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.