The FDA approved the listing of a new drug aducanumab for Alzheimer's disease, but it led to the resignation of three experts. Why?

On June 7, the FDA announced the use of accelerated approval channels to approve the first new Alzheimer's disease drug-Aducanumab (trade name: Aduhelm) since 2003.
The approval of this drug is not only in the treatment of Alzheimer's disease.
A super heavyweight in the past 20 years has triggered a major controversy over the FDA's drug approval standards ^[1]
.

At present, the FDA's decision has led to the resignation of three FDA's peripheral and central nervous system drug advisory committee experts, namely Joel Perlmutter of the University of Washington, David Knopman of the Mayo Medical Center, and Aaron Kesselhein of Harvard University
.

Aaron Kesselhein even called this the worst drug approval decision in the United States recently

Introduction to AD disease

Alzheimer's disease (AD), commonly known as "Alzheimer's disease", is a progressive neurological disease that impairs thinking, memory, and independence, leading to premature death
.

Currently, the disease cannot be stopped, delayed or prevented, and it is an increasingly serious global health crisis affecting patients and their families

According to statistics from the World Health Organization, there are more than 50 million dementia patients in the world, and this number will continue to grow, and is expected to reach 150 million by 2050
.

Every 3 seconds, 1 person worldwide suffers from Alzheimer's disease

At present, the cause and mechanism of Alzheimer's disease are not very clear.
The more recognized pathogenesis of Alzheimer's disease includes: Aβ neurotoxicity mechanism; Tau protein hyperphosphorylation mechanism; gene mutation mechanism; Choline Energetic neuron damage mechanism; excitatory amino acid toxicity mechanism; nerve cell calcium imbalance mechanism; high cholesterol mechanism
.

At present, most of the research and development directions of drugs are aimed at the deposition of β-amyloid (Aβ) plaques, but they are basically wiped out.
The approval of Aducanumab has brought about the resurrection of this target and the conquering of Alzheimer’s disease.
A new hope
.

       Reasons for the controversy after Aducanumab's approval

       Aducanumab is a high-affinity, fully human IgG1 monoclonal antibody targeting the -Aβ conformational epitope
.

It can selectively bind to the amyloid deposits in the brains of AD patients, and then clear the deposits in the brains by activating the immune system

       Aducanumab has been controversial, mainly in two aspects:

       Controversy 1: The results of two key phase III clinical trials are inconsistent

       Before Aducanumab was approved, two crucial phase III clinical trials were initiated: EMERGE and ENGAGE respectively
.

Three experts have jointly published opinion articles on JAMA to evaluate Aducanumab[2].

       For these two diametrically opposed test results, the company cannot give a convincing explanation
.

Moreover, from the detailed data released by Bojian, among patients receiving high-dose aducanumab treatment, ~35% of patients have drug-related cerebral edema, and ~18% to 22.

       Based on the uncertainty of its efficacy and potential safety hazards, after Bojian and Eisai submitted the marketing application of aducanumab, in the expert committee organized by the FDA, almost all experts voted against aducanumab, saying that there was no There is ample evidence to prove the effectiveness of this drug in the treatment of Alzheimer's disease
.

       Controversy 2: At present, researchers have doubts about the view that Alzheimer's disease can be cured by solving the deposition of β-amyloid protein
.

Based on the phenomenon of β-amyloid deposits in the brains of AD patients, researchers have launched a large number of studies in an attempt to find specific drugs for the treatment of Alzheimer's disease

       Regarding Aducanumab, the FDA has chosen "decreased central nervous system Aβ burden" as a possible alternative endpoint with reasonable causality
.

It should be noted that the FDA's current approval of Aducanumab is not completely unconditional, but a "phase 4" clinical study is required

       Why does the FDA have to reject the crowd and accelerate the approval of Aducanumab?

       Up to now, the cause and mechanism of Alzheimer’s disease have not yet been clarified.
At this stage, drug development is based on various hypotheses, including Aβ-amyloid deposition, neurofibrillary tangles, neuroinflammation, traumatic brain injury, etc.
The success rate is only 2.
7%, which is lower than the average success rate in the field of new drug research and development
.
Since entering the 21st century, more than 320 clinical trials have failed, which has become the "Waterloo" of countless pharmaceutical companies
.
Even though many pharmaceutical companies went to the field of Alzheimer's disease one after another, most of them ended in failure
.
Alzheimer's disease has become the hardest hit area for drug research and development
.

       On the other hand, there are currently at least 50 million Alzheimer's disease patients in the world.
By 2050, this number is expected to reach about 150 million
.
In 2018, the global cost of treatment and care has reached trillions of dollars, bringing a heavy burden to patients' families and society
.
Many patients suffer emotional and physical pain in the later stages of the disease, and this pain is long and huge.
At present, there are not many drugs available for Alzheimer's disease clinically, and the improvement of the disease is also very limited
.
The approval of Aducanumab will bring new hope to patients and their families
.

       Approval is only the first step.
Whether clinical doctors and patients can be convinced is the key to the ultimate success of the drug
.
Looking back at Aducanumab a few years later, maybe it will not have the best clinical efficacy and the largest market share, but in any case, it will still be a milestone in the AD battle
.

       Reference source:

       1.
https://       2.
Alexander GC, Emerson S, Kesselheim A S.
Evaluation of aducanumab for Alzheimer disease: scientific evidence and regulatory review involving efficacy, safety, and futility[J].
JAMA, 2021, 325(17): 1717-1718.

       3.
Biogen-Global Alzheimer's Platform Foundation Webinar Aducanumab Data Review.