Safety, tolerability, and efficacy of bepranemab in people living with prodromal-to-mild Alzheimer's disease: a randomised, double-blind, placebo-controlled, Phase 2 trial

Tau aggregation is a defining feature of the pathophysiology of Alzheimer's disease and an appealing therapeutic target, yet tau-directed antibodies tested to date-primarily targeting N-terminal epitopes-have failed to slow tau progression or cognitive decline.

Bepranemab targets the tau mid-region, predicted in cell-based assays to more effectively block neuron-to-neuron tau spread than anti-tau antibodies targeting the N-terminus. We aimed to investigate the safety and efficacy of bepranemab in slowing progression of tau pathology and clinical decline in people with prodromal-to-mild Alzheimer's disease.

This double-blind, placebo-controlled, Phase 2 trial recruited participants across 101 outpatient sites in Europe (eight countries), Canada, and the USA. Participants (aged 50-80 years) with prodromal-to-mild Alzheimer's disease were randomly assigned 1:1:1 (using an interactive response system) to intravenous bepranemab 45 mg/kg, bepranemab 90 mg/kg, or placebo (every 4 weeks for 76 weeks), stratified by diagnosis, apolipoprotein E ɛ4 carrier status, and symptomatic treatment use.

The primary endpoint was change from baseline to week 80 in Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB) total score. Efficacy was assessed in the full analysis set (ie, all randomly assigned participants who received at least a partial dose of trial medication and had at least one valid post-baseline clinic visit and efficacy assessment).

Safety was assessed in all randomly assigned participants who received at least a partial dose of the trial medication. No imputation was done for missing data.

The trial is registered at ClinicalTrials.gov (NCT04867616) and is complete.

Between Aug 24, 2021, and Oct 25, 2022, 466 participants were randomly assigned to bepranemab 45 mg/kg (n=154), bepranemab 90 mg/kg (n=155), or placebo (n=157) at 85 sites. Median age was 72·0 years (IQR 66·0-76·0), 259 (56%) were female, and 207 (44%) were male.

In total, 460 participants were included in the full analysis set: bepranemab 45 mg/kg (n=152), bepranemab 90 mg/kg (n=152), and placebo (n=156). Least-squares mean CDR-SB total score change from baseline to week 80 was 2·15 in the bepranemab 90 mg/kg group and 1·85 in the bepranemab 45 mg/kg group versus 1·81 in the placebo group, with differences versus placebo of 0·34 (95% CI -0·09 to 0·78, p=0·12; 80% CI 0·06 to 0·63) for the bepranemab 90 mg/kg group and 0·04 (-0·40 to 0·47, p=0·87; -0·25 to 0·32) for the bepranemab 45 mg/kg group.

Frequency of treatment-emergent adverse events with bepranemab was similar to the placebo group (139 [9a clinically meaningful level] with bepranemab 45 mg/kg, 140 [9a clinically meaningful level] with bepranemab 90 mg/kg, and 142 [90%] with placebo); no treatment-related neuroinflammatory safety signals were identified clinically or on brain MRI scans. There were adverse events leading to death in four participants in the combined bepranemab groups and six (4%) in the placebo group; none were considered related to the trial treatment.

Treatment with bepranemab was associated with an acceptable safety profile.

However, the primary endpoint was not met. Hypothesis-generating differences favouring bepranemab in tau PET and 14-item Alzheimer's Disease Assessment Scale-Cognitive Subscale should be tested prospectively in trials powered for tau PET outcomes and stratified by baseline tau burden and apolipoprotein E ɛ4 status.