Amyotrophic lateral sclerosis (ALS) therapeutics encompasses the pharmacological, biological, and technological approaches aimed at treating and potentially curing amyotrophic lateral sclerosis.[@bensimon1994] ALS is a progressive neurodegenerative disease affecting upper and lower motor [neurons](/entities/neurons), leading to muscle weakness, paralysis, and ultimately respiratory failure.[@lacomblez1996] The development of effective ALS therapeutics remains one of the greatest challenges in neurology, with only a limited number of FDA-approved treatments currently available. ALS is a progressive neurodegenerative disease affecting upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. The development of effective ALS therapeutics remains one of the greatest challenges in neurology, with only a limited number of FDA-approved treatments currently available. [@bensimon1994]
FDA-Approved Disease-Modifying Therapies
Riluzole (Rilutek)
Riluzole was the first FDA-approved drug for ALS and remains a cornerstone of treatment:[@bensimon1994] [@lacomblez1996]
Amyotrophic lateral sclerosis (ALS) therapeutics encompasses the pharmacological, biological, and technological approaches aimed at treating and potentially curing amyotrophic lateral sclerosis.[@bensimon1994] ALS is a progressive neurodegenerative disease affecting upper and lower motor [neurons](/entities/neurons), leading to muscle weakness, paralysis, and ultimately respiratory failure.[@lacomblez1996] The development of effective ALS therapeutics remains one of the greatest challenges in neurology, with only a limited number of FDA-approved treatments currently available. ALS is a progressive neurodegenerative disease affecting upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure. The development of effective ALS therapeutics remains one of the greatest challenges in neurology, with only a limited number of FDA-approved treatments currently available. [@bensimon1994]
FDA-Approved Disease-Modifying Therapies
Riluzole (Rilutek)
Riluzole was the first FDA-approved drug for ALS and remains a cornerstone of treatment:[@bensimon1994] [@lacomblez1996]
Mechanism of Action: Inhibits glutamate release, reduces excitotoxicity, and modulates sodium channels
Efficacy: Slows disease progression by approximately 2-3 months; improves survival[@writing2017]
Dosage: 50 mg twice daily
Side Effects: Nausea, fatigue, liver enzyme elevations
Clinical Trials: The pivotal trials showed modest but significant survival benefit
Edaravone (Radicava)
Edaravone is a free radical scavenger approved by the FDA in 2017:[@paganoni2020] [@writing2017]
Mechanism of Action: Acts as a potent antioxidant, reducing oxidative stress that contributes to motor neuron death
Efficacy: Shown to slow functional decline in a specific subgroup of patients with forced vital capacity (FVC) ≥80%[@paganoni2020]
Administration: IV infusion for 10 days followed by 14-day drug-free periods
Side Effects: Bruising, headache, gait disturbance
AMX0035 (marketed as RELYVRIO/ALBRIOZA) received FDA approval in September 2022, but the manufacturer voluntarily discontinued the product in April 2024 after negative confirmatory phase 3 results.[@fda2022][@amylyx2024] [@paganoni2020]
Mechanism of Action: A combination of sodium phenylbutyrate and taurursodiol that targets mitochondrial dysfunction and endoplasmic reticulum stress
Efficacy: Initial phase 2 results suggested slower functional decline, but subsequent phase 3 data did not confirm clinical benefit
Dosage: Oral medication, taken once daily
Side Effects: Gastrointestinal symptoms, reduced appetite
Symptomatic Treatments
Muscle Cramps and Spasticity
Baclofen: GABA-B agonist, reduces spasticity
Tizanidine: Alpha-2 adrenergic agonist
Quinine sulfate: Reduces muscle cramps (use limited due to cardiac concerns)
Invasive ventilation: Tracheostomy for advanced disease
Cough-assist devices: Clear secretions
Investigational Therapies in Clinical Trials
Gene-Specific Therapies
SOD1-Targeted Approaches
Tofersen (BIIB067/QALSODY): Antisense oligonucleotide for SOD1-ALS with FDA accelerated approval based on biomarker effects; confirmatory evidence is ongoing[@fda2023]
ASO: Multiple approaches targeting different SOD1 mutations
C9orf72-Targeted Approaches
ASO targeting hexanucleotide repeats: In clinical trials
Small molecule approaches: Targeting dipeptide repeat proteins
Other Genetic Targets
ATXN2: Targeting ataxin-2 intermediate repeats
FUS: Investigational ASO approaches
Neuroprotective Agents
Ceftriaxone: Antibiotic with neuroprotective properties - completed phase 3
Nuedexta: Combination of dextromethorphan and quinidine
Lithium: Phase 2 trials showed mixed results
Tamoxifen: Phase 3 completed with negative results
Stem Cell Therapies
Neural stem cell transplantation: Various trials investigating safety and efficacy
[ALS Biomarkers and Disease Monitoring](/mechanisms/als-biomarkers-and-disease-monitoring)
[Clinical Trials Index](/clinical-trials)
Background
The study of Als Therapeutics has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development. [@kiernan2011]
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions. [@chio2009]