Grasping at straws: the failure of solanezumab to modify mild Alzheimer's disease

The amyloid-beta (Aβ) cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in the treatment of Alzheimer's disease. Solanezumab is a humanized analog of a murine antibody that selectively targets the central domain of the soluble form of Aβ. In the EXPEDITION 1 and 2 Phase 3 clinical trials, solanezumab was shown to be ineffective in subjects with mild-to-moderate Alzheimer's disease, and to have no effect on brain Aβ burden. Areas covered: This evaluation considers the secondary analysis of (EXPEDITION 1 and 2), which led to the EXPEDITION 3 trial of solanezumab in subjects with mild Alzheimer's disease, and the results of EXPEDITION 3. Expert opinion: The secondary analysis of EXPEDITION 1 and 2 was limited to mild Alzheimer's disease, and showed improvements on some scales, but not others. This analysis did not report data on Aβ burden. In my opinion, this was a questionable basis to undertake a further phase trial with solanezumab. The EXPEDITION 3 trial of solanezumab in subjects with mild Alzheimer's disease was terminated early for ineffectiveness. With hindsight, solanezumab should have been discontinued after EXPEDITION 1 and 2, especially as it had not been shown to reduce Aβ burden.