Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder caused by loss of motor neurons in the brain and spinal cord. The majority of patients die within 3 to 5 years from onset. Despite multiple clinical trials and advances in understanding its pathogenesis riluzole, the only FDA approved ALS drug, has only a modest neuroprotective effect and carries a high financial burden to patient and family. While the exact underlying cause of this motor neuron degeneration remains uncertain, candidate mechanisms include glutamate excitotoxicity, free radical-mediated oxidative cytotoxicity, neuroinflammation, mitochondrial dysfunction, autoimmune processes, protein aggregation, and cytoskeletal abnormalities. Rasagiline, a monoamine-oxide inhibitor, is approved for the symptomatic treatment of Parkinson's disease by the FDA. In addition to its symptomatic mechanism, however, rasagiline has broad neuroprotective activities against a variety of neurotoxins in neuronal cell cultures and in animal models. These properties are presumed to arise through effects on mitochondria. In vitro experiments indicate rasagiline stabilizes mitochondria under stress conditions. Those data provided the scientific rationale for a recent Parkinson's disease clinical trial that tested whether rasagiline also has disease-modifying effects that exist independent of its symptomatic activity. The results of this double-blind, delayed-start trial of rasagiline suggested that there may be a neuroprotective effect. Considering that mitochondrial function is altered in both Parkinson's disease and ALS, it is reasonable to consider that rasagiline could have an ALS disease-modifying effect as well. The sponsor reports that it has been demonstrated that rasagiline prolongs survival in the SOD1 mouse model, and in one small retrospective human subjects analysis rasagiline treatment was associated with slower deterioration. The investigators now propose a Phase 2 investigation of rasagiline in ALS. This is an investigator-initiated, multi-center, single dose, placebo controlled six month study of rasagiline in 80 subjects. Sixty subjects will receive rasagiline, and 20 subjects will receive placebo. The investigators will use a "bleed-in" of historical placebo control data to enrich the statistical power. The investigators will also measure several biomarkers of mitochondrial function to determine if rasagiline treatment can affect these measures. The study will be performed at sites in the Western ALS Study group.

Public Health Relevance

Amyotrophic lateral sclerosis (ALS) is a devastating neuromuscular disorder affecting the voluntary motor system. Currently, there is no effective treatment for ALS patients, and more than 90% of ALS patients will die from respiratory failure in 3-5 years after the onset of initial symptoms. In the ALS mouse model, rasagiline has shown delay in disease progression and prolong survival. Should rasagiline prove effective in slowing ALS disease progression, it would have an immediate impact in the management of this severe neurodegenerative disorder.

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University of Kansas
Schools of Medicine
Kansas City
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