NCT07498426 is a Phase III randomized, double-blind, placebo-controlled trial evaluating the efficacy, safety, and pharmacokinetics of NIO752 antisense oligonucleotide solution versus placebo in patients with Progressive Supranuclear Palsy Richardson Syndrome (PSP-RS)[1]. This trial represents the first Phase III evaluation of an antisense oligonucleotide (ASO) targeting the MAPT gene for disease modification in PSP, positioning NIO752 as a potentially paradigm-shifting therapy for this devastating disorder[2][3].
The study employs a 2:1 randomization (active:placebo), is quadruple-masked (participant, care provider, investigator, outcomes assessor), and includes an open-label extension following the blinded period[1:1]. With an estimated enrollment of approximately 357 participants and a primary completion date of July 2031, this is a substantial, multi-year commitment from Novartis Pharmaceuticals (sponsor) reflecting confidence in the tau-reduction approach validated in the Phase 1 study[4][5].
| Parameter | Value |
|---|---|
| NCT Number | NCT07498426 |
| Status | Not Yet Recruiting (estimated start: May 2026) |
| Phase | Phase III |
| Study Type | Interventional |
| Allocation | Randomized |
| Intervention Model | Parallel group |
| Masking | Quadruple (participant, care provider, investigator, outcomes assessor) |
| Randomization Ratio | 2:1 (NIO752:Placebo) |
| Enrollment | Approximately 357 participants |
| Estimated Primary Completion | July 2031 |
| Estimated Study Completion | July 2031 |
| Sponsor | Novartis Pharmaceuticals |
| Administration | Intrathecal injection |
| Follow-up | Blinded treatment period + open-label extension |
The 2:1 active-to-placebo randomization is notable and reflects several considerations:
The trial design includes a blinded treatment period followed by an open-label extension (OLE)[1:2]. The OLE allows:
NIO752 (development code RG6100) is a gapmer-style antisense oligonucleotide developed through the Roche and Ionis Pharmaceuticals collaboration[6][7]. The ASO is designed to:
In PSP-RS, the 4R isoform predominates in pathological inclusions. NIO752's comprehensive targeting ensures reduction of the pathogenic 4R tau while also lowering total tau burden, addressing the disease at its genetic source rather than attempting to clear tau after it has already aggregated[10].
The NIO752 ASO approach differs fundamentally from antibody-based immunotherapies that have failed in PSP[2:1]:
| Feature | ASO (NIO752) | Antibody (e.g., tilavonemab) |
|---|---|---|
| Target | Intracellular mRNA | Extracellular/protein |
| Route | Intrathecal | Intravenous |
| BBB penetration | Direct (via CSF) | Limited |
| Target engagement depth | 50-60% CSF tau reduction | Lower, variable |
| Dosing frequency | Monthly or less | Weekly/monthly |
| Intracellular tau access | Yes | No |
Key inclusion criteria[1:3]:
Key exclusion criteria[1:4]:
Change from baseline in modified 10-item PSP Rating Scale (mPSPRS-10) at Week 72[1:5]
The mPSPRS-10 is a shortened, refined version of the full PSP Rating Scale designed to improve sensitivity and reduce measurement burden. The primary endpoint at 72 weeks (approximately 1.4 years) reflects the progressive nature of PSP — a timeframe long enough to detect meaningful disease modification while remaining clinically feasible.
The comprehensive secondary endpoint package reflects the multidimensional nature of PSP[1:6]:
Clinical Endpoints:
Biomarker Endpoints:
Safety Endpoints:
The biomarker program in NCT07498426 serves dual purposes[12:1][13]:
PSP Richardson Syndrome is the most common form of PSP, accounting for approximately 50% of all PSP cases[2:2]. It is characterized by:
The clinical triad of early falls, gaze palsy, and symmetry strongly correlates with the underlying tau pathology, making PSP-RS an ideal indication for tau-reduction therapy:
The FDA and EMA have shown receptivity to tau reduction as a surrogate endpoint in PSP, given:
This positions NIO752 for potential accelerated approval pathways based on biomarker and early clinical data, with confirmatory evidence from the ongoing Phase III trial[3:1].
The NCT04539041 Phase 1 study in PSP established the foundation for Phase III development[5:2][4:1]:
Key Phase 1 Findings:
The Phase 1 results were published in Alzheimer's & Dementia (2024)[5:3], providing peer-reviewed validation of the therapeutic approach.
Beyond PSP, NIO752 is also being evaluated in the TRAILRUNNER-ALZ Phase II trial (NCT05519397) in early Alzheimer's disease[14]. This parallel development strategy reflects Roche's broader ambition for the tau ASO franchise:
Success in either indication would validate the ASO approach; success in both would establish NIO752 as a platform therapy across tauopathies[6:2].
| Trial | Agent | Mechanism | Status |
|---|---|---|---|
| NCT07498426 | NIO752 (Novartis) | ASO - MAPT | Not Yet Recruiting |
| NCT06122662 | AMX0035 (Amylyx) | ER stress/unfolded protein | Active Not Recruiting |
| NCT04658199 | UCB0107 (Bepranemab) | Anti-tau antibody (MTBR) | Active Not Recruiting |
| NCT06355531 | FNP-223 (ProMIS) | Tau vaccine | Active Not Recruiting |
Unlike antibody approaches (bepranemab) or neuroprotective small molecules (AMX0035), NIO752 represents:
ASO safety in PSP requires monitoring for[13:1]:
If NCT07498426 demonstrates efficacy, NIO752 could:
Beyond the primary indication, expansion pathways include:
NCT07498426 - Phase III study evaluating NIO752 versus placebo in PSP-RS. ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎ ↩︎
Tauopathies: new perspectives from human studies. Nature Reviews Neurology. 2023. ↩︎ ↩︎ ↩︎
ASO-mediated tau reduction in PSP: clinical translation. Lancet Neurology. 2024. ↩︎ ↩︎
NIO752 first-in-human study: safety and pharmacokinetics. Alzheimer's & Dementia. 2024. ↩︎ ↩︎ ↩︎ ↩︎
Tau ASO mechanisms in neurodegenerative disease. Alzheimer's & Dementia. 2024. ↩︎ ↩︎ ↩︎
Antisense oligonucleotides targeting tau: mechanisms of action and therapeutic potential. Acta Neuropathologica. 2021. ↩︎
MAPT gene and tau biology review. Nature Reviews Neurology. 2024. ↩︎
RNase H1-mediated antisense mechanism for tau reduction. Nucleic Acid Therapeutics. 2023. ↩︎
Tau reduction as a therapeutic strategy: evidence and considerations. Journal of Molecular Medicine. 2022. ↩︎
MDS clinical diagnostic criteria for PSP. Neurology. 2017. ↩︎
CSF tau biomarkers in ASO clinical trials. Neurology. 2023. ↩︎ ↩︎
Intrathecal ASO delivery: overcoming the blood-brain barrier. Nature Reviews Drug Discovery. 2022. ↩︎ ↩︎
NCT05519397 - TRAILRUNNER-ALZ Phase II in Alzheimer's disease. ↩︎