Overview
BIIB080 (also known as MAPTRx or IONIS-MAPTRx) is an antisense oligonucleotide (ASO) therapeutic candidate developed by Biogen in partnership with Ionis Pharmaceuticals that targets MAPT mRNA for the treatment of [Alzheimer's disease](/diseases/alzheimers-disease) and progressive supranuclear palsy (PSP). It is designed to reduce the production of all tau protein isoforms in the brain, addressing one of the key pathological hallmarks of tauopathies[@ionis2021][@biogen].
BIIB080 represents one of the most advanced RNA-targeted approaches for tau reduction and has demonstrated the strongest pharmacodynamic signal in humans to date, with dose-dependent reductions in cerebrospinal fluid (CSF) total tau and phospho-tau[@mummery2023].
Mechanism of Action
BIIB080 is a gapmer-type antisense oligonucleotide that:
Binds to MAPT mRNA — The MAPT gene encodes the tau protein, which is involved in microtubule stabilization in [neurons](/entities/neurons)
Triggers RNase H degradation — The ASO-RNA duplex recruits RNase H, which degrades the target mRNA
Reduces tau production — Decreases both 3R and 4R tau isoforms at the transcriptional level
Potential disease modification — By reducing tau at its source, rather than targeting extracellular tau like antibodiesThis approach is mechanistically analogous to [tofersen](/clinical-trials/tofersen-valor) (BIIB067) for SOD1 ALS, which demonstrated significant protein reduction and clinical benefit in open-label extension studies[@miller2020].
Delivery Method
...Overview
BIIB080 (also known as MAPTRx or IONIS-MAPTRx) is an antisense oligonucleotide (ASO) therapeutic candidate developed by Biogen in partnership with Ionis Pharmaceuticals that targets MAPT mRNA for the treatment of [Alzheimer's disease](/diseases/alzheimers-disease) and progressive supranuclear palsy (PSP). It is designed to reduce the production of all tau protein isoforms in the brain, addressing one of the key pathological hallmarks of tauopathies[@ionis2021][@biogen].
BIIB080 represents one of the most advanced RNA-targeted approaches for tau reduction and has demonstrated the strongest pharmacodynamic signal in humans to date, with dose-dependent reductions in cerebrospinal fluid (CSF) total tau and phospho-tau[@mummery2023].
Mechanism of Action
BIIB080 is a gapmer-type antisense oligonucleotide that:
Binds to MAPT mRNA — The MAPT gene encodes the tau protein, which is involved in microtubule stabilization in [neurons](/entities/neurons)
Triggers RNase H degradation — The ASO-RNA duplex recruits RNase H, which degrades the target mRNA
Reduces tau production — Decreases both 3R and 4R tau isoforms at the transcriptional level
Potential disease modification — By reducing tau at its source, rather than targeting extracellular tau like antibodiesThis approach is mechanistically analogous to [tofersen](/clinical-trials/tofersen-valor) (BIIB067) for SOD1 ALS, which demonstrated significant protein reduction and clinical benefit in open-label extension studies[@miller2020].
Delivery Method
BIIB080 is administered via intrathecal injection (lumbar puncture), which bypasses the [blood-brain barrier](/entities/blood-brain-barrier) and allows direct delivery to the central nervous system. This route is necessary because ASOs do not readily cross the BBB when administered peripherally[@rinaldi2018].
Clinical Development
Phase 1 Study (NCT03713905)
The first-in-human Phase 1 study established the safety and tolerability of BIIB080 in patients with mild Alzheimer's disease:
- Design: Randomized, double-blind, placebo-controlled
- Dosing: Single ascending dose and multiple ascending dose cohorts
- Results:
- Dose-dependent reduction in CSF total tau (up to ~50% reduction)
- Dose-dependent reduction in CSF phospho-tau181
- Generally well-tolerated with no major safety concerns
Phase 2 Study (NCT05399888)
- Title: "A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy, Safety, and Tolerability of BIIB080 in Subjects With Mild Cognitive Impairment Due to Alzheimer's Disease or Mild Alzheimer's Disease Dementia"
- Status: Active, not recruiting
- Phase: Phase 2
- Enrollment: 416 subjects
- Primary endpoints: Change in tau PET imaging, cognitive measures
PSP Development
BIIB080 has been studied in PSP, a 4R-tauopathy, through the PASSPORT Phase 1 trial (BIIB080/ISIS 814907). The trial demonstrated dose-dependent CSF tau reduction, establishing proof-of-concept for tau-lowering in PSP[@alzforum].
Biomarker Data
The Phase 1b trial (published in Nature Medicine, 2023) demonstrated significant biomarker effects[@mummery2023]:
| Biomarker | Change | Notes |
|----------|--------|-------|
| CSF total tau | Up to 50% reduction | Dose-dependent |
| CSF phospho-tau181 | Significant reduction | Dose-dependent |
| CSF phospho-tau217 | Significant reduction | Dose-dependent |
These results represent one of the clearest human pharmacodynamic signals in the tau therapeutic field, confirming target engagement and downstream biochemical effects[@mummery2023][@alzforuma].
Comparison to Other Tau-Lowering Approaches
| Therapy | Company | Mechanism | Stage | Key Signal |
|---------|---------|----------|-------|------------|
| BIIB080 | Biogen/Ionis | Tau ASO | Phase 2 | 50% CSF tau reduction |
| NIO752 | Novartis | Tau ASO | Phase 1 | CSF tau reduction |
| Tilavonemab | AbbVie | Anti-tau antibody | Phase 2 | Failed in PSP |
| Semorinemab | Genentech | Anti-tau antibody | Phase 2 | Mixed results in AD |
| Bepranemab | Roche | Anti-tau antibody | Phase 2 | Ongoing |
Advantages of ASO Approach
Direct target reduction — Reduces tau at the source (mRNA level), unlike antibodies that target extracellular protein
Broad isoform coverage — Reduces all tau isoforms (3R, 4R, and 6R)
Clear pharmacodynamics — Direct measurement of CSF tau provides clear target engagement readouts
Potential for combination — Could be combined with amyloid-targeting therapies like [donanemab](/therapeutics/donanemab)Challenges
Intrathecal delivery — Requires lumbar puncture, which is more invasive than IV infusion
Long-term safety — Requires monitoring for off-target effects with chronic dosing
Access — Requires specialized centers for administrationRelevance to PSP
PSP is a 4R-tauopathy characterized by accumulation of 4-repeat tau isoforms in neurofibrillary tangles, tufted [astrocytes](/entities/astrocytes), and coiled bodies. Unlike Alzheimer's disease, PSP has no approved disease-modifying treatments[@alzforum].
BIIB080 is particularly relevant for PSP because:
Upstream targeting — Reduces all tau production, addressing the fundamental pathology
4R tau reduction — Reduces the pathogenic 4R isoform predominant in PSP
Proven engagement — Demonstrated CSF tau lowering in humans
No viable alternatives — Tilavonemab failed in PSP, highlighting need for new approachesBeyond BIIB080, several other antisense oligonucleotide programs are targeting tau reduction:
NIO752 (Novartis)
NIO752 is a tau-targeting ASO developed by Novartis that also binds to MAPT mRNA[@clinicaltrialsgov]:
- Stage: Phase 1 (completed)
- NCT Number: NCT04539041
- Indication: Progressive Supranuclear Palsy
- Route: Intrathecal injection
- Mechanism: Gapmer ASO targeting MAPT, reducing all tau isoforms including 4R tau
- Results: Demonstrated CSF tau lowering in PSP patients, establishing proof-of-concept for this approach
The NIO752 trial was important because it demonstrated that tau ASO approaches could work in 4R-tauopathies like PSP, where the 4R isoform predominates.
Other Preclinical Programs
Several academic groups and pharmaceutical companies have tau-targeting ASO programs in preclinical development:
- University of Pennsylvania/Children's Hospital of Philadelphia: MAPT ASO approaches using different chemistry and delivery strategies
- Mayo Clinic: ASOs targeting specific tau splice variants
- Various Chinese biotech companies: Multiple tau ASO programs in early development
Why ASOs for Tau?
The tau ASO approach offers several advantages over other modalities:
Genetic validation — MAPT mutations cause tauopathies, validating tau reduction as a therapeutic strategy
Broad coverage — Reduces all tau isoforms (3R, 4R, 6R) rather than targeting specific conformations
Upstream intervention — Reduces tau at production rather than after aggregation
Biomarker access — CSF tau provides direct readouts of target engagementClinical Trial Design Considerations
Tau ASO trials face unique challenges:
- Biomarker endpoints — CSF tau serves as a pharmacodynamic marker but clinical correlation remains uncertain
- Disease stage — Likely most effective early in disease course when tau burden is lower
- Combination potential — May synergize with amyloid-targeting therapies
- Long-term treatment — Chronic dosing required for sustained tau reduction
[@clinicaltrialsgov]: ClinicalTrials.gov. [NIO752 in Participants With Progressive Supranuclear Palsy (PSP)](https://clinicaltrials.gov/study/NCT04539041). NCT04539041.
Related Pages
- [Tau Protein](/proteins/tau)
- [MAPT Gene](/genes/mapt)
- [Biogen](/companies/biogen)
- [Ionis Pharmaceuticals](/companies/ionis-pharmaceuticals)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Clinical Trials in PSP](/clinical-trials/progressive-supranuclear-palsy)
- [Tau-Targeting Therapeutics Pipeline](/therapeutics/tau-therapeutics-pipeline)
- [Antisense Oligonucleotide Delivery](/therapeutics/aso-brain-delivery)
- [Intrathecal Delivery](/therapeutics/intrathecal-delivery)
- [4R Tauopathies](/mechanisms/4r-tauopathies)
External Links
- [ClinicalTrials.gov: NCT05399888](https://clinicaltrials.gov/study/NCT05399888)
- [ClinicalTrials.gov: NCT03713905](https://clinicaltrials.gov/study/NCT03713905)
- [Allen Human Brain Atlas](https://brain-map.org/)
- [Biogen Investor Relations](https://investors.biogen.com)
- [Ionis Pharmaceuticals](https://www.ionispharma.com)
References
Unknown, Ionis Pharmaceuticals. (2021). IONIS-MAPTRx demonstrates dose-dependent reduction of tau protein in phase 1/2 study (2021)
Unknown, Biogen. BIIB080 Tau ASO Program (n.d.)
[Mummery CJ, Börjesson-Hanson A, Berber S, et al, Tau-targeting antisense oligonucleotide BIIB080 in Alzheimer's disease: a phase 1b, randomised, placebo-controlled trial (2023)](https://doi.org/10.1038/s41591-023-02326-3)
[Miller T, Cudkowicz M, Shaw PJ, et al, Phase 1-2 Study of SOD1 Antisense Oligonucleotide Tofersen (2020)](https://pubmed.ncbi.nlm.nih.gov/33216194/)
[Rinaldi C, Wood MJA, Antisense oligonucleotides: the next frontier for treatment of neurological disorders (2018)](https://pubmed.ncbi.nlm.nih.gov/29249364/)
ALZFORUM, Tau-Targeting Therapeutics Pipeline (n.d.)
ALZFORUM, BIIB080 Therapeutics Database (n.d.)
ClinicalTrials.gov, NIO752 in Participants With Progressive Supranuclear Palsy (PSP) (n.d.)