Produced by Tiger Sniff Medical Group
Author｜Chen Guangjing
Title Map｜Visual China
Alzheimer’s disease (“AD” for short, also known as Alzheimer’s) is now a miracle drug.
Just a few days ago, Biogen’s official website announced that its global Phase III clinical trial of Lecanemab (lencanemab) jointly developed with Eisai achieved the primary endpoint, significantly improving patients’ health cognitive ability and met all key secondary endpoints. In addition, it was confirmed that amyloid pathology was indeed present in the patient’s brain.
The trial, code-named “Clarity AD,” is focused on patients with mild Alzheimer’s disease and mild cognitive impairment (MCI) caused by Alzheimer’s disease. Based on the results of the trial, this new drug developed based on the “beta amyloid protease hypothesis” (abbreviation: Aβ hypothesis) is likely to become the second Alzheimer’s disease drug approved by the FDA within two years.
Alzheimer’s disease is a neurodegenerative disease that can be almost devastating to sufferers and their families. The official FDA data shows that after the diagnosis of the disease, the average life expectancy of patients is 4 to 8 years. Patients gradually lose memory and cognition, and in advanced stages they are unable to talk or respond to their surroundings.
This disease imposes a huge economic and social burden.
Jia Jianping, a professor of neurology at Xuanwu Hospital of Capital Medical University, pointed out in a recent article that the total number of patients worldwide is about 50 million, and by 2050 this number will reach 152 million. Behind it, China alone consumes nearly 170 billion US dollars every year, which will increase to more than one trillion US dollars in 20 to 30 years.
At present, the cause of the disease is not clear, and there is no specific medicine. There are many drugs under development, mainly based on several main hypotheses. Among them, the “Aβ hypothesis”, which has been in existence for 25 years, is the mainstream, and it is also an area where drug research and development is concentrated. At the same time, this hypothesis and related drugs are also the “topic king” that has caused the most controversy.
Biogen’s Aduhelm (aducanumab, aducanumab), which was approved last year, was delayed until the deadline due to disputes between all parties; , The strong boycott of the insurance industry has not subsided, and even the FDA has very different opinions, and it can only fade out of the market within a year of listing.
Nevertheless, the Aβ hypothesis is considered to be the most likely field of breakthrough. In addition to Lecanemab, which announced the results of the third phase, related products from companies such as Eli Lilly are also breaking through.
The giants are obsessed with this. Is it their confidence in R&D ideas or their unwillingness to fail? Will they succeed this time? Is there really a cure for Alzheimer’s disease?
Hundreds of billions of dollars are spent in the light of day
The results of this trial are encouraging.
According to Biogen’s official website, the Phase III clinical trial Clarity AD enrolled 1,795 patients with early Alzheimer’s disease from around the world.
Results showed that Lecanemab treatment met the primary endpoint, and after 18 months of treatment, the subjects’ CDR-SB (a scale to assess cognitive and functional ability) showed that, The drug slowed clinical decline by 27 percent compared with placebo.
In addition, key secondary endpoints, including changes in brain amyloid levels measured by PET scans and related scales, also yielded statistically significant results. When treated for 18 months, Aβ accumulation in the brains of subjects with early Alzheimer’s disease decreased and disease progression slowed.
Even the most demanding will have to admit that this is a positive result.
According to the company’s public information, Eisai will present specific data at the Alzheimer’s Clinical Trials Conference on November 29, and the research results will also be published in the journal. Before the end of the fiscal year on March 31, 2023, the company will apply for routine approval in the United States and submit applications for marketing authorization in Japan and Europe.
According to the estimates of the Alzheimer’s Association of America, if a drug can delay the onset of Alzheimer’s disease by five years, it can save at least more than 300 billion US dollars in costs. In this sense, if this drug is really effective and can be approved in time, it will be an important contribution not only to pharmaceutical companies, but also to the whole society.
Behind this dawn, businesses and governments have also paid a lot. Statistics from the American Association for Drug Manufacturing and Research show that from 2000 to 2017, pharmaceutical companies spent more than $600 billion on Alzheimer’s disease research. NIH (National Institutes of Health) also invests more than $1 billion annually.
Multinational giants such as Eli Lilly and Roche have spent billions of dollars in failed cases. Not long ago, Merck, which had left the field as early as 2018, returned to the field of Alzheimer’s disease drug research and development, investing about 1.1 billion US dollars in the hope of using Cerevance’s new technology platform to discover new targets for Alzheimer’s disease. point.
Currently, there are 2,974 Alzheimer’s disease-related projects under research around the world, and 907 projects have entered the clinical trial stage.
According to past data, the failure rate of research in this field is as high as 99.8%, and even researchers take failure for granted. This also paved the way for Aduhelm’s fate.
From the data point of view, Biogen and Eisai’s first Aβ antibody drug AduheIn the two phase III trials of lm, the successful one also achieved a “22% reduction in CDR-SB”.
However, because of the two phase III clinical trials, one of which was successful and the other was unsuccessful, and the statistics were unconvincing, it was received by experts from the FDA Expert Advisory Committee, clinicians and medical insurance companies. Payment and other boycotts.
On the day Aduhelm was approved, members of the advisory committee resigned angrily, pointing out that the executive power of “expedited approval” took precedence over science. Some clinicians have publicly stated that they will not issue a prescription for the drug.
Most fatally, the Centers for Medicare and Medicaid Services (CMS) also refused to “pay” for it. And Biogen set the price for Aduhelm at $56,000 per year, which ordinary patients simply cannot afford. This directly led to commercial difficulties.
Because Aduhelm was approved for marketing on an accelerated basis, further research is needed to prove its efficacy according to the rules, and more funds are needed to support it. The failure of commercialization is equivalent to a “death penalty” for this drug.
The end result was that although the FDA approved the product despite pressure, Biogen had to cut back on commercial investment, and even the CEO who promoted the drug was forced to retire early.
Lecanemab does seem to have turned a corner compared to Aduhelm.
Lecanemab’s performance in Phase III clinical trials has won the recognition of investors, and Biogen’s stock price has risen by 40% on the same day.
Only this time, can they really get out of the shadow of failure?
Is there a cure for Alzheimer’s disease?
For the approval of Aduhelm, the FDA has received many accusations, including being coerced by patients, and even speculation that there is a “shady”.
From the FDA’s official statement, they are convinced that they have discovered the possibility of successful Alzheimer’s disease drug development from these controversial data.
In fact, unlike the first generation of drugs developed based on the “Aβ hypothesis”, Aduhelm and Lecanemab are antibody drugs that work against Aβ targets and are Aβ antibodies.
Clinical trial data have shown greater ability to clear Aβ.
“There is a serious error in the perception of the experts that they do not separate quantitative and qualitative.”
Dr. Wang Yaning, former director of the Quantitative Pharmacological Review Office of the Clinical Pharmacological Review Department of the US FDA Drug Review and Research Center, and CEO of Langlai Technology, once pointed out in a live broadcast of Tongzhiyi that past failures The drug did reduce Aβ, but the amount of reduction was too little to cause a qualitative change. This is the main reason for failure.
Wang Yaning said that about 80% of the patients enrolled in Aduhelm had mild cognitive impairment, and Aβ decreased from 40% to 10% after 78 weeks of treatment. This is to remove almost all Aβ, which is very different from previous drugs. There is even a chance of reversing the disease at high enough doses.
In the projects currently under research, more and more companies realize this and work hard on “quantity”. At present, not only Aduhelm and Lecanemab, Lilly’s Donanemab also has a good performance.
And when the results are not so clear, because I am too eager for an effective Alzheimer’s disease drug, I pay more attention to the potential of a new generation of antibody drugs than doubts. Powerful, unwilling to stifle any possibility, the FDA executives rarely overruled and made a decision to approve the drug.
For this controversial approval, Dr. Patrizia Cavazzoni, director of the FDA’s Center for Drug Evaluation and Research, gave an official explanation in the form of an open letter.
According to Dr. Patrizia Cavazzoni’s letter, Alzheimer’s disease is a serious, life-threatening disease for which no cure is known. The data submitted by Biogen is very complex, and there is still “uncertainty” in terms of clinical benefit, which is both the reason for the controversy and the possibility.
The FDA’s decision to approve marketing is also based on careful examination of clinical trial results, soliciting opinions from relevant experts, and listening to the opinions of patient groups. For patients, the benefits outweigh the risks.
Dr. Patrizia Cavazzoni noted that Aduhelm did “sustainably and very convincingly reduce levels of amyloid plaques in the brain,” despite different results from the two Phase 3 trials. He believes that the reduction in plaque is also expected to reduce clinical decline.
From this perspective, Lecanemab’s beautiful Phase III trial data has also justified the FDA and the company’s name.
Actually, this misunderstanding should never have happened.
The key to the problem is that there are too many failures in the development of Alzheimer’s disease drugs. In 2019, Biogen’s internal experts also made wrong judgments based on inertia, and they made early Terminated two pivotal Phase III clinical trials. In the follow-up analysis, the researchers realized that this was a mistaken killing.
After discussions with the FDA, the opportunity for “resurrection” was obtained, but the foundation of trust was broken. In addition, one success and one failure occurred in the third phase of the trial, which complicates the matter and makes it difficult to convince experts – 10 of the 11 experts voted against and 1 abstained.
It should be noted that behind the celebrations, the theoretical basis behind the development of such drugs – the “Aβ hypothesis” itself faces huge challenges.
This year, the authoritative journal Science published an article “fighting” Aβ, a key study suspected of data fraud. At the same time, some new theories are also questioning whether Aβ is the cause of Alzheimer’s disease, or a phenomenon after the onset.
Compared with the “Aβ hypothesis”, virologist Chang Rongshan believes that another pathogenesis study is morebelievable. A research paper on the pathogenesis published earlier this year pointed out that lysosomal damage in the brain is the root cause of illness, and that the increase in beta amyloid is only an external manifestation. “New drug development focuses on repairing lysosomal damage, which may be more effective than the current focus on removing beta amyloid.”
The members of the advisory committee, who will leave angrily in 2021, questioned Aduhelm’s point, a very important one is whether “reduction of brain amyloid plaques” can replace the clinical endpoint of Alzheimer’s disease treatment.
Dr. Patrizia Cavazzoni has also stated that after accelerated approval to market, pharmaceutical companies must also conduct post-marketing studies to verify expected clinical benefits. If the expected clinical benefit is not achieved, the delisting will still be delisted.
In other words, Lecanemab is a mule or a horse in the treatment of Alzheimer’s disease.
In this sense, Aβ-targeted Alzheimer’s disease drugs must stand the test of extensive clinical application in order to win the final approval. This is also the most critical, difficult and uncertain battle.
At the same time, the reality that needs to be faced is that if a patient with Alzheimer’s disease develops to a severe stage, it is irreversible, which also means that this drug has no effect on severe Alzheimer’s disease. Patients with silent disease are powerless, and for new cases, in order to fully play their role, clinical “early detection, early diagnosis, and early treatment” must be achieved.
Before this, how to make clinicians, medical insurance payers, etc. break the prejudice caused by Aduhelm to accept this drug is also a challenge that Biogen and Eisai need to face.