are most problematic in that regard. Is that right? That's correct. So choking episodes are one of the most serious complications seen in patients with Wolfram Syndrome, and there are several things we could... So based on the data of natural history study, these two outcome measures were chosen. The visual acuity and C-peptide levels relatively quickly decline over time. So that's the major reason these two outcome measures were chosen for this particular phase two clinical trial. And neurodegeneration-related phenotypes occur much more slowly. So that's the reason the C-peptide levels and the visual acuity were chosen. However, based on my conversations with the clinical trial participants, it seems like bladder-related outcome measures may change relatively quickly too. So we need to think about other, you know, outcome measures related to neurological functions. We need to keep in mind, vision loss is actually due to the loss of retinal ganglion cells, so that's part of the neurodegeneration. To look at the visual acuity is actually measuring the progression of neurodegeneration. Thank you, Dr. Urano. And Graig Suvannavejh from Mizuho had a follow-up on visual acuity. Can you talk about the change in visual acuity from baseline data and how it improved from the interim to today's readout? ... Sure. So in the interim, we reported a modest improvement of zero point zero five or zero point zero four, as we reported today, with the more mature data. And that improved the visual acuity, and aggregate improved further with a mean improvement in LogMAR score of zero point one one, which is nearly double or a little bit more than double the improvement in the LogMAR. LogMAR is the units for measuring the visual acuity based on number of letters on an eye chart. And I'd just add, too, as Camille highlighted in the presentation, based on natural history studies, you know, we might have expected, you know, a LogMAR progression of zero point zero five nine LogMAR per year, or at least that's what's been seen in published natural history for these participants. So, you know, seeing a you know, a trend in the positive direction was certainly, you know, unexpected and positive, you know, in the study. And I would add as well, just that previously there was one person who went from legally blind to legally sighted, and that improvement was sustained. And now there's a second person who went from legally sighted, or sorry, legally blind to legally sighted. But as I said before, you know, these are great but early, you know, to see those sorts of changes, and people have had Wolfram Syndrome for some time. So, we're quite, you know, cautiously optimistic as well. We did look at the historical changes of these 12 participants, so based on either natural history study or chart review, so we have the data of their visual acuity in the past, actually, past 5, sometimes 10 years. We did see continuous progressive decline in their visual acuity before they started on AMX35. Now their visual acuity is mainly, not all of them, but in most of them, their visual acuity has been stabilized. I think it's important to track their visual acuity in the next, you know, probably 48 weeks or 24 weeks. The more data will be helpful to assess the efficacy of AMX35 on visual acuity. Then Ananda Ghosh from H.C. Wainwright also asked, "Is there any way to use propensity-matched natural history data, or is the sample size too small? Yeah, that is something that we are also evaluating in terms of the natural history data, the scope of the natural history data, to further inform the results that we have now and the possibilities for the future in terms of seeking to have the drug more available to more folks around the world. Yeah, I might just add, definitely, methods we've, you know, certainly, explored in the past as well, and, you know, finding the best way to utilize natural history, I think, in any rare disease and, you know, certainly in Wolfram as well, is essential, you know, to moving a program forward as quickly as possible, as well as to, you know, best informing, you know, our upcoming, you know, clinical work. And then Ananda also asked: "What is the reason behind higher female participants in the trial? It was just by chance, I think, but Dr. Urano, you know that as well. Yes. So I think for this particular clinical trial, we could only recruit adult patients, patients who are older than seventeen, and patients who produces certain amount of C-peptide, which reflects the amount of insulin produced from their own pancreas. And based on our natural history study and registry study, female patients tend to have milder manifestations. So because we could only recruit adult patients, and we could only recruit patients who produced certain amount of C-peptide levels, there was some threshold. When we look at the list, we found more female patients because they tend to have milder manifestations, so that's one of the reasons. If we target the pediatric population, this will most likely change because in pediatric population, they still produce good amount of C-peptide from their own pancreas, and they are still not at their late stage of the disease. So that's one of the reasons. Very helpful. Thank you. Thank you, and then Ananda also asked: "What are the learnings from Helios in terms of future application of AMX35 for related diseases involving abnormality in C-peptide levels? Right. So we are considering other possibilities, and, you know, that is certainly. These results certainly have piqued our interest and have given us better understanding of AMX35 and its potential, so we're looking into possibilities. Yeah, and maybe just underscoring, too, you know, as you go through the diabetes literature, probably the most recent are, you know, teplizumab and baricitinib in Type One diabetes. But it, it is, you know, quite, you know, exciting to see an increase in C-peptide. You know, that's not generally been seen, you know, in the diabetes literature, especially, you know, sustained over time. So, you know, certainly something that we're excited about and, you know, continuing to prosecute. I found the data really interesting. The reason is, you know, they produce more C-peptide, and also their pattern of insulin secretion has changed, and strongly suggesting that endoplasmic reticulum stress levels decreased in beta cells in these participants. Endoplasmic reticulum stress has been shown to play quite important roles in beta cell dysfunction during the pre-diabetes to type two diabetes transition. Also, the activation of autoimmune system in type one diabetes. So reduction of endoplasmic reticulum stress in beta cells by AMX35 could have other potential use. I found the results pretty interesting, and some other, you know, diabetes scientists told me the same, shared the same opinion with me. Interesting. Yeah, we're a little bit over time. We still have several questions here, but, thank you all so much for tuning in. Just try to grab one more here. Are there any other conditions... This is from an investor: Are there any other conditions with a similar pathophysiology of ER stress that this molecule could be expanded to? Yeah, I think as Dr. Urano was saying, I think there's significant literature on ER stress and beta cell dysfunction. And as Dr. Urano was saying, other diabetologists or people who study endocrine diseases, I think are certainly interested by these results. As we've said, there hasn't been a trial we're aware of that's shown an increase in C-peptide, which means endogenous insulin production and secretion, so certainly high on our minds. I'd like to point out two other actually genetic diseases, too. So Pelizaeus-Merzbacher disease is the genetic disorder that's also neurodegenerative disorder, and that's a clear endoplasmic reticulum stress disorder. There are multiple articles showing that endoplasmic reticulum stress is involved. Also, there are WFS1-related autosomal dominant medical conditions, and these medical conditions are related to endoplasmic reticulum stress, for sure, and the patients develop neurodegeneration, some neurodegeneration only, or optic nerve atrophy plus hearing loss only. So there are other genetic disorders clearly has a link to endoplasmic reticulum stress, and I hope we can use AMX35 for the treatment of these disorders. Thank you, Dr. Urano. Josh, Justin, I'll turn it over to you to close us out. Sure. Thanks, Lindsay. Thank you all for joining us today. We're excited with the positive data presented today that show improvement or stabilization across multiple measures of disease progression in Wolfram Syndrome with AMX35 treatment. Based on this data, we believe AMX35 has meaningful potential as a new therapeutic option for people with Wolfram Syndrome, who have an urgent unmet need, with no approved treatments. We're grateful for all of the people participating in Helios, their families and caregivers, Dr. Urano and the team at Washington University, the Wolfram Syndrome community, and everybody who continues to partner with us on this important research. We'd also like to give a special thank you to Stephanie and Raquel, for spending time with the company and the team and helping with the video we shared today. Thank you, everyone, for joining us and for your interest in Wolfram Syndrome. Have a great day.