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Why does Alzheimer's disease become a black hole for pharmaceutical companies when Baijian fails?

2022-05-08 00:55:00Amino observation

 picture source @ Vision China

picture source @ Vision China

writing | Amino observation , author | Lin Xiaochen

As near 20 The first approved Alzheimer's disease in years ( abbreviation AD) New drugs ,Aduhelm It was expected by the market .

But in Biogen In the quarterly report just released ,Aduhelm Sales are only 280 Thousands of dollars , Far less than the initial market season 1600 A positive expectation of $million .

Under business pressure , This year, 3 month Biogen Started a round about Aduhelm The layoffs , I hope to save 5 Billion dollars in costs ;4 month 22 Japan Biogen And voluntarily withdrew Aduhelm Listing applications in Europe .

meanwhile , Previous main push Aduhelm Of CEO Michel Vounatsos Also dismal to step down . These actions mean , stay Biogen In the future planning of , There seems to be no more Aduhelm The location of ,

list 317 Days later ,Aduhelm On the verge of death , Make it the closest thing to beating Alzheimer's “ loser ”. According to the American Association of pharmaceutical research and manufacturers in 2018 The annual report shows , The failure rate of research and development of new drugs for Alzheimer's disease is as high as 99.6%, Now this proportion may rise again .

Countless pharmaceutical companies have lost their halberds , what on earth AD It will become the research and development black hole of pharmaceutical enterprises ?Aduhelm What enlightenment does the failure of commercialization bring ?

01 Anxious Biogen, I'm sorry Aduhelm

stay AD The pharmaceutical company developed “ Death Valley ” in , Failure seems to have become a normal thing . After all, the failure rate is as high as 99.6%.

but Aduhelm My failure is full of regret , If you give it some more time , Maybe the ending of the story will be completely different .

Aduhelm Not without effect , It can effectively reduce amyloid plaque in patients with Alzheimer's disease , And that's what it can get FDA Reasons for approval .

This year, 3 month ,Biogen It was announced again Aduhelm Long term data of phase III clinical trials . data display , In order to 100mg /mL Dose intravenous injection Aduhelm near 2 Two and a half years later , The amyloid protein of the test patient -β Plaque and plasma p-tau181 Two key features “ Significantly reduce the ”.

Even so ,Aduhelm It is still difficult to commercialize . The reason is that many doctors still don't believe Aduhelm Can treat AD, Most doctors are reluctant to prescribe Aduhelm Prescription for . It also makes Aduhelm Sales are far below market expectations .

Especially this year 1 month 13 Japan , The center for Medicare and Medicaid Services in the United States (CMS) Official confirmation , Will be right Aduhelm Implement restrictive coverage draft ,CMS It will only be provided to those patients who pass the clinical trial after examination Aduhelm Medical insurance coverage .

That means ,Aduhelm Almost lost health insurance coverage , The number of patients will be strictly limited . Although at the end of last year ,Biogen Have already put Aduhelm The price of our products is lower 50%, from 5.6 Million dollars down to 2.8 Thousands of dollars , But this is still a high cost that many ordinary American families can't afford .

replay Aduhelm Post IPO performance , We can see Biogen stay Aduhelm The layout is a little too hasty , If they can calm down to further complete the follow-up clinical research , that Aduhelm Maybe we can conquer the market with data .

One side , The original Aduhelm get FDA The approval to go public is full of controversy . During the approval process ,Aduhelm Encounter with FDA The unanimous opposition of the Organizing Committee , but FDA do one 's utmost to hold one 's own opinion against that of the majority , Think Aduhelm It is possible to overturn the current treatment of Alzheimer's disease before it is released .

FDA The organizing committee is composed of experts in the industry , Designed to handle FDA Things that are not right . It's not hard to see. , In the eyes of insiders Aduhelm Not popular . At the time Biogen The most correct approach is not to promote Aduhelm commercial , But trying to convince industry experts .

On the other hand ,Aduhelm The listing is actually conditional , That's after listing Aduhelm A clinical trial is still needed , To prove your strength . obviously FDA Also hope that Biogen Can conquer experts with data , but Biogen Until this year 3 End of month , Just to FDA Handed over the late 4 period ENVISION The final research plan of the experiment , And will 5 Start screening patients in January .

Without the support of the expert group , Lack of clinical data support ,Biogen Just want to Aduhelm Rapid commercialization , This is obviously against the common sense .Aduhelm Despite having nearly 20 The halo of the first new Alzheimer's drug approved in , But this does not convince cautious American doctors , After all, seeing a doctor in the United States is a big deal .

In the final analysis ,Aduhelm The relief is amyloid -β The condition of plaque , But is this amyloid plaque a predisposing factor for Alzheimer's disease , Still controversial , In particular, many pharmaceutical companies have failed in this line one after another before .

Aduhelm What is lacking now is not the ability to commercialize , But practical clinical data , Only the final curative effect can verify its effectiveness .

02 Mysterious Alzheimer's disease

The caution of American doctors is justified , Because today AD Still full of mystery .

1906 year 11 month 3 Japan , In the southwest of Germany 37 At the meeting of psychiatrists , A man named Alois · Alzheimer's doctor , Reported a new mental illness to the world .

When he was an assistant in a psychiatric hospital , Recorded a man named Auguste 50 The condition of a - year-old woman , She was paranoid 、 insomnia 、 Memory disorders 、 Mental illness such as aggression and insanity , And getting sick 5 Died years later .

Later, at Auguste's autopsy , Alzheimer found obvious amyloid plaques and neurofibrillary tangles in her brain tissue , And this is also AD The beginning of discovery .

Over the next few years , Alzheimer's has published three more cases , And in 1911 In, I found a “ Plaque only ” Of patients , Later, amyloid plaques and neurofibrillary tangles were proved to be different stages of the same disease .

People for AD Your understanding starts here , But also stay here . today ,AD It is still one of the most difficult diseases in the world , The medical community still knows little about its pathogenesis , Most medical methods judge the cause of disease by observing the characteristics of patients .

for example , With Aduhelm As a representative of the “Aβ Cascade hypothesis ” It is AD The most typical case features , At the same time, it is also the most mainstream pathological Hypothesis .

In a normal person's brain , There is a large protein amyloid precursor protein (APP), It is cut into by special enzymes β- Amyloid and other short chain amyloid proteins , It won't have any impact . But over time , In the brain for APP The processing efficiency of , So as to gradually form accumulation , That's the plaque .

geneticist John Hardy Find out , quite a lot AD The patient has a genetic mutation , Lead to APP After being cut β- Amyloid becomes more viscous or richer , And they are more likely to suffer from AD. This is it. “Aβ Cascade hypothesis ”.

According to this hypothesis , In theory, humans just have to stop β- Trigger events caused by amyloid accumulation , It can stop AD Happen . But drug development is not as simple as it sounds , There are countless pharmaceutical companies that have failed in this line .

Their roots ,“Aβ Cascade hypothesis ” In fact, there are two treatment routes : Suppress route and clear route .

The inhibition route is mainly through blocking APP Cleavage enzymes , To reduce β- Amyloid production , So as to achieve the purpose of reducing plaque . But it is a pity that , Many needles for β- Clinical trials of secretory enzymes have failed , Pfizer is the biggest driver of this route , Also in the 2018 Announced its withdrawal in AD field .

The clearance route is immunotherapy , It can be divided into active immunotherapy and passive immunotherapy . Active immunotherapy by injection Aβ antigen , To activate the body's immune system , But most test results show that , This practice has serious adverse reactions .

At present, passive immunotherapy is more successful , That is, by injecting Aβ Antibodies to directly eliminate β- Amyloid , So as to avoid the formation of plaque .Aduhelm It is the representative of this therapy , Roche also has the same route 、 Lilly and other companies .

domestically , Hengrui pharmaceutical SHR-1707 It is one of the few domestic products that have entered the clinical stage AD New drugs , The same is true of “Aβ Cascade hypothesis ” Passive immunotherapy .

03 Aduhelm Failure makes the R & D of pharmaceutical enterprises return to rationality

Declining Aduhelm Although full of regret , But it's not a complete failure .

from Biogen In the long-term data of phase III clinical trials released continuously , We can see Aduhelm The data is still positive , You could even say Aduhelm Has achieved the original purpose of the design .

The reason Aduhelm Not accepted by doctors , Because Biogen Eager to commercialize , If Biogen Be able to take advantage of being approved first , Further consolidate clinical data , So believe it Aduhelm Is to be recognized by the market .

but Biogen But they were eager to seize the market at the first time when they were approved , Seems like before Roche and Lilly , Eat the whole 300 ten thousand AD Patient's big cake , Thus ignoring the views of the industry .

Commercialization is blocked , It doesn't mean that Aduhelm No effect , It is Biogen Our strategy failed . Bold and courageous “ Death Valley ” Of Biogen and Aduhelm Still worth remembering .

Look at it from a different angle ,Aduhelm Commercialization failed , For the entire AD It's not a bad thing for the development of the industry . If Aduhelm Sell well , Then it will hit the R & D enthusiasm of several other pharmaceutical companies , Send the wrong signal to the market that the market capacity is greater than the R & D capacity .

Of course , Before clinical data validation , We can't say “Aβ Cascade hypothesis ” Namely AD The positive solution of . Except for starch plaque ,AD There will also be Tau Abnormal protein 、 Iron overload 、 Vascular structural changes 、 High insulin levels , And it gave birth to Tau Protein Hypothesis 、 Iron ion disorder hypothesis 、 Neuroinflammation hypothesis and other routes .

It's not hard to find out ,Aduhelm The crux of the failure of commercialization does not lie in the route itself , But not enough clinical accumulation .

Maybe in the next few years , There will be other routes AD New drugs , Such as “Tau Protein Hypothesis ” etc. . But even so ,“Aβ Cascade hypothesis ” It is also the closest to success so far 、 The most mainstream R & D route .

For pharmaceutical companies , There's no need for Aduhelm Frustrated by the failure of commercialization . When an industry is over focused by capital , Something like Aduhelm Such commercialization is more important than R & D .

Aduhelm The obstruction of commercialization does not mean that there is no curative effect ,“Aβ Cascade hypothesis ” It has not been falsified . Its failure , It's just for humans to AD Our research has returned to rationality again .

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