Why is the development of anti-Aβ antibodies from Bapineuzumab to Donanemab confused?

On May 6, 2021, the data of the anti-Aβ antibody Donanemab developed by Eli Lilly for the treatment of Alzheimer's disease phase II (NCT03367403) was published in the New England Journal of Medicine (NEJM).

The results of clinical trials showed that although Donanemab reached the primary clinical endpoint, none of the four secondary endpoints reached statistical significance.

01

Donanemab clinical trial results

The symptoms of Alzheimer's disease are caused by the loss and death of connections between brain cells.

The Phase II clinical trial called TRAILBLAZER-ALZ recruited 257 patients with Alzheimer's disease, of which 131 received Donanemab monoclonal antibody developed by Eli Lilly and the remaining 126 received placebo-controlled.

The results of the trial showed that patients using Donanemab in the Comprehensive Alzheimer's Disease Assessment Scale (iADRS) score dropped by 6.

In terms of safety and tolerability, the incidence of ARIA-E (Amyloid-related imaging abnormalities-edema) among patients using Donanemab accounted for 26.

02

The failure of anti-Aβ antibody

The amyloid hypothesis began in the 1980s and is currently one of the important theories explaining the causes of AD.

In August 2012, Pfizer and Johnson & Johnson announced the suspension of further research on the anti-Aβ monoclonal antibody Bapineuzumab.

In December 2014, the anti-Alzheimer's drug Gantenerumab, which Roche invested heavily in research and development, failed in phase III clinical trials.

On November 23, 2016, Lilly announced the results of EXPEDITION3: Solanezumab did not achieve the desired effect.

On January 30, 2019, Roche announced the termination of two phase III CREAD I and CREAD 2 clinical studies of Crenezumab in patients with early Alzheimer's disease (prodromal or mild AD patients).

On November 6, 2020, the FDA expert committee voted on the evidence for the clinical research of Biogen’s Aducanumab, and believed that the EMERGE trial could not provide evidence of effectiveness (1 vote for, 8 votes against, and 2 votes for uncertainty).

03

Six questions about the development of anti-Aβ antibodies

Is Aβ the cause of sporadic AD?

Numerous failed Aβ clinical trials seem to indicate that Aβ and AD have no causal effect.

Does Aβ use tau to destroy neurons?

Aβ confers neurotoxicity through secondary effector mechanisms such as tau.

Can APP mutations cause disease by altering the production of Aβ?

Aβ is a product of γ-secretase (including the complex of presenilin 1 or 2) processing APP.

Does presenilin mutation affect the pathogenesis of FAD through Aβ?

The loss of presenilin function (including its γ-secretase function) may lead to familial AD damage.

Does APOEε4 increase risk through Aβ?

Studies have shown that in apolipoprotein E (APOE) heterozygous ε4 carriers, the risk of AD increases by 2 to 3 times, while ε4 homozygous has a 12-fold increase in AD risk.
However, the current accumulated clinical evidence does not support that apolipoprotein E protein inhibits human Aβ clearance.
Whether APOEε4 can increase the risk of Aβ requires more systematic clinical research.

Does Aβ have a function?

The sequence of Aβ is highly conserved throughout vertebrates, and its production is coordinated by the activity of enzymes.
Aβ is present in the brains of all healthy individuals, and the functional role of Aβ may be important when considering therapies that target Aβ.
Physiological concentrations (picomolar and low nanomolar) of Aβ can promote the maturation of undifferentiated neurons, which is necessary for the formation of memory.
Studies have shown that Aβ may be used to regulate or utilize extracellular metal ions to achieve some unknown functions.
In addition, some researchers have put forward the hypothesis that Aβ plays a role in the innate immunity of the brain, which needs to be further explored.

The development of anti-Aβ antibodies has gone through many tribulations from Bapineuzumab to Donanemab.
The reason is still the unclear understanding of the pathogenesis of AD and the result of insufficient understanding of the pathogenesis of Aβ.
A lot of basic research work is still the key to breaking the AD disease.
As the population ageing continues to intensify, the AD market continues to expand, and more pharmaceutical companies have joined the track layout.
It is believed that with the continuous increase in research and development investment, more effective drugs for the treatment of AD will appear.

Reference materials:

https:// Eli Lilly’s Donanemab reached the primary endpoint of Phase 2 clinical trials

[3] The β-amyloid hypothesis meets clinical failure again, and BAN2401 takes the lead in the third clinical phase of Alzheimer's disease!

[4] https:// https://