Long-term safety and tolerability of bapineuzumab in patients with Alzheimer’s disease in two phase 3 extension studies

Abstract

BackgroundImmunotherapy with monoclonal antibodies that target amyloid beta has been under investigation as a treatment for patients with Alzheimer’s disease (AD). The 3000 and 3001 phase 3 clinical studies of intravenous bapineuzumab assessed safety and efficacy in patients with mild to moderate AD recruited in over 26 countries. This article describes the long-term safety and tolerability of bapineuzumab in the extension studies for these two protocols.MethodsThe long-term safety and tolerability of intravenous-administered bapineuzumab in patients with AD was evaluated in apolipoprotein E ε4 allele noncarriers (Study 3002, extension of Study 3000) and apolipoprotein E ε4 allele carriers (Study 3003, extension of Study 3001). Those receiving bapineuzumab in the parent study were continued at the same dose; if receiving placebo, patients began bapineuzumab. Bapineuzumab doses were 0.5 mg/kg in both studies and also 1.0 mg/kg in the noncarrier study. Clinical efficacy of bapineuzumab was also assessed in exploratory analyses.ResultsBecause of lack of efficacy in two other phase 3 trials, the parent protocols were stopped early. As a result, Studies 3002 and 3003 were also terminated. In total, 492 and 202 patients were enrolled in Studies 3003 and 3002, respectively. In apolipoprotein E ε4 carriers (Study 3003), treatment-emergent adverse events occurred in 70.7 % of the patients who originally received placebo and 66.9 % of those who originally received bapineuzumab. In noncarriers, treatment-emergent adverse events occurred in 82.1 % and 67.6 % of patients who received placebo + bapineuzumab 0.5 mg/kg and placebo + bapineuzumab 1.0 mg/kg, respectively, and in 72.7 % and 64.3 % of those who received bapineuzumab + bapineuzumab 0.5 mg/kg and 1.0 mg/kg, respectively. Amyloid-related imaging abnormalities with edema or effusions were the main bapineuzumab-associated adverse events in both studies, occurring in approximately 11 % of placebo + bapineuzumab and 4 % of bapineuzumab + bapineuzumab groups overall. Exploratory analyses of clinical efficacy were not significantly different between groups in either study.ConclusionsIn these phase 3 extension studies, intravenous bapineuzumab administered for up to approximately 3 years showed no unexpected safety signals and a safety profile consistent with previous bapineuzumab trials.Trial registrationNoncarriers (Study 3002): ClinicalTrials.gov NCT00996918. Registered 14 October 2009.Carriers (Study 3003): ClinicalTrials.gov NCT00998764. Registered 16 October 2009.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0193-y) contains supplementary material, which is available to authorized users.

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

“…Because Aβ is highly toxic to neuronal cells, extensive investigations have focused on the inhibition of Aβ production and accumulation as an effort to develop AD therapeutics. For example, a series of drug candidates targeting Aβ processing, including the γ-secretase inhibitor 3 , have been developed and evaluated in clinical trials for AD patients ( Figure 3 ) [ 37 , 38 , 39 ]. Although these drugs had therapeutic effects in AD animal models, they had low efficacies or side effects in AD patients.…”

Long-Term Follow Up of Patients with Mild-to-Moderate Alzheimer’s Disease Treated with Bapineuzumab in a Phase III, Open-Label, Extension Study

“…ARIA-E identified during both extension studies was the main bapineuzumabassociated AE, overall occurring in approximately 11% of placebo→bapineuzumab (pbo→bapi) and 4% of bapineuzumab→bapineuzumab (bapi→bapi) groups. Exploratory analysis showed that clinical efficacy was not significantly different between groups in either study [13].…”

“…Long term safety and tolerability of bapineuzumab in patients with AD were reported in two other extension studies that were terminated early due to lack of efficacy in phase III trials, Study 3002 with noncarriers (NCT00996918) and Study 3003 with carriers (NCT00998764) were continued from their two global phase III parent studies [13]. Patients who were receiving bapineuzumab continued at the same dose and patients receiving placebo began bapineuzumab in the extension studies.…”

The amyloid hypothesis is too good to be true

“…These trials lasted 3 years before they were discontinued due to adverse events and lack of clinical efficacy of bapineuzumab. A report of these two trials by Ivanolu et al [64] is a depressing read. In the 202 people with APOE4, treatment-emergent adverse events (TEAE) occurred in 71% of the people who originally had received placebo and 67% of those who had received bapineuzumab (NC-T00998764).…”

“…These trials "were conducted in accordance with principles set forth in the Declaration of Helsinki and according to good clinical practices established by the International Conference on Harmonisation". Ivanolu et al [64] finish the abstract of their paper by writing: "In these phase 3 extension studies, intravenous bapineuzumab administered for up to approximately 3 years showed no unexpected safety signals and a safety profile consistent with previous bapineuzumab trial." Solanezumab (Lilly) is a humanized mouse monoclonal antibody, which binds to the mid-domain of soluble Aβ peptides but not to the fibrillar form of insoluble Aβ amyloid.…”