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The last July 28th is the 8th World Hepatitis Day. The latest WHO statistics show that chronic hepatitis B and hepatitis C affect approximately 325 million people worldwide, resulting in 1.34 million deaths each year. Nearly 30 million people infected with hepatitis B in China and 7.6 million people infected with hepatitis C. About 330,000 people die each year from cirrhosis and primary liver cancer caused by hepatitis B virus or hepatitis C virus infection. Regardless of the number of people affected by the disease or the difficulty of treatment, the treatment challenge of hepatitis B is much higher than that of hepatitis C.

“Soofibwe has achieved the cure of hepatitis C at the end of 2013, and the current hepatitis B drugs can only achieve the level of sustained suppression of the virus. When can hepatitis B be cured?” This is Dr. Chen Huanming’s thinking in recent years. problem.

In 2018, the new drug development company named “Zhimeng Medicine” founded by Chen Huanming received an early investment from Lenovo Star and anchored the research and development direction in the field of hepatitis B and central nervous diseases. Recently, the reporter interviewed Dr. Chen Huanming, the founder of the company, in Shanghai.

Chen Huanming is a veteran of multinational pharmaceutical companies, small and medium-sized biotechnology companies in the United States, multinational CRO companies, and large domestic pharmaceutical companies. After different types of corporate management styles, the concept of differentiated new drug projects has also shaped him. The height and pattern of the problem. Chen Huanming believes: “The requirements and standards for the development of innovative drugs in the domestic pharmaceutical industry are increasing. Chinese pharmaceutical companies must quickly promote differentiated and differentiated projects with international standards through technological means such as target innovation.”

 

Far-reaching clinical needs

Hepatitis B is a serious disease that once made the Chinese people “smell the color”, but the incidence rate in the United States is much lower than that of hepatitis C. Therefore, in all liver diseases, hepatitis B is not the priority of the American academic and pharmaceutical industry. Chen Huanming’s view is that China is a big country in hepatitis B. The search for hepatitis B cure drugs still depends on Chinese companies to make rapid progress.

In recent years, the state has increased its investment in public health prevention systems. Hepatitis B vaccine will be given to newborns. However, due to the late spread of hepatitis B vaccine in China, China is still a “hepatitis B big country”. More than 50% of the world’s new and dead liver cancer patients caused by hepatitis B occur in China. According to Chen Huanming, hepatitis B and tuberculosis are listed as major national infectious diseases. At present, there are still 90 million carriers of chronic hepatitis B virus in China, of which 30 million need treatment and only 10 million are receiving treatment. If left untreated, there is a high probability that hepatitis will develop into cirrhosis or even liver cancer. Therefore, on the road to cure hepatitis B, there is still a huge unmet need in our country.

Existing anti-hepatitis B virus therapeutic drugs mainly include immunomodulators and nucleoside analogs. Common immunomodulators include interferon (IFN); nucleoside analogues include lamivudine, telbivudine, entecavir, tenofovir, and the like. Although these drugs can effectively inhibit viral replication, they also have significant limitations. For example, α-interferon and polyethylene glycol long-acting interferon in immunomodulators are only effective in 30% of patients with hepatitis B, and the cure rate is about 7% to 8%; the disadvantages are also prominent, requiring injection and expensive, Side effects such as cold-like symptoms or insomnia are obvious and are greatly limited in clinical applications. However, nucleoside drugs do not have a mechanism to completely eliminate the virus. After stopping the drug, the virus quickly rebounds, and long-term use is prone to drug resistance.

 

“Combination Boxing” based on new targets

 

Although both hepatitis C virus (HCV) and hepatitis B virus (HBV) can infect liver cells, they are two completely different viruses: HCV is an RNA virus that does not aggregate to form DNA duplexes and is more easily cleared. HBV is a type of DNA virus that is more stable and more complex in the nucleus, and it is more difficult to remove.

During the replication of HBV, viral DNA enters the host nucleus, and under the action of DNA polymerase, the gaps of both strands are filled to form a supercoiled covalently closed circular DNA (covalently closed circular DNA, cccDNA). ). cccDNA is the original template for HBV pre-genomic RNA replication. It is generally believed that only by clearing the cccDNA in the nucleus can the virus carrying status of hepatitis B patients be completely eliminated, which is the target of antiviral therapy.

Where will the breakthrough point of hepatitis B “cure” in the future? Chen Huanming thinks a little bit: the development of new targets and new mechanisms of action is the premise to study the cure method of hepatitis B, but it is impossible to completely eliminate the virus by single drug alone. The combination drug is the currently recognized hepatitis B cure strategy.

Due to the multiple roles of HBV nucleocapsids in viral replication and virus stability, HBV nucleocapsid inhibitors inhibit autoviral function and block new hepatocyte infection by inhibiting HBV virus assembly and DNA replication to inhibit viral replication. Reduces and eventually eliminates infected liver cells, thereby increasing the cure rate.

Nucleocapsid inhibitors interfere with multiple steps in HBV replication

At present, there are also many companies around the world that are laying out around nucleocapsid inhibitors. For example, Johnson & Johnson hopes to revolutionize hepatitis B therapy for clinical treatment of HIV and HCV through a combination of nucleocapsid inhibitors, RNA interference therapy (si-RNA), and TLR7 agonists. Domestic Qilu Medicine and Dongyang Pharmaceutical also have projects that have entered the clinical development stage with the “nuclear capsid inhibitor” as a breakthrough.

Zhimeng’s small molecule hepatitis B drug CB01 targets the multifunctional nucleocapsid protein, which can inhibit the different stages of viral replication. It is an ideal basic drug for the treatment of hepatitis B by the combination strategy. The company plans to publish preclinical efficacy data for CB01 at the 69th Annual Meeting of the American Association of Liver Diseases (AASLD) in 2018 at the end of the year. The IND will be declared in 2019 and the first phase will be launched in mid-2020.

In addition, Zhimeng also has an immunomodulator CB02 and an HBV surface antigen and e antigen inhibitor. Both products are in the preclinical stage. Chen Huanming also told reporters that Zhimeng’s core product pipeline has different viral targets than existing drugs.

Zhimeng’s future new drug development strategy is to develop a combination of direct antiviral and immunomodulatory therapies around CB01. Chen Huanming hopes to see two aspects in clinical practice: on the one hand, it completely blocks the replication and expression of the virus, on the other hand, by activating the immune function to completely remove the virus.

 

Find a trusted partner

 

Chen Huanming has extensive experience in the development of new drugs. He is a senior expert in the design of new drugs and medicinal chemistry. He also has considerable practical experience in pharmacokinetics, pharmacology, toxicology, and formulation. His deep involvement and responsible projects involve diseases such as antiviral, anti-tumor and neurodegenerative diseases. Many projects have entered the clinical research stage, and several projects have been successfully transferred.

Despite all the battles, Chen Huanming admits that his personal strength is too small. “New drug development is not a successful business for one or two people. It requires close coordination between internal teams and strong support from external partners. This is a necessary condition for the development of new drugs.” Chen Huanming believes in conviction and is also reflected in The name of the company. Zhimeng’s literal meaning “sincere cooperation, handle alliance”. Whether it is an entrepreneurial partner, an external partner, or an investor, Chen Huanming hopes to continue on the basis of sincere trust.

At the beginning of the company’s operation, Zhimeng’s first task was to form a team with complementary experience and sincere cooperation. Chen Huanming is well versed in medicinal chemistry. For this reason, he invited Dr. Zhang Zhijun, who has been engaged in the research and development of viral drugs for a long time, to serve as the company’s chief scientific officer.

Zhang Zhijun holds a Ph.D. in Biology from the University of Birmingham in the United States. He has more than 20 years of experience in research and development of new drugs. He has been responsible for the research and development of HIV, HBV, HCV and bacterial infections in multinational corporations and American universities, and has been involved in the development of viral drugs in Sanofi Asia Pacific. The responsible person has accumulated rich experience in the research and development of antiviral drugs for many years. Zhang Zhijun and Chen Huanming have had many years of cooperation experience overseas. The complementarity and tacit understanding of the two will be beneficial to the efficient promotion of Zhimeng’s projects.

Chen Huanming possesses the unique “critical” vision of scientists. This is not only reflected in the product project, but also in the selection of investment partners. The angel investment that chooses to accept Lenovo Star from many investment institutions is also based on “sincere cooperation” by Chen Huanming. The idea is to consider the decisions made in the long run. On the one hand, it is touched by Lenovo Star’s respect for the professionalism of scientists. On the other hand, it is based on the resources of Legend Holdings, which is backed by Lenovo Star. It can make the company not worry too much about the pressure of funds in the different stages of promotion of new drug projects. .

Combination therapy is the hope of curing hepatitis B. Chen Huanming also hopes to cooperate with more external partners after the project enters the clinical stage. Although hepatitis B treatment is currently mostly a nucleoside analogue or a single use with interferon, he expects that the combined use of different mechanisms of action will become a therapeutic trend. Zhimeng has always established cooperation with the outside world with an open and cooperative attitude.

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