Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s Disease, is a devastating neurodegenerative disorder marked by the death of neurons that control movement. This leads to loss of motor function, respiratory failure, and death, often within just 2-3 years from symptom onset. Causes of the disease are still largely unknown, with only 10% of cases having an identified genetic basis. Only two drugs are currently FDA-approved for the treatment of ALS, and both can only modestly slow disease progression. A recent publication presented exciting clinical results for a new drug combination that targets potential mechanisms of neuronal cell death. This therapy was developed by the biotech company Amylyx in Cambridge, MA, a venture started by founders Joshua Cohen and Justin Klee in a Brown University dorm room, and the funding for the particular trial came from donations from 2014’s ALS Ice Bucket Challenge.
The trial followed the disease progression of 139 ALS patients. Participants were followed over 24 weeks and clinical outcomes were recorded. The main outcome followed by the researchers was the rate of decline on the ALS Functional Rating Scale- Revised, or ALSFRS-R, a clinical scale used to score patients’ motor control and breathing. The rate of change on this scale over time gives doctors an idea of how quickly the disease is progressing. Treated patients scored 2.3 points higher, on average, than the untreated group at the end of the trial. This is equivalent to the treated group having six weeks less disease progression than the untreated group.
Though the exact underlying mechanism for this drug combination has not been confirmed yet, it’s believed that the two drugs address separate causes of neuronal cell death. One cause is when defective proteins clump together in a part of the cell called the endoplasmic reticulum, preventing functional proteins from being properly made and released. The first drug helps proteins fold into their correct form and prevents them from aggregating. The other cause is dysfunctions in how the cell makes energy, which the second drug addresses by changing the composition of the cell substructure responsible for energy production. Together, this drug combination seems to make it less likely for the cell to die due to these two stresses.
While a six-week improvement over 6 months doesn’t sound like much, this is equivalent to about six months in the 2-year expected lifetime of an ALS patient following symptom onset. Additionally, the two cellular stresses that drug combination is believed to target are common in other neurodegenerative disorders. This means that this therapy may be effective for other conditions as well, like Alzheimer’s and Parkinson’s. The next step for these drugs as an ALS treatment is to conduct a larger phase 3 clinical trial, which will give a better picture of how effective this therapy is over longer time periods and in more patients. Other questions still need to be answered, such as how this therapy is influenced by the use of the other FDA-approved ALS drugs, and what dose is optimal for slowing disease progression. In any case, these results could be the first significant step in improving quality of life and lifespan of ALS patients, and potentially patients of other disorders too.
Sabrina Paganoni is an Assistant Professor at Harvard Medical School and a physician scientist at the Healy Center of ALS at Massachusetts General Hospital. Joshua Cohen and Justin Klee are graduates from Brown University and are the CEO and President of Amylyx Pharmaceuticals in Cambridge, MA, respectively.
Managing Correspondent: Andrew T. Sullivan
Press Articles: “Drug Combination Slows Progression of ALS And Could Mark ‘New Era’ In Treatment,” NPR
“New Treatment for Lou Gehrig’s Disease Shows Promise,” The New York Times
Original Journal Article: “Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis,” New England Journal of Medicine
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