BIIB080 (MAPTRx)

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 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^{1Ionis Pharmaceuticals. (2021). IONIS-MAPTRx demonstrates dose-dependent reduction of tau protein in phase 1/2 study2021 · Ionis Press ReleaseOpen reference2Biogen. BIIB080 Tau ASO ProgramInvestor PresentationOpen reference}.

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^{3Tau-targeting antisense oligonucleotide BIIB080 in Alzheimer's disease: a phase 1b, randomised, placebo-controlled trial2023 · Nature Medicine · DOI 10.1038/s41591-023-02326-3Open reference}.

Mechanism of Action

BIIB080 is a gapmer-type antisense oligonucleotide that:

1. Binds to MAPT mRNA — The MAPT gene encodes the tau protein, which is involved in microtubule stabilization in neurons

2. Triggers RNase H degradation — The ASO-RNA duplex recruits RNase H, which degrades the target mRNA

3. Reduces tau production — Decreases both 3R and 4R tau isoforms at the transcriptional level

4. Potential disease modification — By reducing tau at its source, rather than targeting extracellular tau like antibodies

This approach is mechanistically analogous to tofersen (BIIB067) for SOD1 ALS, which demonstrated significant protein reduction and clinical benefit in open-label extension studies^{4Phase 1-2 Study of SOD1 Antisense Oligonucleotide Tofersen2020 · NEJM · PMID 33216194Open reference}.

Delivery Method

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^{5Antisense oligonucleotides: the next frontier for treatment of neurological disorders2018 · Nat Rev Neurol · PMID 29249364Open reference}.

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^{6Tau-Targeting Therapeutics PipelineOpen reference}.

Biomarker Data

The Phase 1b trial (published in Nature Medicine, 2023) demonstrated significant biomarker effects^{3Tau-targeting antisense oligonucleotide BIIB080 in Alzheimer's disease: a phase 1b, randomised, placebo-controlled trial2023 · Nature Medicine · DOI 10.1038/s41591-023-02326-3Open reference}:

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^{3Tau-targeting antisense oligonucleotide BIIB080 in Alzheimer's disease: a phase 1b, randomised, placebo-controlled trial2023 · Nature Medicine · DOI 10.1038/s41591-023-02326-3Open reference7BIIB080 Therapeutics DatabaseOpen reference}.

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

1. Direct target reduction — Reduces tau at the source (mRNA level), unlike antibodies that target extracellular protein

2. Broad isoform coverage — Reduces all tau isoforms (3R, 4R, and 6R)

3. Clear pharmacodynamics — Direct measurement of CSF tau provides clear target engagement readouts

4. Potential for combination — Could be combined with amyloid-targeting therapies like donanemab

Challenges

1. Intrathecal delivery — Requires lumbar puncture, which is more invasive than IV infusion

2. Long-term safety — Requires monitoring for off-target effects with chronic dosing

3. Access — Requires specialized centers for administration

Relevance to PSP

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^{6Tau-Targeting Therapeutics PipelineOpen reference}.

BIIB080 is particularly relevant for PSP because:

1. Upstream targeting — Reduces all tau production, addressing the fundamental pathology

2. 4R tau reduction — Reduces the pathogenic 4R isoform predominant in PSP

3. Proven engagement — Demonstrated CSF tau lowering in humans

4. No viable alternatives — Tilavonemab failed in PSP, highlighting need for new approaches

Related Tau-Targeting ASO Programs

Beyond 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^{2Biogen. BIIB080 Tau ASO ProgramInvestor PresentationOpen reference}0:

• 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:

1. Genetic validation — MAPT mutations cause tauopathies, validating tau reduction as a therapeutic strategy

2. Broad coverage — Reduces all tau isoforms (3R, 4R, 6R) rather than targeting specific conformations

3. Upstream intervention — Reduces tau at production rather than after aggregation

4. Biomarker access — CSF tau provides direct readouts of target engagement

Clinical 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

^{2Biogen. BIIB080 Tau ASO ProgramInvestor PresentationOpen reference}1: ClinicalTrials.gov. NIO752 in Participants With Progressive Supranuclear Palsy (PSP). NCT04539041.

Related Pages

• Tau Protein

• MAPT Gene

• ^{2Biogen. BIIB080 Tau ASO ProgramInvestor PresentationOpen reference}2(/companies/biogen)

• Ionis Pharmaceuticals

• Progressive Supranuclear Palsy

• Clinical Trials in PSP

• Tau-Targeting Therapeutics Pipeline

• Antisense Oligonucleotide Delivery

• Intrathecal Delivery

• 4R Tauopathies

External Links

• ClinicalTrials.gov: NCT05399888

• ClinicalTrials.gov: NCT03713905

• Allen Human Brain Atlas

• Biogen Investor Relations

• Ionis Pharmaceuticals