Efficacy and safety studies of gantenerumab in patients with Alzheimer’s disease

Abstract

Among active and passive anti-β-amyloid (Aβ) immunotherapies for Alzheimer’s disease (AD), bapineuzumab and solanezumab, two humanized monoclonal antibodies, failed to show significant clinical benefits in mild-to-moderate AD patients in large Phase III clinical trials. Another ongoing Phase III trial of solanezumab aims to confirm positive findings in mild AD patients. Gantenerumab is the first fully human anti-Aβ monoclonal antibody directed to both N-terminal and central regions of Aβ. A 6-month PET study in 16 AD patients showed that gantenerumab treatment dose-dependently reduced brain Aβ deposition, possibly stimulating microglial-mediated phagocytosis. Two ongoing Phase III trials of gantenerumab in patients with prodromal or mild dementia due to AD will determine if any reduction in brain Aβ levels will translate into clinical benefits. An ongoing secondary prevention trial of gantenerumab in presymptomatic subjects with genetic mutations for autosomal-dominant AD will verify the utility of anti-Aβ monoclonal antibodies as prevention therapy.

Keywords::

• Alzheimer’s disease
• cognitive disorder
• dementia
• gantenerumab
• monoclonal antibody
• passive immunotherapy
• solanezumab

Financial & competing interests disclosure

This research was supported by Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale (PRIN) 2009 Grant 2009E4RM4Z. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• In neuroimaging and neuropathological studies, both active and passive anti-β-amyloid (Aβ) immunotherapies demonstrated to stimulate Aβ clearance from the brain of patients with Alzheimer’s disease (AD).

• Passive anti-Aβ immunotherapies are under extensive clinical investigation, with several anti-Aβ monoclonal antibodies in Phase III clinical trials.

• Bapineuzumab, a humanized monoclonal antibody recognizing N-terminus of Aβ, showed no treatment benefits in cognitive and functional measures in Phase III clinical trials on AD patients, with relatively high incidence of amyloid-related imaging abnormalities.

• Solanezumab, a monoclonal antibody directed at the mid-region of Aβ, has shown some beneficial cognitive effects in mildly-affected AD patients. A Phase III study in mild AD patients is ongoing to confirm these potential benefits.

• Gantenerumab is the first fully human anti-Aβ monoclonal antibody for the treatment of AD, binding to both N-terminal and central regions of Aβ. It is directed mainly against aggregated Aβ, like fibrillary Aβ and acts by stimulating microglia phagocytic activity.

• A small PET study in AD patients indicated that gantenerumab dose-dependently reducing the cerebral Aβ burden in a relatively short period (6 months).

• Preliminary studies indicated that gantenerumab was generally well-tolerated, but vasogenic edema and microhemorrhages were observed, especially in apolipoprotein E β4 carriers.

• Ongoing Phase III trials of gantenerumab on prodromal or mild stage of AD may clarify whether any reduction in brain Aβ deposits will successfully translate into clinical benefit at well-tolerated doses of gantenerumab.

• An ongoing secondary prevention trial on gantenerumab will determine whether subjects with autosomal dominant AD-causing genetic mutations will benefit from presymptomatic anti-Aβ therapy.