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.
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.
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](/clinical-trials/tofersen-valor) (BIIB067) for SOD1 ALS, which demonstrated significant reduction in SOD1 protein and showed clinical benefit in the open-label extension.
Rationale for PSP
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
Study Design
Phase 1 Study (NCT04539041)
Purpose: Safety, tolerability, and pharmacokinetics
Population: Patients with progressive supranuclear palsy
Dosing: Multiple ascending doses
Endpoints:
Adverse events
Pharmacokinetics
CSF tau levels (pharmacodynamic biomarker)
Inclusion Criteria
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
Exclusion Criteria
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
Results
Safety Profile
Generally well-tolerated
No major safety concerns reported
Establishes feasibility of tau ASO approach
Treatment-emergent adverse events were mostly mild to moderate
Biomarker Data
CSF total tau reduction demonstrated
Dose-dependent target engagement observed
Reduction in both 3R and 4R tau isoforms confirmed
Clinical Endpoints
Primary Endpoints
Incidence and severity of adverse events
Pharmacokinetic profile of NIO752 in CSF
Change in CSF total tau concentration
Secondary Endpoints
Change in CSF phosphorylated tau (p-tau) levels
Clinical measures of disease progression
Neuroimaging markers of neurodegeneration
Significance
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
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
Comparison to Other Tau-Targeting Approaches
| 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 |
Future Directions
The successful completion of Phase 1 establishes a foundation for further development:
Planned Phase 2 Studies
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
Broader Applications
Beyond PSP, the tau ASO approach could potentially benefit patients with:
Corticobasal Degeneration (CBD) — Another 4R tauopathy
[Alzheimer's Disease](/diseases/alzheimers-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.