ALS Therapeutics

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ALS Therapeutics

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ALS Therapeutics

Introduction

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">ALS Therapeutics</th>
</tr>
<tr>
<td class="label">Name</td>
<td><strong>ALS Therapeutics</strong></td>
</tr>
<tr>
<td class="label">Type</td>
<td>Therapeutic</td>
</tr>
</table>

Overview

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]

...

ALS Therapeutics

Introduction

<table class="infobox infobox-therapeutic">
<tr>
<th class="infobox-header" colspan="2">ALS Therapeutics</th>
</tr>
<tr>
<td class="label">Name</td>
<td><strong>ALS Therapeutics</strong></td>
</tr>
<tr>
<td class="label">Type</td>
<td>Therapeutic</td>
</tr>
</table>

Overview

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

Sodium Phenylbutyrate/Taurursodiol (AMX0035; RELYVRIO/ALBRIOZA)

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)
Mexiletine: Sodium channel blocker, reduces muscle excitability

Excessive Salivation (Sialorrhea)

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

Respiratory Support

Non-invasive ventilation (NIV): BiPAP therapy
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
Mesenchymal stem cells: Investigational approaches
Induced pluripotent stem cells (iPSCs): Personalized approaches in development

Small Molecule Approaches

Masitinib: Tyrosine kinase inhibitor - phase 3 trial completed
Branaplam (LMI070): SMN2 splicing modifier - in clinical trials
Nirogen: Novel neuroprotective compound

Repurposed Drugs

Metformin: AMPK activator - in clinical trials
Sodium benzoate: Urea cycle enhancer - phase 2 trial
Statins: Several clinical trials completed

Emerging Treatment Strategies

Antisense Oligonucleotides (ASOs)

ASOs represent a promising approach for genetic forms of ALS: [@miller2012]

Target specific genetic mutations
Can be customized for individual patients
Require intrathecal administration
Several programs in clinical development

Gene Therapy

AAV-based delivery: Potential for long-term expression[@van2017]
CRISPR/Cas9 approaches: For precise genetic correction
Viral vector delivery: To motor neurons

Cell-Based Therapies

Motor neuron replacement: Stem cell-derived motor neurons
Support cell transplantation: Astrocyte replacement
Immunomodulation: Modifying the immune response

Combination Therapies

Given the complex pathophysiology of ALS, combination approaches are increasingly being explored: [@van2017]

Multiple drug combinations
Gene therapy + small molecule
Cell therapy + pharmacological intervention

Clinical Trial Design Challenges

Biomarker Development

[Neurofilament light](/biomarkers/neurofilament-light-chain-nfl) chain (NfL): Promising blood biomarker
Neurofilament heavy chain (pNfH): Disease progression marker
Imaging biomarkers: MR spectroscopy, PET
Electrophysiological markers: CMAP decay

Endpoint Challenges

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

Patient Selection

Genetic stratification: Essential for gene-specific therapies
Disease stage: Early vs. advanced patients
Phenotypic variation: Rate of progression varies

Future Directions

Personalized Medicine

Genetic testing: Identifying specific mutations[@kiernan2011]
Phenotypic profiling: Matching treatments to patient characteristics
Pharmacogenomics: Optimizing drug selection

Biomarker-Driven Trials

Enrichment strategies: Using biomarkers to select patients
Surrogate endpoints: Faster trial completion
Stratified medicine: Tailored approaches

Collaborative Efforts

ALS Association: Funding and coordinating research
NEALS Consortium: Clinical trial network
International Alliance: Global cooperation

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]

Additional evidence sources: [@benatar2012] [@rowland2001] [@fda2022] [@amylyx2024] [@fda2023]

Allen Brain Atlas Resources

[Allen Brain Atlas - Gene Expression](https://human.brain-map.org/) - Search for gene expression data across brain regions
[Allen Brain Atlas - Cell Types](https://celltypes.brain-map.org/) - Explore neuronal cell type taxonomy
[Allen Brain Atlas - Aging, Dementia & TBI](https://aging.brain-map.org/) - Data on aging and traumatic brain injury

External Links

[ALS Association](https://www.als.org/)
[ALS Therapy Development Institute](https://www.als.net/)
[NEALS Clinical Trials Consortium](https://www.neals.us/)
[National Institute of Neurological Disorders and Stroke - ALS](https://www.ninds.nih.gov/)
[Mayo Clinic - ALS](https://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis)
[MedlinePlus - ALS](https://medlineplus.gov/amyotrophiclateralsclerosis.html)
[ClinicalTrials.gov - ALS](https://clinicaltrials.gov/search?cond=ALS)
[PubMed - ALS Therapeutics](https://pubmed.ncbi.nlm.nih.gov/)

References

[Bensimon et al., A controlled trial of riluzole in amyotrophic lateral sclerosis (1994) (1994)](https://doi.org/10.1056/NEJM199403033300901)

[Lacomblez et al., Dose-ranging study of riluzole in amyotrophic lateral sclerosis (1996) (1996)](https://doi.org/10.1016/S0140-6736(96)

[Unknown, Writing Group, Edaravone ALS 19 Study: randomised placebo-controlled trial (2017) (2017)](https://doi.org/10.1016/S1474-4422(17)

[Paganoni et al., Trial of sodium phenylbutyrate-taurursodiol for ALS (2020) (2020)](https://doi.org/10.1056/NEJMoa1916945)

[Miller et al., Riluzole for ALS/MND Cochrane review (2012) (2012)](https://doi.org/10.1002/14651858.CD001447.pub3)

[van Es et al., Amyotrophic lateral sclerosis (2017) (2017)](https://doi.org/10.1016/S0140-6736(17)

[Kiernan et al., Amyotrophic lateral sclerosis (2011) (2011)](https://doi.org/10.1016/S0140-6736(10)

[Chio et al., Prognostic factors in ALS: a critical review (2009) (2009)](https://doi.org/10.3109/17482960802658908)

[Unknown, Benatar and Wuu, Pharmacologic treatment of ALS: current and emerging therapies (2012) (2012)](https://doi.org/10.2147/DDDT.S26505)

[Unknown, Rowland and Shneider, Amyotrophic lateral sclerosis (2001) (2001)](https://doi.org/10.1056/NEJM200105313442207)

Unknown, U.S. FDA, FDA approves treatment for ALS (RELYVRIO) (September 29, 2022) (2022)

Unknown, Amylyx Pharmaceuticals, Voluntary discontinuation of RELYVRIO and ALBRIOZA (April 4, 2024) (2024)

Unknown, U.S. FDA, FDA grants accelerated approval for QALSODY (tofersen) for ALS associated with SOD1 mutation (April 25, 2023) (2023)

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📊 Evidence Profile Foundational

Evidence Balance

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Certainty

100%

Debates

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Incoming

60

Outgoing

76

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

ALS Therapeutics

ALS Therapeutics

Introduction

Overview

FDA-Approved Disease-Modifying Therapies

Riluzole (Rilutek)

ALS Therapeutics

Introduction

Overview

FDA-Approved Disease-Modifying Therapies

Riluzole (Rilutek)

Edaravone (Radicava)

Sodium Phenylbutyrate/Taurursodiol (AMX0035; RELYVRIO/ALBRIOZA)

Symptomatic Treatments

Muscle Cramps and Spasticity

Excessive Salivation (Sialorrhea)

Dysarthria and Communication

Dysphagia and Nutrition

Respiratory Support

Investigational Therapies in Clinical Trials

Gene-Specific Therapies

SOD1-Targeted Approaches

C9orf72-Targeted Approaches

Other Genetic Targets

Neuroprotective Agents

Stem Cell Therapies

Small Molecule Approaches

Repurposed Drugs

Emerging Treatment Strategies

Antisense Oligonucleotides (ASOs)

Gene Therapy

Cell-Based Therapies

Combination Therapies

Clinical Trial Design Challenges

Biomarker Development

Endpoint Challenges

Patient Selection

Future Directions

Personalized Medicine

Biomarker-Driven Trials

Collaborative Efforts

See Also

Background

Allen Brain Atlas Resources

External Links

References

💬 Discussion