Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials

Abstract

BackgroundOur objective was to evaluate the efficacy (clinical and biomarker) and safety of intravenous bapineuzumab in patients with mild to moderate Alzheimer’s disease (AD).MethodsTwo of four phase 3, multicenter, randomized, double-blind, placebo-controlled, 18-month trials were conducted globally: one in apolipoprotein E ε4 carriers and another in noncarriers. Patients received bapineuzumab 0.5 mg/kg (both trials) or 1.0 mg/kg (noncarrier trial) or placebo every 13 weeks. Coprimary endpoints were change from baseline to week 78 on the 11-item Alzheimer’s Disease Assessment Scale–Cognitive subscale and the Disability Assessment for Dementia.ResultsA total of 683 and 329 patients completed the current carrier and noncarrier trials, respectively, which were terminated prematurely owing to lack of efficacy in the two other phase 3 trials of bapineuzumab in AD. The current trials showed no significant difference between bapineuzumab and placebo for the coprimary endpoints and no effect of bapineuzumab on amyloid load or cerebrospinal fluid phosphorylated tau. (Both measures were stable over time in the placebo group.) Amyloid-related imaging abnormalities with edema or effusion were confirmed as the most notable adverse event.ConclusionsThese phase 3 global trials confirmed lack of efficacy of bapineuzumab at tested doses on clinical endpoints in patients with mild to moderate AD. Some differences in the biomarker results were seen compared with the other phase 3 bapineuzumab trials. No unexpected adverse events were observed.Trial registrationNoncarriers (3000) ClinicalTrials.gov identifier NCT00667810; registered 24 Apr 2008.Carriers (3001) ClinicalTrials.gov identifier NCT00676143; registered 2 May 2008.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0189-7) contains supplementary material, which is available to authorized users.

Patients Who Attend Alone at a First Memory Consultation: Are They a Specific Population,or Is It an Instance of Confounding Bias?

“…Studies have tended not to highlight whether patients came alone or accompanied. For example, in the latest studies [22,23] on humanized monoclonal antibodies which failed to prove their effectiveness, this point did not appear, despite a very precise methodology. Likewise, numerous studies have highlighted factors associated with a faster rate of cognitive decline [24,25], but the modalities of the first consultation are also not clearly defined.…”

The role of PI3K/AKT pathway and its therapeutic possibility in Alzheimer's disease

“…Another phase 1 clinical trial for immunotherapy targeting Aβ was completed with GSK933776 [30], but further clinical trials have not yet been started. Besides, AN1792 [31] and Bapimeuzumab [32], which were developed for immunotherapies to reduce Aβ, were tested in several clinical trials for AD patients, but all of them did not reach the primary endpoint or were ceased due to severe adverse effects. Several different drugs reducing Aβ with different mechanisms were also tried for the treatment of AD patients, but all of them unfortunately failed to show efficacy so far: namely, Tramiprosate (a small and orally-administered compound that binds to soluble Aβ and reduces amyloid aggregation and subsequent deposition) did not confirm any efficacy in a randomized, double-blind, placebo-controlled, multi-center study [33]; Tarenflurbil, a selective Aβ42-lowering agent, did not slow cognitive decline or the loss of activities of daily living in patients with mild AD in a phase 3 trial [34]; Semagacestat, a small-molecule-secretase inhibitor reducing Aβ, did not improve cognitive status and patients receiving the higher dose had significant worsening of functional ability [35]; Avagacestat, an arylsulfonamide-secretase inhibitor did not demonstrate efficacy and was associated with adverse doselimiting effects [36]; and intravenous immune globulin (IVIG) was reported not to show any efficacy in a phase 2 and 3 study evaluating safety and effectiveness of IVIG for the treatment of mild-to-moderate AD [37].…”

Lessons from Anti-Amyloid-β Immunotherapies in Alzheimer Disease: Aiming at a Moving Target

“…However, the lack of significant cognitive improvement in either group, together with the negative imaging outcomes, led to the discontinuation of this antibody [25]. Two additional trials with the same structure of ApoE 4 carriers and noncarriers were conducted in multiple countries with a similar lack of functional effectiveness, but without adverse effects [26]. Other studies have reported improved brain volume in imaging and plaque reduction in patients treated with bapineuzumab [27,28], but the relevance of these observations is not clear since functional studies have reported no significant benefits.…”