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About Wolfram syndrome and how it manifests

Thumbnail that links to a video on Vimeo of Raquel, a young woman sharing her experience living with Wolfram syndrome.

Raquel shares her experience of living with Wolfram syndrome

About Wolfram syndrome and how it manifests

Wolfram syndrome is a rare, monogenic neurodegenerative disease that progressively impacts multiple organs and systems. Wolfram syndrome is characterized by childhood-onset diabetes mellitus, optic nerve atrophy, and neurodegeneration. Common manifestations of Wolfram syndrome include diabetes mellitus and diabetes insipidus, gradual vision loss leading to blindness, hearing loss, neurogenic bladder, difficulties with balance and coordination, and difficulty breathing that can lead to respiratory failure.1-5

Disease pathology and potential intervention

The majority of people with Wolfram syndrome carry mutations in the WFS1 gene, which encodes a protein called wolframin that spans the membrane of the endoplasmic reticulum (ER). Loss of wolframin function leads to ER stress and impaired mitochondrial dynamics, which lead 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. Because of the clear link between WFS1 mutations and ER stress, Wolfram syndrome is considered a prototypical ER stress disorder.1, 5-9

AMX0035 is hypothesized to mitigate cell death in Wolfram syndrome by reducing ER stress and mitochondrial dysfunction. In preclinical models, treatment with AMX0035 improved WFS1 protein expression, increased insulin secretion, and inhibited beta cell death in cells derived from people with Wolfram syndrome. AMX0035 also prevented cell death in neuronal cells derived from people with Wolfram syndrome and significantly delayed progression of the diabetes phenotype in a WFS1-knock-out preclinical model.10

Prevalence of Wolfram syndrome and Amylyx program status

There are currently no approved therapies for the approximately 3,000 people in the U.S., and more around the world, living with Wolfram syndrome. The FDA and the European Commission granted Orphan Drug Designation to AMX0035 for the treatment of Wolfram syndrome in November 2020 and August 2024, respectively.

We initiated HELIOS (NCT05676034), a 12-participant, single-site, single-arm, open-label, Phase 2 clinical trial designed to evaluate the safety and tolerability of AMX0035 and various measures of endocrinologic, neurologic, and ophthalmologic function in adult participants living with Wolfram syndrome.

In May 2025, we announced positive Week 48 data from the Phase 2 open-label HELIOS clinical trial of AMX0035 in adults living with Wolfram syndrome. Consistent with the HELIOS trial’s previously presented primary efficacy outcome of improvement in pancreatic function, as measured by C-peptide response to a mixed-meal tolerance test at Week 24, treatment with AMX0035 through Week 48 demonstrated continued and sustained improvement in pancreatic beta cell function.

Treatment with AMX0035 from Week 24 to Week 48 also showed sustained improvements or stabilization in glycemic control, as measured by hemoglobin A1c (HbA1c) and time in target glucose range assessed by continuous glucose monitoring, as well as visual acuity. All participants with available measurements met the responder criteria, defined as either improvement or no change, on both the Patient Global Impression of Change (PGI-C) and Clinician Global Impression of Change (CGI-C) at Weeks 24 and 48, indicating stability or improvement in their Wolfram syndrome-related symptoms. Results from qualitative on-study interviews further supported the potential positive impact of AMX0035 on symptom burden.

The safety profile of AMX0035 in HELIOS Week 48 data were consistent with prior safety data from the studies of AMX0035. All adverse events (AEs) were mild or moderate, and there were no serious AEs related to AMX0035 treatment.

Data from participants at Week 48 and ongoing discussions with the FDA will inform the design of a Phase 3 trial of AMX0035 in Wolfram syndrome.

  1. Urano F. (2014). Wolfram syndrome iPS cells: the first human cell model of endoplasmic reticulum disease. Diabetes, 63(3), 844–846. https://doi.org/10.2337/db13-1809.
  2. Pallotta, M. T., Tascini, G., Crispoldi, R., Orabona, C., Mondanelli, G., Grohmann, U., & Esposito, S. (2019). Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives. Journal of translational medicine, 17(1), 238. https://doi.org/10.1186/s12967-019-1993-1.
  3. Lee EM, Verma M, Palaniappan N, Pope EM, Lee S, Blacher L, Neerumalla P, An W, Campbell T, Brown C, Hurst S, Marshall B, Hershey T, Nunes V, López de Heredia M and Urano F (2023) Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders. Front. Genet. 14:1198171. http://doi.org/10.3389/fgene.2023.1198171.
  4. Leslie M. (2021). A revealing flaw. Science (New York, N.Y.), 371(6530), 663–665. https://doi.org/10.1126/science.371.6530.663.
  5. Matsunaga, K., Tanabe, K., Inoue, H., Okuya, S., Ohta, Y., Akiyama, Urano F. (2016). Wolfram Syndrome: Diagnosis, Management, and Treatment. Current diabetes reports, 16(1), 6. https://doi.org/10.1007/s11892-015-0702-6.
  6. Fraser FC and T Gunn. J Med Genet. 1977;14(3): 190-193. http://doi.org/10.1136/jmg.14.3.190.
  7. Silvestri, F., Tromba, V., Costantino, F., Palaniappan, N., & Urano, F. (2022). Two Cases of Wolfram Syndrome Who Were Initially Diagnosed With Type 1 Diabetes. AACE Clinical Case Reports, 8(3), 128-130. https://doi.org/10.1016/j.aace.2022.01.001.
  8. Mishra, R., Chen, B. S., Richa, P., & Yu-Wai-Man, P. (2021). Wolfram syndrome: new pathophysiological insights and therapeutic strategies. Therapeutic advances in rare disease, 2, 26330040211039518. https://doi.org/10.1177/26330040211039518.
  9. Samara A, Rahn R, Neyman O, Park KY, Samara A, Marshall B, Dougherty J, Hershey T. Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses. Orphanet J Rare Dis. 2019 Dec 3;14(1):279. http://doi.org/10.1186/s13023-019-1260-9.
  10. Kitamura, R. A., Maxwell, K. G., Ye, W., Kries, K., Brown, C. M., Augsornworawat, P., Hirsch, Y., Johansson, M. M., Weiden, T., Ekstein, J., Cohen, J., Klee, J., Leslie, K., Simeonov, A., Henderson, M. J., Millman, J. R., & Urano, F. (2022). Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome. JCI Insight, 7(18). https://doi.org/10.1172/jci.insight.156549.

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