¶ ALS Therapeutic Landscape — Programs by Phase and Modality
Amyotrophic lateral sclerosis (ALS) has entered a transformative period with the 2023 FDA approval of tofersen (Qalsody) for SOD1-ALS 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.
| 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2022 (withdrawn 2024) |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 |
| 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 |
| 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 |
| 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) |
| 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 |
flowchart LR
A["Genetic\nDrivers"] --> B["SOD1\nASO"]
A --> C["C9orf72\nASO/GT"]
A --> D["FUS\nASO"]
A --> E["ATXN2\nASO"]
B --> F["FDA Approved\n(Qalsody 2023)"]
C --> G["Phase 1/2\n(WVE-003)"]
D --> H["Phase 2\n(ION363)"]
E --> I["Phase 1\n(ION541)"]
F --> J["Neuroprotection\nMotor Neuron Preservation"]
G --> J
H --> J
I --> J
style A fill:#e1f5fe,stroke:#333
style F fill:#c8e6c9,stroke:#333
style J fill:#f3e5f5,stroke:#333
style G fill:#fff9c4,stroke:#333
style H fill:#fff9c4,stroke:#333
style I fill:#fff9c4,stroke:#333
| 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) |
| 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 |
- |
| 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 |
| 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 |
- |
| 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 |
| Program |
Target |
Company |
Phase |
Status |
| siRNA-SOD1 |
SOD1 |
Alnylam |
Preclinical |
- |
| miRNA targeting |
Multiple |
Academic |
Preclinical |
- |
| 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 |
| 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 |
| 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
| 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 |
| Drug |
Decision |
Date |
| Tofersen (Qalsody) |
FDA Approved (SOD1-ALS) |
April 2023 |
| AMX0035 (Relyvrio) |
Voluntarily withdrawn by manufacturer |
October 2024 |
ALS platform trials enable efficient evaluation of multiple investigational agents against shared placebo controls. The Healey Center for 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 |
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.