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Bapineuzumab

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

Year of Publication: 2014

Authors: Stephen Salloway, Reisa Sperling, Nick C. Fox, ..., for the Bapineuzumab 301 and 302 Clinical Trial Investigators

Journal: New England Journal of Medicine

Citation: N Engl J Med 2014;370:322-33

Link: https://www.nejm.org/doi/full/10.1056/NEJMoa1304839

Clinical Question

Does intravenous bapineuzumab improve cognitive and functional outcomes compared to placebo in patients with mild-to-moderate Alzheimer's disease?

Bottom Line

Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease despite treatment differences in biomarkers observed in APOE ε4 carriers. The lack of clinical efficacy may be due to dose limitations imposed by ARIA-E or intervention at too advanced a disease stage.

        Major Points
        Two separate phase 3 trials conducted: one in APOE ε4 carriers (n=1121) and one in noncarriers (n=1331)
No significant differences in coprimary outcomes (ADAS-cog11 and DAD) between bapineuzumab and placebo in either study
The 2.0 mg/kg dose was discontinued early due to high rates of symptomatic ARIA-E
In carriers, bapineuzumab reduced brain amyloid accumulation on PIB-PET (difference −0.101 SUVR, P=0.004) and CSF phospho-tau (difference −6.75 pg/mL, P=0.005)
No significant biomarker differences observed in noncarriers in pooled analyses
36% of APOE ε4 noncarriers had negative amyloid PET at baseline, raising concerns about diagnostic accuracy
ARIA-E incidence was dose-dependent and increased with APOE ε4 allele number (27.3% in homozygotes vs 11.4% in heterozygotes)
The trial suggests that anti-amyloid treatment may need to start earlier in disease course

      

Design

Study Type: Two parallel, multicenter, randomized, double-blind, placebo-controlled phase 3 trials

Randomization: 1

Blinding: Double-blind; patients, caregivers, investigators, and outcome assessors blinded to treatment allocation

Enrollment Period: December 2007 through April 2012 (carriers); December 2007 through June 2012 (noncarriers)

Follow-up Duration: 78 weeks

Centers: 218

Countries: United States, Canada, Germany, Austria

Sample Size: 2452

Analysis: Modified intention-to-treat analysis using mixed model for repeated measures (MMRM); model included treatment, visit, treatment-by-visit interaction, baseline score, baseline score-by-visit interaction, baseline MMSE category, APOE ε4 copy number (carriers only), use of cholinesterase inhibitor/memantine, and age

Inclusion Criteria

Age 50 to 88 years
Probable Alzheimer's disease per NINCDS-ADRDA criteria
MRI consistent with Alzheimer's disease
MMSE score 16 to 26
Hachinski Ischemic Scale score ≤4

Exclusion Criteria

Neurologic disease other than Alzheimer's disease
Brain MRI showing ≥2 microhemorrhages, prior hemorrhage >1 cm³, ≥2 lacunar infarcts, prior infarct >1 cm³, or space-occupying lesions
Major psychiatric disorder
History of stroke or seizures
Treatment with cognitive enhancers other than stable doses of acetylcholinesterase inhibitors or memantine

Arms

Field	Control	Bapineuzumab 0.5 mg/kg - Carriers	Control	Bapineuzumab 0.5 mg/kg - Noncarriers	Bapineuzumab 1.0 mg/kg - Noncarriers
Intervention	Placebo intravenous infusion every 13 weeks for up to 6 infusions	Bapineuzumab 0.5 mg/kg intravenous infusion every 13 weeks for up to 6 infusions	Placebo intravenous infusion every 13 weeks for up to 6 infusions	Bapineuzumab 0.5 mg/kg intravenous infusion every 13 weeks for up to 6 infusions	Bapineuzumab 1.0 mg/kg intravenous infusion every 13 weeks for up to 6 infusions
Duration	78 weeks	78 weeks	78 weeks	78 weeks	78 weeks

Outcomes

Outcome	Type	Control	Intervention	P-value
Change from baseline to week 78 in ADAS-cog11 score (range 0-70, higher = worse) and DAD score (range 0-100, higher = better)	Primary
PIB-PET SUVR change (Carriers)	Secondary	0.102 ± 0.026 increase	0.001 ± 0.021 increase	0.004
CSF phospho-tau change (Carriers)	Secondary	0.95 ± 1.83 pg/mL increase	−5.80 ± 1.49 pg/mL decrease	0.005
Brain volume loss rate (Carriers)	Secondary	18.7 ± 0.59 mL/year	19.9 ± 0.50 mL/year	0.13
CDR-Sum of Boxes change (Carriers)	Secondary	3.0 ± 0.2	3.3 ± 0.1	0.25
MMSE change (Carriers)	Secondary	−4.5 ± 0.2	−4.7 ± 0.2	0.50
ARIA-E - Carriers	Adverse	1 (0.2%)	103 (15.3%)
ARIA-E - Carriers Heterozygotes	Adverse		58/508 (11.4%)
ARIA-E - Carriers Homozygotes	Adverse		45/165 (27.3%)
ARIA-E - Noncarriers 0.5 mg/kg	Adverse	1 (0.2%)	14 (4.2%)
ARIA-E - Noncarriers 1.0 mg/kg	Adverse	1 (0.2%)	31 (9.4%)
ARIA-E - Noncarriers 2.0 mg/kg	Adverse	1 (0.2%)	20 (14.2%)
Fall - Carriers	Adverse	64 (14.3%)	100 (14.9%)
Headache - Carriers	Adverse	48 (10.7%)	78 (11.6%)
Any adverse event - Carriers	Adverse	88.8%	92.6%
Death - Carriers	Adverse	5 (1.1%)	15 (2.2%)

Subgroup Analysis

Prespecified subgroup analyses by baseline AD severity (mild MMSE ≥21 vs moderate) showed no significant differences in primary endpoints. An alternative threshold of MMSE ≥20 for mild disease showed potential benefit on DAD (P<0.05) in noncarriers at both doses, but ADAS-cog11 remained non-significant at all cutoffs.

Criticisms

Doses may have been too low to achieve clinical efficacy; higher doses limited by ARIA-E
Patients with established dementia may be too far along in the disease course for amyloid-targeting therapy to be effective
36% of APOE ε4 noncarriers were amyloid-negative at baseline, raising concerns about misdiagnosis
No biomarker differences seen in noncarriers despite similar treatment regimen
Treatment duration of 78 weeks may be insufficient to demonstrate disease modification
Greater brain volume loss observed with bapineuzumab (though non-significant), raising questions about accelerated atrophy

Funding

Janssen Alzheimer Immunotherapy Research and Development and Pfizer

Based on: Bapineuzumab (New England Journal of Medicine, 2014)

Authors: Stephen Salloway, Reisa Sperling, Nick C. Fox, ..., for the Bapineuzumab 301 and 302 Clinical Trial Investigators

Citation: N Engl J Med 2014;370:322-33

Content summarized and formatted by NeuroTrials.ai.

Bapineuzumab

(2014)

Objective

Bapineuzumab - To assess whether intravenous bapineuzumab improves cognition and function in patients with mild-to-moderate Alzheimer’s disease, stratified by APOE ε4 carrier status.

Study Summary

• Bapineuzumab did not improve cognition or function in either APOE ε4 carriers or noncarriers.
• Amyloid and tau biomarker improvements were seen, particularly in APOE ε4 carriers.
• Amyloid-related imaging abnormalities (ARIA-E) were common, especially at higher doses.

Intervention

Two parallel, phase 3, multicenter, randomized, double-blind, placebo-controlled trials. APOE ε4 carriers received 0.5 mg/kg bapineuzumab or placebo every 13 weeks for 78 weeks. Noncarriers received 0.5 or 1.0 mg/kg or placebo. Primary outcomes: ADAS-cog11 and Disability Assessment for Dementia (DAD). Secondary: PET amyloid (PIB), CSF phospho-tau, and MRI volumetrics.

Inclusion Criteria

Age 50–88, diagnosis of probable Alzheimer’s disease, MMSE 16–26, MRI consistent with AD, stable on acetylcholinesterase inhibitors or memantine. Excluded: other neurologic disease, stroke, seizures, dementia mimics.

Study Design

Arms: Bapineuzumab 0.5 mg/kg vs 1.0 mg/kg vs Placebo (stratified by APOE ε4 carrier status)

Patients per Arm: Carrier study: 0.5 mg/kg: 658; Placebo: 432 Noncarrier study: 0.5 mg/kg: 314; 1.0 mg/kg: 307; Placebo: 493

Outcome

• ADAS-cog11: No significant difference (Carrier: –0.2, P=0.80; Noncarrier: –0.3 to +0.4, all P>0.6)
• DAD: No significant differences (Carrier: –1.2, P=0.34; Noncarrier: +0.9 to +2.8, P>0.07)
• PET Amyloid (SUVR): Significant difference in carriers at 0.5 mg/kg (Δ –0.101, P=0.004); not in noncarriers
• CSF Phospho-Tau: Carriers: Δ –6.75 pg/mL vs placebo (P=0.005); Noncarriers: No significant pooled effect, but 1.0 mg/kg showed Δ –6.19 pg/mL (P=0.009)
• MRI brain volume: No significant differences
• ARIA-E: Carrier group: 15.3%; Noncarrier: up to 14.2% at highest dose

Bottom Line

Major Points

Two separate phase 3 trials conducted: one in APOE ε4 carriers (n=1121) and one in noncarriers (n=1331)
No significant differences in coprimary outcomes (ADAS-cog11 and DAD) between bapineuzumab and placebo in either study
The 2.0 mg/kg dose was discontinued early due to high rates of symptomatic ARIA-E
In carriers, bapineuzumab reduced brain amyloid accumulation on PIB-PET (difference −0.101 SUVR, P=0.004) and CSF phospho-tau (difference −6.75 pg/mL, P=0.005)
No significant biomarker differences observed in noncarriers in pooled analyses
36% of APOE ε4 noncarriers had negative amyloid PET at baseline, raising concerns about diagnostic accuracy
ARIA-E incidence was dose-dependent and increased with APOE ε4 allele number (27.3% in homozygotes vs 11.4% in heterozygotes)
The trial suggests that anti-amyloid treatment may need to start earlier in disease course

Study Design

Study Type: Two parallel, multicenter, randomized, double-blind, placebo-controlled phase 3 trials
Randomization: Yes
Blinding: Double-blind; patients, caregivers, investigators, and outcome assessors blinded to treatment allocation
Sample Size: 2452
Follow-up: 78 weeks
Centers: 218
Countries: United States, Canada, Germany, Austria

Primary Outcome

Definition: Change from baseline to week 78 in ADAS-cog11 score (range 0-70, higher = worse) and DAD score (range 0-100, higher = better)

Control	Intervention	HR/OR	P-value
-	-	-	-

Limitations & Criticisms

Doses may have been too low to achieve clinical efficacy; higher doses limited by ARIA-E
Patients with established dementia may be too far along in the disease course for amyloid-targeting therapy to be effective
36% of APOE ε4 noncarriers were amyloid-negative at baseline, raising concerns about misdiagnosis
No biomarker differences seen in noncarriers despite similar treatment regimen
Treatment duration of 78 weeks may be insufficient to demonstrate disease modification
Greater brain volume loss observed with bapineuzumab (though non-significant), raising questions about accelerated atrophy

Citation

N Engl J Med 2014;370:322-33

View Original Publication →

Bapineuzumab

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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