Alzheimer’s disease, known as Senile Dementia among the folk, is like an “eraser” in the patient’s mind that will gradually obliterate his memory and thinking and judgment abilities. According to the statistics released by Alzheimer’s Disease International (ADI), there are about 48 million patients across the world now, and a new one will appear per three seconds. Among them, Chinese patients account for 20% or so. Its treatment still puzzles the world. Moreover, the harms of Alzheimer’s disease will be increasingly obvious with the trend of the aging of population.

Picture Source: I Am an Actor: Match-ups (ZJTV)

There are only a few of drugs in clinical use for the treatment of Alzheimer’s disease (AD) across the world. Major pharmaceutical companies have invested heavily in the development of new drugs over the past 20 years, but most of them failed. And no new drugs have gone on sale since 17 years ago.

 

However, on November 2, there was encouraging news. The National Medical Products Administration conditionally approved the application for registration and listing of GV-971 (Trade name: Jiu Qi Yi”), which is used to treat mild-to-moderate Alzheimer’s disease (AD) and improve the cognition of the patients.

GV-971 was jointly developed by the Shanghai Institute of Materia Medica under the Chinese Academy of Sciences, Ocean University of China and Shanghai Green Valley Pharmaceutical Co., Ltd., after a 22-year study. It is a homegrown innovative drug with complete independent intellectual property rights and also the world’s first multi-targeting and carbohydrate-based innovative drug for the treatment of AD. Thanks to the pilot of marketing authorization holder system in drug companies in Shanghai to promote their innovative research and development results, the drug can go on sale quickly to benefit AD patients and families.

This China self-developed and the world’s first brain–gut axis-targeting innovative drug to treat AD will provide new

treatment options for AD patients.

The drug being approved and available has not only filled the gap in this field across the world, but also met the expectation of the AD patients who are in urgent need of treatment drugs.

A total of 1,199 subjects participated in the clinical trials of GV-971 in phase I, II and III. The phase-III clinical trials, led by the Shanghai Mental Health Center under the Shanghai Jiao Tong University School of Medicine and the Peking Union Medical College Hospital, were conducted by 34 level-A tertiary hospitals across China. In these trials, a total of 818 subjects were observed after taking the drug. And the entire process of these trials were managed by the IQVIA Holdings Inc. (QuintilesIMS originally), which is the world’s largest institution for outsourcing services of new drug research and development.

 

According to results of the phase-III clinical research lasting for 36 weeks, GV-971 can significantly improve the cognition impairment of mild-to-moderate AD patients. Compared with the placebo group, the cognitive functions - which are considered as main efficacy indicators - in GV-971 group, have been greatly improved, with its average score in ADAS-COG dropping by 2.54 points (P < 0.0001). GV-971 can improve cognitive functions of AD patients in the way characterized by having continuous and steady functions of improvement after taking effect rapidly. In addition, GV-971 is relatively safe to take, with its adverse event rate the same as the placebo group.

 

According to @Voice of Chinese Academy of Sciences, Shanghai Green Valley Pharmaceutical Co., Ltd. has made preparations for the production and sales of GV-971, which will be go on sale within this year.

Picture Source: Shanghai Institute of Materia Medica under the Chinese Academy of Sciences

 

With unremitting efforts of 22 years, breakthroughs are made in the field of carbohydrate-based drugs.

 

In September this year, the research team led by Geng Meiyu published an article on the Cell Research, which reveals the function mechanism of GV-971 inhibiting AD.

HTTPS://DOI.ORG/10.1038/S41422-019-0216-X

 

According to the introduction to GV-971, GV-971 are marine oligosaccharide moleculars extracted from seaweeds. Different from traditional antibody-based drugs, it can capture beta-amyloid protein (AB) in a multi-point, multi-fragment and multi-state manner and restrain the fibrilization of beta-amyloid protein (AB), with the already-formed beta-amyloid protein (AB) fibri depolymerized to non-toxic monomer. According to the latest research, GV-971 can reduce neuronal inflammation in the brain to prevent the progression of AD by restoring the balance of intestinal flora and remodeling the body’s immune homeostasis.

 

In a report on www.minmouse.com.cn, Geng Meiyu said, “According to the pathogenesis of AD found in the research of GV-971, eating kelp and drinking yogurt often can prevent seniors from AD.” She added that her team would make further research to expand the indications of GV-971, such as Parkinson’s disease, depression, sleep disorders, autoimmune diseases and others.

 

“Because traditional mainstream drugs are often single-targeting, the drugs that can prevent people from AD and stop the progression of AD can be hardly found now.” said Geng Meiyu. She also told us, “Carbohydrate chain is one of the three major substances of life. As the chemical structure of carbohydrate chain is difficult to be discovered, carbohydrate is a long-neglected target and the field of carbohydrate-based drugs, like a sleeping giant, is waiting to be awakened by people.”

 

Since 1997, when the research team led by Geng Meiyu found the first chemical compound related to AD, they have been engaged in the drug development for 22 years. “I have ever felt lonely, because while other people are discovering small molecule drugs, we are studying treating AD patients with carbohydrate drugs, which is an unprecedented, enormous challenge in terms of structure determination, quality control, preparation process, modeling, evaluation system and metabolic process in vivo.” said Geng Meiyu. However, she is proud that her team has persisted in the research and never stopped. She added, “We persisted in it first because of the sense of mission as a scientist. Later, after we gradually knew the strong demands of AD patients for treatment drugs, the sense of mission became an urgent desire, which has gone beyond our interest in science and finally grown into an extremely powerful support for our research.” To develop a therapeutic drug for AD treatment as soon as possible, Geng Meiyu has not published a relevant paper for so many years. During the research period, her everyday route was limited to the way between her home and the laboratory.

 

Shanghai Observer

 

On November 3, the Chinese Academy of Sciences and Shanghai Municipal People’s Government jointly held a press conference to reveal key information about the research and development and marketing progresses of GV-971. In the press, the questions, including “when can GV-971 be available?” and “why do we need to restore intestinal flora balance first to treat AD?” were answered one by one on the spot.

Press Conference

GV-971 is approved for listing “conditionally”.

 

On the website of the National Medical Products Administration, GV-971 is approved for listing “conditionally”. According to the explanation, the applicant is required by the National Medical Products Administration to continue researches in the pharmacological mechanism and long-term safety and effectiveness of GV-971 after GV-971 goes on sale, to improve analytical methods of oligosaccharide and submit relevant test data on time.

 

In response, Geng Meiyu, a researcher from the Shanghai Institute of Materia Medica under the Chinese Academy of Sciences explained, “That GV-971 is ‘approved for listing conditionally’ is because the formal report on the carcinogenicity of GV-971 in rats in a long term has not been included in the application materials of GV-971. However, the experiment has been finished with complete statistical results, which show that GV-971 has nothing to do with carcinogenicity.”

 

According to the introduction of Geng Meiyu, in general, the applicant materials of a new drug cannot be submitted and new drug certificate not be issued until all its formal reports are finished and included in the materials. However, in view of great demand of AD patients for treatment drugs and the good results of the experiment on rats to discover the carcinogenicity of GV-971 in in a long term, the National Medical Products Administration approved its listing and requires that the research team submit the left materials needed within three months.

 

“New drug research is a long-term process and its results need to be tested with more patients. Now our basic research is just the tip of the iceberg. Our next step is to follow the requirements of the National Medical Products Administration to do the revaluation and real-world research after GV-971 goes on sale.” said Geng Meiyu.

 

Shanghai Green Valley Pharmaceutical Co., Ltd. is now actively promoting the international phase-III multi-center research.

 

Start from intestines to treat the brain disease?

 

GV-971 is the world’s first brain-gut axis-targeting drug for AD treatment, which represents an entirely new technical route.

 

According to the introduction of the research team, the preclinical function mechanism of GV-971 indicates that GV-971 improves the cognition impairment of AD patients through restoring the intestinal flora balance, restraining the abnormal increase of specific metabolites in the intestinal flora, decreasing peripheral and central inflammations and reducing the precipitation of beta-amyloid protein (AB) and the hyperphosphorylation of tau protein. The unique function mechanism of brain–gut axis-targeting has provided an important scientific basis for in-depth understanding of the clinical efficacy of GV-971.

 

In recent years, people have had an increasingly deep understanding of gastrointestinal flora. A large number of studies have shown that gastrointestinal flora is closely related to metabolic diseases (obesity, diabetes, non-alcoholic fatty liver, etc.), cerebrovascular diseases, neuropsychiatric disorders and tumors. The existing researches have proved that intestinal flora imbalance is closely related to autism, depression, Parkinson’s disease, AD and other diseases.

 

The research of Geng Meiyu’ team indicates: In the progression of AD, beta-amyloid proteins (AB) precipitate and tau proteins are phosphorylated, so the composition of intestinal flora changes. Then the metabolites become abnormal, which stimulates peripheral immune inflammations and promotes the infiltration of inflammatory immune cells TH1 into the brain, so that the M1-type gitter cells in the brain are activated. Finally, it leads to the development of neuroinflammation associated with AD and then cognition impairment. After one takes GV-971, his intestinal flora is restored, abnormal metabolites reduced, the infiltration of peripheral inflammatory immune cells into the brain prevented and the neuroinflammation restrained. At the same time, the precipitation of beta-amyloid proteins (AB) and the phosphorylation of tau proteins are decreased, so his cognition impairment is improved. In that way, the purpose of GV-971 to treat AD is achieved.

 

The clinical researchers of phase III are “very satisfied” with its efficacy.

 

As for the efficacy of GV-971, an issue of most concern to people, Xiao Shifu, Lead Researcher of the clinical research of GV-971 of phase III and Professor at the Shanghai Mental Health Center under the Shanghai Jiao Tong University School of Medicine, introduces: The clinical research of phase Ⅲ has the following main characteristics:

 

First, it is the longest case - control study with drug cases and pure placebo cases across the world, with its longest control time reaching nine months.

 

Second, based on the research experience of Phase Ⅱ, the clinical research of phase III is stricter in terms of diagnostic criteria. The potential subjects for the experiment have gone a more rigorous and difficult process of selection, with the failure rate of selection reaching nearly 50%. It took four years to do the phase III research, which has proved that research is a long process.

 

The present assessment tool for efficacy is possibly not sensitive to the pharmaceutical effect of GV-971 on mild AD patients. Just like people take exams. When the questions in papers are easy to answer, all students can get relatively high marks. AD is progressive, that is, when the disease becomes relatively severe, it develops faster. In phase III, the efficacy of GV-971 is proven to be better and more obvious.

 

At present, the main efficacy indicators of drugs are like those of exam papers. In ADAS-COG, the overall improvement of AD patients is shown with the average score of AD patients dropping by 2.54 points. For only relatively moderate AD patients, the score drops by nearly 5 points, which shows a more obvious development. “In the representative research with placebo cases and Donepezil cases lasting for 6 months, in which 34 randomized, double-blind, case-control studies are conducted, the score drops by 2.01 points. In comparison with that, our score drops by 2.54 points, which, in my view, is very satisfying efficacy.” said Xiao Shifu.

Research and Development Team Photo

 

GV-971 will be available before the end of December.

 

When will GV-971 be available? “Before the end of December.” answered Lyu Songtao, President of Shanghai Green Valley Pharmaceutical Co., Ltd.

 

Lyu added, “In order to meet the needs of more AD patients, Shanghai has given 40 mu of land for production and construction in the Zhangjiang Science City to Shanghai Green Valley Pharmaceutical Co., Ltd. We will try to start the construction within the year and complete it in three years. When completed, this factory can meet the medication needs of two million AD patients a year.”

 

According to him, this factory has been designed entirely in accordance with GMP standards of America. By the time it is completed, the application for the new drug of GV-971 listing in America will perhaps be approved. The new drug will be exported from Zhangjiang Science City to the world in the future.

 

The price of GV-971 is to be decided.

 

As for the price of GV-971, Lyu Songtao said, “Its price will be both affordable for common people and internationally competitive.” The final price of GV-971 needs to be decided after views of all sides are coordinated.