UCB's bepranemab, an investigational anti-tau antibody, has demonstrated encouraging results in a Phase 2a study for individuals with prodromal to mild Alzheimer's disease. The TOGETHER study (AH0003) investigated the safety, efficacy, and tolerability of bepranemab, which targets the mid-region of the tau protein. Data presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) meeting in Madrid, Spain, revealed that bepranemab slowed tau accumulation and cognitive decline in the overall study population, with more pronounced effects observed in specific subgroups.
Overall Study Population Results
While the primary endpoint, the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) total score at Week 80, did not show a significant difference between bepranemab and placebo, key secondary endpoints indicated positive trends. 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, as measured by the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) total score, was reduced by 21-25% with bepranemab treatment versus placebo.
Subgroup Analysis Highlights Enhanced Efficacy
Subgroup analyses revealed more pronounced treatment benefits in participants with low tau burden at baseline and APOε4 non-carriers. In this subgroup, high-dose bepranemab (90mg/kg) slowed tau accumulation in key brain regions by 63-67% at Week 80 compared to placebo. Clinical disease progression, measured by the change in CDR-SB between baseline and Week 80, was slowed by 29%. Secondary and exploratory endpoints, including measures of Activities of Daily Living, showed a 41-54% reduction in disease progression at Week 80.
Conversely, in participants with high tau at baseline who were also APOε4 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 exhibited 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 across treatment arms. The most frequently 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%).
Study Design and Patient Population
The TOGETHER study is a Phase 2a double-blind, placebo-controlled trial with three arms, randomizing patients to placebo, low-dose bepranemab, or high-dose bepranemab. A total of 466 patients participated in the study and were treated in the double-blind phase for 80 weeks. The majority of participants have now entered a 48-week open-label extension (OLE) period, with planned bepranemab treatment for 44 weeks, followed by a safety follow-up visit 20 weeks after the last infusion.
Mechanism of Action
Bepranemab is a monoclonal antibody (mAb) that specifically targets a mid-region epitope of human tau. This region is thought 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.
"We are deeply encouraged by the proof-of-concept data for bepranemab, which highlight its potential to impact early Alzheimer’s disease progression," said Alistair Henry, Chief Scientific Officer at UCB. "This strengthens our belief in the value of targeting the mid-region of tau as an important strategy in altering the trajectory of the disease."
