NIO752 is an antisense oligonucleotide (ASO) developed by Novartis that targets MAPT mRNA, aiming to reduce production of all tau protein isoforms including the pathogenic 4R tau that accumulates in PSP.
| Parameter |
Value |
| NCT Number |
NCT04539041 |
| Status |
Completed |
| Phase |
Phase 1 |
| Sponsor |
Novartis Pharmaceuticals |
| Intervention |
NIO752 (tau-targeting ASO) |
| Route |
Intrathecal injection |
NIO752 is a gapmer-type antisense oligonucleotide that:
- Binds to MAPT mRNA — The MAPT gene encodes the tau protein
- Triggers RNase H degradation — Leads to degradation of the target mRNA
- Reduces tau production — Decreases both 3R and 4R tau isoforms
- Potential disease modification — By reducing tau burden upstream
This approach is analogous to tofersen (BIIB067) for SOD1 ALS, which demonstrated significant reduction in SOD1 protein and showed clinical benefit in the open-label extension.
PSP is a 4R tauopathy characterized by:
- Abnormal accumulation of 4-repeat (4R) tau isoforms
- Neurofibrillary tangles composed of hyperphosphorylated tau
- Progressive neuronal loss in brainstem and subcortical structures
By reducing total tau production, NIO752 aims to:
- Decrease pathological tau accumulation
- Slow disease progression
- Potentially reverse or halt neurodegeneration
- Purpose: Safety, tolerability, and pharmacokinetics
- Population: Patients with progressive supranuclear palsy
- Dosing: Multiple ascending doses
- Endpoints:
- Adverse events
- Pharmacokinetics
- CSF tau levels (pharmacodynamic biomarker)
Participants in the NIO752 trial likely met criteria including:
- Diagnosis of probable PSP according to NINDS-SPSP criteria
- Age 40-80 years
- Disease duration typically 1-5 years
- Ability to undergo lumbar puncture
- Stable on permitted medications
Key exclusion criteria typically included:
- Significant medical conditions that could interfere with study participation
- Prior participation in other clinical trials within specified timeframes
- Contraindications to intrathecal administration
- Significant cognitive impairment that would preclude participation
- Generally well-tolerated
- No major safety concerns reported
- Establishes feasibility of tau ASO approach
- Treatment-emergent adverse events were mostly mild to moderate
- CSF total tau reduction demonstrated
- Dose-dependent target engagement observed
- Reduction in both 3R and 4R tau isoforms confirmed
- Incidence and severity of adverse events
- Pharmacokinetic profile of NIO752 in CSF
- Change in CSF total tau concentration
- Change in CSF phosphorylated tau (p-tau) levels
- Clinical measures of disease progression
- Neuroimaging markers of neurodegeneration
NIO752 represents a first-in-class approach for tau reduction:
- Direct target reduction — Unlike small molecules that modulate tau phosphorylation or aggregation, ASOs reduce tau at the source
- Broad applicability — Could work across 4R tauopathies (PSP, CBD, AGD)
- Validated mechanism — Similar approach successful in SOD1 ALS with tofersen
- Disease modification — Potential to modify disease course by addressing underlying tau pathology
¶ Challenges and Considerations
- Delivery — Intrathecal administration required, limiting broader applicability
- Duration — Long-term dosing may be needed for sustained benefit
- Biomarkers — Need to validate surrogate endpoints that predict clinical benefit
- Patient selection — Could be enhanced with genetic or biomarker stratification
- Timing — Optimal intervention likely earlier in disease course before irreversible neuronal loss
| Approach |
Mechanism |
Route |
Stage |
| NIO752 |
ASO - reduce tau production |
Intrathecal |
Phase 1 |
| Tilavonemab |
Antibody - clear extracellular tau |
IV |
Phase 2 |
| Semorinemab |
Antibody - block tau spread |
IV |
Phase 2 |
| LMTM |
Tau aggregation inhibitor |
Oral |
Phase 3 |
The successful completion of Phase 1 establishes a foundation for further development:
- Evaluation of clinical efficacy in larger PSP patient cohorts
- Assessment of disease modification using clinical progression measures
- Exploration of combination approaches with other therapeutic modalities
Beyond PSP, the tau ASO approach could potentially benefit patients with:
- Corticobasal Degeneration (CBD) — Another 4R tauopathy
- Alzheimer's Disease — Where tau pathology is a key driver of neurodegeneration
- Primary Tauopathies — Including argyrophilic grain disease and familial tauopathies
The ability to reduce tau production regardless of the specific pathological form makes this approach potentially valuable across multiple neurodegenerative conditions characterized by tau pathology.