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About PSP and how it manifests

Microscopic view of tau protein, colored a blue-gray to contrast against a navy blue backdrop.

“You know, have to keep moving forward because you have an 8- and a 10-year-old and their life can’t just implode…just because this thing has happened…but what do you tell your kids about their [father’s prognosis] when you don’t know?”

– AUDREY, WIFE AND CARETAKER WHO LOST HER HUSBAND JEFF TO PSP

About PSP and how it manifests

Progressive supranuclear palsy (PSP) is a sporadic, rare, fatal neurodegenerative disease that can affect movement, gait, balance, cognition, eye movements, swallowing, and speech. People living with PSP have a life expectancy of six to eight years after symptom onset.1-3

Disease pathology and potential intervention

PSP is considered a tauopathy based on the strong genetic link between tau variants and disease development and the presence of abnormal tau protein deposits in the brain. Tau is a protein naturally found in the body that plays a role in stabilizing the microtubules that provide structure to cells, particularly in neuronal axons. In PSP, alterations to the structure of tau drive degeneration, and while the precise mechanism is still unclear, two processes are thought to contribute:6,7,9

  • Tau dysfunction leading to depolymerization of microtubules and axonal defects.
  • Pathologic aggregation of abnormal tau.

Similar to other neurodegenerative diseases, the pathophysiologic changes underlying PSP are likely multifactorial, including genetic mutations, endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and neuroinflammation.4-8

AMX0035 is designed to simultaneously mitigate ER stress and mitochondrial dysfunction, key contributors to tau dysfunction and aggregation, and therefore has the potential to influence PSP pathophysiology. AMX0035 was generally well-tolerated. A higher percentage of patients in the AMX0035 arm had gastrointestinal adverse events. However, no SAEs were attributed to AMX0035 in the trial.

Chart demonstrating that avexitide reduced daily rates of hypoglycemia by greater than 50% in 2 Phase 2 PBH clinical trials.

Prevalence of PSP and Amylyx program status

PSP affects approximately seven in 100,000 people worldwide, and there are currently no disease-modifying therapies approved for the treatment of PSP.10-11 We initiated ORION (NCT06122662), a global, randomized, double-blinded, placebo-controlled Phase 2b/3 clinical trial to assess the efficacy, safety, and tolerability of AMX0035 compared to placebo in people living with PSP. Data from an interim analysis of ORION are expected in mid-2025.

  1. Golbe, L. I., & Ohman-Strickland, P. A. (2007). A clinical rating scale for progressive supranuclear palsy. Brain, 130(6), 1552–1565. https://doi.org/10.1093/brain/awm032.
  2. Viscidi, E., Litvan, I., Dam, T., Juneja, M., Li, L., Krzywy, H., Eaton, S., Hall, S., Kupferman, J., & Höglinger, G. U. (2021). Clinical Features of Patients With Progressive Supranuclear Palsy in an US Insurance Claims Database. Frontiers in Neurology, 12. https://doi.org/10.3389/fneur.2021.571800.
  3. ‌Swallow, D. M. A., Zheng, C. S., & Counsell, C. E. (2022). Systematic review of prevalence studies of progressive supranuclear palsy and corticobasal syndrome. Movement Disorders Clinical Practice. https://doi.org/10.1002/mdc3.13489.
  4. ‌Coughlin, D. G., & Litvan, I. (2020). Progressive supranuclear palsy: Advances in diagnosis and management. Parkinsonism & Related Disorders, 73, 105–116. https://doi.org/10.1016/j.parkreldis.2020.04.014.
  5. Park, H. K., Ilango, S. D., & Litvan, I. (2021). Environmental Risk Factors for Progressive Supranuclear Palsy. Journal of Movement Disorders, 14(2), 103–113. https://doi.org/10.14802/jmd.20173.
  6. Shoeibi, A., Olfati, N., & Litvan, I. (2019). Frontrunner in Translation: Progressive Supranuclear Palsy. Frontiers in Neurology, 10. https://doi.org/10.3389/fneur.2019.01125.
  7. ‌Stamelou, M., Respondek, G., Giagkou, N., Whitwell, J. L., Kovacs, G. G., & Höglinger, G. U. (2021). Evolving concepts in progressive supranuclear palsy and other 4-repeat tauopathies. Nature Reviews Neurology, 17(10), 601–620. https://doi.org/10.1038/s41582-021-00541-5.
  8. ‌Stamelou, M., de Silva, R., Arias-Carrion, O., Boura, E., Hollerhage, M., Oertel, W. H., Muller, U., & Hoglinger, G. U. (2010). Rational therapeutic approaches to progressive supranuclear palsy. Brain, 133(6), 1578–1590. https://doi.org/10.1093/brain/awq115.
  9. ‌Sarkar S. (2018). Neurofibrillary tangles mediated human neuronal tauopathies: insights from fly models. Journal of genetics, 97(3), 783–793.
  10. ‌Lyons, S., et al. Journal of Neurology. 2023 June 8. Epub ahead of print. https://doi.org/10.1007/s00415-023-11791-2.
  11. ‌Swallow, D. M. A., et al. Movement Disorders Clinical Practice. 2022 Jun 28;9(5):604-613. https://doi.org/10.1002/mdc3.13489.

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