Safety, tolerability and biomarker results of bepranemab in participants with progressive supranuclear palsy: a randomised, multicentre, double-blind, placebo-controlled, phase 1b trial.

Background: Preclinical evidence suggests targeting the mid-region of tau as a viable therapeutic strategy in diseases such as progressive supranuclear palsy (PSP): a rare, fatal, neurodegenerative tauopathy with no currently approved treatments. Bepranemab is a recombinant, humanised, full-length immunoglobulin G4 monoclonal antibody binding to a mid-region tau epitope. We assessed safety, tolerability and pharmacokinetics of bepranemab in participants with PSP. Methods: PSP003 (NCT04185415), a multicentre, double-blind, placebo-controlled, phase 1b study, recruited participants in hospital settings across 13 centres. Participants (aged ≥40 years) met Movement Disorder Society-PSP criteria for possible/probable PSP, could walk ≥5 steps with minimal/no assistance and were stable on treatment for ≥2 weeks prior to baseline. Participants were randomised 3:1 to receive intravenous bepranemab (90 mg/kg) or placebo every 4 weeks for 52 weeks. Primary endpoint: incidence of treatment-emergent adverse events (TEAEs) from baseline to last visit. Results: Twenty-five participants were enrolled (male: 44%; bepranemab n=18, placebo n=7). Seventeen (94.4%) in the bepranemab group reported ≥1 TEAE (five participants; ten investigational medicinal product (IMP)-related TEAEs), versus placebo (n=7; 100%). In the bepranemab and placebo groups, respectively, three participants (16.7%) and one participant (14.3%) discontinued due to TEAEs. Incidence of IMP-related TEAEs and severe TEAEs was similar between groups; no deaths were reported. Reduction (80.41%) in mean free tau cerebrospinal fluid levels was observed in the bepranemab group. Conclusions: Multiple doses of bepranemab 90 mg/kg were well tolerated with an acceptable safety profile in participants with PSP. High target occupancy was observed.