Anti-amyloid-β protein agents for the treatment of Alzheimer’s disease: an update on emerging drugs

ABSTRACT

Introduction

Currently available Alzheimer’s disease (AD) therapeutics are only symptomatic, targeting cholinergic and glutamatergic neurotransmissions. Several putative disease-modifying drugs in late-stage clinical development target amyloid-β (Aβ) peptide and tau protein, the principal neurophatological hallmarks of the disease.

Areas covered

Phase III randomized clinical trials of anti-Aβ drugs for AD treatment were searched in US and EU clinical trial registries and principal biomedical databases until May 2020.

Expert opinion

At present, compounds in Phase III clinical development for AD include four  anti-Ab monoclonal antibodies (solanezumab, gantenerumab, aducanumab, BAN2401), the combination of cromolyn sodium and ibuprofen (ALZT-OP1), and two small molecules (levetiracetam, GV-971). These drugs are mainly being tested in subjects during early AD phases or at preclinical stage of familial AD or even in asymptomatic subjects at high risk of developing AD. The actual results support the hypothesis that elevated Aβ represents an early stage in the AD continuum and demonstrate the feasibility of enrolling these high-risk participants in secondary prevention trials to slow cognitive decline during the AD preclinical stages. However, a series of clinical failures may question further development of Aβ-targeting drugs and the findings from current ongoing Phase III trials will hopefully give light to this critical issue.

KEYWORDS:

• Monoclonal antibodies
• aducanumab
• solanezumab
• gantenerumab
• BAN2401
• ALZT-OP1
• Alzheimer’s disease
• cognitive disorders
• levetiracetam
• GV-971

Article highlights

• At present, available drugs for treating Alzheimer’s disease (AD) are only symptomatic, targeting cholinergic and glutamatergic neurotransmissions.

• In the last two decades, disease-modifying drugs for AD have been pursued without any significant clinical success.

• Drugs directed against amyloid-β (Aβ), the hypothesized initial cause of AD, have failed both in early and advanced stages of the disease.

• At present, compounds in Phase III clinical development for AD include four anti-Ab monoclonal antibodies (solanezumab, gantenerumab, aducanumab, BAN2401), the combination of cromolyn sodium and ibuprofen (ALZT-OP1), and two small molecules (levetiracetam, GV-971).

• These drugs in Phase III clinical development are mainly being tested in subjects during early AD phases or at preclinical stage of familial AD or even in asymptomatic subjects at high risk of developing AD.

• A series of clinical failures may question further development of Ab-targeting drugs and the findings from current ongoing Phase III trials will hopefully give light to this critical issue.

• In the last 5 years, alternative approaches to the treatment of AD have emerged, some of which have already produced promising, if limited, results in early therapeutic trials.

Declaration of interest

The authors have no 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.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This study was funded by the Italian Ministry of Health with ‘Ricerca Corrente 2019’ Grant.