“Alzheimer’s” saved? Lenovo voted for 2 Tsinghua professors, focusing on Alzheimer’s disease

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author｜Xu Minghui

Recently, 60-year-old Yu Minhong started learning mathematics.

is not for the purpose of opening up a new way for New Oriental, nor is it to live to learn. He hopes that by studying mathematics, he “reduces the possibility of developing Alzheimer’s disease.”

In medicine, “Alzheimer’s” is also known as Alzheimer’s disease (AD).

This is a disease larger than epilepsy and second only to lung cancer in mortality. One case of Alzheimer’s disease occurs every 3 seconds in the world.

And among the more than 10 million patients in China, there are 1.22 million people who are “middle-aged” dementia”. According to WHO data, up to 12.5% ​​of middle-aged people (41-60 years old) in China suffer from Alzheimer’s disease.

Pharmaceutical companies are the greatest hope for this group.

However, reality is often cruel. If you are an innovative drug, you will die in the near future, and if you are an innovative drug for Alzheimer’s disease, you will die in a lifetime. Regarding AD drug development, a phrase often mentioned in the industry is “99% failure rate”.

Among the top ten causes of death globally, the only disease that lacks an effective treatment is Alzheimer’s disease. Zheimer’s disease.

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“Are you a sister?”

Huan’s mother’s rhetorical question completely broke Ren Huan, who was working in Shanghai. She hid in the bathroom and cried: “I always thought that I would be the last person in this world she forgets.”

Ren Huan’s mother is one of the more than 10 million Alzheimer’s patients in China.

4 years ago, Huan’s mother was just a little lost, and she often took the wrong car when she went out. Later, she began to forget what happened recently, and the topics she just talked about would be fleeting in her mind.

Later, Mommy Huan gradually became demented, disabled, and even incontinent. In the end, she even forgot her closest people…

Alzheimer’s in people It has been 121 years since it was discovered in the world, but so far there is no medicine that can eliminate it. The 6 drugs approved by the US FDA can only relieve symptoms.

In 1901, German physician Allers Alzheimer discovered a 51-year-old ‘s case. In 1906, the patient died. 1907 years, Alzheimer’s published research results were included in the medical literature…

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However,due to the difficulty of obtaining research materials and the lack of in vivo imaging technology, the research on Alzheimer’s disease is very slow.

It was not until around 1990 that there was a breakthrough in “the cause of Alzheimer’s disease” .

At that time, a young Australian named Claude Wischik went to Cambridge University to study. He isolated “Tau protein” from plaques in the brains of Alzheimer’s patients, and first proposed that Tau protein may be the cause of Alzheimer’s disease.

Not long after, a substance called “beta amyloid” also came out.

Massachusetts General Hospital scientists have discovered gene mutations in Alzheimer’s patients The mutation causes amyloid beta to accumulate in the brain. They believe that beta amyloid, which accumulates in the brain, is the culprit that causes Alzheimer’s disease.

There are more than 50 million Alzheimer’s patients worldwide, which is undoubtedly a blue ocean.

The huge market demand drives major pharmaceutical companies to join the research and development of AD drugs middle. According to the Pharmaceutical Research and Manufacturers Association of America (PhRMA), since 1998, pharmaceutical giants such as Roche, Bayer, and Merck have invested more than $600 billion in this field.

However, most of the funds were wasted, and nearly half of the new drugs were even in the first clinical phase. . The “battle situation” was extremely tragic.

Data show that from 1998 to 2017, 146 Alzheimer’s disease drugs failed in clinical practice worldwide , the clinical failure rate exceeds 97%.

1993-2003 was the peak period for AD drug listing.

In the past ten years, 5 innovative drugs for the treatment of Alzheimer’s disease have been approved by the FDA. They are Tacrine from First Horizon, Donepezil from Eisai in Japan, Rivastigmine from Novartis in Switzerland, Galantamine from Johnson & Johnson in the United States, and Memantine from Merz in Germany.

However, after 2003, there has been no new drug in the AD sub-track for 16 consecutive years. Tacrine was also withdrawn from the U.S. market in 2012 because of its strong liver toxicity.

Lilly’s Solanezumab had high hopes because it was one of the few to survive clinical trials Phase II drugs. But unfortunately, Solanezumab retired Eli Lilly’s CEO and did not go public, and finally died in the third phase.

Hundreds of millions of dollars in investment and uncertain prospects have made many pharmaceutical companies “disarm and surrender” .

Pfizer, with a market value of one trillion, has announced that due to high research and development costs and poor efficacy, it will no longer Try to develop new drugs to treat Alzheimer’s disease.

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On the other side of the ocean, a group of people began to find another way.

China is one of the countries with the largest number of Alzheimer’s patients. According to the “China Alzheimer’s Disease Report 2021” data, the number of existing Alzheimer’s disease and other dementia cases in China in 2019 was 13.24 million, about one-fifth of the global total.

Also, nearly 13% of Alzheimer’s patients in China are still “young”.

40-year-old Hu Junjie is an Alzheimer’s patient. Hu JunJie is cheerful and runs a delicatessen with her husband in Dezhou, Shandong. Four years ago, she suffered from Alzheimer’s disease. Hu Junjie, who used to be able to sing and dance, can’t remember the lyrics and tunes now.

Like Hu Junjie, there are 1.22 million Chinese people who have Alzheimer’s disease at a young age . According to WHO data, middle-aged people aged 41-60 account for 12.51% of Alzheimer’s patients in China.

Geng Meiyu is Hu Junjie’s Shandong fellow and a researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences.

Alzheimer’s disease is one of her research directions. At that time, the international pharmaceutical giants fell on AD drugs one after another. At that time, the “brain-gut axis” began to enter Geng Meiyu’s field of vision.

Since it’s not enough to make a fuss on the brain, why not try to make a fuss in the stomach?

The so-called “brain-gut axis” is the close connection between the brain and the gut, which can interdependent. For example, when people are emotionally stressed, they can cause diarrhea, abdominal pain and other reactions.

According to Geng Meiyu, GV-971 (Nine Phase One) inhibits the specific metabolism of intestinal flora by inhibiting The abnormal increase of the product can reduce peripheral and central inflammation, thereby improving cognitive dysfunction and treating Alzheimer’s disease.

Zhong Yi, a professor at the School of Life Sciences, Tsinghua University, and Wang Jian, a professor at the School of Pharmacy, Tsinghua University, started from the “forgetting mechanism”.

“The forgetting mechanism is too active in Alzheimer’s patients, and this control knob named ‘Rac1’ can be adjusted Mechanism of forgetting.” Zhong Yi said that by targeting the Rac1-mediated forgetting switch as a target to design a treatment plan, it may be possible to find a way to treat Alzheimer’s disease.

New drug research and development requires a lot of investment. Zhong Yi found Lenovo, and Geng Meiyu joined Lu Songtao.

On April 13 this year, Zhuokai Bio, founded by Zhong Yi, completed tens of millions of yuan The B++ round of financing was exclusively invested by Legend Capital, a subsidiary of Lenovo. Zhuokai Bio was founded by Zhong Yi in 2001, but it was not until 2015 that it received financing for the first time.

Zhuokai Biotech, which has received financing, has also accelerated its pace of new drug research and development.

In 2017, Zhuokai Biotech completed the molecular screening of targeting Rac1 and established the research and development of small molecule drug JK-50561 Pipeline; in March 2021, JK-50561 obtained the implied approval for clinical trials from the Center for Drug Evaluation of the State Food and Drug Administration, and completed the first enrollment in September.

As the world’s first new drug for the treatment of Alzheimer’s disease from the perspective of amnesia, currently, JK-50561 clinical The Phase Ia trial is nearing completion and is expected to enter Phase II clinical trials in the second half of this year.

On the other side, Geng Meiyu introduced GV-971 to Lu Songtao of Green Valley Pharmaceutical.

Lv Songtao was once a health care product leader. After the separation from Shi Yuzhu, Lv Songtao captured many elderly people with the Chinese Lingzhi Bao, which was packaged as an “anti-cancer drug”. Later, Green Valley was frequently sued, and its products were named many times for publishing illegal advertisements.

After retreating at the Taihu School of Buddhist Master Nan Huaijin for more than a year, Lu Songtao vowed to be “the most anticipated thing by mankind” medicine”, Geng Meiyu came with GV-971.

In November 2019, there were no new drugs on the global Alzheimer’s disease market for 16 years. The curse was broken, and the China Food and Drug Administration conditionally approved GV-971 as a national Class I new drug, which is also my country’s first original drug for the treatment of Alzheimer’s disease.

According to Lu Songtao’s statement, as long as you take this medicine, after 6-9 months, mild to moderate Symptoms of Alzheimer’s patients are significantly reduced.

You can even write novels for publication.

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It sounded like a big rush, but I didn’t expect to kill Professor Rao halfway.

Late night on January 21, 2021, Rao Yi, a tenured professor of Peking University, sent a letter to the Chinese academic community. Shocking report letter. Geng Meiyu and the GV-971 that she led and developed were pushed to the forefront.

There are three main points of controversy: academic fraud, unclear mechanism of action, and insufficient clinical trials.

The issue of academic fraud, the official has concluded that “there is no fraud”. However, there are still many doubts about the drug effect of GV-971 itself.

On the one hand, the phase III clinical cycle of GV-971 is too short, only 36 weeks. You know, Eli Lilly’s Solanezumab was still considered effective at 40 weeks, but at 80 weeks, the drug proved ineffective. On the other hand, GV-971 is “conditionally marketed” in China, that is, pharmacological mechanism and safety research still needs to be carried out after it is marketed.

However, this does not affect the GV-971 riding the wind and waves in the market.

GV-971 has been on the market for 23 days, and its sales have reached 179 million yuan. Out of stock is the norm. Just three months ago, GV-971 was approved by the FDA and is currently undergoing an international Phase II clinical trial.

This experience of ice and fire is also deeply experienced by American pharmaceutical giant Biogen.

One and a half years after GV-971 was approved by the China Food and Drug Administration, 2021 In June 2009, Biogen’s Aducanumab (Aducanumab) was approved by the FDA, becoming the sixth new AD drug approved by the FDA in history.

That night, Bojian’s stock price soared, triggering two circuit breakers, and the company’s market value increased by 100 billion yuan a day. Some experts even predict that aducanumab will become the “next-generation drug king”, with peak sales or over 10 billion US dollars.

Contrary to the optimistic reaction from the market, there was a backlash from the scientific community.

Because clinical trials have shown that Alzheimer’s patients in No. 301 have improved cognitive performance after using aducanumab There was no statistical significance, but the cognitive ability of No. 302 patients improved to a certain extent, which was statistically significant. In other words, some statistical results are not true and credible.

In addition, the patient experienced significant side effects after using aducanumab.

From the data published by Biogen, 35% of patients in the phase III trial received high-dose aducanumab Cerebral edema occurs, and microbleeds occur in about 20% of patients.

In November 2020, FDA convened an external panel of experts to discuss the Aducanumab Biologics License Application .

At that time, experts agreed that there was no “strong evidence” that the drug was effective, and thus denied the drug. The marketing application of Bojian’s new drug. But now, after a lapse of seven months, aducanumab was suddenly approved again, causing dissatisfaction in the academic community.

Harvard bioethicist Kesselheim even believes that “the approval of Aducanumab may be the worst in recent U.S. history. Drug approval decisions.”

But it is undeniable that it is these seemingly “bad decisions” that make drugs Enterprises have the urge to continue research and development, and it has also brought hope to millions of Alzheimer’s patients.

After the approval of Aducanumab, Eli Lilly is not to be outdoneto Take a small step forward. The Alzheimer’s drug donanemab was granted breakthrough therapy designation by the US FDA. On April 8 this year, Donanemab just applied for clinical application in China.

Domestic pharmaceutical companies are also accelerating the research and development of new drugs for Alzheimer’s disease.

On February 28, Simcere (2096.HK) and German company Vivoryon Announced that SIM0408, a new Alzheimer’s disease drug jointly developed by the two parties in China, was approved by the Center for Drug Evaluation of the State Food and Drug Administration and entered clinical trials in China.

The OAB-14 jointly developed by Xinhua Pharma (000756.SZ) and Shenyang Pharmaceutical University has been discovered All stages of work, such as drug design, drug preliminary toxicity evaluation, etc.

In addition, there are Kanghong Pharmaceutical (002773.SZ), Changchun High-tech (000661.SZ) and other pharmaceutical companies have made arrangements in the field of Alzheimer’s disease. According to incomplete statistics, in 2021, there will be 74 financing events in the field of Alzheimer’s disease.

This is a race between China and the United States, and it is also a treatment for Alzheimer’s disease Patient Relay.

Although the approval of some new drugs may seem like a “bad decision” and the capital on the market may seem ruthless, they are patients The only life-saving straw that can be caught.

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