Good afternoon, and thank you all for joining us today to discuss the interim data from the phase II HELIOS clinical trial of AMX0035 in Wolfram syndrome, and the treatment landscape for people living with this disease. With me on the call today are Josh Cohen and Justin Klee, our co-CEOs, Dr. Camille Bedrosian, our Chief Medical Officer, and Dr. Fumihiko 'Fumi' Urano, principal investigator of the phase II clinical trial in Wolfram syndrome, and the Samuel E. Schechter Professor of Medicine at Washington University School of Medicine in St. Louis. Joining us for Q&A will be Jim Frates, our Chief Financial Officer. If you would like to ask a question, you may do so at any point during the event by submitting a question in the Q&A panel on your browser.
Before we begin, I would like to remind everyone that any statements we make or information presented on this call that are not historical facts are forward-looking statements that are made based on our current beliefs, plans, and expectations, and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements include, but are not limited to, our expectations with respect to AMX0035, statements regarding regulatory and clinical developments, the impact thereof, and the expected timing thereof. Actual events and results could differ materially from those expressed or implied by any forward-looking statement. You are cautioned not to place any undue reliance on these forward-looking statements, and Amylyx disclaims any obligation to update such statements unless required by law. Now, I'll turn the call over to Justin.
Thank you, Lindsay, and good afternoon. Thank you for joining us today to discuss our program evaluating AMX0035 for the treatment of Wolfram syndrome, a program we have been working on for nearly seven years. Josh and I founded Amylyx over a decade ago to develop new treatments to address the enormous unmet needs in neurodegenerative diseases. Our lead candidate, AMX0035, is designed to slow or mitigate cell death, the fundamental cause of neurodegeneration, through simultaneous mitigation of endoplasmic reticulum stress and mitochondrial dysfunction. These two connected pathways are dysregulated in many diseases, and if left unchecked, can lead to cell death and degeneration. Wolfram syndrome is one of these diseases.
Wolfram syndrome is a genetic disease caused by mutations in WFS1 that cause endoplasmic reticulum stress and mitochondrial dysfunction, leading to multi-organ cell dysfunction and death, starting with beta cells in the pancreas, then neurons in the visual system, auditory system, and throughout the body. Years of research looking at cellular and animal model studies showed that AMX0035 had the ability to dampen the impact of ER stress and mitochondrial dysfunction across beta cells and neurons impacted by WFS1 mutations, and thereby potentially stabilizing, and in some cases, improving cellular functioning and viability. After promising preclinical data, we are pleased to share today data from the planned interim analysis from our open-label phase II HELIOS trial, evaluating AMX0035 in Wolfram syndrome. I'll now turn the call over to Josh to share more about our Wolfram syndrome program, and then to Dr.
Fumihiko Urano, our close collaborator and one of the world's foremost experts in Wolfram syndrome. And last, to Amylyx's Chief Medical Officer, Dr. Camille Bedrosian, to present the clinical data.
Thank you, Justin. Several years ago, a family affected by the disease reached out to us and connected us with Dr. Urano at WashU, who was studying Wolfram syndrome. This introduction led to our R&D team working with WashU to conduct in vitro and in vivo studies to evaluate the potential of AMX0035 in Wolfram syndrome. These studies had very promising results, some of which were published in the Journal of Clinical Investigation Insight. In November 2020, the U.S. FDA granted an orphan drug designation to AMX0035 for the treatment of Wolfram syndrome, and we started work together towards what would become HELIOS. We dosed our first participant in the HELIOS trial in April 2023, and we believe this trial will provide key insights to guide future studies that will hopefully support regulatory filings in the future. As Drs.
Urano and Bedrosian will discuss, we are highly encouraged by the improvement in C-peptide levels, the primary endpoint of HELIOS, which we observed through 24 weeks. C-peptide is an established, objective laboratory measure of pancreatic beta cell function and glycemic control. Given the progressive nature of the disease, a stabilization of C-peptide levels would have been an exciting result within itself, so seeing an improvement in these levels was unexpected. We believe that the clinical activity we observed in our HELIOS trial suggests AMX0035 has the potential to significantly impact disease progression in people living with Wolfram syndrome. Given the rarity of Wolfram syndrome, the incredibly urgent unmet need, and lack of disease-modifying therapies, we plan to engage with regulatory authorities in the near future to align on the development path. We expect top-line data for all 12 participants at the 24-week time point at, at...
in the second half of this year. We are pleased to be on the call today to review our initial data, and we are so honored to be joined by Dr. Fumihiko Urano, an expert in Wolfram syndrome.
... I will now turn the call over to Dr. Urano. Operator, please put the slides back up.
Thank you, Mr. Klee, Mr. Cohen, for the kind introduction. I am Dr. Fumihiko Urano from Washington University School of Medicine. I am the Samuel E. Schechter Professor of Medicine and direct the Wolfram syndrome Clinic and Basic Science and Clinical Research programs on Wolfram syndrome there. Today, I'm gonna tell you about Wolfram syndrome and our therapeutic development for the disease. Here are my disclosures. My research on Wolfram syndrome revolves around extensive collaboration. I have partners both in the United States and around the globe, including patient organizations spanning various countries. I am deeply grateful for their collaborative spirit and the generous sharing of their expertise with my team. I have three objectives today. First, I will summarize two types of Wolfram syndrome and related disorders. Then I will share lessons and stories from past and current Wolfram syndrome clinical studies.
And then finally, I will emphasize the need for cooperation with patient organizations and industry partners, especially Amylyx, in this case. What is Wolfram syndrome? Wolfram syndrome is characterized by juvenile-onset diabetes, and the onset of juvenile-onset diabetes is around age six. As you know, there are some treatments for diabetes mellitus. Around age 11, Wolfram syndrome patients develop optic nerve atrophy. In many cases, sadly, this can lead to vision loss in many of our patients. Around age 14, patients start developing deafness, and there are some treatments for deafness, including hearing aids and cochlear implants. Diabetes insipidus occurs around age 13. Diabetes insipidus is a medical condition. This is different from diabetes mellitus. It's a medical condition that causes the fluids in the body to become out of balance.
That prompts the body to make large amounts of urine, and it also causes a feeling of being thirsty even after having something to drink. There is treatment for this, for this, called DDAVP. It's a pill. Neurodegeneration starts to appear during the later years of adolescence, and this can lead to the death of our patients. Wolfram syndrome is a genetic disease. There are two causative genes. These are WFS1 and CISD2. There are two types of Wolfram syndrome. Wolfram syndrome type one is caused by mutations in the WFS1 gene. Wolfram syndrome type two is caused by mutations in the CISD2 gene. Most patients, more than 95% of patients with Wolfram, have Wolfram syndrome type one. Prevalence is 1 in 250,000-700,000.
However, we have reason to believe that this number of patient is an underestimation of the actual count, and I will discuss this later again. Patients have two mutated copies of WFS1 or CISD2. As you know, we all have two copies of WFS1 gene, one from our father, one from our mother. Usually, the patients with Wolfram syndrome, their parents are carriers, which means they have one mutated copy and one good copy. If a patient inherits mutated copies from both parents, they develop Wolfram syndrome. Through our clinical studies, we learned that Wolfram syndrome type one is a spectrum of disorders. Some patients have milder manifestations, while the other patients have more severe manifestations, and there are some underlying reasons for those. Females tend to have milder symptoms than males. Patients who carry two or one missense WFS1 gene mutations tend to have milder symptoms.
This is a technical, but what I mean by that is that there are specific types of mutations that are associated with milder symptoms. Patients who carry two frame shift nonsense WFS1 variants have more severe symptoms, and 40% of the patients in our cohort have this form of disease. We call it classic form. Interestingly, we found a WFS1 gene mutation associated with a very mild form of Wolfram syndrome. This variant, WFS1 c.1672C>T variant, is a common variant in Ashkenazi Jewish population, and the carrier frequency is around 2.5%-3% in this population. Based on my calculation, if we include the mild forms of Wolfram syndrome patients, prevalence could be one in 70,000, which means we may have 5,000 patients with Wolfram syndrome in the United States. Next slide.
Here is a summary of Wolfram syndrome and WFS1-related disorders. As I just mentioned, that Wolfram syndrome patients have two mutated copies in the Wolfram WFS1 gene. We discovered that sometimes one mutated copy, some specific one mutated copies, could cause some medical conditions, such as hearing loss only, optic nerve atrophy, and hearing loss only. We discovered three variants, WFS1 variants, that can cause neonatal diabetes, which means diabetes within 12 months of their lives, congenital cataracts, sensorineural deafness, hypotonia, developmental delay, and intellectual disability. My point is, two mutated copies, to have two mutated copies cause Wolfram syndrome. However, some one mutated copies could cause medical conditions, and because molecular mechanisms of these different medical conditions are related, we could potentially treat all of these medical conditions with one medication. Next slide, please.
Through our clinical studies, we identified three major complications of Wolfram syndrome in addition to diabetes mellitus and optic nerve atrophy and vision loss. Neurogenic bladder is one of the common complications seen in patients with Wolfram syndrome, and this is a very challenging medical condition because patients cannot control the movement of their bladder because of the part of the neurodegeneration. Then, even adult people may experience accidents, and if a bladder does not work well and cannot push out urine well, then patient may need to do their self-catheterization to remove urine. So this is a very, very challenging medical condition. Respiratory failure is a scary complication of the Wolfram syndrome. This is associated with the brainstem atrophy, the part of neurodegeneration.
Because brainstem controls our breathing and swallowing, the brainstem atrophy could cause breathing problems, and some patients stop breathing while they are sleeping, so they need positive pressure when they sleep. Choking events are scary complication of the Wolfram syndrome. This is also related to brainstem atrophy because brainstem controls our swallowing, too. So when they are eating, if food gets into their lungs, that can cause choking. Also, that can lead to aspiration pneumonia. Aspiration pneumonia is one of the major causes of death in patients with Wolfram syndrome. So we manage our patients in the Wolfram Clinic, and we accept both out-of-state patients and also patients from abroad. And here is our contact information.
Because Wolfram syndrome is such a rare medical condition, many doctors don't know how to manage their conditions, so we are trying to create the consensus clinical guidelines in collaboration with REDCap. This is a cloud-based system to create consensus clinical guidelines. This was facilitated by the NORD and patient organizations. We learned a lot through our clinical studies of Wolfram syndrome. However, to develop new treatments for this devastating disorder, we need to understand the mechanisms of the disease. In the past 22 years, my research team has been studying the mechanisms of Wolfram syndrome and revealed that Wolfram syndrome is a prototype endoplasmic reticulum disorder. Endoplasmic reticulum is a cellular compartment performing many important biological functions, including regulation of cellular stress levels, regulation of calcium levels in cells, and maturation of newly synthesized proteins.
So loss of function of WFS1 protein caused by mutations in the WFS1 gene can lead to high levels of cell stress, called endoplasmic reticulum stress, mitochondrial dysfunction, and dysregulation of cellular calcium levels. We also learned that in the past 22 years, there are other medical conditions associated with endoplasmic reticulum stress and dysfunction. Some of these conditions are genetic diseases, including Pelizaeus-Merzbacher disease and Wolcott-Rallison syndrome. These are also neurodegenerative diseases. Some common disorders or medical conditions, such as type 2 diabetes or aging, are also associated with endoplasmic reticulum stress and dysfunction.... Based on the molecular mechanisms of Wolfram syndrome, here is our therapeutic development pipelines and timeline. When considering the molecular mechanisms of Wolfram syndrome and therapeutic development, imagine it as a river. Like a river, there are upstream and downstream components of this.
The very upstream of this river is mutations in the WFS1 gene, as we discussed, which leads to subsequent endoplasmic reticulum stress and mitochondrial dysfunction. These events trigger a cascade of downstream events, ultimately resulting in death and the degeneration of insulin-producing cells in the pancreas, retinal ganglion cells in the eyes, and neurons in the brain. The very downstream consequences of this river are diabetes, vision loss, and neurodegeneration. Initially, we tried to target endoplasmic reticulum stress using existing medication. We studied existing medication called dantrolene sodium for the treatment of Wolfram syndrome because dantrolene sodium targets endoplasmic reticulum stress. We started preclinical study of this medication in cell and animal models of Wolfram syndrome in 2010. In 2017, we started the trial of dantrolene sodium in patients with Wolfram syndrome.
In 2019, 19 patients completed their phase I b, two-way study. Next slide, please. We published the data in the JCI Insight in 2021, and in short, we did not see statistically significant improvement in diabetes, vision, or neurological functions during the duration of the trial. But we learned our lessons from this clinical trial. Next slide, please. Lessons learned from the dantrolene repurposing trial was the following: It was cost effective because generic was already available, the less expensive than developing new drugs. Faster development, because we already knew the safety profile of this medication very well, so it clearly speeded up the drug development process. Outcome measures. We learned about outcome measures, how we assess the efficacy of the medication. We learned that the mixed meal tolerance test, which utilized, was not sufficient. I will discuss this later.
Also, we realized their beta cell functions could potentially improve during the duration of the trial, and the visual acuity could improve during the duration of the trial. Based on the data from 19 patients, we did see some improvement in a few patients. Two challenges. That the medication was clearly not designed to treat patients with Wolfram syndrome. Also, limited patent protection. Limited patent protection, which can limit financial incentives for pharmaceutical companies to invest in repurposing efforts. So based on this information, we shifted our attention to new drugs, and we identified AMX0035 as a candidate treatment for Wolfram syndrome. Next slide, please. Because AMX0035 has chemical structure targeting endoplasmic reticulum stress and mitochondrial dysfunction. So we started a collaboration with Amylyx in the summer of 2017. I still have the email that was sent to Mr. Justin Klee and Mr. Josh Cohen in 2017, and our collaboration was facilitated by patient organizations, Unravel Wolfram syndrome, led by Dr. Sarah Gladstone, Ellie White Foundation
Y-axis shows cell death levels, and X-axis shows their names of treatment. Interestingly, we used three different lines from three different patients. As you can see in this slide, AMX0035 treatment reduced cell death levels in Wolfram syndrome patient-derived brain cells.... Interestingly, PBA and TUDCA, these are components of the AMX0035. These compounds, PBA only or TUDCA only, could also reduce cell death levels. By combining these two, which is AMX0035, we could see synergistic effect on suppressing cell death levels. Next slide, please. Mitochondrial dysfunction is also involved in the pathogenesis of Wolfram syndrome. So we treated Wolfram patient-derived iPSC-derived neural progenitor cells with AMX0035, and then assessed mitochondrial functions by monitoring cellular respiration. By treating these cells with AMX0035, we could improve mitochondrial functions. We have published these preclinical data in JCI Insight in 2022.
We also included data in our animal models, and also we included data showing that AMX0035 could improve insulin secretion. Based on these preclinical data, we have set up the clinical trial of AMX0035 in patients with Wolfram syndrome. We are interested in three different domains of Wolfram syndrome: diabetes, visual acuity, and the neurological functions. Next slide, please. We are particularly interested in beta cell functions, which means the functions of remaining insulin-producing cells and the visual acuity. How we measure remaining insulin-producing cells functions? We decided to use mixed meal tolerance test, which was utilized for the previous dantrolene trial, but we modified it. We ask our participant to fast overnight, no food overnight. Then we ask our participant to take a drink called Boost, that contains high carbohydrate, lipid, and protein.
We draw blood from our participants at -10 minutes, zero minutes of the Boost, and 15 minutes, 30, 60, 90, 120, 180, and 240-minute time points. Then we look at their C-peptide levels. C-peptide levels reflect the amount of insulin produced from their own pancreas, so C-peptide levels should go up during the mixed meal tolerance test. Instead of using 30 minutes, we decided to use 240-minute mixed meal tolerance test. We also measure visual acuity using Snellen chart. Then Snellen chart data is converted into logMAR score. If you see well, your logMAR score number is lower, and if you don't see well, your logMAR score is larger. Next slide, please. The reason we are interested in measuring C-peptide was C-peptide levels progressively decrease in patients with Wolfram syndrome, based on our previous studies.
Also, we decided to use 240 minutes mixed meal tolerance test because in normal, healthy individual or patients who have developed diabetes due to single gene mutations, their C-peptide levels go up and go down during the mixed meal tolerance test. In patients who have a genetic form of diabetes, their peak tend to come later time points. If you are healthy, your peak of the C-peptide production is at 60 minutes. Next slide, please. We are also very interested in assessing visual acuity and retinal nerve fiber layer thickness in patients with Wolfram syndrome, because both visual acuity and average retinal nerve fiber layer thickness decrease, decline during the progression of the disease in Wolfram syndrome. We are measuring these during our clinical trial. Next slide, please.
Here is our trial team, and I appreciate their hard work and dedication to this project of our trial team at Washington University and also Amylyx Pharmaceuticals. They have been working very hard, and I really, really appreciate their efforts. This video shows how we prepare AMX0035 for patients for the trial participants. Can you activate the video? So AMX0035 comes as powder in the sachet. Then we dissolve the powder in water. Then we dissolve the AMX in water and ask our participants to take it. They take it. They take this medication twice a day. Next slide, please. So the data of this ongoing clinical trial will be shown by Dr. Bedrosian later in this presentation.
Before I end my presentation, I want to emphasize the significance of working with patient organizations, because it's important to raise awareness for Wolfram syndrome. It's. And we need to work with patient organizations to achieve this goal. Also, patient organizations facilitate collaboration between academic researchers, like myself, and industry. And indeed, our collaboration with Amylyx was facilitated by patient organizations and patient mothers. Next slide, please. We have been working with patient organizations to host their scientific Wolfram syndrome Symposium, and one of the pictures shows their International Wolfram syndrome Symposium, taken at Wolfram syndrome Symposium, hosted by Wolfram syndrome UK and Snow Foundation. Also, we have been working with Snow Foundation and Ellie White Foundation and Unravel Wolfram syndrome to raise awareness of the disease. It takes a village to achieve a cure for Wolfram syndrome. To improve clinical care, we need Wolfram syndrome Clinic.
To raise awareness, we need to work with patient organizations. We need funds to do research. Those could be donations and grants. And also, we need to work with their industry partners to develop cutting-edge treatment and bring these new treatments to patients. This is my last slide. I'd like to dedicate my presentation to my mother, who recently passed away, and she was a fantastic pediatrician and also their family doctor, and she was the greatest supporter of my research on Wolfram syndrome. So thank you for your attention, and I will hand over the presentation to Dr. Bedrosian, who is also their female physician and industry leader in the rare disease domain. Thank you.
Thank you so much, Dr. Urano. Your presentation was very informative, and I appreciate your kind words as well. Good afternoon, everyone. As you learned from Dr. Urano, Wolfram syndrome is a rare, fatal, monogenetic neurodegenerative disorder that progressively impacts multiple organs and systems. As Dr. Urano indicated, the disease manifests in childhood initially, presenting as diabetes mellitus that progresses over time. Also in childhood, optic nerve atrophy begins and ultimately progresses to blindness. I reiterate these key manifestations, as we will be sharing the interim results of AMX0035's impact on these systems in the HELIOS study. The majority of people with Wolfram syndrome carry mutations in the WFS1 gene, which encodes a protein that spans the membrane of the endoplasmic reticulum, called... Loss of wolframin function leads to ER stress and consequently impaired mitochondrial dynamics, which in turn leads to dysfunction and apoptosis of cells.
Because of the clear link between WFS1 mutations and ER stress, Wolfram syndrome is considered a prototypical ER stress disorder. Pancreatic beta cells and neurons are particularly vulnerable to the loss of wolframin activity. So how many people actually have Wolfram syndrome? Like most rare diseases, incidence and prevalence studies on Wolfram syndrome are limited. The literature often cites a few studies that were performed quite some time ago, prior to the identification of the WFS1 gene, and thus molecular genetic testing. These studies estimate a U.S. prevalence of anywhere between 500-3,400 cases. More recent studies evaluating genetic causes of diabetes indicate that Wolfram syndrome may be more common than the older studies estimate. One example is shown in the bottom row of the table on this slide, with extrapolation to the U.S. population.
We share this example less to support a specific number, but rather to indicate more work is needed to understand the true incidence and prevalence. We found Dr. Urano's perspective on these points enlightening as well. Wolfram syndrome is a genetic disorder that is generally misdiagnosed at first. Now that the Wolfram syndrome gene has been identified, genetic testing can provide a definitive diagnosis and should shorten the time to diagnosis from initial symptoms. It is likely that definitive testing, together with evaluation of potential therapies, will further enhance disease awareness. Under- or misdiagnosis has been seen in many rare diseases, including the examples summarized in the table shown on the right of this slide. Amylyx is committed to supporting awareness and the diagnostic efforts. Both Dr.
Urano and I have mentioned that Wolfram syndrome is a prototypical ER stress disorder, with this stress impacting mitochondrial dynamics and leading to cellular dysfunction as and cell death. The scientific rationale for AMX0035 on Wolfram syndrome is strong, as it targets both the ER and mitochondria, and has been shown to reduce both ER stress and cell death synergistically in a variety of models. In the next few slides, we'll preview the preclinical data in Wolfram syndrome. Apologies, we will review the preclinical data. As Dr. Urano mentioned, his lab performed a series of preclinical efficacy studies to evaluate AMX0035's effect on different pathophysiological aspects of the disease. Models of ER stress, mitochondrial dysfunction, and some of the clinical manifestations were characterized using several non-clinical approaches. First, patient-derived iPSCs, or pluripotent stem cells, with homozygous WFS1 mutations were used to generate pancreatic beta cells and neuronal progenitor cells.
These cells exhibit hallmark features of Wolfram syndrome, as noted. Second, a WFS1 knockout mouse model, which shows a diabetic phenotype and dysfunction in insulin response to glucose stimulation, was used as an in vivo model of poor pancreatic beta cell function. This slide summarizes patient-derived beta cell models. In the series of graphs, the pink bars represent AMX0035 treatment, and the blue bars represent controls. First, on the far left, AMX0035 treatment increases WFS1 protein levels, indicating that treatment is working on the root cause of the disease. This impact led to significantly improved patient-derived beta cell viability and survival, as shown in the graphs in the middle panel. The substantially reduced magnitude of the pink bars representing AMX0035 treatment indicates that there is significantly less beta cell death. This translated to improved insulin secretion, as shown in the graphs in the panel on the far right.
This series of experiments evaluated three patient-derived neuronal cell models to understand the impact of AMX0035 on neuronal cell death. Once again, the pink bars represent AMX0035, and the blue bars represent controls. Each purple bar represents one of the two AMX0035 components alone. We can see that AMX0035 results in the least cell death compared to the control, as well as either component individually. The last preclinical model is the WFS1 knockout mouse model, mimicking some of the clinical manifestations. Once again, the pink lines and bars represent AMX0035 treatment, the blue lines and bars represent controls, and the green, the wild-type mouse. Both graphs illustrate that AMX0035 significantly delay the progression of the diabetic phenotype. So to summarize, studies of several non-clinical models of Wolfram syndrome supported the potential of AMX0035 in addressing the etiology of Wolfram syndrome.
These preclinical data provided strong evidence to proceed to a clinical study, HELIOS, in people living with Wolfram syndrome. Now we'll review how progression is measured in Wolfram syndrome as a foundation for discussion of HELIOS trial design and interim results. Wolfram syndrome has a variety of clinical manifestations, as shown in the left figure, which means there are several potential measures we could evaluate in a clinical trial. For today's presentation, we will focus on measuring the progression of diabetes mellitus, vision loss, and overall symptom burden. Starting with measures of diabetes progression, the first measure of interest is C-peptide. Here, we are studying the ability of the pancreatic beta cells to produce insulin. As shown in the figure on the right, there is a series of steps in processing and secreting insulin that include C-peptide.
C-peptide levels are a well-established surrogate marker of pancreatic function and glycemic control and have been used as primary outcome in several major diabetes trials because C-peptide is secreted in a 1:1 ratio with insulin, degraded at a slower rate, is not cleared by the liver, can be measured in the blood, is not confounded by external insulin use, and has been shown to predict future diabetic complications and glycemic control. C-peptide levels are assessed following a mixed meal tolerance test, or MMTT, also mentioned by Dr. Urano. This test is a physiological stimulation test using a standardized liquid meal ingested in the morning after an overnight fast, followed by timed measurements over a predetermined time period. In this study, we evaluated beta cell response through 240 minutes, or 4 hours.
C-peptide is expected to progressively decline over time in Wolfram syndrome, confirmed by a recent natural history study, as noted on the slide. Because of this, HELIOS was designed to measure a slowing of the decline. Hemoglobin A1C in plasma is 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 want C-peptide to be higher with improved pancreatic response, A1C should decrease as diabetes is better controlled. In Wolfram syndrome, we would expect A1C levels to stay stable if blood glucose is well controlled with exogenous insulin and diet. Over time, it may become more difficult for A1C levels to remain stable as disease and glucose intolerance progresses. Moving from measures of glycemic control to measures of visual acuity.
The measure here is a Snellen Eye Chart, with which we are all familiar when we visit our optometrist or ophthalmologist. In Wolfram syndrome, visual acuity is expected to worsen over time, also as shared by Dr. Urano…. As shown on the right from a recent natural history study, visual acuity declined over time in all participants. Some had faster declines than others, but all declined. We also sought to understand patient and clinician-reported outcomes on a more global holistic scale, so we included the patient and clinician-reported global impression of change. 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.
So now on to the results of the HELIOS study, as well as the trial design, including interim efficacy and safety. First is study design. HELIOS is an open-label study in which all participants receive AMX0035 for up to 96 weeks. The primary endpoint is to evaluate beta cell function, as measured by C-peptide levels at 24 weeks. We also present 12-week results today. Adults aged 17 years or older with a genetically confirmed diagnosis of Wolfram syndrome were eligible for the trial. Importantly, participants were required to have insulin-dependent diabetes at baseline due to Wolfram syndrome, and also were required to have some residual pancreatic function at baseline, so they could respond to a mixed meal tolerance test. Participants also were required to wear a continuous glucose monitor for the study duration, and the use of GLP-1 agonist was not permitted during HELIOS.
The data we are sharing today are from an interim analysis performed as of data cutoff date of March 5th, 2024, when eight participants had completed their 24-week assessment. HELIOS is fully enrolled with 12 participants. There have been no dropouts or discontinuations thus far. As noted, the efficacy data presented today are from the eight participants who have completed their week 24 assessments. There are four more recently enrolled participants who have not yet reached week 24, and therefore are not included in the efficacy portion of the interim analysis. They are summarized in the demographic data, as well as included in available safety data reported. 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 five years, and median age at diagnosis was 20 years.
The age of onset of Wolfram syndrome manifestations align to natural history, with diabetes occurring first, followed by vision loss. A variety of endpoints are being measured in HELIOS, as summarized on this slide. The interim analysis we share today is largely focused on diabetes and vision assessments in eight participants. Later this year, the final week 24 data will include 12 participants and the additional assessments. The primary endpoint of HELIOS is the change in C-peptide levels over time, a measure of residual pancreatic beta cell function. Here is a graph of the mean C-peptide levels after a mixed meal tolerance test. The y-axis is the mean C-peptide level. The x-axis shows the time course of mixed meal tolerance test. The curves represent three different assessments during HELIOS. Dark blue dashed line is screening, teal is 12 weeks, and orange is 24 weeks.
In Wolfram syndrome, where a deterioration in beta cell function is expected to result in a decrease in C-peptide response during AMX0035 treatment. During AMX0035 treatment, we instead see improvement in beta cell function, as evidenced by the increased C-peptide response. Here, we are visualizing the C-peptide data in a different way. Specifically, we are looking at the area under the MMTT C-peptide curve that we just reviewed in the last slide. The area under the curve, or AUC, provides a single numeric estimate of C-peptide response at various time points. Consistent with the previous graph, we see an improvement in C-peptide response at both weeks 12 and 24. Shown on the left are the week 12 C-peptide responses at 90, 120, and 240 minutes in the MMTT.
The same time points for week 24 are shown on the right. As a reminder, the expectation is for C-peptide response to decrease over time on Wolfram syndrome, since it is, since it is a neurodegenerative progressive disease. So actually, our initial goal in HELIOS was to see a slowing in this decrease. However, here we are seeing an improvement in C-peptide response, both at weeks 12 and 24, compared to screening. We also evaluated the change in delta C-peptide at weeks 12 and 24, as shown on this slide. Change in delta C-peptide provides insight into changes in beta cell responsiveness over time. Positive values indicate increased responsiveness, while negative values indicate decreased responsiveness. Here, we see an increase in delta C-peptide at both weeks 12 and 24, compared to baseline.
Shown on the left is the week 12 change from baseline at 90, 120, and peak in the MMTT, and the same time points for week 24 are shown on the right. Again, the expectation is for delta C-peptide to decrease over time in Wolfram syndrome, as the mutations in WFS1 drive beta cell dysfunction and apoptosis with AMX0035, although we are seeing an improvement in beta cell responsiveness, both at weeks 12 and 24, compared to screening. Looking at the C-peptide response at the individual level, seven of the eight participants are showing a shorter time to peak C-peptide at week 24, compared to screening. This shorter time indicates improved pancreatic function. The pancreas is able to respond more quickly to a glucose challenge, the MMTT, than at screening.
The stars indicate those who have responded more rapidly to the glucose challenge by at least 30 minutes. We just shared several analyses of pancreatic beta cell function in this interim analysis of eight participants, and now I turn to Dr. Urano. Dr. Urano, we welcome your perspective on all these data. What do they tell you about the potential of AMX0035 in Wolfram syndrome?
Thank you, Dr. Bedrosian. I think this, these results are pretty encouraging. The reason, because of the two reasons. First, beta cell dysfunction can cause the delayed glucose-stimulated insulin secretion, and in patients treated with AMX0035, we see rapid, more rapid response to glucose-stimulated insulin secretion. In this case, actually, mixed meal tolerance, the Boost-mediated glucose, and Boost-mediated insulin secretion. So this is good sign. And also, we know that Wolfram syndrome patients, their C-peptide levels decline over time, progressively decline. And during this trial, in the first six months in eight patients, we saw an increase in C-peptide levels. So both of these are pretty encouraging results.
Thank you very much. Now we'll move on to the secondary endpoints. The larger C-peptide values we saw with the primary endpoint were associated with lower hemoglobin A1C values. Shown on the left are the overall findings among the eight participants in this interim analysis, and 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 get more difficult for levels to remain stable as disease progresses. Contrary to the natural history of the disease, here we are seeing an improvement in glycemic control at week 24, compared to screening. We also assessed changes in the degree of glycemic control through continuous glucose monitoring.
Specifically, we evaluated the change from baseline to week 22 in the overall time and target glucose range, which is defined as the percentage of time glucose values are between 70 and 180 milligrams per deciliter, a well-recognized way of assessing changes in glucose metabolism. Again, shown on the left are the overall findings among the eight participants in this interim analysis, and on the right are the individual results. Consistent with hemoglobin A1C findings, the majority of participants demonstrated increased time and target glucose range from screening to week 24, with the majority meeting of goal times in range, as defined by the recommendations from an international consensus report endorsed by the American Diabetes Association and the American Association of Clinical Endocrinologists. Dr. Urano, I turn to you again.
What are your perspectives on these additional measures of glucose metabolism, including hemoglobin A1C and time in range, target glucose range?
Yes, I think both of these are associated with the increased levels of C-peptide. It has been shown in Type 1 diabetes patients, not in Wolfram, it has been shown in Type 1 diabetes patients, higher levels of C-peptide is associated with better glycemic control. So the improvement in hemoglobin A1C and the improvement in continuous glucose monitoring data are both associated with the improved beta cell functions, treated, patients treated with AMX0035.
Thank you, Dr. Urano. Very helpful. Now on to the next. As mentioned earlier, optic atrophy represents a significant morbidity in Wolfram syndrome. There are no proven effective medical treatments for optic nerve atrophy in Wolfram syndrome at this time, and visual acuity is expected to decline over time in all people living with Wolfram syndrome. We evaluated the effects of AMX0035 on best-corrected visual acuity over 24 weeks, and as shown on the left, we saw a trend toward potential visual acuity improvement compared to screening. On the right, when looking at the individual data, five of eight participants experienced improvement in visual acuity in at least one eye, and this includes one participant who was blind at baseline, who now has some vision in one eye. Dr. Urano, we would appreciate your perspective on these data as well.
This is pretty encouraging because the vision loss is the most devastating symptom in patients with Wolfram syndrome. And so we sent out questionnaires to our patients suffering from Wolfram syndrome and found that poor vision is the most troublesome symptom in most of our patients. So this is pretty encouraging, and I think this reflects the fact, this is my speculation, but probably the remaining retinal ganglion cells are working better after the treatment with the AMX0035. I think it is unlikely that AMX0035, based on the mechanisms of action, increases the number of retinal ganglion cells, but functions of remaining cells could be improved, and that's what I speculate. And we need to see more data at later time points and more patients.
Very helpful. Thank you, Dr. Urano. Now on to the next slide. Given the many potential manifestations of Wolfram syndrome that go beyond diabetic and visual acuity measures, we wanted to understand symptom burden on a more global, holistic scale. Shown on the left is the patient-reported global impression of change, and the same is shown on the right from the clinician perspective. For the majority of participants, both by self and clinician report, improvements in symptom burden were noted. 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 met responder criteria at weeks 12 and 24. Again, Dr. Urano, we would appreciate your perspective on these data as well.
I found this result pretty encouraging because of two reasons. The first reason is that during the dantrolene sodium trial, we assessed their quality of life, patient-reported quality of life during the treatment. After the 6 months treatment, we did not see any improvement in their quality of life of our participants in the dantrolene trial. Clearly, you know, it's difficult to exclude the placebo effect for this endpoint, but I found this very interesting because this is something I did not see during the dantrolene trial.
Also, I think clinician-reported impression of change is also interesting, because we always assign different doctors to assess this, and it seems like it's consistent between different doctors. So because of these two reasons, I found this result pretty interesting and encouraging-
Yeah
... but we need to get more data on this for sure.
Yeah. Thank you very much. Very helpful also. Now turning to safety findings. In HELIOS, the safety findings were consistent with previous AMX0035 clinical trial data. Namely, AMX0035 was generally well-tolerated. Diarrhea was the most common treatment-emergent adverse event. It is important to note that while nearly all participants reported at least one treatment-emergent adverse event, none led to discontinuation. So in summary, the available clinical data reinforce and build on our preclinical findings. From the perspective of diabetic measures, we would expect to see progressively declining pancreatic function and worsening glycemic control based on the natural history of the disease. By contrast, in HELIOS, we see partial reversal of diabetic phenotypes with AMX0035. We also have early evidence of some improvements in visual acuity with AMX0035.
And finally, importantly, from the perspective of the investigating clinician and the participants in the trial, we've seen an improvement in perceived symptom burden with AMX0035. As a reminder, these are interim findings, and more detail will become available as participants undergo additional follow-up. We are excited about the potential impact of AMX0035 for people living with Wolfram syndrome. We are most grateful to the Wolfram community, including those participating in HELIOS, their loved ones, Dr. Urano, and the entire clinical staff at Washington University in St. Louis, for their support in these important efforts and the HELIOS trial. I will now turn back the call to Justin and Josh.
Thank you, Camille. And echoing, Camille, we're deeply grateful to all of the people participating in HELIOS, their families and caregivers, Dr. Urano and the team at WashU, and the Wolfram syndrome community, who continue to partner with us on this important research. To recap what we've shared today, we believe there is strong scientific rationale to study AMX0035 in Wolfram syndrome. Wolfram syndrome is a progressive, fatal genetic disease caused by mutations in WFS1 that cause endoplasmic reticulum stress and impaired mitochondrial dynamics. There is a clear match between the mechanism of AMX0035 and Wolfram syndrome, as demonstrated in our compelling preclinical data across cell types. And in the interim analysis data shared today, AMX0035 demonstrated improvement or stabilization across measures in different organ systems, including pancreatic function, glycemic control, vision, and overall disease burden.
With this data in hand, we are evaluating options for future development and planning to engage with regulatory authorities to align on the development path. We expect top-line data for all 12 participants at week 24, in the second half of 2024. We know Wolfram syndrome has clear, urgent, unaddressed needs, and we are committed to working expeditiously on behalf of the thousands of people living with Wolfram syndrome in the U.S., and individuals and families around the world. Now, I would like to open the call up for questions.
... Thanks, Josh. Just as a reminder, if anybody wants to submit a question, you can just put it into the chat. Our first question comes from Mike DiFiore at Evercore. What-- On that point, what could the development path forward look like? Is there a universally accepted regulatory endpoint that can be used for Wolfram trials?
So, you know, that we are, we would be the first drug, you know, ever approved in Wolfram syndrome, so I do think we are paving a new path here. But I think, you know, it's likely that regulators will look for what they often look for, which is clinically meaningful evidence of benefit. Here we're looking at outcomes across, many different domains of the disease. We're looking across diabetic phenotypes, across the visual phenotypes, and, you know, importantly as well, across the patient's perception of how they're doing. And I think those are the types of things that, you know, you know, ultimately can, can become convincing that, you know, that there is a clinically meaningful difference. But maybe I'll pass to Camille if you wanna add anything else there as well.
Sure. I to reiterate, this is a very rare disease for which there really haven't been any industry studies that are seeking to address, in a fulsome manner, Wolfram syndrome and be made available for the community. It is a very rare disease, and as such, we would consider the pathway forward consistent with other rare diseases, where the population is relatively small, relatively smaller trials would be adequate. In this case, we have objective measures as well, C-peptide, which we'll explore as potential, you know, endpoints together with the impressions of change, et cetera, that we've had. So we look forward to our discussions going forward and putting forth proposals to the regulatory agencies, so that we can proceed to, as the data hold up, proceed to seek approval for this indication.
Mike also noted that there were a few patients who didn't improve on many of the endpoints. Are there any inferences to be gained here in terms of baseline characteristics? Did these non-improvers have any biomarkers, et cetera, in common?
Maybe first I'd say that if you actually look across the endpoints, we kept the color coding consistent, so that may help, you know, when looking back at the slides. Every patient shows an improvement in at least one of the outcomes, so there are not patients that did not, you know, did not show anything. But I also want to again, you know, kind of reiterate the expectation of this disease's progression. This is a, you know, a fatal disease where people progress and lose critical functions. So to see improvement is unexpected, it's surprising, and to see it consistently, you know, this effect is not being driven by one patient or two patients. This effect is being driven across the study, you know, which I think is very encouraging to us.
I might ask Dr. Urano . I know you were commenting on this during the presentation, but just a little more on, you know, what you might expect to see in people with Wolfram syndrome, and why therefore you're encouraged by the data here?
So I have been encouraged by the current results because of the improvement in the diabetes-related outcome measures. In my personal opinion, as a physician treating patients with Wolfram syndrome, there are two clinically significant outcomes of treatment for Wolfram syndrome. These are decrease in insulin dose and stabilization or improvement in the visual acuity. And as Mr. Cohen and Mr. Klee, Dr. Bedrosian commented that, you know, these should decline over time in patients with Wolfram syndrome. So if we can improve a little bit, that's significant. And it's worth noting that AMX0035 was originally developed for neurodegenerative disorders, not for diabetes. So if it improves diabetes in Wolfram syndrome, that strongly suggests that AMX0035 targets upstream mechanisms of the Wolfram syndrome. This means it should improve multiple downstream consequences, including vision and potentially neurological problems.
Thank you so much. Mike also asked, "What gives us confidence that we're using the right dose?
Yeah, it's a great question. So, you know, I think we've selected our dose, you know, kind of going back even to the preclinical data, you know, the mouse data as well, and we've tried to target a similar concentration range, when we've been in clinic. But it, you know, it's something that we certainly will continue to explore. Wolfram syndrome also, you know, has pediatric onset. So as we pursue the pediatric population, we'll certainly look to dose there as well.
Great! Our next set of questions comes from Corinne Jenkins at Goldman Sachs. Dr. Hirano, what is a clinically meaningful improvement in Wolfram syndrome patients?
So I just mentioned two things. There are two clinically significant improvement, vision and insulin dose. The reason insulin dose is important is that if a patient starts producing more insulin from their own pancreas, it's much easier for them to control their blood sugar levels because they need to use less insulin or other diabetes medications. That can also reduce the incidence of hypoglycemia or hyperglycemia. So a decrease in insulin dose is very important. Well, in this case, we saw a slight improvement in visual acuity in this patient population treated with AMX0035. And as I just mentioned, we sent out the questionnaires to all the patients who we know with Wolfram syndrome, regarding their most troublesome symptom.
The most troublesome symptom, by far number one, was their low vision. So these two are the most important, clinically significant outcomes, and that's why we chose these actually outcome measures for this, particular clinical trial.
Thanks, Dr. Urano. The next set of questions comes from Charlie Yang at Bank of America: Are there preclinical data looking at GLP-1s versus AMX0035, and how do they compare?
Maybe I'll pass to Dr. Urano to start there. I know you have a lot of experience in that space.
Yes, that's a really good question. So we don't have data comparing the difference between GLP-1 and AMX0035 side by side. I want to mention that GLP-1, GLP-1 receptor agonist and AMX0035 have different mechanisms of action on the endoplasmic reticulum or endoplasmic reticulum stress. AMX0035 reduces endoplasmic reticulum stress and improves mitochondrial function. GLP-1 receptor agonists act differently on endoplasmic reticulum. It weakly activates the endoplasmic reticulum stress response, and then makes these cells more resistant to endoplasmic reticulum stress-mediated cell death. So in short, we did not compare, or we did not do a side-by-side comparison of GLP-1 receptor agonist and AMX0035. But my guess is that because these two different medications target different pathways, we may see synergistic effect by taking both GLP-1 receptor agonist and AMX0035.
Many of our patients are actually taking GLP-1 receptor agonist because it is an approved medication for the diabetes treatment. For this particular trial, in the first 48 weeks, we have asked our participants to not take GLP-1 receptor agonist to remove this one of the confounding factors. In the future, maybe we should see, or we should study the synergistic effect of AMX and the GLP-1 receptor agonist. This is pretty important because GLP-1 receptor agonist is widely taken in patients with Wolfram syndrome.
Charlie asked, too: How are you thinking about a pivotal trial design in terms of patient inclusion criteria, with or without GLP-1s?
Yeah. So, we're still, you know, in discussions with the regulatory authorities and otherwise, so we have not presented a final pivotal trial design. You know, I'd say as we think about Wolfram, there are many different... You know, there may be a couple different populations we wanna focus on, including both pediatric and also, you know, adult people with Wolfram syndrome. And I'd add that while, you know, I think, there's a lot of excitement, maybe appropriately so, around GLP-1s, even with GLP-1s, you know, Wolfram remains, you know, a progressive disease. And so it's, you know, important, you know, that the other manifestations of the disease beyond, let's say, just the diabetic phenotype also need to be addressed.
I think that's, you know, part of the value in seeing things like the global symptom burden and otherwise, that we see, you know, in the majority of participants improving, or at least being stable, in the HELIOS trial. That's why those things are so valuable, 'cause those go beyond just the diabetic phenotypes.
Yeah, just underscoring that. So if you think about the mechanism of Wolfram syndrome, it's caused by WFS1 mutations, which cause ER stress and mitochondrial dysfunction, and thereby reducing cellular function in the cell type, as well as eventually cell death. So that's why you first see loss of function in the beta cells, and then cell death, and then in various parts of the nervous system. So I think what we know about the GLPs today is mostly about how they work in diabetes, right? But it's not getting at the heart of Wolfram syndrome, which is caused by these WFS1 mutations.
And then the last question from Charlie is: For the individual who was blind, how long was he blind for? Could it be a spontaneous recovery?
Maybe pass to Dr. Urano.
That is a very good question. So out of 8 patients, I think two patients are legally... Actually, three patients are legally blind. And so I'm not so sure a spontaneous recovery of the vision loss happens under any circumstances, so we need to see more data in this population. But I think spontaneous recovery is unlikely.
Thanks, Dr. Urano. The next question comes from Graig Suvannavejh at Mizuho: What additional information will we receive at the top-line data readout?
... Yeah, so one, I'd probably refer a little back to the slide that had kind of the full set of endpoints. We focused on a series of key endpoints for this interim analysis. We'll have the full set of endpoints, you know, when we have the full data analysis. And then I think importantly as well, we'll have all 12 participants having completed 24 weeks as well, which should give, you know, a larger sample size as well in analyzing these results.
What are the next steps for the program? What data are required for phase III? Would that design look similar to a phase II? What would be the best way to find patients, and are there any screening tools being worked on?
So I'd say first, you know, the real goal of this trial was to both evaluate the outcomes and evaluate the potential of AMX0035 in Wolfram syndrome. As was mentioned, the original design or goal of the trial was to see if we could slow progression in a progressive disease. What we're seeing across multiple systems now is, in fact, stabilization or improvement, so, and in a reasonably short period of time. So I think that's very encouraging. So I think the next steps are to propose sort of the next plans with the regulatory authorities. And then in terms of the next trials, we've already started to discuss that with Dr. Urano. I think that there are...
With results like this, I think I can say there's a lot of excitement in the Wolfram syndrome community. And I think the question will be: how do we run studies in the right populations? And it may be multiple different types, so that we can see, we can properly evaluate this multi-organ multisystem disease. But to start, when we're seeing effects across pancreatic function, potentially visual functioning, sort of whole disease with a global impression, we're very encouraged.
Yeah, and just one marginal comment as well. You asked about finding patients as well. One, you know, I'll definitely have Dr. Urano add, but, there is a genetic test, you know, for the vast majority, you know, for the WFS1, you know, mutations. So, you know, there, there is testing available, to be able to find this disease as well as, you know, various clinical workups. But I, I pass to Dr. Urano to, to add more detail there.
Yes. So we can certainly find more patients for sure. The reason is, so I don't anticipate any difficulties, as we are receiving a significant number of calls and emails from patients who are interested in participating in the ongoing this clinical trial. We have already recruited 12 for this trial, so we cannot enroll anyone else. But we are getting so many calls and emails. And one of the challenges we may face is that we have so many potential patients who can participate. But if we set the strict inclusion and exclusion criteria, we may need to exclude many patients. So for example, if we exclude patients who are not producing, you know, enough amount of C-peptide, we have to exclude many patients.
Or if we exclude patients who have low vision, we may need to exclude many patients, and we cannot recruit any pediatric patients right now. And so, in my personal opinion, we have a better chance to see a improvement in pediatric patients who are still at the early stage of the disease. It's difficult to see the efficacy of any treatment in patients at late stage of... Well, at later stages of patients with Wolfram syndrome. So these are the things we should discuss with the-- I should discuss with the Amylyx team, with the, Dr. Bedrosian and Mr. Klee and, Mr. Cohen.
Thanks, Dr. Urano. The next question comes from an investor. Week 24 C-peptide data looked numerically worse over time, or, sorry, worse than week 12. Is the effect waning over time?
Yeah. So I'd say, first of all, we don't think so. You know, we think that first, it's really important to note that we expect that this marker would progress over time. And so, you know, again, to be still seeing an improvement at 24 weeks was even more impressive than seeing an improvement, you know, at 12 weeks, where more time has elapsed and more time has passed. I think additionally, when we look at week 24 across all the other outcomes, we're seeing some of those, the, you know, benefits on C-peptide start to manifest in other manifestations of diabetes, whether that's the HbA1c, the time and range or otherwise. And of course, you know, we're seeing that, you know, global impression of change both at week 12 and week 24.
You know, if anything, you know, it seems that you know, going in the right direction. So we don't think that there's you know, a particular waning here, and we're still seeing that unexpected improvement at 24 weeks.
Dr. Urano is, obviously, you're seeing the participants in the study. We'd love your thoughts there as well.
Right. So first of all, you know, their beta cell functions should decline over time, so even slight improvement is still encouraging. And also, we need to wait for the additional results at 36- and 48-week time points, because we have started getting data at 36- and 48-week time points in some of our participants, and there is a possibility that their beta cells may start producing more insulin again. But because we are still getting data, we just need to wait. I think there is a reason, there might be a reason that we see some decline at the 24-week time point as compared to 12-week time point. And most likely, there are two different insulin-producing cell populations in patients with Wolfram syndrome.
So beta cell, where beta cell population still secreting some insulin, although they are undergoing stress, and the beta cell population that has stopped producing insulin due to the high level of endoplasmic reticulum stress. In the first 12 weeks, maybe AMX0035 act on the first population, which is their cells producing, still producing insulin, although they are experiencing, experiencing endoplasmic reticulum stress. And because these beta cells need, can secrete more insulin because of the AMX and reduction of endoplasmic reticulum stress, these beta cells may get a little tired, then may start producing a little less insulin. But my hope is the AMX0035 continues reducing endoplasmic reticulum stress levels in the second population, which has the frequent population that has stopped producing any insulin.
If we can wake up these cells with AMX0035 by reducing endoplasmic reticulum stress, we should start seeing the upregulation of C-peptide levels again. So, you know, we have many explanations on the beta cell data we have seen, what we have obtained so far, but my impression is that we should wait for this data at 36- and 48-week time point. Also, we are supposed to see the decline in beta cell functions, you know, so the slight improvement is still clinically meaningful.
Thank you. Our next question comes from Basma Radwan at Leerink What is the regulatory path for approval in Wolfram syndrome, and have you started to engage with the FDA yet?
Yeah, I think that's our, that's our next main step. You know, we will be defining, together with the, with the agency, the regulatory path in Wolfram syndrome. I think in Wolfram, as in, in many other diseases, the key question is showing, you know, clinically meaningful data. And that's what we will be, you know, working to, you know, convince and, and show, ultimately that, that, that we have, and that we, you know, can continue to generate, as well. And as, as Dr. Bedrosian, shared as well, this is also a very rare disease, and that always goes into the consideration, you know, for the path to approval as well.
One other important point, as Dr. Bedrosian was saying as well, while this is Wolfram syndrome, there are no approved treatments for Wolfram syndrome. These are very well-known objective measures. C-peptide, time and range, HbA1c, visual acuity, et cetera. These are very well-known and clearly meaningful outcomes.
Our next question comes from Ananda Ghosh at HC Wainwright: Although a monogenic disease, data from earlier trials indicate heterogeneity based on the mutation types and the Wolfram syndrome, one gene, how are you thinking about heterogeneity aspects of the disease?
Well, I'll certainly pass quickly to Dr. Urano, but I'll just say that my own view is that this is an area where translational medicine is really powerful. And so we can test certain mutations in vitro, in vivo, preclinically, and then see how those things translate into people living with the disease, which is why this has been a collaboration. Among many reasons, it's why it's been a collaboration we've been so excited about for many years. But Dr. Urano, I'll pass to you for more.
Yes, so that's definitely a great question. There is heterogeneity in patients with Wolfram syndrome based on the types of mutations in the WFS1 gene they have. So what we did, in my presentation, I showed the data of the three lines, three iPS lines from patients with Wolfram syndrome. However, we actually tested more lines during our preclinical study phase, and we chose lines that carry, you know, mutations associated with mild manifestations, and we chose lines from patients who have the more severe manifestations. So in short, we treated the patient-derived cells, and we treated both lines derived from patients with severe manifestations and mild manifestations, and different types of mutations. And in all the lines, we saw some beneficial effects, you know, improvement in cell survival and the improvement in mitochondrial functions.
So because we are targeting the common molecular pathways altered in Wolfram syndrome patients, we should see beneficial effects in all the patients, in all the patients who have Wolfram syndrome, because we are targeting the common molecular pathways altered in most of the patients. To see the efficacy of AMX0035, we may need to choose some specific population because there is a possibility that some specific patient population carrying a specific types of mutations are more responsive to AMX0035 treatment. So that's something we need to think carefully for the next phase of the trial, and because we need to be careful because we don't want to exclude too many patients.
The next question comes from an investor: "Is there any chance of an accelerated approval given unmet need?
Yeah, I mean, so I'd say that the field has long discussed C-peptide as a you know, validated surrogate marker, and that's usually what the type of thing FDA looks at for, you know, accelerated approval. That being said, we're in the early you know, we're just starting those discussions. So I don't wanna you know, state what will or will not be the regulatory path you know, quite yet.
Are these interim findings statistically significant?
They are across, you know, many of the time points. So yes, across many of the time points, but again, this was a exploratory initial study, so we weren't really kinda... You know, that wasn't essentially the goal of the study, but yes. You know, as you can kinda look at the error bars, you can see pretty clearly that these are, these are pretty statistically robust findings.
The next question comes from Joel Beatty at Baird: "Would it be feasible to run a randomized controlled trial of AMX0035 in Wolfram syndrome?
I think it depends on the regulatory feedback, and of course, the impression of the data here. Again, the original goal of the study was to see if AMX0035 could slow progression. We're seeing evidence of stabilization or even improvement. So I think, well, we'll discuss that with the regulatory authorities.
The next question comes from an investor: "If AMX0035 is approved for Wolfram syndrome, how long do you expect patients to stay on treatment?
Well, maybe I'll pass that to Dr. Urano to answer that question.
Yes. So patients with Wolfram syndrome may need to take AMX0035 for life, similar to how patients with hyperlipidemia take statins for life, and they may be able to stop taking it if a cure for Wolfram syndrome is achieved through maybe gene editing therapy, but it will certainly take time to achieve that. So in short, they need to take AMX0035 for life, similar to how patients with hyperlipidemia take statins for life.
Thanks, Dr. Urano, and I might just add as well, one very encouraging thing in HELIOS as well, was that we had no dropout. So over six months, we've seen, you know, 100% of the patients complete the study.
Just a quick follow-up from that investor: "If AMX is approved for Wolfram syndrome, who would you prescribe it to? Would you prescribe it to all patients, or a certain subset?
Maybe I'll pass that to Dr. Urano.
Yeah.
Yes. I would, I would prescribe it to all patients who have Wolfram syndrome, regardless of the stage of the disease they are in. This includes those who have not yet developed all the characteristic symptoms, such as diabetes and optic nerve atrophy. This is particularly important for patients who have a mild form of the disease or are in the early stages of the disease, especially children. In short, I would prescribe it to all the patients, even though who are at the late stage of the disease, but probably it's more important to prescribe this to patients who are at the early stage or early stages of the disease, including children. I think the study in children is very important.
Thank you. Okay, we are at time. I... We see a few other questions in the chat, and we'll absolutely get back to folks. Thank you, everyone, so much for joining, and I'll turn it back to Justin to close us out.
Well, first of all, yeah, thank you all very much for joining us. Thank you for the great questions. We're both encouraged by the data, but also appreciate the opportunity to get to share more about Wolfram syndrome, which is a really unmet need. I'd say a real heartfelt thank you also to the participants in the study and their families. This has been a wonderful collaboration, and we are so excited to continue that collaboration together. And then a special, special thank you to Dr. Fumihiko Urano, who is both a world leader in this space, has been a wonderful collaborator over many years, and is one of the kindest, most passionate doctors I've had the privilege of working with as well.
Thank you all very much, and we look forward to talking more about this. Thank you.
Thank you.