Amyloid-β 11C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials

Abstract

Objective: To evaluate the effects of bapineuzumab on brain β-amyloid (Aβ) burden using (11)C-Pittsburgh compound B ((11)C-PiB)-PET.

Methods: Two phase 3 clinical trials, 1 each in apolipoprotein APOE ε4 carriers and noncarriers, were conducted in patients with mild to moderate Alzheimer disease dementia. Bapineuzumab, an anti-Aβ monoclonal antibody, or placebo, was administered by IV infusion every 13 weeks for 78 weeks. PET substudies assessed change in brain fibrillar Aβ over 71 weeks using an (11)C-PiB-PET standardized uptake value ratio (SUVr) global cortical average (GCA) comprising the average SUVr from 5 cortical regions of interest with cerebellar gray matter as the reference region.

Results: A total of 115 carriers and 39 noncarriers were analyzed. The difference (δ) in mean baseline to 71 week change in (11)C-PiB-PET GCA between bapineuzumab and placebo was significant in carriers (0.5 mg/kg vs placebo δ = -0.101; p = 0.004) and in pooled analyses of both carriers and noncarriers (0.5 mg/kg vs placebo δ = -0.068; p = 0.027; 1.0 mg/kg vs placebo δ = -0.133; p = 0.028) but not in the noncarrier trial separately. Analyses by individual region of interest and in mild disease yielded findings similar to the main trial results.

Conclusions: The (11)C-PiB-PET imaging results demonstrated reduction of fibrillar Aβ accumulation in patients with Alzheimer disease treated with bapineuzumab; however, as no clinical benefit was observed, the findings are consistent with the hypotheses that bapineuzumab may not have been initiated early enough in the disease course, the doses were insufficient, or the most critical Aβ species were inadequately targeted.

Trial registration: ClinicalTrials.gov NCT00574132 NCT00575055.

Figure 1. Distribution of ¹¹C–Pittsburgh compound B-PET global cortical average at baseline among APOE ε4 carriers and noncarriers

A total of 6.5% (8/123) of APOE ε4 carriers had baseline scans with global cortical average (GCA) <1.35 compared with 36.1% (21/61) of noncarriers. PiB = Pittsburgh compound B; SUVr = standardized uptake value ratio.

Figure 2. Model-estimated effect of bapineuzumab on Aβ burden in carriers, noncarriers, pooled studies, and by disease severity

Treatment differences were observed in the carrier study and in the pooled study results. Treatment differences appeared more prominent in participants with mild disease (carrier placebo/bapineuzumab [Bapi]: A, 40/75; D, 18/40; G, 22/35; noncarrier placebo/0.5 mg/kg/1.0 mg/kg: B, 15/12/12; E, 7/6/9; H, 8/6/3; pooled placebo/0.5 mg/kg/1.0 mg/kg: C, 55/87/12; F, 25/46/9; I, 30/41/3).

Figure 3. Pons-based standardized uptake value ratio: model-estimated change from baseline to week 71

Similar to the results using the cerebellum as a reference region, a treatment difference in carriers was also observed when the pons was used as the reference region (carrier placebo/bapineuzumab [Bapi]: 40/75; noncarrier placebo/0.5 mg/kg/1.0 mg/kg: 15/12/12). SUVr = standardized uptake value ratio.