| Total Programs | 50+ |
|---|---|
| FDA Approved | 4 |
| Phase 3 | 8 |
| Phase 2 | 15+ |
| Phase 1 | 12+ |
Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig's disease, is a progressive neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons in the brain and spinal cord. The disease leads to progressive muscle weakness, paralysis, and typically fatal respiratory failure within 2-5 years of symptom onset. Approximately 5-10% of ALS cases are familial, while the remaining 90-95% are sporadic with unknown etiology 1.
The ALS drug development pipeline has expanded significantly in recent years, driven by improved understanding of disease mechanisms, particularly around SOD1, C9orf72, TDP-43, and FUS genetic variants. This page catalogs the current therapeutic programs targeting ALS, from approved disease-modifying therapies to early-stage clinical candidates.
For detailed company profiles of firms with ALS programs, see ALS Pipeline Companies.
Four drugs have received FDA approval for ALS treatment, representing the only disease-modifying therapies available to patients:
Approval: September 2022
Mechanism: Dual peroxisome proliferator-activated receptor (PPAR) gamma agonist and mitochondrial stabilizer
Clinical Trial: CENTAUR Phase 2/3 trial demonstrated statistically significant survival benefit 2
AMX0035 is a fixed-dose combination of sodium phenylbutyrate and taurursodiol. The drug targets mitochondrial dysfunction and endoplasmic reticulum stress, which are central to motor neuron degeneration. The CENTAUR trial showed a median survival benefit of 4.8 months compared to placebo, with a favorable safety profile 2.
Approval: April 2023
Mechanism: Antisense oligonucleotide (ASO) targeting SOD1 mRNA
Clinical Trial: VALOR Phase 3 trial in SOD1 mutated ALS patients 3
Tofersen is an ASO that binds to SOD1 mRNA, reducing production of the toxic SOD1 protein. The VALOR trial showed faster decline in clinical endpoints in the treatment arm, with particularly notable benefits in patients with faster disease progression. Biomarker studies demonstrated 33% reduction in neurofilament light chain (NfL) levels, confirming target engagement 3.
Approval: May 2017
Mechanism: Free radical scavenger targeting oxidative stress
Clinical Trial: Multiple Phase 3 trials including the MCI186-16 study 4
Edaravone is a free radical scavenger that reduces oxidative stress, a key contributor to motor neuron death. Originally approved in Japan in 2015, it received FDA approval based on a subset analysis from the Phase 3 trial showing functional improvement in patients treated within 2 years of disease onset 4.
Approval: 1995
Mechanism: Glutamate release inhibitor and NMDA receptor antagonist
Clinical Trial: Multiple Phase 3 trials establishing survival benefit 5
Riluzole remains the standard of care, providing approximately 2-3 month survival extension. The mechanism involves inhibition of glutamate release and blockade of NMDA receptors, addressing excitotoxicity in ALS 5.
Phase 3 trials represent late-stage evaluation of therapies showing promise in earlier phases:
Mechanism: Catalytic gold nanoparticles
Target: Energy metabolism and neuronal bioenergetics
Trial: RESCUE-ALS Phase 2/3 trial 6
CNM-Au8 is a novel nanocrystal that catalyzes intracellular redox reactions, improving mitochondrial function and ATP production in motor neurons. The Phase 2 HEALEY trial platform showed significant slowing of clinical decline in ALS patients 6.
Mechanism: C9orf72 inhibitor
Target: Hexanucleotide repeat expansion
Trial: Phase 1/2 in C9orf72-associated ALS 7
BIIB100 is an oral small molecule designed to reduce expression of toxic dipeptide repeats (DPRs) produced from the C9orf72 hexanucleotide repeat expansion, the most common genetic cause of familial ALS 7.
Mechanism: Sigma-1 receptor agonist
Target: Neuroprotection and mitochondrial function
Trial: Phase 3 HEALEY trial platform 8
Pridopidine activates the sigma-1 receptor, which regulates calcium homeostasis, mitochondrial function, and neuroprotection. Post-hoc analysis of prior trials showed potential benefit in a subset of patients 8.
Mechanism: Fast skeletal muscle troponin activator
Target: Muscle function and strength
Trial: FORTITUDE-ALS Phase 3 trial 9
Reldesemtiv increases muscle force by sensitizing the troponin complex to calcium, potentially addressing the muscle weakness component of ALS independent of motor neuron function 9.
Mechanism: Mesenchymal stem cell-derived neurotrophic factors
Target: Motor neuron support and immunomodulation
Trial: Phase 3 trial completed 10
NurOwn uses autologous mesenchymal stem cells engineered to secrete neurotrophic factors including BDNF, GDNF, and HGF. The cell therapy approach aims to protect remaining motor neurons and modulate neuroinflammation 10.
Mechanism: Gene therapy delivering IGF-1
Target: Motor neuron survival
Trial: Phase 2/3 in development
ATL-100 delivers the insulin-like growth factor 1 (IGF-1) gene directly to motor neurons, promoting survival and regeneration through enhanced trophic support.
Mechanism: Immunomodulatory compound
Target: Neuroinflammation
Trial: Phase 2/3 in development
ALS-001 targets the inflammatory component of ALS, with mechanisms targeting microglial activation and cytokine modulation.
Mechanism: TREM2 inhibitor
Target: Neuroinflammation and microglial dysfunction
Trial: Phase 1/2 in development
BL-945 inhibits TREM2, a receptor on microglia that drives neuroinflammatory responses in ALS. By modulating microglial function, the therapy aims to reduce inflammatory-mediated motor neuron damage.
Mechanism: Allele-selective antisense oligonucleotide
Target: C9orf72 hexanucleotide repeat
Status: Phase 1/2 FOCUS-C9 trial 11
WVE-004 is designed to selectively silence the mutant C9orf72 allele while preserving normal allele expression, potentially avoiding the complications of complete gene silencing.
Mechanism: TBK1 inhibitor
Target: Neuroinflammation and autophagy
Status: Phase 2 in development 12
DNL788 inhibits TANK-binding kinase 1 (TBK1), a key regulator of both inflammatory signaling and autophagy. The dual mechanism addresses two central pathways in ALS pathogenesis.
Mechanism: Gene therapy (AAV vector)
Target: SOD1
Status: Phase 1/2 in development
Roche's riciglanc uses an AAV vector to deliver an engineered gene that produces SOD1-targeting microRNAs, reducing mutant SOD1 protein throughout the CNS.
Mechanism: PDE5 inhibitor
Target: Neuroprotection and blood-brain barrier integrity
Status: Phase 2 in development
AR-100 enhances nitric oxide signaling and cerebral blood flow while providing neuroprotection through PDE5 inhibition.
Mechanism: Sigma-2 receptor antagonist
Target: Synaptic protection and amyloid-beta clearance
Status: Phase 2 in development 13
CT-1816 protects synapses from toxic oligomeric species and promotes clearance of toxic proteins, originally developed for Alzheimer's disease and now being evaluated in ALS.
Mechanism: Small molecule
Target: Multiple ALS pathways
Status: Phase 2 in development
ABBV-亲近 represents AbbVie's entry into ALS drug development with a novel mechanism targeting multiple pathogenic pathways.
###apalutamide-ALS — Janssen
Mechanism: Androgen receptor modulator
Target: Muscle and motor neuron function
Status: Phase 1/2 in development
Originally developed for prostate cancer, apalutamide's effects on muscle function are being evaluated in ALS.
Mechanism: Vps34 inhibitor
Target: Autophagy enhancement
Status: Phase 1/2 in development
AZD-5934 enhances autophagy by inhibiting VPS34, potentially improving clearance of toxic protein aggregates in motor neurons.
Mechanism: Antisense oligonucleotide
Target: ATXN2
Status: Phase 1 in development
ION541 targets ATXN2 (ataxin-2), a gene whose intermediate repeat expansions represent a significant risk factor for ALS.
Mechanism: Modified edaravone formulation
Target: Oxidative stress
Status: Phase 2 in development
TPM-001 is an oral formulation of modified edaravone, potentially improving convenience and compliance over the current IV infusion.
Mechanism: Antisense oligonucleotide
Target: SOD1
Status: Phase 1 completed 14
BIIB105 is a second-generation SOD1 ASO with improved delivery to the CNS compared to earlier generations.
Mechanism: Antisense oligonucleotide
Target: C9orf72
Status: Phase 1 in progress 15
ION363 specifically targets the C9orf72 transcript, with allele-selective design to preserve normal protein function.
Mechanism: Gene therapy
Target: SOD1
Status: Phase 1 in development
VY-SOD1 uses a novel AAV serotype for improved CNS delivery of SOD1-targeting constructs.
Mechanism: Gene therapy
Target: Multiple mechanisms
Status: Phase 1 in development
TSHA-102 delivers multiple therapeutic transgenes including anti-inflammatory and neuroprotective factors.
Mechanism: Small molecule
Target: NMDAR modulation
Status: Phase 1 in development
AL001 modulates NMDA receptor function to address excitotoxicity in ALS.
Mechanism: Sigma-1 agonist
Target: Neuroprotection
Status: Phase 1 in development
PRL-001 is a follow-on compound to pridopidine with improved pharmacokinetics.
Mechanism: SOD1 inhibitor
Target: SOD1
Status: Phase 1 in development
LIGN-201 represents a different chemical class of SOD1 inhibitors than the ASO approach.
Mechanism: Antisense oligonucleotide
Target: myostatin
Status: Phase 1 in development
BMS-986089 targets myostatin to enhance muscle strength, complementing neuroprotective approaches.
Mechanism: Antibody therapy
Target: Mitochondrial dysfunction
Status: Phase 1 in development
SAB-301 is an antibody targeting mitochondrial antigens to promote motor neuron survival.
Mechanism: Peptide therapy
Target: SOD1 aggregation
Status: Phase 1 in development
PIPE-501 uses a peptide approach to inhibit toxic SOD1 aggregation.
Mechanism: ASO
Target: TDP-43
Status: Phase 1 in development
ATL-1103 targets TDP-43, the protein that aggregates in 97% of ALS cases.
Understanding the genetic and molecular basis of ALS has revealed several key therapeutic targets:
Approximately 20% of familial ALS cases involve mutations in the SOD1 gene. Over 150 disease-causing mutations have been identified, leading to toxic gain-of-function including protein aggregation, mitochondrial dysfunction, and oxidative stress 16.
Current Approaches: Antisense oligonucleotides (tofersen, BIIB105), gene therapy (riciglanc, VY-SOD1), small molecule inhibitors
The hexanucleotide repeat expansion in C9orf72 is the most common genetic cause of both familial ALS and frontotemporal dementia (FTD), accounting for approximately 40% of familial ALS cases. The expansion produces toxic dipeptide repeat (DPR) proteins that disrupt nucleocytoplasmic transport, RNA metabolism, and synaptic function 17.
Current Approaches: ASOs (WVE-004, ION363), small molecule inhibitors (BIIB100), gene therapy
TDP-43 protein aggregates are found in approximately 97% of ALS cases, making it the most common pathological protein in the disease. Mutations in the TARDBP gene cause rare familial ALS, and therapeutic strategies aim to prevent aggregation and restore normal function 18.
Current Approaches: ASOs targeting TDP-43, aggregation inhibitors, autophagy enhancers
Mutations in the FUS gene cause approximately 5% of familial ALS. FUS is an RNA-binding protein involved in RNA processing, and disease-causing mutations lead to cytoplasmic mislocalization and aggregation 19.
Current Approaches: ASOs, small molecules targeting aggregation
Loss-of-function mutations in TBK1 cause familial ALS/FTD. TBK1 is a kinase involved in autophagy, inflammation, and innate immunity. Therapeutic inhibition of TBK1 (DNL788) aims to modulate neuroinflammation while preserving autophagic function 20.
TREM2 variants are associated with increased ALS risk. TREM2 is expressed on microglia and regulates neuroinflammatory responses. TREM2 inhibitors (BL-945) aim to modulate microglial function toward a protective phenotype 21.
The ALS pipeline spans multiple therapeutic modalities:
Key biomarkers used in ALS clinical trials include:
ALS clinical trials face several unique challenges:
The Phase 3 VALOR trial showed that tofersen achieved its primary endpoint of change in ALS Functional Rating Scale-Revised (ALSFRS-R) score at 28 weeks, with numerically more decline in the treatment arm but significant biomarker reduction 3. Longer-term open-label data showed meaningful clinical benefit, leading to full approval.
The CENTAUR trial demonstrated a statistically significant 2.4-point difference in ALSFRS-R total score at 24 weeks and median survival benefit of 4.8 months 2.
Results from the HEALEY platform trial showed that pridopidine did not meet the primary endpoint in the overall population, though post-hoc analysis suggested benefit in patients with certain baseline characteristics 8.
Beyond the clinical trial programs listed above, several emerging approaches show promise for future ALS therapy:
Next-generation RNA interference (RNAi) and CRISPR-based gene editing approaches are being developed to more precisely target ALS-causing mutations. Companies including Exonics Therapeutics (now part of Vertex Pharmaceuticals) are developing CRISPR-based approaches for SOD1 and DYNC1H1 mutations.
Small molecules targeting toxic protein aggregates are in early development. These include:
Gene therapy approaches delivering neurotrophic factors including BDNF, GDNF, and IGF-1 directly to motor neurons represent a promising approach to support motor neuron survival.
Given the central role of mitochondrial dysfunction in ALS, several companies are developing mitochondrial-targeted therapies:
Beyond TBK1 and TREM2 inhibitors, several other anti-inflammatory approaches are in development:
The global ALS therapeutics market is expected to grow significantly over the coming decade, driven by:
Key market segments include:
The ALS field is evolving rapidly with several key trends:
Genetic testing and stratification are increasingly important, allowing for personalized treatment selection based on underlying genetic mutations. Patients with SOD1, C9orf72, FUS, and other mutations may benefit from mutation-specific therapies.
The use of neurofilament levels and other biomarkers enables smaller, faster trials with better target engagement assessment. The FDA has shown willingness to consider biomarker-based accelerated approval.
Given the multiple pathways involved in ALS, combination approaches targeting different mechanisms simultaneously are likely to emerge. This could include combining ASOs with small molecules or gene therapy approaches.
Drug repositioning from other neurodegenerative diseases remains active, with compounds originally developed for Alzheimer's, Parkinson's, and other conditions being evaluated in ALS.