Background: Progressive Supranuclear Palsy (PSP) is a rare, fatal neurodegenerative tauopathy with no approved disease-modifying therapies. The spread of tau pathology, potentially mediated by extracellular N-terminal (N-t) tau, is a key therapeutic target. Monoclonal antibodies emerge as a treatment option for this disease.

Methods: A systematic review was conducted using the PubMed, Embase, and Cochrane databases, with the terms “progressive supranuclear palsy,” “monoclonal antibody,” and their variations, connected by the Boolean operator AND. The inclusion criteria were cohort studies or randomized trials, while the exclusion criteria involved studies with patients presenting associated psychiatric or neurological comorbidities, interventions other than monoclonal antibody therapy, and abstracts without full-text articles. The Rayyan platform was used for blinded screening by two reviewers. Among the 713 articles identified, after removing duplicates, only 3 met the inclusion and exclusion criteria.

Results: All studies reported acceptable safety profiles, similar to placebo. Boxer et al. established robust target engagement for gosuranemab, reducing unbound CSF N-t tau by 91–97% at day 85. This potent biochemical effect was confirmed by Dam et al., which showed a 98.11% reduction in unbound CSF N-t tau at week 52 (P<0.0001). Despite this, Dam et al. failed its primary efficacy endpoint: the adjusted mean change in the PSPRS score at week 52 was 10.4 (gosuranemab) versus 10.6 (placebo) (Difference -0.2, P=0.8483). Secondary endpoints were also negative. Similarly, Höglinger et al. assessing tilavonemab confirmed target engagement with significant reductions in CSF free tau (P<0.0001). However, this trial also failed its primary PSPRS endpoint (4000mg vs placebo: Diff 1.0, P=0.46) and was terminated early for futility.

Conclusions: N-t tau monoclonal antibodies gosuranemab and tilavonemab successfully and potently engage their target in the CSF of PSP patients and are well tolerated. However, Dam et al. and Höglinger et al. conclusively demonstrate that this specific mechanism, neutralizing extracellular N-terminal tau, does not translate into clinical efficacy or slow disease progression in symptomatic PSP.