Potential novel targets for Alzheimer pharmacotherapy: II. Update on secretase inhibitors and related approaches

Abstract

The prevailing theory regarding Alzheimer disease (AD) is that insoluble amyloid β-peptide (Aβ) plays a critical role in the cortical plaques characteristic of the disease. Because Aβ is formed from the sequential splicing of amyloid precursor protein (APP) catalysed by 'secretase' enzymes (α, β and γ), clinical trials of secretase inhibitors will either result in beneficial pharmacotherapy or, if negative, cast doubt on the role of Aβ in AD. With recent clinical trial failures, is the Aβ theory wrong? Literature searches were conducted on the topics of secretases and clinical trials, including PubMed searches, United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected and evaluated for relevance and quality. Several direct-acting (e.g. CTS-21166, LY2811376) and indirect-acting (e.g. ACI-91) β-secretase inhibitors and several γ-secretase inhibitors (e.g. avagacestat, JNJ-40418677 and semagacestat) have not fared well in early clinical trials due to the lack of efficacy or concerns over possible serious side effects. The failures of secretase inhibitors in clinical trials appear to bring into question the long-hypothesized association between AD and Aβ production. However, the disease might have been too advanced in these patients to benefit from this type of therapy (mainly preventive). Secretase inhibitors are still being studied, along with new diagnostic tools, with the hope of testing patients earlier, that is, with less advanced disease. If these trials also fail, the prevailing view of the role of Aβ in AD will truly be in doubt.