Amyotrophic lateral sclerosis (ALS) therapeutics encompasses the pharmacological, biological, and technological approaches aimed at treating and potentially curing amyotrophic lateral sclerosis.1 ALS is a progressive neurodegenerative disease affecting upper and lower motor neurons, leading to muscle weakness, paralysis, and ultimately respiratory failure.2 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.
Riluzole was the first FDA-approved drug for ALS and remains a cornerstone of treatment:1
- Mechanism of Action: Inhibits glutamate release, reduces excitotoxicity, and modulates sodium channels
- Efficacy: Slows disease progression by approximately 2-3 months; improves survival3
- Dosage: 50 mg twice daily
- Side Effects: Nausea, fatigue, liver enzyme elevations
- Clinical Trials: The pivotal trials showed modest but significant survival benefit
Edaravone is a free radical scavenger approved by the FDA in 2017:4
- 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%4
- 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.1112
- 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
¶ 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)
- Mexiletine: Sodium channel blocker, reduces muscle excitability
- Glycopyrrolate: Anticholinergic, reduces saliva production
- Scopolamine: Transdermal patch
- Botulinum toxin injections: To salivary glands
¶ Dysarthria and Communication
- Speech therapy: Augmentative and alternative communication (AAC) devices
- Eye-tracking technology: For patients with minimal movement
¶ Dysphagia and Nutrition
- Percutaneous endoscopic gastrostomy (PEG) tube: Maintains nutrition
- Thickened liquids: Reduces aspiration risk
- Non-invasive ventilation (NIV): BiPAP therapy
- Invasive ventilation: Tracheostomy for advanced disease
- Cough-assist devices: Clear secretions
- Tofersen (BIIB067/QALSODY): Antisense oligonucleotide for SOD1-ALS with FDA accelerated approval based on biomarker effects; confirmatory evidence is ongoing13
- ASO: Multiple approaches targeting different SOD1 mutations
- ASO targeting hexanucleotide repeats: In clinical trials
- Small molecule approaches: Targeting dipeptide repeat proteins
- ATXN2: Targeting ataxin-2 intermediate repeats
- FUS: Investigational ASO approaches
- 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
- Neural stem cell transplantation: Various trials investigating safety and efficacy
- Mesenchymal stem cells: Investigational approaches
- Induced pluripotent stem cells (iPSCs): Personalized approaches in development
- Masitinib: Tyrosine kinase inhibitor - phase 3 trial completed
- Branaplam (LMI070): SMN2 splicing modifier - in clinical trials
- Nirogen: Novel neuroprotective compound
- Metformin: AMPK activator - in clinical trials
- Sodium benzoate: Urea cycle enhancer - phase 2 trial
- Statins: Several clinical trials completed
ASOs represent a promising approach for genetic forms of ALS:
- Target specific genetic mutations
- Can be customized for individual patients
- Require intrathecal administration
- Several programs in clinical development
- AAV-based delivery: Potential for long-term expression6
- CRISPR/Cas9 approaches: For precise genetic correction
- Viral vector delivery: To motor neurons
- Motor neuron replacement: Stem cell-derived motor neurons
- Support cell transplantation: Astrocyte replacement
- Immunomodulation: Modifying the immune response
Given the complex pathophysiology of ALS, combination approaches are increasingly being explored:
- Multiple drug combinations
- Gene therapy + small molecule
- Cell therapy + pharmacological intervention
- Neurofilament light chain (NfL): Promising blood biomarker
- Neurofilament heavy chain (pNfH): Disease progression marker
- Imaging biomarkers: MR spectroscopy, PET
- Electrophysiological markers: CMAP decay
- ALSFRS-R: Primary endpoint in most trials - subject to variability
- Survival: Requires large, long trials
- Forced vital capacity (FVC): Respiratory measure
- Composite endpoints: Combining multiple measures
- Genetic stratification: Essential for gene-specific therapies
- Disease stage: Early vs. advanced patients
- Phenotypic variation: Rate of progression varies
- Genetic testing: Identifying specific mutations7
- Phenotypic profiling: Matching treatments to patient characteristics
- Pharmacogenomics: Optimizing drug selection
- Enrichment strategies: Using biomarkers to select patients
- Surrogate endpoints: Faster trial completion
- Stratified medicine: Tailored approaches
- ALS Association: Funding and coordinating research
- NEALS Consortium: Clinical trial network
- International Alliance: Global cooperation
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.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Bensimon et al., A controlled trial of riluzole in amyotrophic lateral sclerosis (1994)
- Lacomblez et al., Dose-ranging study of riluzole in amyotrophic lateral sclerosis (1996)
- Writing Group, Edaravone ALS 19 Study: randomised placebo-controlled trial (2017)
- Paganoni et al., Trial of sodium phenylbutyrate-taurursodiol for ALS (2020)
- Miller et al., Riluzole for ALS/MND Cochrane review (2012)
- van Es et al., Amyotrophic lateral sclerosis (2017)
- Kiernan et al., Amyotrophic lateral sclerosis (2011)
- Chio et al., Prognostic factors in ALS: a critical review (2009)
- Benatar and Wuu, Pharmacologic treatment of ALS: current and emerging therapies (2012)
- Rowland and Shneider, Amyotrophic lateral sclerosis (2001)
- U.S. FDA, FDA approves treatment for ALS (RELYVRIO) (September 29, 2022)
- Amylyx Pharmaceuticals, Voluntary discontinuation of RELYVRIO and ALBRIOZA (April 4, 2024)
- U.S. FDA, FDA grants accelerated approval for QALSODY (tofersen) for ALS associated with SOD1 mutation (April 25, 2023)