Summary of Alzheimer's disease drug development pipeline

Alzheimer's disease (AD) continues to increase with the size of the elderly populati.
There are currently 2 million AD dementia patients in the United States, and the number will reach 17 million by 205In addition to AD patients in the dementia stage, there are approximately 10 million mild cognitive impairment (MCI) individuals in the United States, of which half (5 million) are caused by .
In the United States, the total number of patients with symptomatic AD (MCI due to AD and AD dementia) is 12 milli.
The estimated 2021 cost of caring for someone with Alzheimer's disease and related dementia (ADRD) is $355 billi.
The global prevalence of AD dementia will increase from the current 50 million to 150 million by 2050, with the majority of affected individuals living in low- and middle-income countri.
Due to the increasing number of AD patients and the growing public health crisis posed by the disease, treatments are urgently needed to prevent, delay onset, slow progression, and improve AD sympto.
Despite the halo of the first "magic drug" approved by the FDA in the past 20 years, Biogen's Alzheimer's disease (AD) treatment drug Aduhelm (aducanumab) has experienced twists and turns since its launch, and has been controversi.
Aducanumab is an anti-amyloid monoclonal antibody, and two other monoclonal antibodies (donanemab and lecanemab) are under review by the.

Food and Drug Administration (FD.
As of January 25, 2022, a total of 143 related drugs have been identified in 172 AD treatment tria.
Of these, there were 31 drugs in 47 Phase III trials; 82 drugs in 94 Phase II trials; and 30 drugs in 31 Phase I tria.
Figure 1 shows all drug compounds (biologics and small molecules) currently in clinical trials for .
The most common drugs being studied were DMT (119 drugs; 82% of all drugs in trials); 24 (18%) were symptomatic drugs, including 14 (8% of all drugs in trials) that targeted cognition Enhancer drugs and 10 (9% of all drugs in the trial) designed to treat neuropsychiatric and behavioral sympto.
Of the DMTs, 40 (36% of DMTs) were biologics and 79 (64% of DMTs) were small molecul.
Twenty (18%) DMTs had amyloid, 13 (19%) tau, 23 (13%) inflammation, and 19 (16%) synaptic plasticity/neuroprotection as their main mechanism targets , respective.
FigureDrugs in Clinical Trials for Alzheimer's Disease in 2021 Clinical Phase III There are a total of 31 drugs in 47 Phase III trials (Figures 1 and 2, Table
Twenty-one (68%) drugs in phase III trials were DMTs, including five (11%) biologics and 16 (56%) small molecul.
There were five (11%) putative cognitive enhancers and five (11%) drugs targeting behavioral sympto.
CADRO mechanisms represented in stage III DMT include amyloid (6 drugs; 26% of DMT); synaptic plasticity/neuroprotection (4; 19%); oxidative stress (3; 13%); metabolism and bioenergetics tau (1; 8%); inflammation (1; 8%); proteostasis/proteinopathy (1; 8%); vasculature (1; 8%); and gut - Brain axis (1; 8.
Figure 2 shows a CADRO-based drug MOA in a phase III stu.
Of these, 13 (42%) were repurposing treatments already approved for other indications (8 = DMT; 2 = cognitive enhancer; 3 = treatment of neuropsychiatric symptom.
In the past year (2021), 4 trials have been completed or terminat.
FigureMechanism of Action of Drugs in Phase III Studies TableAlzheimer's Disease Drug Development Phase III Drugs (Clinicaltria.
gov Access Date: January 25, 2022) The 6 Phase III trials are prevention trials, and enrollment has been Cognitively normal subjects at known risk for AD (preclinical AD); 1 trial enrolled both preclinical subjects and subjects with MCI to mild AD dementia (DIAN-TU trial); 17 trials Trials enrolled early AD defined as prodromal AD and mild AD dementia; 11 trials included subjects with mild to moderate AD dementia; 12 trials included subjects with mild to severe AD dement.
Phase III trials included an average of 791 subjects per trial, with a total of 37,184 subjects required for all ongoing phase III tria.
The DMT prevention trials included an average of 1058 participants and had a mean duration of 362 wee.
DMT trials focusing on prodromal AD or prodromal AD/mild AD dementia had an average of 991 participants and a mean duration of 243 wee.
DMT trials recruiting subjects with mild to moderate AD dementia included an average of 776 subjects with a mean duration of 162 wee.
Mean treatment exposure was 159 weeks in the prevention trials, 105 weeks in the prodromal AD or prodromal AD/mild AD dementia trials, and 48 weeks in the mild to moderate AD dementia tria.
The mean duration of the cognitive enhancer trial was 167 weeks, including 24 treatment weeks, and it is planned to recruit an average of 392 participan.
The median duration of the neuropsychiatric symptom treatment trials was 218 weeks, including 18 weeks of treatment, with an average of 478 participan.
A total of 82 drugs were included in the 94 phase II trials of clinical phase II (Figures 1 and 3, Table
Seventy-one (86%) drugs in phase II trials were DMTs, including 26 biologics and 45 small molecul.

There are seven putative cognitive enhancers and four drugs that target behavioral sympto.

CADRO mechanisms represented in Phase II DMT therapy include inflammation (17 drugs); synaptic plasticity/neuroprotection (12); amyloid (11); tau (9); metabolism and bioenergetics (4); neuronal Transmitter receptors (3); protein homeostasis/proteinopathies (3); vasculature (3); neurodevelopment (2); growth factors and hormones (2); epigenetic regulators (2); ApoE, Lipid and lipoprotein receptors (1); oxidative stress (1); and cell death (
Figure 3 shows the mechanism of action of CADRO-based drugs in a phase II stu.

In the past year (2021), 23 Phase II trials have been completed or terminat.
FigureMechanism of Action of Drugs in Phase II Studies TableAlzheimer's Disease Drug Development Phase II Drugs (clinicaltria.

gov Access Date: January 25, 2022) Four (4%) Phase II trials were prevention trials , enrolled cognitively normal subjects known to be at risk for AD (preclinical AD); 3 (3%) trials enrolled both preclinical subjects and subjects with MCI to mild AD dementia;49 Early AD (defined as prodromal AD and mild AD dementia) were enrolled in 1 (52%) trials; 34 (36%) trials involved subjects with mild to moderate AD dementia; 2 (2%) trials involved mild to moderate AD dementia Subjects with severe to severe AD dementia; 2 (2%) trials enrolled healthy voluntee.

Phase II trials included an average of 127 subjects per trial, with a total of 11,938 subjects required for all ongoing phase II tria.

The DMT prevention trials included an average of 151 participants and had an average duration of 284 wee.

DMT trials focusing on prodromal AD or prodromal AD/mild AD dementia had an average of 138 participants and a mean duration of 198 wee.

DMT trials recruiting subjects with mild to moderate AD dementia included an average of 107 subjects with a mean duration of 172 wee.

The mean treatment exposure was 97 weeks in the prevention trial, 53 weeks in the prodromal AD or prodromal AD/mild AD dementia trial, and 31 weeks in the mild to moderate AD dementia tri.

Recruitment periods for the DMT trials were prophylaxis (145 weeks), prodromal AD and prodromal AD/mild AD dementia (117 weeks), and mild to moderate AD dementia (118 week.

The mean duration of the Phase II cognitive enhancer trial was 127 weeks, including 27 treatment weeks, with an average of 105 participan.
The median duration of the phase II trials for the treatment of neuropsychiatric symptoms was 150 weeks, including 8 weeks of treatment, with an average of 122 participan.

There are 30 drugs in 31 phase I trials in clinical phase I (Figure 1, Table
There are 27 DMTs in Phase I trials, including 9 biologics and 18 small molecul.

CADRO mechanisms represented in Phase I DMT therapy include inflammation (5 drugs); epigenetic regulators (4); amyloid (3); tau (3); protein homeostasis/proteinopathy (3) Synaptic Plasticity/Neuroprotection (3); Neural Development (2); Vascular System (2); Cell Death (1); and Metabolism and Bioenergetics (
Biomarkers Of the 31 phase III DMT trials, 6 trials (19%) used amyloid positron emission tomography (PET) as the inclusion criterion and 6 trials (19%) used amyloid PET or cerebrospinal fluid ( CSF) amyloid ind.

Five (16%) phase III DMT trials used CSF-amyloid/tau ratio or amyloid PET as inclusion criteria, and one trial used plasma phosphorylated tau protein (p-ta.

Thirteen (42%) phase III DMT trials did not use biomarkers as study inclusion criter.

A phase III trial of a cognitive enhancer entered the study using either CSF amyloid or CSF t.

Of the phase II studies, 12 (14%) DMT trials used amyloid PET as inclusion criteria, 5 (6%) used CSF amyloid or amyloid ratio, and 12 (14%) used amyloid PET or CSF amyloid assessme.
Six (7%) phase II DMT trials used CSF-amyloid/tau ratio as inclusion criterion, 4 (5%) used CSF-amyloid/tau ratio or amyloid PET, and 3 (4 %) using tau PET and 1 trial (1%) using amyloid PET or CSF-t.

Thirty-nine phase II trials (47%) did not require biomarker-based diagnostic confirmation at study enrollme.

Of the phase III DMT trials, 19 (61%) used biomarkers as supportive outcom.

Amyloid PET was used in 10 (32%) and tau PET in 7 (23%) to support clinical outcom.

In phase II studies, 46 DMT trials (55%) had biomarkers as supportive outcomes (11 amyloid PET; 10 tau PE.

TableBiomarkers used as outcome measures or inclusion criteria in phase II and III DMT trials (clinicaltria.

gov date of access: January 25, 2025) FigureAnalysis of drug targets in different clinical trials Xiaobian summary AD Clinical trials target a robust range of biological processes, including most biological processes identified in the CADRO classificati.

With the approval of the monoclonal antibody aducanumab, other amyloid and tau protein abnormalities, inflammation and synaptic dysfunction have also made progress in the AD drug development pipeli.

Despite the challenges posed by the current pandemic, the number of clinical trials has increas.

Biomarkers are increasingly used in clinical trials, including their use in diagnosis and outcom.

Advances in target identification, drug discovery and clinical trial approaches increase confidence that more and better treatments will emerge from the AD drug development pipeline
Reference: Cummings J, Lee G, Nahed P, et .

Alzheimer's disease drug development pipeline: 202 Alzheimers Dement (N.

2022;8(1):e1229 Published 2022 Maydoi:11002/trc12295