Skip to main content
Amylyx logo
Amylyx logo

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 October 2024, we announced positive topline data from HELIOS, which showed improvement in pancreatic function, as measured by C-peptide response after 24 weeks of treatment with AMX0035, the study’s primary efficacy endpoint, in contrast to the expected decrease in pancreatic function with disease progression.

Chart showing increased mean C-peptide production at 120 minutes in response to the mixed meal tolerance test in HELIOS.

Similar overall improvements or stabilization were observed across all secondary endpoints, including hemoglobin A1c (HbA1c), time in target glucose range assessed by continuous glucose monitoring, and visual acuity. Patient- and physician-reported global impressions of change showed disease stability or improvement in all participants, meeting prespecified responder criteria. The safety profile of AMX0035 in HELIOS was consistent with prior safety data. AMX0035 was generally well-tolerated. All adverse events (AEs) were mild or moderate, and there were no serious AEs related to AMX0035 treatment.

We continue to engage with the FDA and other stakeholders to inform a Phase 3 program and expect to provide an update in 2025.

  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.

Pipeline

We are tackling some of medicine’s toughest problems to serve communities with high unmet needs. To accomplish this, we are advancing a pipeline in which we’ve matched investigational therapies with diseases in which they can make the greatest impact.

VIEW FULL PIPELINE

Featured Publications

Read all publications