Two Phase 3 Trials of Bapineuzumab in Mild-to-Moderate Alzheimer's Disease

Abstract

BACKGROUND Bapineuzumab, a humanized anti–amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer’s disease. METHODS We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer’s disease — one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. RESULTS There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were −0.2 (P = 0.80) and −1.2 (P = 0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were −0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. CONCLUSIONS Bapineuzumab did not improve clinical outcomes in patients with Alzheimer’s disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.)

Long-Term Cognitive Improvement After Benfotiamine Administration in Patients with Alzheimer’s Disease

“…These results reveal two important messages: (1) the progression of brain dysfunction in the dementia stage of AD can be halted and even improved, and (2) the alteration of cognitive capability is independent of brain amyloid accumulation, which is consistent with previous results showing that the reduction of brain amyloid accumulation by vaccines, antibodies, or b-and c-secretase inhibitors has little beneficial effect on the cognitive ability and disease progression of AD patients [1][2][3][4]. The brain has the most abundant energy consumption in the human body, and the maintenance of its function is dependent on energy metabolism.…”

“…To date, almost all clinical trials aiming to halt or delay AD progression have failed. Particularly, multiple approaches such as vaccines, antibodies, and b or c-secretase inhibitors, have been exploited to reduce amyloid deposition in the brain but have little beneficial effect on the cognitive ability of AD patients [1][2][3][4]. Generally, the failure in cognitive improvement is attributed to the fact that these therapies were performed on patients at the dementia stage of AD, and this may be too late.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Some cognitive and functional improvements were observed in a subset of apolipoprotein E ε4 noncarriers [17], which prompted 4 additional phase 3 trials. Two completed trials failed to show effect on either cognitive or functional outcomes, and the other trials were discontinued [10]. Gantenerumab was shown to bind to cerebral Aβ in APP/presenilin 1 (PS1) transgenic mouse model, to reduce amyloid burden in mouse brain, and to prevent the formation of new plaque [19].…”

“…Accordingly, Aβ-based therapeutics have been extensively investigated in preclinical models and clinical trials. Most prominently, phase 3 trials have been performed on drugs that lower Aβ by inhibiting its production [7,8] and lowering its levels by immunotherapy [9,10], all of which failed to reach their respective clinical endpoints. There is an urgent need, therefore, for fresh approaches to treat AD.…”

Prevention Studies in Alzheimer’s Disease: Progress Towards the Development of New Therapeutics

“…For instance, there may have been too much focus on Ab, which may not be the right target for an effective AD treatment [13][14][15], or the drugs tested so far may not have been targeting the right form of amyloid [16]. Furthermore, the AD subjects recruited to these trials may have been very heterogeneous and not all may have had evidence of amyloid plaques [17]. Finally, a widely held belief is that intervening at the dementia stage may be too late, and that putative disease-modifying agents, particularly anti-amyloid therapies, should be initiated earlier in the disease process [18][19][20][21].…”