Amylyx Pharmaceuticals, Inc. (AMLX) Earnings Call Transcript & Summary

Good afternoon, and thank you all for joining us. We are very pleased to announce positive top line results from the Phase II HELIOS clinical trial of AMX0035 and 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 are also thrilled to have Dr. Fumihiko Urano, join us today. Dr. Urano is the principal investigator of HELIOS and the Samuel E. Schecter 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. [Operator Instructions] Before I turn it over to Camille, I would like you all to hear from [ Rachel ], a person living with Wolfram syndrome. [Presentation]

Good morning, everyone. As we just heard from [ Rachel ], Wolfram syndrome initially presents as juvenile onset diabetes norite. 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 30s. We estimate that there are approximately 3,000 people in as well from syndrome in the U.S. Currently, there are no therapies specifically approved for Wolfram syndrome. Wolfram syndrome is a monogenic disease caused by mutation of WFS1 gene. The WFS1 gene encodes a protein call Wolfram that spans the Emdoplastic Reticulum, or ER membrane. Loss of Wolfram and function leads to ER stress and consequently impaired mitochondrial dynamics, two connected pathways that when disregulated lead to multi-organ cell dysfunction and death, starting with beta cells in the pancreas and the 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. AMX0035 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 AMX0035. Our Wolfram syndrome program started more than 8 years ago, years of research looking at cellular and animal model studies showed the therapeutic potential of AMX0035. Specifically, AMX 35 improved WFS1 protein expression, increased insulin secretion and inhibited beta cell death and cells derived from people with Wolfram syndrome. AMX0035 also prevented cell death of neuronal cells derived from people as Wolfram syndrome. Furthermore, AMX0035 significantly delayed progression of the diabetes phenotype in a WFS1 knockout mouse model. These compelling results were published in the Journal of Clinical Investigation Insights in 2022. Following these promising preclinical data, we initiated the Phase II 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 received AMX0035 for up to 96 weeks of 1 site. The HELIOS trial was designed to assess key measures of pancreatic function, visual acuity and overall symptom burden. The primary endpoint is the valuation 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 age 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 close 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 they completed their week 24 assessments. As of the cutoff date, 10 participants have completed their week 36 assessment and 6 participants have completed their week 48 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 and 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 2 to 3 months. Whereas we look for C-peptide levels to be higher with improved pancreatic function, we look for A1c levels to stabilize or decrease the blood glucose as well controlled with exogenous insulin and diet. Another frequently used measure of glycemic control is time and 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 this [ known, an eye chart ]. And Wolfram syndrome, visual acuity is expected to worsen over time. As shown on the right, from a recent 10-year analysis of 38 individuals as Wolfram syndrome. Visual acuity declined over time in nearly all participants with a mean flow 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 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 AMX0035, we later determined that 1 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 1 of the 2 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 pro protocol cohort. Now on to the HELIOS efficacy and safety results. The priority hypothesis was that AMX0035 may slow progression of disease manifestations. As we had shared, the data presented in improvement or stabilization on key outcomes, measuring the progression of diabetes, visual decline and overall disease burden in adult participants that is resulting Wolfram syndrome. Today, we are pleased to share positive top line data from HELIOS for all 12 participants who completed 24 weeks of treatment as well as longer-term data on participants who completed 36 and 48 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 24. We also included weeks 36 and 48. Here, we show the mean change from baseline in C-peptide AUC over 120 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 design in beta cell -- decline, excuse me, in beta cell function. Instead, we are seeing an improvement in C-peptide response across all we've 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 reach 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, and 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 we've shown compared to screening. When we look at the individual results shown on the right, 9 of 11 participants demonstrated reduced or stable Hemoglobin A1c levels from screening to the latest available time point in the pro protocol cohort. We are encouraged by these results as most participants demonstrated an improvement in the control of blood glucose, as you measured by Hemoglobin A1c, and these improvements were sustained over time. We also assess changes in the degree of glycemic control through continuous glucose monitoring. Specifically, we evaluated the change from baseline in the overall time and 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 it 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, where we are also seeing improvement in glycemic control across all weeks show compared to screening. Nine of 11 participants in the pro protocol cohort demonstrated stable or increased time and target glucose range from screening to the latest available time point. Overall, this increased time and target glucose range was sustained over all weeks. As we heard from Rachel, 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 and nearly all people living in Wolfram syndrome. We evaluated the effects of AMX0035 on best corrective visual acuity from participants that reach weeks 24 and 48. As shown on the left, we saw a trend to our potential visual acuity improvement compared to screening. On the right, when looking at individual data, 8 of 11 participants in the pro protocol cohort demonstrated improved or stable visual acuity in their best eye. This is particularly encouraging -- a particularly encouraging data set against a recent 10-year analysis of 38 individuals with Wolfram syndrome in whom visual acuity declined over time in nearly all participants was 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 change. A general approach uses an [indiscernible] impact of a potential treatment. Both use a 7-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 pro protocol cohort responder criteria at week 24. And the self and clinician reported responders were sustained for participants who reached weeks 36 and 48. Turning to safety and tolerability. Safety findings and Helios were consistent with previous AMX0035 clinical trial data, namely AMX0035 was generally well tolerated and no new safety signals were identified. Diarrhea was the most common treatment-emergent adverse event. All cases 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. Well, good evening, depending on where you are. So the data Dr. Bedrosian has just shown, it's 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 the C-peptide and also Hemoglobin A1C levels. suggesting that we reduced beta-cell endoplasmic reticulum stress and improved beta cell function. And that implies that AMX0035 reduced enterprise 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. AMX0035 may be impacting multiple organ systems, not on beta cells but also eye cells and the brain cells. The past passion of change and the [indiscernible] change improvement seems 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 Rachel 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. Heating tolerance and colding tolerance are also common in patients with Wolfram syndrome. One patient has also told me that her headaches have become less frequent. Sharp studding 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 AMX0035 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 monogenetic disease, caused by mutations in WFS1 that result in endoplastic urticulum stress and impaired mitochondrial dynamics. Let me sell that. We believe there is a clear link between the mechanism of AMX0035 and the pathophysiology of Wolfram syndrome. In the data shared today, AMX0035 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 AMX0035. In addition, results indicate some improvement in visual acuity with AMX0035. Finally, importantly, from the perspective of the investigating clinicians and the participants in the trial, results again indicate an improvement or stabilization in perceived symptom burden, AMX0035. And 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 AMX0035 from 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 AMX0114 program and the readout of top line data from the ebexatide Phase III 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 Lindsey, who will moderate the Q&A.

Thanks, Jim. [Operator Instructions] 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 AMX0035 use on Wolfram?

Yes. So currently, patients with Wolfram syndrome are getting only symptomatic treatments. So as Dr. Bedrosian just mentioned, that Wolfram syndrome is characterized by juvenile onset diabetes, [indiscernible] and neurodegeneration. And there are some treatments for diabetes for sure. And also, there are some treatments for managing way for ways to manage the condition by physical therapy for some symptoms related to neurodegeneration. However, there is currently no treatment for that can delay hold was reverse the progression of Wolfram syndrome. So that's quite important -- so that's why it's so quite important developer therapy that can stop the progression, hold the progression of Wolfram syndrome. And AMX0035 has such a potential.

Our first set of questions comes from Corinne Jenkins from Goldman Sachs. What's -- just to start out, what's on your wish list as you approach regulators regarding the Phase III 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 III study, to conduct a study that has the possibility to lead us toward an approval, and hence, have AMX0035 available to participants or people really living with Wolfram syndrome. As soon as possible, there's a tremendous unmet need, as you heard from Rachel earlier.

Yes. And maybe just adding to Camille's comments as well. Given these are our goal is, of course, to move as quickly as we can to help people in need. We think we're looking at important and meaningful outcomes, outcomes like C-peptide, Hemoglobin A1c, visual acuity, et cetera. And the ultimate size of the trial will be defined by the number of patients we need to observe a meaningful difference on those. But those kind of conversations that work with FDA is ongoing, but we look to present on 2025, the further details there.

Yes. And I'll just add one other thing is that 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, that's another critical discussion to have as we proceed with the Phase III trial.

And Corrine 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 experience and benefit?

So first part of your question, Corrine, that participant has not reached week 36 or 48 in the study, so not in either of those data sets. 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 end point, 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 AMX0035 with slow progression. We actually, as Justin just mentioned, are seeing improvements in C-peptide levels, 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 ill. So we'll discuss with them and identify together with them what is most appropriate from a clinical trial perspective.

And maybe if I can, Dr. Urano, and just maybe to hear from you as well what you view as kind of a meaningful difference in Wolfram as well? Because I think, especially as regulators think about these, a big question is 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 AMX0035 is not a diabetes drug. For sure. So AMX0035 was originally developed for the treatment of neurodegenerative conditions. So if the data -- 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 if -- 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.

And the last question from Corinne Jenkins 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 12, 24, 36 and 48 week time points?

Sure. The decline in C-peptide as a 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. What -- and I, again, will underscore that the people we're studying are adults who had this condition, decades, if you will. And so their beta cells already have undergone quite a bit of degeneration and death sell loss. And yet we're seeing some improvement. With 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 current suggested.

So I'd like to point out two things related to the data on C-peptide levels. So we see an increase in C-peptide levels in general, the participants who started on AMX0035 35 weeks ago or 36 weeks ago, it depends on the patient. And that's quite encouraging because in most of our patients, C-peptide levels decreased 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. So in nondiabetic individuals, their pancreas should secrete C-peptide, which is insulin -- secrete insulin right away. So in 60 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 [indiscernible]. 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 in their beta cells are reduced. That's probably good for other cell types. 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 move to the [indiscernible] time points.

That's very helpful and important to the body is responding as it should to help with the glucose from allele, for example.

Only marginal comment too. We also included a publication and helpful in the presentation that shows kind of the natural history for C-peptide and Wolfram, if that's helpful to review further as well.

Our next question comes from Charlie Yang from Bank of America. 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 criteria are 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 significant 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 pro protocol cohort.

And I'll just add, taking learnings from it as well. We'll certainly have a kind of genetic review in trials as we go forward to prevent this. But looking at the participant as well, they were normal across the measures, C-peptide, HbA1c, visual acuity throughout the trial. So they kind of came in normal and the data we have on them today remains normal on those metrics.

I'd like to comment on this participant. So it's -- I think it's important to realize that Wolfram syndrome is a spectrum of disorder. So some patients have milder manifestations and some patients have more severe manifestations. And the stability of the disease is mainly determined by the types of the mutations in the WFS1 gene. And the participant who has been excluded from the data analysis had so-called mild genetic mutations, and the participants still had both optic [ navatrophy ] and diabetes meritas. So clinically, she had Wolfram syndrome. However, genetically, she does not have the severe form of Wolfram syndrome, as I say.

Our next set of questions comes from Mike DiFiore at Evercore ISI. It seems that Seat 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 increasing at 36 and 48 weeks. Any early thoughts you could share on the primary point -- time point for the upcoming Phase III trial, how much temporal variability is acceptable by the FDA?

Good question. Thank you very much, Mike. Again, we are -- 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 weeks and 24 weeks. What is important, as you noted, also is a sustained response from [indiscernible] from 36 to 40, 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 III program and move forward for people with Wolfram syndrome.

And then Mike also had a follow-up that one outlier patients seem 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 [ three to tenfold ] higher levels. It was well within a normal range, in particular, the stimulated C-peptide level peak. But it stay 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? These show 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 and individuals who are adults. They've had decades of progressive loss of optic nerve or retinal ganglia cell loss. So the fact that there is even stabilization 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 -- we'll be able to potentially see other indications and other manifestations and other consequences, I should say, in AMX0035. 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.

Yes. And so Mike, to your question, just to sort of underscore what Camille was saying, I think, again, it's a good surprise to see now not just 1 but 2 people both from legally blind to legally sighted. Should we expect that in late-stage participants, 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 and C-peptide why were data measured at 90 minutes in the interim readout in 120 minutes in today's readout?

Yes. So thank you, Graig. We actually measure the area under the curve out to 240 minutes in the interim. And we have noticed to the diabetes, literature in the diabetes world, the 120 minutes is the generally accepted time frame 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 is tends to stabilize or go back to baseline, if you will, after the mixed meal challenge. So that's the reason.

And Graig also asked what could the development pass forward considerations for a pivotal trial design? And when should we expect to find out more about the Phase III 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 ask when? We anticipate, in 2025.

And then Joel Beatty for 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 Rachel 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 advanced AMX0035 through a pivotal study and onboard when and if and as the data support. And there might have been another part to that question, Lindsey?

No. That was it. 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 is 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.

Yes. And 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, there's 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 and other measures of glycemic control is 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 than patients Hemoglobin A1C levels decreased over time. And I think it's important to monitor their Hemoglobin A1C levels as well as the instant use for a longer period of time. Because what I have seen so far is that the C-peptide levels start increasing pretty fast. Even after 3 or 6 months' time point, we see an increase in C-peptide levels and decreasing Hemoglobin A1C levels occurred more slowly. So I think it's important to monitor Hemoglobin A1C levels and insulin instant use the dose of insulin our participants take for a longer period of time. That's quite important information.

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 were discussing actively with the FDA. So please stay tuned.