UCB's bepranemab, an investigational anti-tau antibody, has demonstrated encouraging Phase 2a data in slowing tau accumulation and cognitive decline in individuals with prodromal to mild Alzheimer's disease. The TOGETHER study (AH0003) results, presented at the 2024 Clinical Trials on Alzheimer's Disease (CTAD) meeting, suggest a potential impact on early Alzheimer's disease progression by targeting the mid-region of the tau protein.
TOGETHER Study Results
The Phase 2a trial was a double-blind, placebo-controlled study with three arms, randomizing patients to placebo, low-dose bepranemab, or high-dose bepranemab. A total of 466 patients participated in the study for 80 weeks. While the primary endpoint, Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score at Week 80, did not show a beneficial effect in the overall study population, key secondary endpoints revealed significant improvements.
Treatment with bepranemab (45mg/kg and 90mg/kg) slowed the rate of tau accumulation in key brain regions by 33%-58% compared to placebo at Week 80. Furthermore, cognitive decline was reduced by 21-25% versus placebo, as measured by the change between Baseline and Week 80 in the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) total score.
Subgroup Analysis
In a pre-defined subgroup of patients with low tau burden at baseline and APOE4 non-carriers (approximately 50% of the study population), high-dose bepranemab (90mg/kg) showed even more pronounced effects. This subgroup experienced a 63%-67% reduction in the rate of tau accumulation in key brain regions versus placebo at Week 80. Clinical disease progression, as measured by the change in CDR-SB between Baseline and Week 80, was slowed by 29%.
Additionally, secondary/exploratory endpoints, including measures of Activities of Daily Living, showed a 41-54% slowing of disease progression at Week 80 in this subgroup. However, in participants with high tau at Baseline who were also APOE4 carriers, high-dose bepranemab showed no benefit across almost all clinical endpoints, with effects on CDR-SB, A-iADL-Q and ADCS-ADL scores favoring the placebo arm.
Safety and Tolerability
Bepranemab demonstrated an acceptable safety profile and was generally well tolerated. The incidence of brain haemorrhagic and inflammatory changes was similar between the placebo and bepranemab treatment arms. Treatment Emergent Adverse Events (TEAEs), drug-related TEAEs, and TEAEs leading to dropout were comparable between the treatment arms. The most reported TEAEs were infections and infestations (placebo 50.3% / bepranemab 50.2%), nervous system disorders (placebo 40.1% / bepranemab 35.2%) and musculoskeletal disorders (placebo 26.8% / bepranemab 28.3%).
Mechanism of Action
Bepranemab is a monoclonal antibody (mAb) that specifically targets a mid-region epitope of human tau. The mid-region of tau is believed to be essential for tau aggregation and a key driver of neurodegeneration in Alzheimer’s disease. By targeting this region, bepranemab aims to prevent tau seeding and propagation, potentially slowing disease progression.
