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 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[1][2].
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[3].
BIIB080 is a gapmer-type antisense oligonucleotide that:
This approach is mechanistically analogous to tofersen (BIIB067) for SOD1 ALS, which demonstrated significant protein reduction and clinical benefit in open-label extension studies[4].
BIIB080 is administered via intrathecal injection (lumbar puncture), which bypasses the 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[5].
The first-in-human Phase 1 study established the safety and tolerability of BIIB080 in patients with mild Alzheimer's disease:
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[6].
The Phase 1b trial (published in Nature Medicine, 2023) demonstrated significant biomarker effects[3:1]:
| 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[3:2][7].
| 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 |
PSP is a 4R-tauopathy characterized by accumulation of 4-repeat tau isoforms in neurofibrillary tangles, tufted astrocytes, and coiled bodies. Unlike Alzheimer's disease, PSP has no approved disease-modifying treatments[6:1].
BIIB080 is particularly relevant for PSP because:
Beyond BIIB080, several other antisense oligonucleotide programs are targeting tau reduction:
NIO752 is a tau-targeting ASO developed by Novartis that also binds to MAPT mRNA[8]:
The NIO752 trial was important because it demonstrated that tau ASO approaches could work in 4R-tauopathies like PSP, where the 4R isoform predominates.
Several academic groups and pharmaceutical companies have tau-targeting ASO programs in preclinical development:
The tau ASO approach offers several advantages over other modalities:
Tau ASO trials face unique challenges:
Ionis Pharmaceuticals. (2021). IONIS-MAPTRx demonstrates dose-dependent reduction of tau protein in phase 1/2 study. Ionis Press Release. 2021. ↩︎
Biogen. BIIB080 Tau ASO Program. Investor Presentation. ↩︎
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. Nature Medicine. 2023. ↩︎ ↩︎ ↩︎
Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1-2 Study of SOD1 Antisense Oligonucleotide Tofersen. NEJM. 2020. ↩︎
Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018. ↩︎
ALZFORUM. Tau-Targeting Therapeutics Pipeline. ↩︎ ↩︎
ALZFORUM. BIIB080 Therapeutics Database. ↩︎
ClinicalTrials.gov. NIO752 in Participants With Progressive Supranuclear Palsy (PSP). ↩︎