Gosuranemab (BIIB092) - Anti-Tau Antibody Trial in Progressive Supranuclear Palsy
Gosuranemab (formerly BIIB092) is an anti-tau monoclonal antibody developed by Biogen that targets extracellular tau protein. The drug was evaluated in a Phase 2 clinical trial for Progressive Supranuclear Palsy (PSP) but was terminated due to lack of efficacy[1]. This trial represents one of the most significant failures in the anti-tau antibody field and provides critical lessons for future therapeutic development in tauopathies.
| Parameter | Value |
|---|---|
| NCT Number | NCT03068468 |
| Phase | Phase 2 |
| Status | TERMINATED (2019) |
| Sponsor | Biogen |
| Mechanism | Anti-tau monoclonal antibody (N-terminal tau) |
| Target | Extracellular tau protein |
| Population | PSP patients (Richardson syndrome) |
PSP is a 4R-tauopathy characterized by the accumulation of hyperphosphorylated 4-repeat tau isoforms in neurofibrillary tangles, tufted astrocytes, and coiled bodies in subcortical and brainstem structures[2]. The tau protein plays a central role in disease pathogenesis, making it an attractive therapeutic target.
Gosuranemab was designed based on the hypothesis that extracellular tau—released from dying neurons—mediates prion-like spreading of pathology throughout the brain[3]. The antibody was intended to:
This approach differed from intracellular-targeting strategies and represented a novel mechanistic hypothesis for disease modification in tauopathies.
The Phase 2 trial employed a randomized, double-blind, placebo-controlled design:
The trial included biomarker assessments to evaluate target engagement:
The Phase 2 trial in PSP was terminated early after interim analysis showed that the primary endpoint was unlikely to be met[1:1]. The trial failed to demonstrate significant clinical benefit compared to placebo:
The biomarker data revealed important insights:
The most widely cited explanation for failure relates to disease stage[4]:
Implication: Future trials may need to target pre-symptomatic or prodromal populations where tau pathology is more limited.
Several factors may have limited adequate target engagement[5]:
Implication: Alternative delivery methods (intrathecal, focused ultrasound) or different epitope targets may improve engagement.
The fundamental mechanism hypothesis may have been flawed[6]:
Implication: Intracellular-targeting approaches (ASOs, small molecules) may be more effective than extracellular-targeting antibodies.
PSP presents unique challenges compared to Alzheimer's disease[7]:
Implication: PSP may require different therapeutic approaches than AD; direct tau production reduction (ASOs) may be more appropriate.
The absence of robust biomarkers for target engagement complicated development[8]:
Implication: Development of better biomarkers for tau biology and treatment response is critical.
PSP-specific trial design issues may have contributed[9]:
Earlier intervention is critical
Improve brain penetration
Target the right tau species
Develop better biomarkers
Refine trial design for PSP
The gosuranemab failure contributed to a paradigm shift in tau therapeutic development[10]:
| Trial | Drug | Mechanism | Outcome | Key Learnings |
|---|---|---|---|---|
| PASSPORT | Gosuranemab | Anti-tau antibody | Failed | Extracellular targeting insufficient |
| NCT02460094 | Tilavonemab | Anti-tau antibody | Failed | Timing, target selection issues |
| NCT02880956 | Semorinemab | Anti-tau antibody | Mixed | Different effects in AD subpopulations |
| NCT03068467 | AbbVie programs | Various | Failed | 4R-tauopathies challenging |
The failure of antibody approaches shifted focus to tau-lowering ASOs[11]:
Alternative modalities under development:
Based on lessons from gosuranemab:
ClinicalTrials.gov. Study of BIIB092 in Participants With Progressive Supranuclear Palsy (PASSPORT). ↩︎ ↩︎
Boxer AL, Yu JT, Golbe LI, et al. New directions in clinical trials for tauopathies. Nat Rev Neurol. 2021. ↩︎
Yamada K, Cirrito JR, Stewart FR, et al. In vivo detection of sporadic and aggregated tau in the human brain. Neuron. 2011. ↩︎
Fotuhi M, M蹄ian V, Szabo P, et al. Time to treatment initiation in neurodegenerative disease: A review of preclinical and clinical evidence. Neurobiol Aging. 2019. ↩︎
Sigurdsson EM. Tau-focused immunotherapy: A promising strategy for treating Alzheimer's disease and other tauopathies. Acta Neuropathol Commun. 2019. ↩︎
Guo JL, Lee VM. Cell-to-cell transmission of pathogenic tau proteins in Alzheimer's disease and related tauopathies. Acta Neuropathol. 2014. ↩︎
Dickson DW, Ahmed Z, Algom AA, et al. Neuropathology of variants of progressive supranuclear palsy. Mov Disord. 2010. ↩︎
Blennow K, Zetterberg H. The past and future of Alzheimer's disease fluid biomarkers. J Alzheimers Dis. 2018. ↩︎
Boxer AL, Lang AE, Grossman M, et al. Clinical trial designs for progressive supranuclear palsy. Mov Disord. 2016. ↩︎
Wilcock GK. The future of Alzheimer's disease: A matter of targeting. Brain. 2019. ↩︎
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. ↩︎