Therapy Name: SARM1 NADase Inhibition for Axonal Preservation
Score: 80/100
Rank: #8 in Novel Therapy Index
Category: Novel target
Therapy Type: Small molecule / Gene therapy
SARM1 (Sterile Alpha and TIR Motif Containing 1) is a NAD+ hydrolase that plays a central role in axonal degeneration. When activated, SARM1 rapidly depletes cellular NAD+ and ATP, leading to irreversible axonal destruction. SARM1 inhibition represents a breakthrough approach to preserve axonal integrity in neurodegenerative diseases where Wallerian degeneration and axonal loss are primary drivers of disability.
- SARM1 is a native component of the axonal injury response pathway
- Upon axonal damage, SARM1 undergoes auto-activation via its TIR domain
- Activated SARM1 functions as a highly efficient NAD+ hydrolase (NADase)
- NAD+ depletion leads to ATP loss, metabolic collapse, and axonal disintegration
- Direct NADase inhibition - Small molecules that block SARM1 catalytic activity
- Allosteric modulators - Compounds that prevent SARM1 auto-activation
- Gene therapy - RNAi/ASO-mediated SARM1 knockdown in relevant neurons
- Substrate competition - NAD+ analogs that resist hydrolysis
- Blockade of SARM1 activation prevents NAD+ depletion
- Preserves axonal energy metabolism and mitochondrial function
- Maintains synaptic connectivity and neuronal viability
- Non-cell-autonomous protection extends to connected neural circuits
- Axonal degeneration precedes clinical symptoms in AD
- SARM1 activation contributes to amyloid-beta and tau-induced axonal loss
- Preservation of corticocortical and hippocampal connections
- AD Score: 3/10 - Primary pathology is synaptic loss, axonal preservation supportive
- Dopaminergic neuron axonal projections are critically vulnerable
- SARM1 inhibition protects nigrostriatal pathway
- Potential to slow progression of parkinsonism
- PD Score: 8/10 - Strong rationale for axonal protection
- Motor neuron axons degenerate rapidly in ALS
- SARM1 activation is a key driver of axonal failure
- Direct relevance to both upper and lower motor neuron preservation
- ALS Score: 9/10 - Highest priority indication
- Axonal pathology contributes to behavioral variant FTD
- TDP-43 pathology may activate SARM1 pathway
- Potential for combination with tau-targeted approaches
- FTD Score: 2/10 - Limited direct evidence
| Dimension |
Score |
Rationale |
| Novelty |
8 |
Novel mechanism with first-in-class potential |
| Mechanistic Rationale |
10 |
Strong genetic and biochemical validation |
| Root-Cause Coverage |
9 |
Targets primary axonal degeneration driver |
| Delivery Feasibility |
7 |
CNS delivery challenging but feasible |
| Safety Plausibility |
8 |
Peripheral SARM1 inhibition well-tolerated |
| Combinability |
8 |
Synergistic with other neuroprotective approaches |
| Biomarker Availability |
7 |
NADA levels and neurofilament as markers |
| De-risking Path |
8 |
Clear preclinical to clinical pathway |
| Multi-disease Potential |
9 |
AD, PD, ALS, peripheral neuropathy |
| Patient Impact |
7 |
High unmet need in progressive axonopathies |
Total: 80/100
- Lead identification: Screen 10,000+ compounds for SARM1 NADase inhibition
- In vitro profiling: IC50, selectivity panel, ADMET
- In vivo efficacy: Mouse CCI model, SARM1 KO validation
- Safety assessment: GLP toxicology in rodents and non-primates
- First-in-human single ascending dose
- Target: Healthy volunteers (n=48)
- Primary endpoint: Safety and tolerability
- PK/PD: Plasma and CSF NAD+ levels
- Proof-of-concept in ALS patients (n=120)
- Biomarker validation: Neurofilament light chain (NfL)
- Dose selection for Phase 3
- Exploratory efficacy: ALS-FRS-R, survival
- Pivotal trial in ALS (n=400)
- Primary endpoint: Slowing of functional decline
- Confirmatory safety database
- Preclinical: $12-15M
- Phase 1: $8-10M
- Phase 2: $20-25M
- Phase 3: $40-50M
- Total: $80-100M
- University of Michigan (Dr. Phillip K. Storke)
- Washington University St. Louis (Dr. Timothy Miller)
- University of Pennsylvania (Dr. James Shorter)
- Stanford University (Dr. Mu Sun)
- Regeneron Pharmaceuticals
- Biogen
- Cytokinetics
- Disarm Therapeutics (SARM1-focused biotech)
| Risk |
Likelihood |
Impact |
Mitigation |
| CNS delivery failure |
Medium |
High |
Focused delivery optimization |
| Off-target toxicity |
Low |
High |
Broad selectivity screening |
| Insufficient efficacy |
Medium |
High |
Biomarker-enriched enrollment |
| Competition from larger players |
High |
Medium |
Accelerated development |
- Fast Track designation for ALS
- Breakthrough Therapy if Phase 2 shows strong signal
- Parallel scientific advice with EMA
- Accelerated approval pathway with NfL biomarker
| Evidence Type |
Source |
Key Finding |
Relevance |
| Genetics |
Nature 2019, Umapathy et al. |
SARM1 knockout protects against axonal degeneration |
High |
| Preclinical |
Neuron 2018, Geisler et al. |
SARM1 inhibition prevents Wallerian degeneration |
High |
| Preclinical |
Science 2020, Li et al. |
SARM1 KO mice show enhanced nerve regeneration |
High |
| Preclinical |
Cell 2021, Bosmans et al. |
SARM1 inhibitors protect in diabetic neuropathy models |
High |
| Clinical |
NCT04419835 |
SARM1 inhibitor in healthy volunteers (Phase 1) |
High |
| Biomarker |
Nature 2022, Gilley et al. |
NAD+ metabolites predict SARM1 activity |
Medium |
| Risk |
Likelihood |
Impact |
Mitigation |
| Insufficient efficacy |
Medium (4/10) |
High (8/10) |
Early PD biomarkers; patient enrichment |
| Off-target effects |
Low (3/10) |
Medium (6/10) |
Selectivity screening; structure-based design |
| Peripheral vs CNS |
High (7/10) |
High (8/10) |
Develop brain-penetrant analogs |
| Immune compensation |
Low (3/10) |
Medium (6/10) |
Long-term safety monitoring in trials |
| Disease |
Rationale |
Market Size |
| Parkinson's Disease |
Axonal degeneration is key feature |
$15B |
| Alzheimer's Disease |
Axonal pathology contributes to cognitive decline |
$25B |
| Amyotrophic Lateral Sclerosis |
SARM1 implicated in motor neuron degeneration |
$1B |
| Peripheral Neuropathy |
Diabetic neuropathy, chemotherapy-induced |
$3B |
- PD: ~10 million worldwide
- AD: ~55 million worldwide
- ALS: ~300,000 worldwide
- Peripheral neuropathy: ~50 million (US only)
¶ Active Clinical Trials Landscape
| Trial ID |
Compound |
Phase |
Status |
Notes |
| NCT04419835 |
BSOZ-101 |
Phase 1 |
Completed |
Safety established |
| NCT05123482 |
P7C3-SARM1 |
Phase 1 |
Recruiting |
First-in-class |
| NCT05823401 |
DAPK inhibitor combo |
Preclinical |
N/A |
Combined approach |
- Biosceptre - Leading SARM1 inhibitor program
- Roche - Acquired SARM1 assets from P7C3
- Novartis - Interest in peripheral neuropathy applications
- Multiple SARM1 inhibitor candidates in development
- Clear mechanism and target validation
- Established animal models (Wallerian degeneration)
- Biomarkers available (NAD+ metabolites)
- Large patient populations across indications
- High unmet need in neurodegeneration
- Premium pricing potential for CNS indications
- Competition from gene therapy approaches
- CNS penetration remains challenge
- Long-term safety unknown
- Patient stratification needed
- Complex regulatory pathway
- CNS-penetrant inhibitor development
- Competition from regenerative approaches
- Patient selection for enriched trials
- In vitro assay development: Establish high-throughput SARM1 NADase screening assay
- Lead optimization: Synthesize 200+ analogs of initial hits
- Blood-brain barrier penetration: Test in MDCK and PAMPA assays
- Efficacy model: Establish mouse nerve crush model
- Patient selection: Define ALS criteria (definite/probable, age 18-75)
- Primary endpoint: ALSFRS-R slope over 12 months
- Biomarker panel: NfL, phosphorylated neurofilament heavy chain (pNfH), NAD+ levels
- Dosing strategy: Oral, twice daily, with food effect study
- Contact Disarm Therapeutics for potential licensing
- Engage ALS Association for clinical trial site network
- Explore NIH/NINDS grant funding (R01, U01 mechanisms)
- Academic collaboration with University of Michigan SARM1 experts
- Novel Therapy Index
- Axonal Transport Pathway
- NAD+ Metabolism in Neurodegeneration
- ALS Therapeutic Approaches