Pharmacotherapy for Alzheimer’s disease: what’s new on the horizon?

ABSTRACT

Introduction

Alzheimer’s disease (AD) is a debilitating disease, with no cure. Recently, a monoclonal antibody (aducanumab) directed toward amyloid aggregates was approved as a disease-modifying treatment (DMT) for the disease. Other compounds (symptomatic or DMTs) are at different stages of clinical trial development.

Areas covered

The authors conducted a search on PUBMED, MEDLINE, and clinicaltrials.gov for compounds in phase III clinical trials for cognitive impairment due to AD. Mechanisms of action and clinical trial data related to these compounds are discussed in this paper.

Expert Opinion

There is an unmet need for both treatment approaches (symptomatic and DMTs) to improve outcomes in individuals at different stages of the AD continuum. Future trials with symptomatic therapies should rely on biomarkers to improve enrollment of participants with pure AD. More sensitive, innovative, and composite assessment tools should be used. Given the complexity and heterogeneity of AD, combining several DMTs with synergistic mechanisms of action is a promising approach to achieve a significant impact on reversing cognitive decline. We recommend testing DMTs early on in the disease continuum, even in asymptomatic individuals at risk for AD. Longer duration of follow-up in clinical trials with DMTs is recommended.

KEYWORDS:

• Alzheimer’s
• pharmacotherapy
• symptomatic
• disease-modifying treatment
• clinical trial

Article highlights

• Alzheimer’s disease is the leading cause of dementia worldwide, with no cure.

• Symptomatic treatments currently in phase III clinical trials include octohydroaminoacridine succinate, oligomannate, BPDO-1603, guanfacine, hydralazine, gingko biloba, caffeine, and renew NCP-5.

• Disease-modifying treatments currently in phase III trials are mostly amyloid-based; they include lecanemab, gantenerumab, solanezumab, donanemab, crenezumab, verubecestat, and azeliragon.

• These therapies have failed to reverse cognitive changes despite significant impact on biomarkers of amyloid pathology or neurodegeneration, questioning the appropriate stage at which they should be tested.

• Leuco-methylthioninium (methylene blue) is the only tau-based disease-modifying agent that reached phase III trials, but had failed to achieve significant impact on cognition.

• Alzheimer’s disease is a complex disorder, with multiple etiologies; requiring a combination of several therapeutic targets in future phase III trials to achieve better cognitive outcomes.

This box summarizes key points contained in the article.

Declaration of interests

G Grossberg is a consultant for Acadia, Alkahest, Avanir, Axsome, Axovant Therapeutics, Biogen, BioXcel, Genentech, Karuna, Lundbeck, Novartis, Otsuka, Roche, and Takeda; has received research support from NIA, Janssen, and Genentech/Roche; and is on the safety monitoring committee for Anavex, EryDel, Newron, Intra-Cellular Therapies, Merck, and Newron. 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.

Reviewer disclosures

A peer reviewer on this manuscript is developing a drug going into human trials for Alzheimer’s. All other peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.