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    • The increased occurrence of ARIA E in APOE

    2024-04-18

    The increased occurrence of ARIA-E in APOE ε4 carriers in phase 2 studies resulted in separate protocols for carriers and noncarriers in the subsequent phase 3 studies. Two 18-month trials comprising 1121 carriers and 1331 noncarriers with mild to moderate AD tested doses of bapineuzumab that varied by study administered intravenously every 13 weeks (21). Neither study revealed significant treatment differences in the primary outcomes (ADAS-Cog11 and Disability Assessment for Dementia). Evidence of mild target engagement was observed for APOE ε4 carriers only, as treatment groups differed in change in Sulindac sulfone synthesis Aβ burden by 11C-PiB-PET (22) and cerebrospinal fluid (CSF) phosphorylated tau concentrations. Negative baseline 11C-PiB-PET scans were found in 36% of APOE ε4 noncarriers, suggesting the necessity of incorporating biomarker evidence of disease into eligibility criteria in future trials. ARIA-E occurred in 15.3% of APOE ε4 carriers who received bapineuzumab 0.5 mg/kg, including 11.4% of heterozygotes and 27.3% of homozygotes. In the noncarrier study, ARIA-E was identified in 4.2%, 9.4%, and 14.2% of participants receiving 0.5, 1.0, and 2.0 mg/kg. The 2.0-mg/kg dose was discontinued early in the trial because of a high rate of symptomatic ARIA-E. Following these results, all bapineuzumab trials were discontinued in August 2012.
    Solanezumab Solanezumab (LY2062430; Eli Lilly and Company, Indianapolis, IN), a humanized IgG1 mAb, binds the mid-domain of Aβ (residues 16–26) and increases clearance of monomers (23). Studies in transgenic PDAPP mice demonstrated that m266 (the murine precursor of solanezumab) reduced brain Aβ burden without binding Aβ deposits 24, 25, opening the possibility of targeting the soluble pool of Aβ. Phase 1 and 2 studies of solanezumab revealed evidence of target engagement by dose-dependent increases in plasma and CSF total Aβ 26, 27. In the phase 2 study of mild to moderate AD, 12 weeks of solanezumab treatment yielded a dose-dependent increase in CSF-free Aβ42, suggesting a shift in equilibria sufficient to mobilize Aβ42 from plaques (27). The first phase 3 studies—EXPEDITION 1 and EXPEDITION 2—were 18-month trials of solanezumab 400 mg versus placebo (administered intravenously every 4 weeks) in 1012 and 1040 participants with mild to moderate AD (28). The original co-primary outcomes in both studies were the ADAS-Cog11 and Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) (29). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the ADAS-Cog14 in the mild AD subgroup (28). Solanezumab did not demonstrate significant benefit for the primary outcomes in either study but showed a favorable safety profile, as the incidence of ARIA-E was 0.9% with solanezumab and 0.4% with placebo. A prespecified subgroup analysis of pooled data from EXPEDITION 1 and EXPEDITION 2 showed Endonucleases in participants with mild AD, there was a 34% slowing of decline for the ADAS-Cog14 and 18% for the instrumental items of the ADCS-ADL (ADCS-iADL) (23). Therefore, a third phase 3 trial, EXPEDITION 3 (NCT01900665), restricted to mild-stage AD, was launched in July 2013. Owing to the high rate of cases negative for the Aβ biomarker in EXPEDITION 1 and EXPEDITION 2, the EXPEDITION 3 trial required PET showing positive Aβ for eligibility. In December 2016 at the Clinical Trials on Alzheimer’s Disease meeting, the negative results of EXPEDITION 3 were presented (30). In 2129 participants with mild AD (confirmed by positive Aβ on PET), solanezumab provided a nonsignificant 11% slowing of decline on the primary outcome, the ADAS-Cog14. This effect size was smaller than in the pooled subgroup analysis from EXPEDITION 1 and EXPEDITION 2. Several secondary outcomes favored solanezumab, including the Clinical Dementia Rating Sum of Boxes (CDR-SB), Mini-Mental State Examination (MMSE), and ADCS-iADL; however, these analyses were not corrected for multiplicity. Solanezumab had no effect on Aβ and tau PET biomarkers. Based on the results of EXPEDITION 3, the development of solanezumab for dementia was discontinued.