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About ALS and how it manifests

Person living with ALS being helped by caregiver out of electric wheelchair.

About ALS and how it manifests

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal neurodegenerative disorder caused by motor neuron death in the brain and spinal cord. Motor neuron loss in ALS leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis, and, eventually, death.1,2

“When you’re diagnosed with ALS, you’re no longer on the human clock, you’re on the ALS clock. Every passing day is a lifetime to an ALS patient, and ALS patients don’t have time to wait.”

– Cali, ALS caregiver

Disease pathology and potential intervention

Decades of scientific literature and published data demonstrate that calpain-2 (CAPN2), a protein involved in neurofilament biology, plays an essential role in axonal degeneration, which is a critical effector in the progression of various neurodegenerative diseases including ALS. Axonal degeneration disrupts neural connectivity and contributes to disease pathology.

Axonal degeneration is a key early contributor to the pathogenesis of ALS. Preclinical studies in ALS models suggest that the inhibition of CAPN2 may mitigate axonal degeneration and improve neuron survival, highlighting CAPN2 inhibition as a potential therapeutic approach. Additional preclinical evidence demonstrating the critical role of CAPN2 in ALS pathology include:

  • CAPN2 levels are elevated in people with ALS3,4
  • Inhibition of calpain-2 has shown therapeutic benefit in ALS models5
  • Calpain-2 acts as a primary protease that cleaves neurofilament light chain (NfL), a broadly researched biomarker for axonal degeneration in ALS6-8
  • Calpain-2 also cleaves TAR DNA-binding protein 43 (TPD-43), a protein associated with ALS4

AMX0114 is an Amylyx-developed, investigational antisense oligonucleotide (ASO) targeting CAPN2 for the potential treatment of ALS. In preclinical studies, treatment with AMX0114 resulted in potent, dose-dependent, and durable reduction in CAPN2 mRNA and calpain-2 protein levels in disease-relevant cell models of axonal degeneration. This translated to improved neuronal survival, including in a model of TDP-43 ALS, and reductions in extracellular NfL levels across multiple disease models and paradigms of neuronal injury. AMX0114 was well-tolerated in in vivo preclinical safety studies.

Chart demonstrating that AMX0114 reduces extracellular neurofilament light chain levels in multiple models.

Prevalence of ALS and Amylyx program status

ALS is defined as a rare disease, but it affects as many as 30,000 adults in the U.S.9 and 3,000 in Canada.10 The most common form of the disease is sporadic ALS, with more than 90% of people with ALS showing no clear family history.12

LUMINA, a Phase 1, multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose clinical trial evaluating the safety and biological activity of AMX0114, began recruiting in February 2025. Amylyx expects early data from LUMINA in 2025.

  1. Brown, R. H., & Al-Chalabi, A. (2017). Amyotrophic Lateral Sclerosis. New England Journal of Medicine, 377(2), 162–172. https://doi.org/10.1056/nejmra1603471.
  2. Al-Chalabi, A., Hardiman, O., Kiernan, M. C., Chiò, A., Rix-Brooks, B., & van den Berg, L. H. (2016). Amyotrophic lateral sclerosis: moving towards a new classification system. The Lancet Neurology, 15(11), 1182–1194. https://doi.org/10.1016/s1474-4422(16)30199-5.
  3. ‌Ueyama, H. et al. Journal of the Neurological Sciences. 1998;155(2):163-169.
  4. Yamashita, T. et al. Nature Communications. 2012;3:1307. https://doi.org/10.1038/ncomms2303.
  5. Rao M. V., et al. Journal of Neurochemistry. 2016;137(2):253-65. https://doi.org/10.1111/jnc.16160.
  6. Zimmerman, U. J., et. al. Biochemistry. 1982; 17;21(17):3977. https://doi.org/10.1021/bi00260a012.
  7. Ma, M., et al. Neurobiology of Disease. 2013; 56:34-46. https://doi.org/10.1016/j.nbd.2013.03.009.
  8. Lombardi, V., et al. Scientific Reports. 2020;26;10(1):10774. https://doi.org/10.1038/s41598-019-54310-y.
  9. Mehta P., et al. Amyotrophic Lateral Sclerosis Frontotemporal Degeneration. 2023:1-7. https://doi.org/10.1080/21678421.2023.2245858.
  10. Shoesmith, C. et al. CMAJ. 2020;192(46):E1453-E1468. https://doi.org/10.1503/cmaj.191721.
  11. ALS Society of Quebec website. http://sla-quebec.ca/en/about-als/. Accessed March 6, 2023.
  12. Chen, S., Sayana, P., Zhang, X., & Le, W. (2013). Genetics of amyotrophic lateral sclerosis: an update. Molecular Neurodegeneration, 8(1), 28. https://doi.org/10.1186/1750-1326-8-28.

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