Investigational BACE inhibitors for the treatment of Alzheimer’s disease

ABSTRACT

Introduction: The amyloid hypothesis of Alzheimer’s disease (AD) states that brain accumulation of amyloid-β (Aβ) oligomers and soluble aggregates represents the major causal event of the disease. Several small organic molecules have been synthesized and developed to inhibit the enzyme (β-site amyloid precursor protein cleaving enzyme-1 or BACE1) whose action represents the rate-limiting step in Aβ production.

Areas covered: We reviewed the pharmacology and clinical trials of major BACE1 inhibitors.

Expert opinion: In transgenic mouse models of AD, BACE1 inhibitors dose-dependently lower Aβ levels in brain and cerebrospinal fluid (CSF) but the evidence for attenuation or reversal cognitive or behavioral deficits is very scanty. In AD patients, BACE1 inhibitors robustly lower plasma and CSF Aβ levels and reduce brain plaques but without cognitive, clinical, or functional benefit. To date, seventeen BACE1 inhibitors have failed in double-blind, placebo-controlled clinical trials in patients with mild-to-moderate or prodromal AD, or in cognitively normal subjects at risk of developing AD. Several of these studies were prematurely interrupted due to toxicity or cognitive and behavioral worsening compared to placebo-treated patients. Elenbecestat, the last BACE1 inhibitor remaining in late clinical testing for AD, was recently discontinued due to safety concerns.

KEYWORDS:

• BACE inhibitors
• BACE1
• BACE2
• Alzheimer’s disease

Article highlights

• Several potent BACE1 inhibitors have been developed to decrease Aβ generation and lower subsequent Aβ oligomer formation and hence decrease neuronal and glial cytotoxicity and slow cognitive decline in AD patients.

• Evidence for positive behavioural effects of BACE1 inhibitors in animal models of AD is very scanty. Few studies have shown BACE1 inhibitors to reverse or attenuate memory and behavioural deficits in transgenic mouse models of AD.

• Despite strong target engagement and achieving up to 80–90% cerebrospinal fluid Aβ reductions in humans, BACE1 inhibitors trialled in patients with mild-to-moderate or prodromal AD, or in cognitively healthy subjects at risk of developing AD, have failed to demonstrate significant slowing of cognitive decline.

• Moreover, recent full disclosure of the results of such trials has revealed significant cognitive and clinical worsening in subjects receiving BACE1 inhibitors that has led to premature interruption of such trials.

• The reasons for these disappointing results are unclear, but probably include BACE1 vs BACE2 selectivity, the nonselective inhibition of BACE1 activity on substrates besides APP (which are known to be important for diverse biological functions) or even the accuracy of the theory that Aβ accumulation is responsible for AD.

• BACE1 is not a viable therapeutic target in AD.

This box summarizes key points contained in the article.

Declaration of interest

BP Imbimbo is an employee at Chiesi Farmaceutici. He is listed between the inventors of numerous patents by Chiesi Farmaceutici on anti-Alzheimer drugs. M Watling is a consultant at TranScrip Partners. 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

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

Additional information

Funding

This paper was not funded.