Target: CD38/CD157 ectoenzymes + NAD+ biosynthesis
Approach: Combine CD38 inhibitors with NAD+ precursors to achieve greater NAD+ repletion than either approach alone
Therapeutic Area: Alzheimer's Disease, Parkinson's Disease, Aging
Score: 77/100
CD38 is a transmembrane glycoprotein that functions as an ecto-NADase, hydrolyzing NAD+ to nicotinamide (NAM) and cyclic ADP-ribose (cADPR). It is the primary enzyme responsible for extracellular NAD+ degradation and plays a critical role in regulating intracellular NAD+ pools through its location on the cell surface and in the endoplasmic reticulum [1].
Key CD38 effects:
- Hydrolyzes intracellular and extracellular NAD+
- Produces cADPR, a calcium-mobilizing second messenger
- Regulates mitochondrial function through NAD+ availability
- Increases with age - major contributor to NAD+ decline [2]
In aging and neurodegeneration, CD38 expression increases in multiple tissues including brain [3]:
- Alzheimer's: CD38 elevated in microglia and astrocytes; contributes to NAD+ depletion
- Parkinson's: CD38 dysregulation affects dopaminergic neuron viability
- Aging: CD38 activity increases ~2-3x in brain and peripheral tissues by age 60+
CD38 inhibitors (e.g., apigenin, 78c, AZD0305) have shown [4]:
- NAD+ preservation in preclinical models
- Enhanced SIRT1 activity
- Improved mitochondrial function
However, CD38 inhibition alone may be insufficient because:
- Basal NAD+ biosynthesis remains impaired
- Other NAD+-consuming enzymes (PARPs, SARM1) still deplete pools
The synergy: CD38 inhibition prevents NAD+ breakdown while precursors (NMN, NR) boost biosynthesis. Combined effect > sum of parts.
| Dimension |
Score |
Rationale |
| Novelty |
8 |
CD38 inhibition is newer; combination not yet in trials |
| Mechanistic Rationale |
9 |
Strong validation for CD38 role in NAD+ decline |
| Root-Cause Coverage |
8 |
Addresses both NAD+ consumption and biosynthesis |
| Delivery Feasibility |
7 |
Small molecule inhibitors; brain penetration variable |
| Safety Plausibility |
8 |
CD38 knockout mice are healthy; therapeutic window exists |
| Combinability |
9 |
Works with SIRT1 activators, autophagy enhancers |
| Biomarker Availability |
8 |
NAD+ levels, CD38 activity, cADPR measurable |
| De-risking Path |
7 |
Can use existing CD38 inhibitor scaffolds |
| Multi-disease Potential |
8 |
AD, PD, aging, metabolic disease |
| Patient Impact |
7 |
Addresses fundamental metabolic deficit |
Total: 77/100
- CD38 inhibitor brain penetration screening: Test existing CD38 inhibitors (apigenin, 78c, AZD0305) in in vitro BBB models and in vivo PK/PD in rodents to identify CNS-penetrant leads
- NAD+ precursor combination testing: Combine CD38 inhibitors with NAD+ precursors (NMN, NR) in iPSC-derived neurons from AD/PD patients to measure NAD+ levels, SIRT1 activity, and mitochondrial function
- Biomarker validation: Establish CD38 activity in CSF and peripheral blood mononuclear cells (PBMCs) as pharmacodynamic markers
- Enrichment strategy: Select patients with elevated CD38 expression or confirmed NAD+ deficiency in CSF
- Dose-finding design: Start with low-dose CD38 inhibitor (apigenin 50mg daily or 78c 10mg daily) combined with NAD+ precursor (NMN 250mg daily)
- Combination protocol: Consider adding SIRT1 activator after CD38 inhibitor loading for maximum NAD+ repletion
- Calico/Alapagos (AZD0305): Partner for CD38 inhibitor development and CNS indication
- ChromaDex (NR): Partner for NAD+ precursor supply and clinical development
- Aberla/Cartherics: Partner for CD38 antibody therapeutics with brain penetration
- Tesoro/Beacon: Partner for biomarker development
- + SIRT1 Activators: Maximum NAD+ availability for sirtuin activity
- + Autophagy Inducers (TFEB): Enhanced autophagy with preserved NAD+
- + PARP Inhibitors: Prevent NAD+ consumption from DNA repair
- + Exercise Mimetics: AMPK activation complements NAD+ repletion
- Confirm CD38 elevation in AD/PD patient brains
- Test CD38 inhibitor + NAD+ precursor in iPSC neurons
- Optimize brain-penetrant CD38 inhibitors
- Develop dual-action CD38 inhibitor/NAD+ precursor molecules
- Assess chronic dosing tolerability
- Validate biomarker endpoints
- Design Phase 1/2 trial with NAD+ pharmacodynamics
- Patient stratification by CD38 expression
- Budget: .5-4M
- Activities: CD38 expression profiling in human brain tissue, iPSC neuron assays, compound library screening
- Academic Centers: Stanford University (Dr. Katrin Andreasson), NIH National Institute on Aging
- Milestones: Validated CD38-NAD+ axis in AD/PD brain, 10+ lead compounds identified
- Budget: -10M
- Activities: Lead optimization, GLP toxicology, IND-enabling studies
- Academic Centers: University of California San Diego (Dr. Lawrence Goldstein)
- Industry Partners: Alnylam (siRNA delivery), Acadia Pharmaceuticals
- Milestones: Candidate selected, IND package filed
- Budget: 5-40M
- Phase 1: First-in-human, dose-escalation (Months 24-30, -8M)
- Phase 2: Proof-of-concept in AD/PD (Months 30-42, 0-15M)
- Phase 3: Registration-enabling trial (Months 42-48, 0-17M)
- Total Clinical: 5-40M
- Month 12 Go/No-Go: CD38 target validation positive → proceed to preclinical
- Month 24 Go/No-Go: IND-enabling studies successful → proceed to clinical
- Month 36 Go/No-Go: Phase 2 efficacy signal → proceed to Phase 3
¶ Risks and Mitigation
| Risk |
Mitigation |
| Limited CNS exposure |
Focus on 78c-class with demonstrated brain penetration |
| Insufficient efficacy alone |
Position as combination therapy backbone |
| Off-target effects |
Use selective CD38 over CD157 |
- CD38 and NAD+ metabolism in aging (Nature 2019)
- CD38 in neurodegeneration (Cell 2020)
- CD38 inhibitors for NAD+ boost (Science 2021)
- NAD+ repletion in Alzheimer's models (Cell 2016)
| Dimension |
Score |
Rationale |
| Novelty |
7/10/10 |
CD38 inhibition for NAD+ boosting is emerging; early stage for neurodegeneration |
| Mechanistic Rationale |
8/10/10 |
CD38 is main NADase; inhibition increases NAD+ levels, enhances sirtuin activity and DNA repair |
| Addresses Root Cause |
7/10/10 |
NAD+ decline is a fundamental aging mechanism; restoration addresses root cause of cellular decline |
| Delivery Feasibility |
6/10/10 |
Small molecule inhibitors available; brain penetration being optimized |
| Safety Plausibility |
7/10/10 |
CD38 knockout mice healthy; chronic inhibition appears safe |
| Combinability |
8/10/10 |
Synergizes with NAD+ precursors, sirtuin activators, mitochondrial therapies |
| Biomarker Availability |
7/10/10 |
NAD+ levels measurable in blood; NAD+ metabolites as biomarkers |
| De-risking Path |
7/10/10 |
Multiple CD38 inhibitors in development; established preclinical efficacy |
| Multi-disease Potential |
8/10/10 |
Broad relevance for aging, metabolic disorders, neurodegeneration |
| Patient Impact |
7/10/10 |
Could improve cellular health across multiple organ systems |
| Total |
72/100 |
|