June 20, 2021

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Why is the approval of Alzheimer drug: Aducanumab highly controversial?

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Why did FDA approve Aducanumab for AD even most experts objected?

Why is the approval of Biogen Alzheimer’s antibody drug: Aducanumab highly controversial or even more harmful?



Why is the approval of Alzheimer drug: Aducanumab highly controversial?  On June 7,  FDA approved the  Biogen’s beta-amyloid antibody drug Aducanumab for use in patients with Alzheimer’s disease (the most common type of Alzheimer’s disease).

Why is the approval of Alzheimer drug: Aducanumab highly controversial?

This is the first time the FDA has approved a drug for Alzheimer’s disease since 2003. However, Biogen Aducanumab is destroying the entire Alzheimer’s drug evaluation criteria.

In the short term, it may cause a large number of similar ineffective drugs to be listed, and in the long term it will cause related research and development areas. fall back.



1. The scientific principle of Aducanumab

The scientific principle of Aducanumab is rooted in the amyloid hypothesis of Alzheimer’s disease. The cognitive abilities of patients with Alzheimer’s disease will decline severely over time. These are shown in many movies and TV dramas, and everyone may have some impressions. Alzheimer’s disease is still a very common disease among the elderly. With the aging of the population, it has an increasing impact on many countries. The research and development of related drugs has also been very urgent.

A characteristic of Alzheimer’s disease is the large deposits of beta-amyloid in the patient’s brain. The deposition of these amyloid proteins may be an important factor leading to the decline of patients’ cognitive ability. A natural scientific hypothesis is: if these amyloids are eliminated, then Alzheimer’s disease may be treated-not necessarily curing or restoring cognitive ability, but it may slow the rate of cognitive decline.

Aducanumab is an antibody used to eliminate amyloid-it can bind to amyloid and cause the latter to be eliminated by human cells. The pathogenic hypothesis of amyloid is the most influential scientific theory in Alzheimer’s field, so there are many drugs developed for amyloid. Aducanumab is not the only antibody used to eliminate amyloid. Pharmaceutical giants Li Roche and Eli Lilly also have similar antibody drugs in clinical trials.

In addition to using antibodies to eliminate amyloid, there is a large class of drugs under development that inhibit the synthesis of amyloid, mainly BACE inhibitors. Many pharmaceutical companies involved in the development of Alzheimer’s disease also have such clinical trial drugs.




2. On what basis is Aducanumab approved?

After talking about the principle and scientific basis of Aducanumab, let’s look at the basis for its approval.

Why was Aducanumab approved this time? Is it shown to relieve the patient’s cognitive decline?

It’s not. Biogen has conducted two Phase III clinical trials with basically the same design. The high-dose group in one of the trials showed improvement in clinical indicators. But the same dose did not work in another experiment. The low-dose group did not improve in either test. With this result, we cannot conclude that a certain dose of Aducanumab can improve the patient’s condition.

In addition, there are improved groups here, which are divided after the test is completed, not before the test. This further increases the risk that the analysis has a “biased” effect, and that “improved” is just a false positive possibility.

Therefore, the basis for Aducanumab’s approval is not that it shows the ability to improve the patient’s condition-in fact, we have evidence that it may not have this ability at all.

The FDA’s approval basis is clearly stated in the press release provided today: In multiple trials, Aducanumab has shown the ability to clear amyloid, and this ability is in line with the dose relationship and the treatment time relationship.

That is to say, the basis of FDA approval is that Aducanumab has a function designed for amyloid-antibody itself-it can eliminate amyloid. This standard is probably the same as that of an actor who is a good actor because he can read lines.

Why can we use this standard instead of improving clinical indicators? The reason given by the FDA is that it believes that the removal of amyloid should be related to the improvement of clinical indicators. In other words, it believes that amyloid can be used as a biomarker for Alzheimer’s disease. As long as you improve this biomarker, the condition will also improve.



3. Are the approval criteria reasonable?

It can be clearly stated that the criteria for Aducanumab’s approval are completely nonsense, which does not conform to a large amount of scientific evidence, and even the basic logic does not make sense.

The most critical of the standards given by the FDA is that it determines that as long as the drug can clear amyloid, it can improve or delay Alzheimer’s disease. This is a kind of nonsense, and there is no need to find other evidence. According to the results of the two Phase III clinical trials that Biogen used to support Aducanumab’s approval, this theory can be falsified.

Aducanumab has shown the ability to clear amyloid in multiple trials, and it has shown this ability in two phase three clinical trials. But for the same removal of amyloid, only some patients in one trial benefited, and patients with the same conditions in the other trial did not benefit.

Such a result can be understood as “as long as the amyloid is removed, the condition can be improved or the progression of the disease can be delayed”? It should be that even if the amyloid is removed, the condition may not be improved or not.

Moreover, Aducanumab is not the first drug to clear amyloid. Multiple amyloid antibody drugs and BACE inhibitors all clear amyloid and have not shown improvement in multiple phase III clinical trials. And among these guys, only a small number of them have failed once, and most of them are of the type of repeated defeats.

Because of so many failures of the same type, many scientists are now wondering whether there is a problem with the amyloid hypothesis itself. At least the elimination of amyloid does not directly correspond to the improvement of the disease.

The FDA’s standard is to directly use a scientific hypothesis as a scientific fact, and it is also a hypothesis that has been falsified many times.



4. Serious harm to related fields

After the news of Biogen’s approval came out, some people believed that it would promote the development of new drugs for Alzheimer’s disease. This may be wishful thinking. The more likely reality is that a lot of similar drugs will see opportunities to take shortcuts, hoping to get market opportunities under the same standard of releasing water, and at the same time squeeze out the research and development space of other different types of Alzheimer’s drugs.

First of all, as we mentioned, Aducanumab is not the only drug that targets amyloid. There are many drugs of the same type and the same mechanism under research, and many of them have been abandoned because they have not shown efficacy in clinical trials. Many of the previously “failed” drugs did not fail to eliminate amyloid, but failed to relieve the condition. According to the current approved standards for Aducanumab, many new drugs for Alzheimer’s disease are lying in the trash cans of many pharmaceutical companies.

It is foreseeable that the brothers and sisters of this type of Aducanumab will soon make an impact on making the second new drug for Alzheimer’s disease. And Aducanumab has given a successful formula-as long as the amyloid protein is reduced. As a drug designed to reduce amyloid, this threshold has been so low that it does not exist.

Secondly, due to the sudden disappearance of the entry barrier for drugs targeting amyloid, the funding for drug research and development will inevitably tilt in this direction, leading to a sharp drop in the survival space for other types of Alzheimer’s drug research and development. Drugs targeting amyloid can be marketed by reducing amyloid, and drugs with other mechanisms may not be able to go this way. And even if you want to go, you will be at a congenital disadvantage compared to those drugs that directly target amyloid.

Originally, the final judgment standard for Alzheimer’s drug development is the same-you can really improve the disease. To put it bluntly, regardless of whether the cat is white or black, it is a good cat that can catch mice. The launch of Aducanumab directly opened a dedicated channel for amyloid drugs. It becomes a good cat if a white cat can catch a mouse or not. A black cat still has to continue to catch the mouse to be a good cat. How can the black cat live like this?

A large amount of funds and scientific research forces are biased towards amyloid drugs with suspicious effectiveness, squeezing out potential drug research and development of other mechanisms, and the harm to Alzheimer’s research and development will be long-term.

In addition, although the FDA requires Biogen to continue to complete trials that prove that Aducanumab improves clinical indicators after the market, the reality is that these post-marketing supplementary trials are time-consuming and difficult to control. Some rare disease drug companies even did not even start trials for many years after the drug was marketed.

One argument is that the FDA requires Biogen to complete it within 9 years, but what if it is not completed in 9 years? Can the FDA say that you have not completed it and I will let you off the market? It is still possible to fail the market (it is estimated that it will be very difficult due to patient pressure, etc.). After 9 years, Biogen said that my test was only half done. Can the FDA say that I will not continue to give you time at this time and immediately delist?

Aducanumab is priced at 56,000 US dollars a year, and now there are millions of Alzheimer’s patients eagerly awaiting any new treatment. Within a few years, billions of dollars may be spent on a drug that is likely to be ineffective, and at the same time, the research and development funds for the potentially effective drug will be transferred to the same kind of ineffective drug.

This is the huge harm caused by the listing of Aducanumab. This is also a questionable listing standard, and the latter will have a long-term impact in the entire field.




(source:internet, reference only)

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