Objective: Clinical trials evaluating AD drugs targeting different pathology other than amyloid hypothesis

Citation: Li-Kai Huang et al. Clinical trials of new drugs for Alzheimer disease. Journal of Biomedical Science. 2020; 27:18

Introduction:

The seriousness of Alzheimer’s disease (AD) accounts for more than 60 % worldwide. Presently, few drugs are available for the treatment of AD, of those cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate receptor, can only inhibit dementia symptoms for a limited period of time but cannot stop or reverse disease progression. Exact causes of AD still remains unclear, but various hypothesis such as senile plaque consisting of amyloid beta and neurofibrillary tangles is known to every one of us. On the basis of the amyloid hypothesis, many clinical trials (2016-2019) were conducted on amyloid clearing therapy but without success. Because of this inevitable reason, clinical trials focusing more on other pathology or different stages of AD started in 2019.

Table 1: Failed phase 3 trials on anti-amyloid therapy in AD since 2016

Year

Drug

Mechanism



Subjects

 

Reason of failure

2016

Solanezumab

Monoclonal antibody



Mild to Prodromal AD

Lack of efficacy

2016 & 2018

Verubecestat

BACE inhibitor

Mild to moderate AD, Prodromal AD

Lack of efficacy

2018

Atabecestat

BACE inhibitor

Preclinical AD

 

Toxicity

Lanabecestat

BACE inhibitor

Early AD

 

Lack of efficacy

2019

Aducanumab

Monoclonal antibody

Early AD

Lack of efficacy

 

Multiple clinical trials are still ongoing which are testing several possible interventions aimed at various targets, including anti-amyloid and anti-tau interventions, neurotransmitter modification, anti-neuroinflammation and neuroprotection interventions, and cognitive enhancement, and interventions to relieve behavioural psychological symptoms.

In this article, it is observed that ongoing clinical trials which are on anti-amyloid and non anti- amyloid therapy have commenced in 2019 with many of them completed with promising results, some are in the phase of recruiting while few are in still active phase with estimated completion by end of 2020 or 2021, few are terminated due to reasons such as lack of efficacy, could not achieve primary endpoints, funding limitations and low enrolment rate etc.

Table 2: Ongoing phase 3 trials on anti-amyloid therapy in AD in 2019

Clinical trial agent

Mechanism

Target and purpose

Landmark trial

Status

Plasma exchange with albumin 1

immunoglobulin

Plasma exchange

Remove amyloid

–

Completed

Crenezumab



Monoclonal antibody directed at oligomers

Remove amyloid



CREAD

Completed



Gantenerumab



Monoclonal antibody

Remove amyloid



Graduate 1 and 2, DIAN-TU

Recruiting





Solanezumab

Monoclonal antibody



Remove amyloid and prevent aggregation

EXPEDITION 1, 2 and 3



Active, not recruiting

Table 3: Ongoing phase 3 trials on non anti-amyloid therapy in AD in 2019

Clinical trial agent

Mechanism



Target and purpose

Status



Azeliragon

Microglial activation inhibitor,

antagonist of the receptor for advanced glycation end products

Amyloid-related and antineuroinflammatory; disease modifying therapy

Terminated



OPC-34712 (brexpiprazole)

A partial agonist at serotonin 5-hydroxytryptamine1A and dopamine D2 receptors and an antagonist at serotonin 5-hydroxytryptamine2A

Neurotransmitter based; BPSD (agitation)

Completed

Insulin (Humulin® R U-100)

Metabolic

Metabolic; symptomatic cognitive enhancer



Completed



MK-4305 (suvorexant)

Orexin antagonist

BPSD (sleep)

Completed

TRx0237 (LMTX)

Tau stabilizers and aggregation inhibitors



Anti-tau; disease-modifying therapy

Completed



Vitamin D3 (cholecalciferol)

Agonist of vitamin D receptor and other membrane-based receptors such as MARRS

Metabolic; symptomatic cognitive enhancer

Completed

Because of the failure of anti-amyloid clinical trials since 2016, many researchers got an opportunity to challenge the amyloid hypothesis and shift the therapy focus to populations at prodromal or preclinical stages with positive diagnostic biomarkers. By targeting different pathology of AD and with the probable success of these clinical trials, we could expect two or more drugs in the management of AD in near future.