Alzheimer's disease treatment can be expected in the future

If you have watched the TV series "Everything is Good" in the fire in 2019, you will beat your chest to Su Daqiang, who is "possessed" in it, but "Su Daqiang" who suffers from Alzheimer's disease at the end of the play successfully "washes white".

As the aging of society becomes more and more obvious, senile-related diseases are showing a high incidence, and Alzheimer's disease is particularly typical

A study in the United States shows that caring for patients with Alzheimer's disease takes a long time and is stressful.

Statistics: CICC Corporate Trust International Consulting

The cause is unknown, and there are many hypotheses

So far, the pathogenesis of Alzheimer's disease is still unclear, but there are many hypotheses about its pathogenesis, of which three are the most important

The first is the cholinergic injury hypothesis

The second hypothesis is the β-amyloid hypothesis

The third hypothesis is the tau protein hypothesis

In addition to the above three hypotheses, there are dozens of other hypotheses such as gene mutation theory, inflammatory response theory, oxidative stress theory, calcium imbalance theory, brain-gut axis theory, etc.

Amyloid plaques in the brain are one of the goals of Alzheimer’s disease treatment[2]

Almost the entire army was wiped out, and the FDA smashed its "golden sign"!

Nearly 20 years before 2021, the field of new drug research and development for neurodegenerative diseases was almost wiped out.

·In 2012, Johnson/Pfizer's monoclonal antibody drug bapineuzumab failed miserably in Phase III clinical trials.

In 2014, Roche's monoclonal antibody gantenerumab also failed in the large-scale phase III.

· In 2016, Eli Lilly’s new drug solanezumab for Alzheimer's disease, which has received much attention, failed in a phase III clinical trial and did not experience a significantly greater delay in cognitive decline;

· In 2017, Merck announced the termination of the Phase III clinical trial of Verubecestat, a new Alzheimer's disease drug, EPOCH (protocol017), and determined that it is "almost impossible to get a positive clinical result";

· In May 2018, Johnson & Johnson announced that it had terminated the Phase II/III study of the BACE inhibitor atabecestat

·In June 2018, Eli Lilly/AstraZeneca announced the termination of the global phase III project of lanabecestat (oral BACE inhibitor) for the treatment of Alzheimer’s disease.

When the cause is unknown, the blind tries to see the whole picture like an elephant

On June 7, the field of Alzheimer’s disease ushered in a sensational event: the FDA accelerated the approval of Bojian/Eisai’s Aβ (β-amyloid) antibody Aduhelm (aducanumab) based on the alternative endpoint of biomarkers.

This approval immediately caused an uproar

Why does the FDA go against the vote of the panel members to ensure that aducanumab is listed? It's simple, the huge patient demand can't wait
.

Maria Carrillo, Chief Scientific Officer of the Alzheimer's Rights Group in Chicago, said in a statement: "History has shown us that approving the first drug in a new category can revitalize the field, increase investment in new therapies, and encourage more changes.
Big innovation
.
We are full of hope.
This is the beginning of both the drug and the better treatment of Alzheimer’s disease
.
”

The sparks start a prairie fire, the wind is surging

The accelerated approval of Aducanumab has indeed given pharmaceutical companies a shot in the heart to overcome Alzheimer's disease
.
Since then, the development of the AD field and the entire central nervous system (CNS) field has been unprecedentedly high
.
Today, Alzheimer's disease has undoubtedly become one of the busiest and most concerned treatment areas, which was never expected a few months ago
.

According to Insight database statistics, after Aducanumab, 6 Aβ antibodies have entered phase III clinical trials, and 4 are still under development; in the field of Tau antibodies, 4 phase II clinical projects are under global development
.
Roche Gantenerumab, Eli Lilly Donanemab, Bojian/Eisai Lecanemab have all expressed their hope to submit new drug listing applications in the second half of this year
.

Aβ/Tau antibody is a new drug with rapid progress

Insight database collation

Roche and Eli Lilly: Actively seek FDA listing

Gantenerumab is an Aβ monoclonal antibody introduced by Roche from Morphosys
.
Although it had failed, Roche still insisted on developing this product, and its phase 3 clinical trial is still in progress
.
Roche CEO SeverinSchwan said in a recent interview that Roche will complete Gantenerumab's Phase III trial in the second half of 2022
.
On July 26, Roche negotiated with the US FDA on Gantenerumab
.

According to a study published in "Natural Medicine" [3] in June this year, Gantenerumab improved the levels of many biomarkers in patients with hereditary Alzheimer's disease
.
Among trial participants with dominant inherited Alzheimer's disease (DIAD), treatment with Roche Gantenerumab can reduce the biomarkers of disease and neurodegenerative diseases in the brain, which can cause early-onset memory loss and Other symptoms
.

Gantenerumab treatment significantly reduced brain amyloid deposits

Eli Lilly’s donanemab is an antibody drug targeting N3pG-modified Aβ protein
.
N3pG is a modified beta amyloid plaque.
By targeting this subtype, donanemab can specifically bind to amyloid plaques in the brain, thereby promoting the elimination of amyloid plaques
.
The drug has been certified as a breakthrough therapy by the FDA
.

Donanemab mechanism of action

In the TRAILBLAZER-ALZ trial, patients treated with donanemab had an average reduction of 84 centiloid units compared to baseline amyloid plaques at 76 weeks, with a baseline value of 108 (less than 25 centiloid units are considered typical amyloid Negative protein scan results)
.

At the just-concluded AAIC meeting, Eli Lilly updated the biomarker analysis results of the TRAILBLAZER-ALZ study.
In most patients treated with donanemab, the beta amyloid load decreased rapidly during the first 24 weeks of treatment, and the higher the baseline level, the decrease The faster the rate, heralding a possible treatment plan for Alzheimer's disease
.

Eli Lilly said it plans to submit Donanemab's Biologics Licensing Application (BLA) through the accelerated approval process later this year
.
To warm up this new drug, Eli Lilly adjusted its corporate structure in August and created a new neuroscience business unit.
From this, Anne White, who previously led the oncology department, will continue to exert in-depth efforts in this field in the future
.

BMS, GSK.
.
.
betting on Alzheimer's disease

On June 25, Bristol-Myers Squibb (BMS) and Prothena jointly announced that BMS had exercised the option of the global neuroscience research and development cooperation agreement reached by the two parties before and obtained the US development rights for the Tau protein antibody therapy PRX005 under study
.

PRX005 is a potential "best-in-class" anti-Tau protein antibody, combined with the microtubule binding domain (MTBR) of Tau protein, is a potential treatment for Alzheimer's disease (AD)
.
A number of pre-clinical studies have proved that, compared with other anti-tau antibodies, PRX005 has shown superior ability in binding, intercepting and blocking the internalization of pathogenic tau cells and reducing downstream neurotoxicity
.

In July 2021, GlaxoSmithKline and Alector announced a global strategic cooperation to develop and commercialize two clinical-stage, potentially first-class monoclonal antibodies AL001 and AL101, aimed at increasing the level of pregranulin (PGRN)
.
PGRN is a key regulator of immune activity in the brain, and its genetic connection with a variety of neurodegenerative diseases makes it one of the most attractive genetic verification targets for the development of new immunological treatments
.

Mechanism of action of AL001 and AL101

The test results published in AAIC-2021 showed that AL001 showed good safety and tolerability, and quickly restored the level of PGRN protein in plasma and cerebrospinal fluid (CSF)
.

AL001 treatment slows down the clinical progression of the patient's disease

From: AAIC

Summarize

History has shown us that the approval of the first new drug in the same field will inject vitality into related fields
.
In the field of new drug development related to Alzheimer's disease, from a desperate situation to constant controversy, from repeated defeats to regaining confidence, we are groping forward in the dark
.

In conquering AD, people from all walks of life are advancing and launching new treatment methods
.
Regardless of the fate of these drugs in the end, at least the efforts made in solving the problem of major human diseases and reducing the burden on the family society will be remembered forever
.
In the field of Alzheimer's disease treatment, the future can be expected!

Reference materials:

1.
NicholsE,SzoekeCEI,VollsetSE,etal.
Global,regional,and nationalburdenofAlzheimer's disease and otherdementias,1990-2016:asystematic analysisfortheGlobalBurdenofDiseaseStudy2016[J].
TheLancetNeurology.
2019,18(1):88-106.

2.
MullardA.
LandmarkAlzheimer'sdrugapprovalconfoundsresearchcommunity.
Nature.
2021Jun;594(7863):309-310.
doi:10.
1038/d41586-021-01546-2.
PMID:34103732.

3.
Salloway, S.
, Farlow, M.
, McDade, E.
etal.
Atrial ofgantenerumaborsolanezumabindominantly inherited Alzheimer'sdisease.
NatMed 27, 1187-1196 (2021).

4.
Yin Ruijia, Guan Li, Bai Chunhua, Ma Xinle, Song Lingyang, Meng Ting.
Development progress of anti-Alzheimer's disease drugs targeting Tau protein[J].
Biochemical Engineering,2021,7(01):170- 172.