Investigational Alzheimer Drugs Fail to Improve Cognition or Function in Phase III Trials
Brandy R. Matthews, MD
Anti-amyloid therapies disappoint in mild-to-moderate disease.
The amyloid hypothesis of Alzheimer disease (AD) suggests that overproduction or abnormal clearance of the amyloid-beta (Aβ) peptide is critical to the early pathogenesis of AD. Two investigational monoclonal antibodies designed to decrease amyloid burden in patients with AD were recently assessed in phase 3 clinical trials. Both antibodies were tested in two industry-sponsored trials.
In one trial, researchers randomly administered intravenous bapineuzumab — which recognizes both soluble and aggregated Aβ — or placebo periodically for 78 weeks to patients with mild-to-moderate AD; 1121 patients were APOE ?4 carriers and 1331were noncarriers. At the conclusion of the trials, scores on a cognitive scale (cognitive subscale of the Alzheimer's Disease Assessment Scale [ADAS-cog11]) and a disability scale (Disability Assessment for Dementia) did not differ between the treatment and placebo groups regardless of APOE status. In a subset of patients, including the bapineuzumab-treated APOE ?4 carriers, biomarker data revealed a significant decrease, relative to the placebo group, in phosphorylated tau level in cerebrospinal fluid (CSF) and a relative stabilization of plaque deposition on Pittsburgh Compound B positron emission tomography (PIB-PET) amyloid imaging. The drug was relatively well tolerated, with an expected, observable increase in amyloid-related imaging abnormalities with edema or hemorrhage on serial structural magnetic resonance images.
Solanezumab, which binds to soluble Aβ only, was tested in two placebo-controlled trials with 1012 (EXPEDITION 1) and 1040 (EXPEDITION 2) patients with mild-to-moderate AD. Solanezumab also failed to distinguish itself from placebo on a cognitive measure (ADAS-cog11/ADAS-cog14) and a functional measure (Alzheimer's Disease Cooperative Study-ADL scale) by 80 weeks. However, in EXPEDITION 2, solanezumab recipients with mild AD had significantly better scores than placebo recipients on the ADAS-cog14 at week 64. Biomarker data in these trials did not reveal any differences in CSF tau measures nor any changes in amyloid burden between treatment groups using florbetapir-PET amyloid imaging. The drug was also relatively well-tolerated, with an expected, observable increase in amyloid-related imaging abnormalities with edema or hemorrhage on serial structural MRIs.
Citation(s):
Salloway S et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014 Jan 23; 370:322.
Doody RS et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N Engl J Med 2014 Jan 23; 370:311.
