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Wolfram syndrome is a rare, monogenic neurodegenerative disease that progressively impacts multiple organs and systems. Wolfram syndrome is characterized by childhood-onset diabetes, optic nerve atrophy, and neurodegeneration. Common manifestations of Wolfram syndrome include diabetes mellitus, optic nerve atrophy, central diabetes insipidus, sensorineural deafness, neurogenic bladder, and progressive neurologic difficulties. The prognosis of Wolfram syndrome is poor, and many people with the disease die prematurely mainly from respiratory failure.1-5

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 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). Genetic and experimental evidence suggests that ER dysfunction is a critical pathogenic component of Wolfram syndrome. Loss of wolframin function leads to ER stress and 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.1, 5-9

AMX0035 (sodium phenylbutyrate [PB] and taurursodiol [TURSO, also known as ursodoxicoltaurine]) is hypothesized to reduce neuronal cell death in Wolfram syndrome by simultaneously mitigating ER stress and mitochondrial dysfunction. Preclinical studies have provided evidence that AMX0035 may reduce cell death and improve cellular function including in neuronal and pancreatic beta cells, specifically in Wolfram syndrome models.10

Amylyx announced positive topline data from the Phase 2 HELIOS (NCT05676034), clinical trial of AMX0035 in 12 adults living with Wolfram syndrome. The study 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.

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 FDA and the European Commission granted Orphan Drug Designation to AMX0035 for the treatment of Wolfram syndrome in November 2020 and August 2024, respectively.

  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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