ALS Therapeutic Landscape — Programs by Phase and Modality

ALS Therapeutic Landscape — Programs by Phase and Modality

Overview

Amyotrophic lateral sclerosis (ALS) has entered a transformative period with the 2023 FDA approval of tofersen (Qalsody) for SOD1-ALS[@mendell2023] and a rapidly expanding pipeline spanning gene therapy, antisense oligonucleotides, small molecules, biologics, and cell-based approaches. This page provides a living map of the ALS therapeutic landscape organized by clinical phase and therapeutic modality.

Programs by Clinical Phase

Approved

| Drug | Company | Modality | Target/Mechanism | Year |
|------|---------|----------|-----------------|------|
| Riluzole | Sanofi | Small molecule | Glutamate antagonist | 1995 |
| Edaravone (Radicava) | Mitsubishi Tanabe | Small molecule | Free radical scavenger | 2017 |
| AMX0035 (Relyvrio) | Amylyx | Small molecule combo | Sodium phenylbutyrate + taurursodiol | 2022 (withdrawn 2024) |
| Tofersen (Qalsody) | Biogen | ASO | SOD1 mRNA knockdown | 2023 |

Phase 3

ALS Therapeutic Landscape — Programs by Phase and Modality

Overview

Amyotrophic lateral sclerosis (ALS) has entered a transformative period with the 2023 FDA approval of tofersen (Qalsody) for SOD1-ALS[@mendell2023] and a rapidly expanding pipeline spanning gene therapy, antisense oligonucleotides, small molecules, biologics, and cell-based approaches. This page provides a living map of the ALS therapeutic landscape organized by clinical phase and therapeutic modality.

Programs by Clinical Phase

Approved

| Drug | Company | Modality | Target/Mechanism | Year |
|------|---------|----------|-----------------|------|
| Riluzole | Sanofi | Small molecule | Glutamate antagonist | 1995 |
| Edaravone (Radicava) | Mitsubishi Tanabe | Small molecule | Free radical scavenger | 2017 |
| AMX0035 (Relyvrio) | Amylyx | Small molecule combo | Sodium phenylbutyrate + taurursodiol | 2022 (withdrawn 2024) |
| Tofersen (Qalsody) | Biogen | ASO | SOD1 mRNA knockdown | 2023 |

Phase 3

| Drug | Company | Modality | Target/Mechanism | NCT | Status |
|------|---------|----------|-----------------|-----|--------|
| Masitinib | AB Science | Small molecule | CSF1R/Tyro3/Axl tyrosine kinase inhibitor | NCT03142602 | Completed; awaiting FDA decision |
| Reldesomstat (CK-2017357) | CytoKinetics | Small molecule | Fast skeletal muscle troponin inhibitor | NCT05538663 | Active, not recruiting |
| CNM-Au8 | Clene Nanomedicine | Catalytic nanocrystals | NADH oxidase, energy metabolism | NCT04098406 | Active |
| BHV-0223 | Biohaven | Small molecule | Glutamate modulator | NCT05279208 | Active |
| Tofersen | Biogen | ASO | SOD1 (confirmatory trial) | NCT04856982 | Ongoing |

Phase 2

| Drug | Company | Modality | Target | NCT | Status |
|------|---------|----------|--------|-----|--------|
| Pridopidine | Prilenia | Small molecule | Sigma-1 agonist | NCT04676646 | Active |
| ARA-290 | Araim Pharmaceuticals | Peptide | Innate repair receptor agonist | NCT05415085 | Active |
| ANX005 | Annexon Biosciences | Antibody | C1q complement inhibitor | NCT04559438 | Active |
| AL001 | Alector | Antibody | Progranulin modulator | NCT05130922 | Active |
| WVE-003 | Wave Life Sciences | ASO | C9orf72 | NCT05868564 | Active |
| ION363 (jacifusen) | Ionis/Biogen | ASO | FUS | NCT04768972 | Active |
| PrimeC | Neurodynamics | Small molecule combo | Multiple (neuroinflammation, iron dysregulation, TDP-43) | NCT04098406 | Phase 2b completed |

Phase 1

| Drug | Company | Modality | Target | NCT | Status |
|------|---------|----------|--------|-----|--------|
| BIIB100 | Biogen/Ionis | ASO | C9orf72 | NCT04215930 | Completed |
| ION541 | Ionis/Biogen | ASO | ATXN2 | NCT04494256 | Active |
| DNL788 | Denali Therapeutics | Small molecule | SOD1 | NCT05789202 | Active |
| Verdiperstat | Biohaven | Small molecule | Myeloperoxidase inhibitor | NCT04438638 | Completed (HEALEY platform) |
| AP-004 | Aprinoia Therapeutics | Antibody | Tau PET tracer | NCT05435053 | Phase 1 (for ALS biomarkers) |

Preclinical (Key Programs)

| Drug/Program | Company/Lab | Modality | Target | Stage |
|-------------|-------------|----------|--------|-------|
| AAV.C9orf72 | Prevail Therapeutics/Lilly | Gene therapy | C9orf72 | Preclinical |
| CRISPR-based SOD1 editing | Multiple academic | Gene editing | SOD1 | Preclinical |
| Exosome delivery platform | Various | Delivery | Multiple | Early preclinical |
| T cell therapy (Treg) | Several | Cell therapy | Immune modulation | Preclinical |

Programs by Therapeutic Modality

ALS Pipeline Visualization

Antisense Oligonucleotides (ASOs)

| Program | Target | Company | Phase | Status |
|---------|--------|---------|-------|--------|
| Tofersen (Qalsody) | SOD1 | Biogen/Ionis | Approved | On market (2023) |
| BIIB100 | C9orf72 | Biogen/Ionis | Phase 1 | Completed |
| ION363 (jacifusen) | FUS | Ionis/Biogen | Phase 2 | Active |
| WVE-003 | C9orf72 | Wave Life Sciences | Phase 1/2 | Active |
| ION541 | ATXN2 | Ionis/Biogen | Phase 1 | Active |
| BIIB078 | C9orf72 | Biogen/Ionis | Phase 1 | Discontinued (2022) |

Gene Therapy (AAV)

| Program | Target | Company | Vector | Phase | Route |
|---------|--------|---------|--------|-------|-------|
| AAV.SOD1 | SOD1 | Apic Bio/uniQure | AAV9 | Preclinical | Intrathecal |
| AAV.C9orf72 | C9orf72 | Prevail Therapeutics/Lilly | AAV9 | Preclinical | Intrathecal |
| AAV-FUS | FUS | Various academic | AAV9 | Preclinical | Intrathecal |
| YTX-773 | Multiple | Yumanity | AAV | Preclinical | - |

Small Molecules

| Program | Target/Mechanism | Company | Phase | Status |
|---------|-----------------|---------|-------|--------|
| Masitinib | CSF1R/Tyro3/Axl inhibitor | AB Science | Phase 3 | Awaiting FDA decision |
| Reldesomstat | Fast skeletal troponin inhibitor | CytoKinetics | Phase 3 | Active |
| CNM-Au8 | Catalytic nanocrystals, NADH oxidase | Clene Nanomedicine | Phase 3 | Active |
| BHV-0223 | Glutamate modulator | Biohaven | Phase 3 | Active |
| Pridopidine | Sigma-1 agonist | Prilenia | Phase 2 | Active |
| ARA-290 | Innate repair receptor agonist | Araim | Phase 2 | Active |
| DNL788 | SOD1 inhibitor | Denali | Phase 1 | Active |
| PrimeC | Neuroinflammation, iron dysregulation, TDP-43 | Neurodynamics | Phase 2b | Completed |
| Verdiperstat | Myeloperoxidase inhibitor | Biohaven | Phase 2 | Completed (HEALEY platform) |
| CuATSM | Mitochondrial copper delivery | Clene Nanomedicine | Phase 1 | Planning |

Biologics (Antibodies, Proteins)

| Program | Target | Company | Phase | Status |
|---------|--------|---------|-------|--------|
| AL001 | Progranulin | Alector | Phase 2/3 | Active |
| AL101 | Progranulin | Alector | Phase 1 | Active |
| ANX005 | C1q complement | Annexon | Phase 2 | Active |
| TREM2 antibodies | TREM2 | Various | Preclinical | - |

Cell Therapy

| Program | Cell Type | Company | Phase | Status |
|---------|-----------|---------|-------|--------|
| NurOwn | MSC-NTF cells | BrainStorm Cell | Phase 3 | Completed (2024) |
| MSC therapy | Mesenchymal stem cells | Various | Phase 1-2 | Active |
| iPSC-derived motor neurons | iPSC neurons | Various academic | Preclinical | - |
| Tregs | Regulatory T cells | Several | Phase 1 | Active |

RNA Therapeutics (siRNA, miRNA)

| Program | Target | Company | Phase | Status |
|---------|--------|---------|-------|--------|
| siRNA-SOD1 | SOD1 | Alnylam | Preclinical | - |
| miRNA targeting | Multiple | Academic | Preclinical | - |

Emerging Modalities

| Modality | Approach | Key Programs | Maturity |
|----------|----------|-------------|----------|
| CRISPR/base editing | Correct SOD1/C9orf72 mutations | Academic | Preclinical |
| Exosome/EV delivery | Engineered vesicle payload delivery | Academic | Early preclinical |
| Muscle-directed gene therapy | Neurotrophic factor expression from muscle | Academic/biotech | Preclinical |
| Neuroimmune modulation | Regulatory T cell therapy, microglial reprogramming | Multiple | Phase 1-2 |

Genetic Subtypes & Targetable Populations

| Gene | % of fALS | % of sALS | Therapeutic Approaches | Key Programs |
|------|-----------|-----------|----------------------|-------------|
| SOD1 | ~20% | ~2% | ASO (tofersen approved), gene therapy, small molecules | Biogen (Qalsody), Denali (DNL788) |
| C9orf72 | ~40% | ~5-10% | ASO, gene therapy, small molecules | Wave (WVE-003), Ionis, Prevail |
| FUS | ~5% | <1% | ASO | Ionis (ION363) Phase 2 |
| TARDBP (TDP-43) | ~5% | ~1% | Small molecules, ASO | Multiple preclinical |
| ATXN2 | modifier | modifier | ASO (for SCA2, ALS modifier) | Ionis (ION541) Phase 1 |
| TBK1 | ~2-3% | <1% | Small molecules | Preclinical |
| VCP | ~1-2% | <1% | Small molecules | Preclinical |

Failed Programs (Lessons Learned)

| Drug | Company | Modality | Reason for Failure | Year |
|------|---------|----------|--------------------|------|
| Relyvrio (AMX0035) | Amylyx | Small molecule | Phase 3 PHOENIX negative; voluntarily withdrawn | 2024 |
| BIIB078 | Biogen | ASO (C9orf72) | Discontinued — efficacy concerns | 2022 |
| Ceftriaxone | Various | Antibiotic | Phase 3 failed to meet primary endpoint | 2019 |
| Lithium | Various | Small molecule | Mixed results, insufficient efficacy | 2010s |
| Tamoxifen | Various | Small molecule | Phase 3 negative | 2012 |
| Creatine | Various | Dietary supplement | Phase 3 negative | 2009 |
| Minocycline | Various | Antibiotic | Phase 3 negative; worsened outcomes | 2007 |

Key Trial Results and Data Readouts

Recent Positive Results

| Drug | Company | Trial | Key Findings | Year |
|------|---------|-------|--------------|------|
| Tofersen | Biogen/Ionis | VALOR + OLE | Reduced neurofilament light chain (NfL); FDA approved for SOD1-ALS | 2023 |
| PrimeC | Neurodynamics | PARADIGM (Phase 2b) | Reduced functional decline; modulated disease-relevant biomarkers; well-tolerated | 2023-2024 |
| Masitinib | AB Science | AB10015 | Prolonged survival in Phase 3; awaiting FDA decision | 2023 |
| NurOwn | BrainStorm | Phase 3 | Completed; showed positive trends in subgroup analysis | 2024 |

Regulatory Decisions

| Drug | Decision | Date |
|------|----------|------|
| Tofersen (Qalsody) | FDA Approved (SOD1-ALS) | April 2023 |
| AMX0035 (Relyvrio) | Voluntarily withdrawn by manufacturer | October 2024 |

Cross-Links

Understanding the therapeutic landscape for ALS requires examining its underlying mechanisms and the key molecular players involved in disease pathogenesis. The fundamental [ALS mechanisms](/diseases/amyotrophic-lateral-sclerosis) provide the foundation for therapeutic development, with research focusing on several critical genetic and protein targets that drive neurodegeneration.

Central to many therapeutic approaches are the major genetic contributors to ALS, including [SOD1](/genes/sod1) and [C9orf72](/genes/c9orf72), which represent some of the most well-characterized disease-causing mutations. These genetic insights have led to the development of targeted interventions, particularly [gene silencing therapy](/therapeutics/gene-silencing-therapy) strategies that aim to reduce the expression of toxic proteins. In addition to genetic targets, protein aggregation involving [TDP-43](/proteins/tdp-43-protein) and [FUS](/proteins/fus-protein) represents another crucial therapeutic avenue, as these proteins play essential roles in RNA metabolism and their dysfunction contributes significantly to motor neuron death.

The clinical development of these therapeutic approaches is supported by specialized research institutions, with the [Healey Center for ALS](/institutions/healey-center-als) serving as a leading hub for translating scientific discoveries into clinical applications. This is further complemented by the growing ecosystem of [ALS pipeline companies](/companies/als-pipeline-companies) that are advancing novel therapeutics through various stages of development. The success of these therapeutic efforts increasingly depends on robust [ALS biomarkers](/biomarkers/als-biomarkers-and-disease-monitoring), which are essential for patient stratification, monitoring treatment response, and accelerating clinical trial timelines.

Platform Trials

ALS platform trials enable efficient evaluation of multiple investigational agents against shared placebo controls. The [Healey Center for ALS](/institutions/healey-center-als) at Massachusetts General Hospital operates the most prominent platform trial in ALS, testing multiple agents simultaneously with a shared master protocol. This approach reduces patient enrollment burden, accelerates timelines, and enables cross-trial comparison of outcomes.

| Platform | Institution | Agents Tested | Design |
|----------|-------------|---------------|--------|
| HEALEY ALS Platform Trial | Sean M. Healey & AMG Center for ALS, Mass General | Verdiperstat, BHV-0223, CNM-Au8, Pridopidine | Platform RCT, shared placebo |

Therapeutic Strategy by Disease Stage

ALS presents a therapeutic challenge at multiple stages of the disease continuum. The following matrix maps mechanisms to disease stages:

| Stage | Pathophysiology | Therapeutic Strategy | Key Programs |
|-------|-----------------|---------------------|-------------|
| Pre-symptomatic (genetic carriers) | Mutation present, no symptoms | Neuroprotection, gene silencing | Tofersen (SOD1), ASOs for C9/FUS |
| Early symptomatic | Motor neuron loss begins | Disease-modifying agents | Masitinib, Pridopidine, AL001 |
| Established ALS | Significant motor neuron loss | Combination approaches | AMX0035 (withdrawn), cell therapy |
| Late-stage | Severe impairment | Symptom management | Riluzole, Edaravone (symptomatic) |

This landscape page is maintained as a living document — updated monthly as trial results read out and new programs enter the pipeline.

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [Bacterial Enzyme-Mediated Dopamine Precursor Synthesis](/hypothesis/h-7bb47d7a) — <span style="color:#ffd54f;font-weight:600">0.44</span> · Target: TH, AADC

Purinergic Signaling Polarization Control represents another high-confidence therapeutic avenue with a score of 0.74, targeting both P2RY1 and P2RX7 receptors to modulate cellular signaling cascades. In addition to these approaches, Mechanosensitive Ion Channel Reprogramming has garnered significant attention with a score of 0.65, specifically targeting PIEZO1 and KCNK2 channels to address mechanotransduction defects in motor neurons.

Several moderate-confidence hypotheses offer alternative therapeutic strategies. Lipid Droplet Dynamics as Phenotype Switches, scoring 0.57, targets DGAT1 and SOAT1 to modulate cellular metabolism and lipid homeostasis. This is complemented by VCP-Mediated Autophagy Enhancement (scored at 0.54), which targets VCP to restore proper protein clearance mechanisms that are disrupted in ALS.

Lower-confidence but potentially innovative approaches include Bacterial Enzyme-Mediated Dopamine Precursor Synthesis, with a score of 0.44 targeting TH and AADC enzymes. This is further supported by the Multi-Modal CRISPR Platform for Simultaneous Editing and Monitoring approach, scoring 0.42, which targets disease-causing mutations while incorporating integrated reporters for real-time monitoring of therapeutic effects.

These therapeutic hypotheses are extensively supported by related analyses examining key mechanistic aspects of ALS pathogenesis. TDP-43 phase separation therapeutics for ALS-FTD provides crucial insights into protein aggregation mechanisms, while RNA binding protein dysregulation across ALS FTD and AD offers a broader perspective on shared pathological features across neurodegenerative diseases. CRISPR-based therapeutic approaches for neurodegenerative diseases explores the technical feasibility and optimization of gene editing strategies. Additionally, both microglial subtypes in neurodegeneration — friend vs foe and astrocyte reactivity subtypes in neurodegeneration examine the complex roles of glial cells in disease progression, helping to inform targeted therapeutic interventions that can distinguish between protective and harmful glial responses.