BACKGROUND:

Alzheimer's disease (AD) is a globally prevalent neurodegenerative condition, clinically characterized by progressive memory loss and gradual impairment of cognitive functions. Bapineuzumab is a fully humanized monoclonal antibody that binds to neurotoxic amyloid proteins in the brain, enhancing their clearance. We performed this systematic review and meta-analysis to evaluate the safety and efficacy of bapineuzumab in patients with mild to moderate Alzheimer's disease.

METHODS:

We performed a web-based literature search of PubMed, Ovid, EBSCO, Scopus, Embase, Cochrane CENTRAL, and web of science using the relevant keywords. Data were extracted from eligible records and pooled as mean difference (MD) or risk ratio (RR) values with their 95% confidence interval (CI), using Review Manager software (version 5.3 for windows). Heterogeneity was measured by Chi-square and I-square tests.

RESULT:

The pooled effect estimate from six randomized clinical trials (n = 2380) showed that bapineuzumab significantly reduced the cerebrospinal fluid concentration of phosphorylated tau proteins (Standardized MD = -5.53, 95% CI [-8.29, -2.76]). However, the bapineuzumab group was not superior to the placebo group in terms of change from baseline in Alzheimer's disease assessment scale (ADAS)-Cog11 (MD = 0.14, 95% CI [-0.72, 0.99]), disability assessment for dementia (DAD) scale (MD = 1.35, 95% CI [-1.74, 4.43]), and mini-mental state examination (MMSE) scores (MD = 0.08, 95% CI [-0.31, 0.47]). Regarding safety, bapineuzumab increased the risk of serious treatment-emergent adverse events (RR = 1.18, 95% CI [1.02, 1.37]) and cerebral vasogenic edema (RR = 40.88, 95% CI [11.94, 135.95]). All bapineuzumab doses (0.15, 0.5, 1, and 2 mg/kg) were similar to placebo in terms of change from baseline in ADAS-cog11, DAD, and MMSE scores, except for the 0.15 mg/kg dose, which caused a significant worsening on the ADAS-cog11 scale (MD = 5.6, 95% CI [0.22, 10.98]).

CONCLUSIONS:

Considering the lack of clinical efficacy, combined with the significant association with serious adverse events, bapineuzumab should not be used to treat patients with mild to moderate AD. Future studies should investigate the effect of combining bapineuzumab with other therapeutic strategies and reevaluate the efficacy of targeting amyloid β proteins in AD therapy.

Introduction: Alzheimer's disease (AD) is a globally prevalent neurodegenerative condition, clinically characterized by progressive memory loss and gradual cognitive functions impairment. Passive immunotherapy with monoclonal antibodies such as bapineuzumab has been proven to reduce amyloid ß protein load in the brain in preclinical and human trials. We performed a systematic review of published randomized clinical trials (RCTs) to investigate the safety and efficacy of bapineuzumab in patients with mild to moderate AD.

METHODS:

A computer literature search of PubMed, OVID, EBSCO, Scopus, EMBASE, Web of Science, and Cochrane CENTRAL has been conducted using relevant keywords. Eligible studies were included after abstract and full text screening. Heterogeneity was measured by chi-square and I-square tests. Statistical analysis was performed by Review Manager Version 5.3 for windows.

RESULTS:

Six RCTs (n= 2380) were eligible for the final analysis. The overall effect estimate did not favor bapineuzumab over placebo regarding the clinical outcomes including; ADAS-Cog11 (MD = 0.14, 95% CI [-0.72, 0.99]), DAD (MD = 1.35, 95% CI [-1.74, 4.43]), CDR-SOB (MD = 0.21, 95% CI [-0.07, 0.49], and MMSE (MD = 0.08, 95% CI [-0.31, 0.47]). Analysis of the key biomarker outcomes showed that bapineuzumab significantly reduced the concentration of phosphorylated tau proteins (SMD =-5.53, 95% CI [-8.29,-2.76]). However, bapineuzumab was not superior to placebo in terms of SUVR (SMD =-0.56, 95% CI [-1.24, 0.13]) and MRI whole-brain volume measurement (SMD = 0.09, 95% CI [-0.02, 0.21]). In terms of safety, bapineuzumab increased the risk of serious TEAEs (RR= 1.18, 95% CI [1.02-1.37]) and amyloid related imaging abnormalities (RR = 40.88, 95% CI [11.94, 135.95]). None of the other adverse events were higher in the bapineuzumab group compared to placebo group.

CONCLUSION:

Although bapineuzumab effectively reduced phosphorylated tau protein CSF concentration, this was not associated with improved clinical outcomes. Moreover, bapineuzumab significantly increased the risk of serious TEAEs and amyloid related imaging abnormalities. In light of the current evidence, bapineuzumab should not be used for treatment of patients with mild to moderate AD.

Background: This clinical trial aimed to assess the effect of monthly subcutaneous bapineuzumab, a monoclonal anti-amyloid antibody, on cerebral amyloid burden, cognition, and functional ability, and to estimate the incidence of amyloid-related imaging abnormalities-edema/ effusion (ARIA-E) with this treatment regimen. Methods: Subjects (50-89 years old, n=146) with mild to moderate AD (MMSE 18-26) and increased amyloid burden on florbetapir PET were randomized to 2, 7 or 20 mg/mo subcutaneous bapineuzumab or placebo in a 1:1:1:1 ratio. Florbetapir PET was to be repeated after 6, 12, and 24 months; MRI (to assess for ARIA-E) every 3 months; and the 11 item ADAS-Cog and DAD at 3, 6, 12, 18, and 24 months. With the negative efficacy results of 2 trials of intravenous bapineuzumab reported in August, 2012, this protocol was amended to reduce the treatment duration to 12 months. Results: Baseline demographics and results are presented in the Table. There was a statistically significant reduction from baseline to month 12 in mean florbetapir PET global cortical average standard uptake value ratio (GCA SUVr) for 7 mg/mo, but no significant differences relative to placebo for any dosage. There were no differences relative to placebo for clinical outcomes at month 12. Only 2 cases of ARIA-E occurred, at 6 months in an ApoE e 4 noncarrier receiving 20 mg/mo (2.7%), and at 9 months in a carrier receiving 2 mg/mo (2.7%). Both cases were asymptomatic, resolved after interruption of bapineuzumab, and did not recur on rechallenge. Conclusions: Monthly SC injections of bapineuzumab 2, 7, and 20 mg for 12 months were generally well tolerated. The incidence proportion of asymptomatic ARIA-E appeared lower for monthly subcutaneous dosages than for equivalent q3m intravenous dosages in prior studies 1. However, the current study did not demonstrate a statistically significant treatment effect on amyloid burden as assessed by florbetapir PET. It is possible that the lack of demonstrable effects on biomarkers and clinical outcomes is related to the truncated treatment duration from 24 to 12 months. (Table Presented).

Background: Brain atrophy and ventricular enlargement are welldescribed phenomena in AD, reflecting the extent of neurofibrillary pathology and cumulative neuronal and synaptic loss. In this randomized controlled trial, the effect of bapineuzumab, a monoclonal anti-amyloid antibody, on rate of change of whole brain, ventricular, and hippocampal volume in subjects with mild to moderate AD was assessed with volumetric MRI (vMRI). These findings were compared to those seen in a large observational dataset, the Alzheimer's Disease Neuroimaging Initiative (ADNI-1). Methods: Subjects with mild to moderate AD (MMSE 18-26) and evidence of amyloid burden of florbetapir PET were randomized to 2, 7, or 20 mg/mo of subcutaneous (SC) bapineuzumab or placebo. 3DT1 MRI was obtained at baseline and every 3 months thereafter and volumetric analyses were performed at 6 month intervals. The planned treatment duration was shortened from 24 to 12 months after the negative results of 2 Phase 3 IV bapineuzumab studies became known. The boundary shift integral (BSI) method was used to measure annualized rate of change from baseline in brain, ventricular, and hippocampal volumes (BBSI, VBSI, and HBSI, respectively), and a mixed-effect model for repeated measures (MMRM) analysis assessed treatment effects at the 6 and 12 month visits. Results: A total of 118 subjects had at least one followup vMRI. There were no significant treatment differences in BBSI, VBSI, or RHBSI, but LHBSI was significantly greater for subjects receiving 20 mg/mo bapineuzumab, and there was a trend for 7 mg/mo (Table). Annualized volume loss were similar for placebo treated subjects and subjects with mild AD in ADNI-1. Conclusions: In this small sample, SC bapineuzumab was associated with a slight reduction in left hippocampal volume at a dosage of 20 mg/mo, equivalent to 0.5 mg/kg every 3 months IV. Similar rates of brain volume loss were seen in this clinical trial population as in the mild AD subjects in the ADNI-1 dataset.

Background: Brain atrophy and ventricular enlargement are well-described phenomena in AD, reflecting the extent of neurofibrillary pathology and cumulative neuronal and synaptic loss. In this randomized controlled trial, the effect of bapineuzumab, a monoclonal anti-amyloid antibody, on rate of change of whole brain, ventricular, and hippocampal volume in subjects with mild to moderate AD was assessed with volumetric MRI (vMRI). These findings were compared to those seen in a large observational dataset, the Alzheimer's Disease Neuroimaging Initiative (ADNI-1). Methods: Subjects with mild to moderateAD(MMSE 18-26) and evidence of amyloid burden of florbetapir PET were randomized to 2, 7, or 20 mg/mo of subcutaneous (SC) bapineuzumab or placebo. 3DT1 MRI was obtained at baseline and every 3 months thereafter and volumetric analyses were performed at 6 month intervals. The planned treatment duration was shortened from 24 to 12 months after the negative results of 2 Phase 3 IV bapineuzumab studies became known. The boundary shift integral (BSI) method was used to measure annualized rate of change from baseline in brain, ventricular, and hippocampal volumes (BBSI, VBSI, and HBSI, respectively), and a mixedeffect model for repeated measures (MMRM) analysis assessed treatment effects at the 6 and 12 month visits. Results: A total of 118 subjects had at least one followup vMRI. There were no significant treatment differences in BBSI, VBSI, or RHBSI, but LHBSI was significantly greater for subjects receiving 20 mg/mo bapineuzumab, and there was a trend for 7 mg/mo (Table). Annualized volume loss were similar for placebo treated subjects and subjects with mild AD in ADNI-1. Conclusions: In this small sample, SC bapineuzumab was associated with a slight reduction in left hippocampal volume at a dosage of 20 mg/mo, equivalent to 0.5 mg/kg every 3 months IV. Similar rates of brain volume loss were seen in this clinical trial population as in the mild AD subjects in the ADNI-1 dataset. (Table Presented).

Background: This clinical trial aimed to assess the effect of monthly subcutaneous bapineuzumab, a monoclonal anti-amyloid antibody, on cerebral amyloid burden, cognition, and functional ability, and to estimate the incidence of amyloid-related imaging abnormalities-edema/ effusion (ARIA-E) with this treatment regimen. Methods: Subjects (50-89 years old, n=146) with mild to moderate AD (MMSE 18-26) and increased amyloid burden on florbetapir PET were randomized to 2, 7 or 20 mg/mo subcutaneous bapineuzumab or placebo in a 1:1:1:1 ratio. Florbetapir PETwas to be repeated after 6, 12, and 24 months; MRI (to assess for ARIA-E) every 3 months; and the 11 item ADAS-Cog and DAD at 3, 6, 12, 18, and 24 months.With the negative efficacy results of 2 trials of intravenous bapineuzumab reported in August, 2012, this protocol was amended to reduce the treatment duration to 12 months. Results: Baseline demographics and results are presented in the Table. There was a statistically significant reduction from baseline to month 12 in mean florbetapir PET global cortical average standard uptake value ratio (GCA SUVr) for 7 mg/mo, but no significant differences relative to placebo for any dosage. There were no differences relative to placebo for clinical outcomes at month 12. Only 2 cases of ARIA-E occurred, at 6 months in an ApoE e 4 noncarrier receiving 20 mg/mo (2.7%), and at 9 m onths in a carrier receiving 2 mg/mo (2.7%). Both cases were asymptomatic, resolved after interruption of bapineuzumab, and did not recur on rechallenge. Conclusions: Monthly SC injections of bapineuzumab 2, 7, and 20 mg for 12 months were generally well tolerated. The incidence proportion of asymptomatic ARIA-E appeared lower for monthly subcutaneous dosages than for equivalent q3m intravenous dosages in prior studies 1. However, the current study did not demonstrate a statistically significant treatment effect on amyloid burden as assessed by florbetapir PET. It is possible that the lack of demonstrable effects on biomarkers and clinical outcomes is related to the truncated treatment duration from 24 to 12 months.1. Salloway et al, N Engl J Med 2014;370:322-33. (Table Presented).

Introduction: Alzheimer's disease (AD) is characterized by the presence of an elevated burden of amyloid plaques in the brain. The predominant component of these plaques is Aβ protein, particularly a 42-amino acid isoform (Aβl-42) that is derived from a larger amyloid precursor protein. The hypothesis underlying this program is that administration of an antibody against Aβ will reduce the formation or mediate the removal of plaque, in patients with AD and lead to a beneficial clinical effect. Bapineuzumab is a humanized anti-amyloid- beta monoclonal antibody in development for the treatment of AD. Bapineuzumab, given intravenously (IV), is being evaluated in a phase 3 clinical trial program designed to evaluate its efficacy as a potential disease modifier based on a combination of clinical and biomarker evidence. Separate trials have been designed for apolipoprotein E (APOE) e4 allele carriers and non-carriers as phase 2 data suggested possible safety differences between these populations. Objectives: The objective of this session is to present results from two randomized, double-blind placebo controlled studies of bapinueuzumab IV in AD patients who are APOE e4 carriers and non-carriers. Discussion: These two studies randomized and dosed over 2,000 AD patients with mild to moderate dementia (MMSE 16-26). Following a 6 week screening period, patients received either bapineuzumab (0.5mg/kg) or placebo by IV infusion every 13 weeks and were followed until study endpoint at 78 weeks. The co-primary clinical endpoints are change in the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS- Cog) and the Disability Assessment for Dementia (DAD) at week 78. Biomarker substudies assessing effects of bapineuzumab on PiB-PET brain amyloid burden, cerebrospinal fluid (CSF) phospho-tau, and brain volume were included. Statistical analyses will be performed to estimate treatment differences at study endpoint through mixed models for repeated measures and analysis of covariance. ADAS-Cog, DAD, and biomarker endpoints (PiB PET, CSF phospho-tau, volumetric MRI) as well as safety data will be presented. Conclusion: These clinical trials are designed to provide a robust evaluation of the efficacy and safety of bapineuzumab in AD patients with mild to moderate dementia who are APOE e4 carriers and APOE e4 noncarriers.

INTERVENTION:

Product Name: AAB‐001 Pharmaceutical Form: Solution for injection INN or Proposed

INN:

Bapineuzumab CAS Number: n/a Current Sponsor code: AAB‐001, WAY 203740 Other descriptive name: anti‐Abeta Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 20‐ Pharmaceutical form of the placebo: Solution for injection Route of administration of the placebo: Intravenous use

CONDITION:

Enfermedad de Alzheimer Alzheimer Disease ; MedDRA version: 9.1 Level: PT Classification code 10012271 Term: Dementia Alzheimer's type

PRIMARY OUTCOME:

Main Objective: To investigate efficacy of multiple doses of intravenously (IV) administered bapineuzumab compared with placebo in subjects with mild to moderate AD as measured by change in scores from baseline to week 78 in the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS‐Cog) and the Disability Assessment for Dementia (DAD) (co‐primary measures). Primary end point(s): ADAS‐Cog and DAD. Secondary Objective: To investigate the safety and efficacy of multiple doses of intravenously (IV) administered bapineuzumab compared with placebo in subjects with mild to moderate AD as measured by change in scores from baseline to week 78 in the Neuropsychological Test Battery (NTB) and the Clinical Dementia Rating Sum of Boxes (CDR‐SOB) (key secondary measures). Safety objectives include the incidence and severity of treatment‐emergent adverse events (TEAEs), and clinically important changes in safety assessment results.

INCLUSION CRITERIA:

1) Signed and dated written informed consent obtained from the subject or the subject’s legally acceptable representative (if applicable) in accordance with the local regulations. The subject’s caregiver must also consent to participate in the study. 2) Man or surgically sterile or postmenopausal woman, aged =50 to <89 years. 3) Diagnosis of probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke‐Alzheimer’s Disease and Related Disorders Association (NINCDS‐ADRDA) criteria. 4) MMSE score of 16 to 26, inclusive. 5) Rosen Modified Hachinski Ischemic Score =4. 6) Lives at home with appropriate caregiver capable of accompanying the subject on all clinic visits, or community dwelling with caregiver capable of accompanying the subject on all clinic visits and visiting with the subject approximately 5 times per week for the duration of the study. 7) Screening visit brain MRI scan consistent with the diag

The study will evaluate the safety and effectiveness of bapineuzumab for the treatment of mild to moderate Alzheimer disease. Subjects will be in the study for six months and will receive subcutaneous injections once per week.

This is a study to evaluate the efficacy and safety of multiple doses of bapineuzumab in patients with mild to moderate Alzheimer Disease. Patients will receive either bapineuzumab or placebo. Each patient\'s participation will last approximately 1.5 years.