Eight Potential Alternative/Off-Label Treatments for ALS Identified by Researchers

Researchers have identified 8 alternative and off-label treatments (AOTs) which may have efficacy for targeting some of the multiple, overlapping pathogenic mechanisms thought to underly amyotrophic lateral sclerosis (ALS), such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. Their research, published in Annals of Neurology, discusses the potential of these AOTs for use in combination to achieve meaningful clinical benefit as a more effective approach to ALS treatment. The study authors note that the human clinical trials included in this review are small, flawed, and have limitations in their design.

The 8 AOTs include:

• Acetyl-L-carnitine
• Antiretrovirals
• Clenbuterol
• L-Serine
• Methylcobalamin
• Nicotinamide riboside/pterostilbene
• Quinidine/dextromethorphan
• Tamoxifen

The review article is based on 15 years of data from ALSUntangled, a group that has been systematically evaluating AOTs for ALS since 2009. The review article authors focused on AOTs with plausible mechanisms of action (MOA) and data from ≥1 human trial that suggest meaningful clinical benefit.

Specific findings reported for each of the 8 AOTs include:

• Acetyl-L-carnitine: Plausible MOA affecting oxidative stress, mitochondrial dysfunction, and microbiome alteration and, in clinical trials, was associated with trends towards slower functional decline particularly in self-care abilities, but data did not reach statistical significance.
• Antiretrovirals: Plausible MOA affecting microbiome alteration and antiretroviral activity, and their use was associated with slower progression on the ALS Functional Rating Scale–Revised (ALSFRS-R) and reduced biomarkers of neuroinflammation.
• Clenbuterol: Plausible MOA affecting neuroinflammation and mitochondrial dysfunction and was associated with significantly slower forced vital capacity (FVC) decline and improved muscle strengths in clinical trials.
• L-Serine: Plausible MOA affecting neuroinflammation and mitochondrial alteration and was associated with slowed ALSFRS-R progression.
• Methylcobalamin: Plausible MOA affecting neuroinflammation, oxidative stress, mitochondrial dysfunction, and microbiome alteration and was associated with improved ventilator-free survival and slowed ALSFS-R decline patients with early-stage ALS.
• Nicotinamide riboside/pterostilbene: Plausible MOA affecting neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity and was associated with improvements in ALSFRS-R, FVC, and muscle strength.
• Quinidine/dextromethorphan: Plausible MOA affecting neuroinflammation and oxidative stress and was associated with improved bulbar function including speech, swallowing, and sialorrhea (hypersalivation).
• Tamoxifen: Plausible MOA affecting neuroinflammation, oxidative stress, microbiome alteration, and retroviral activity and was associated with improved survival and slower decline in muscle function.

The authors conducted this research to spur innovation in the development of new therapies for ALS.