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The Financial Times issued a statement last week saying that thanks to the Chinese government’s regulatory support and growing interest in the investment community, China BioPharma has ushered in a booming era and has attracted many global pharmaceutical industry executives, especially multinationals. Pharmaceutical company talents.

On a global scale, many countries have high hopes for biosimilar drugs. Although Europe and the United States have already approved a variety of biosimilar drugs, China’s large population of patients and the backflow of high-end biopharmaceuticals have made this area still have a lot of room for growth. PharmExec pointed out that the development of biosimilar drugs in China is on the rise.

At present, the development of biosimilar drugs in the world mainly focuses on a series of biopharmaceuticals whose patents are or will soon expire, mainly including adalimumab, infliximab, etanercept, rituximab, and bevacizumab. Anti, trastuzumab and so on.

According to incomplete statistics, the FDA has approved 10 biosimilars and 7 monoclonal antibodies; EMA has approved 40 biosimilars and 14 monoclonal antibodies. Unfortunately, there is no real biosimilar drug approved in China yet.

To change this situation, the State Food and Drug Administration (CFDA) has issued a series of encouraging policies to promote the research and development of Chinese biological analogs. For example, in February 2015, the “Technical Guidelines for R & D and Evaluation of Biologically Analogous Drugs (Trial)” defined the application procedures, registration requirements, and categories of biosimilar drugs.

After several years of development, some companies in China have already crossed the curve in front of the car, and some companies are changing to adapt to new changes. This article summarizes the biological similar drugs for six heavily-researched drugs such as adalimumab, international approvals, and players who have run faster in China.

Rituximab

Rituximab was developed by Roche and was approved by the FDA and EMA in 1997 and 1998 respectively. Its main indications are non-Hodgkin’s lymphoma, chronic lymphocytic leukemia and rheumatoid arthritis. In 2016, rituximab (Row Bros.)’s global revenue reached US$7.2 billion and the Chinese market was approximately US$160 million.

Rituximab is a human and mouse chimeric monoclonal antibody with a degree of humanization of 60% to 70%. The target is a transmembrane phosphoprotein CD20 on the surface of B lymphocytes. The core technique is to replace the mouse with a human constant region. The constant region of the murine antibody retains the variable region sequence.

Currently, rituximab is one of the most effective drugs for non-Hodgkin’s lymphoma, and its use in combination with chemotherapy has been approved as first-line treatment, and has been shown to significantly improve the survival rate of patients. Clinical trials have shown that combined use of rituximab and CHOP chemotherapy can increase the overall response rate of invasive NHL patients to 83% and the complete remission rate to 76%.

So far, the EU has approved two biosimilar drugs of rituximab, including Celltrion’s Truxima (for different indications during the sale, also known as Blitzima, Rituzena and Ritemvia) and Sandro’s Rixathon under Novartis. /Riximyo.

On April 21, 2000, Matilda officially entered the Chinese market. At the same time, a group of Chinese bio-pharmaceutical companies are quick to start the “imitation” road.

The fastest one is Fu Hong Han Lin. January 29, 2018, Fuhong Hanlin rituximab injection for the treatment of non-Hodgkin’s lymphoma and rheumatoid arthritis in the listing application was included in the priority review. This is China’s first biosimilar drug to be listed and is expected to become the first domestic biosimilar drug to enter the market.

Both Cinda and China Cell Engineering have entered phase III clinical trials. Among them, Cinda Bio’s IBI301 was jointly developed with the U.S. pharmaceutical giant Eli Lilly and won major national special support in 2014. Preclinical data indicate that all major IBI301 features (including master-slave structure, heterogeneity, biological activity, and process-related impurities) are highly similar to those of rituximab. Preclinical pharmacology studies show that the pharmacokinetics and toxicity characteristics are also very similar to those of the original study.

Adalimumab

Adalimumab is a star product of Epstein, which has consistently ranked among the best-selling drugs in the world from 2012 to 2017. In 2017, global sales revenue totaled 18.4 billion U.S. dollars. However, Xiu Mei Le’s performance in the Chinese market is relatively bleak. In 2016, China’s total revenue was only 31 million US dollars, less than 0.01% of the global market.

Adalimumab was approved by the FDA on December 31, 2002 and approved by EMA on September 8, 2003. Approved indications include ankylosing spondylitis, Crohn’s disease, psoriasis, juvenile idiopathic arthritis, psoriatic arthritis, ulcerative colitis, cutaneous suppurative sweaty, and uveitis.

The United States has approved two adalimumab biosimilars: Amjevita Amgen and Cyltezo Boehringer Ingelheim. The EU has approved four of them, Amgevita and Cyltezo, and Amgen’s Solymbic and Samsung’s Imraldi.

On February 26, 2012, Adalimumab entered the Chinese market. At present, there are nearly 20 pharmaceutical companies in China preparing for imitation. Among them, Biotec, Xinda Bio and Fuhong Hanlin are among the top few.

Analysts expect that even though the original research and repairing Mei Le does not show similar strong global sales in China, with the appearance of biologically similar drugs with more affordable prices, it is convinced that in the future China will see a surge in the use of adalimumab.

Infliximab

In 2017, the total global income of infliximab reached 7.15 billion U.S. dollars. However, its sales in China are still unclear. The available data is that in 2015, China sold only 50 million US dollars, which is less than 0.6% of the global total market share.

Infliximab (a gram) is another popular anti-TNFa monoclonal antibody developed by Janssen, a Johnson & Johnson company. It was approved by the FDA and EMA in 1998 and August 1999, respectively. Currently approved for the treatment of inflammation-related diseases, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque type psoriasis.

To date, only two infliximab biosimilars have been approved in the United States. They are Inflectra (infliximab-dyyb) from Pfizer/Celltrion and Ixifi (infliximab-qbtx) from Pfizer. The EMA approved 3 products, Pfizer’s Inflectra, Celltrion’s Remsima and Samsung Bio’s Flixabi.

On May 17, 2007, Funk officially listed in China for the treatment of rheumatoid arthritis, ankylosing spondylitis, and Crohn’s disease. Since then, the development of biosimilar drugs in the country has entered the era of chase. Baimai Bo and Hai are the top two companies.

Etherap

Etanercept is a fusion protein of recombinant human TNF-α receptor and human IgG-Fc and is the world’s first TNF inhibitor for rheumatoid arthritis and ankylosing spondylitis. The original research was first developed by Anjin, which was successively approved by the FDA and EMA in November 1998 and February 2000 respectively.

Etanercept competitively blocks the binding between TNF-[alpha] and its cell surface receptors, thereby limiting excess TNF-[alpha] in vivo and inhibiting induced aberrant immune responses and inflammatory processes. It is mainly used for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, plaque psoriasis and compulsive spondylitis.

Currently, the FDA-approved biosimilar drug is only Sandoz’s Erelzi; EMA has approved Erelzi and Benipali from Samsung Bio.

On February 26, 2010, etanercept entered the Chinese market. Compared with other original biological drugs, the time was relatively late.

However, the biosimilar drug of etanercept started earlier. The Yisip (injection of recombinant human type II tumor necrosis factor receptor antibody fusion protein for injection) was launched earlier in 2005, earlier than the original research. Target market. Shanghai Saijin Biological and Hisun Pharmaceutical ranked second and third in their category, and were approved for listing in 2011 and 2015 respectively.

It is worth noting that due to their structural differences and the lack of head-to-head clinical trials, these products are not considered as biosimilar drugs internationally.

Trastuzumab

The total sales of trastuzumab (Herceptin) in 2017 reached US$7.441 billion, ranking fifth among the top 15 best-selling drugs in the world. At the same time, it is the second-best-selling antitumor drug in China, with a revenue of US$159 million in 2016, accounting for approximately 2.8% of the global market.

The original study of trastuzumab (Herceptin) was originally developed by Genentech, which was acquired by Roche. It was approved by the FDA and EMA in September 1998 and August 2000, respectively.

Trastuzumab is an anti-HER2 monoclonal antibody. By binding to HER2, the binding of human epidermal growth factor to HER2 can be blocked, resulting in reduced growth of cancer cells. At present, its main approved indications include breast cancer, metastatic gastric cancer, metastatic esophageal cancer and borderline cancer overexpressing HER2.

Up to now, only two kinds of trastuzumab biosimilar drugs have entered the market in the world. They are FDA-approved Ogivri (developed by Mylan/Biocon) and EMA-approved Ontruzant (Samsung Bio).

On September 5, 2002, trastuzumab was approved by CFDA to enter China. Fuhong Hanlin, Jiahe Biological and Anke Biosimilar drugs all entered Phase III clinical research and are competing to become the first product to be approved for listing.

Bevacizumab

In 2017, bevacizumab (Avastin) had a total global income of US$7.096 billion. In 2016, China’s sales reached 70 million U.S. dollars, which was the fourth-best-selling oncology drug in the country.

Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) developed by Roche, was approved by the FDA and EMA on February 26, 2004 and January 12, 2005, respectively.

So far, there is only one biosimilar drug on the market. Mvasi (bevacizumab-awwb), jointly developed by Amgen and Aierjian, has been listed in the United States and the European Union.

On February 26, 2010, Bevacizumab entered the Chinese market. At present, Qilu Pharmaceutical and Xinda Biological are all conducting Phase III clinical trials for the development of the first echelon; Fuhong Hanlin is in the second echelon, there is a product into Phase I clinical trials.

The future of biosimilar medicine in China?

Faced with an increase in the number of returned overseas talents, the research and development of Chinese biological agents is rapidly maturing. The relevant policies of the CFDA may further promote the development of biological similar drugs in China. But there are also people who are pessimistic: the road ahead of biosimilar drugs is not all good; especially because the cost of production considers a series of new challenges to production.

Indeed, compared to chemical drugs, biosimilar drugs have some special characteristics. The latter has a longer cycle, higher costs, and higher investment risks.

The first is high-tech requirements. Due to the production of biosimilar drugs in cells, their effectiveness and safety may vary from lot to lot, and control of quality and critical technologies during the development process is critical. Many steps, including cell culture, product processing and purification, storage, etc., will affect the final results. Therefore, regulators, especially the United States and Europe, need a lot of clinical information and data on biosimilar drugs before they are approved. This ultimately translates into its higher production costs.

In general, successful development of biosimilar drugs takes 8 to 10 years or more, investment can be as high as 250 million US dollars (China’s R & D investment threshold is generally 200 to 400 million yuan), and the requirements of the original research head-to-head clinical trials, Raise the barrier of entry directly. In contrast, chemicals only take 3 to 5 years, and their investment costs are between 2 million and 3 million US dollars.

Others believe that the price cuts of biosimilar drugs will not be as big as chemical generic drugs. On the one hand, how can sales and pricing constrain the market for biosimilar drugs; on the other hand, in the case of significant price cuts by the original research, it will compete with the original research and strive to be included in the scope of national medical insurance reimbursement.

On April 12, 2018, the State Department tried to further promote China’s medical system, especially in the field of advanced and refractory cancer, and issued zero tariff on imported anti-cancer drugs. Then, the “zero tariff” can be described as the “salary pay” in the original research price. Roche Herceptin’s recent out-of-stock supply also appears to have revealed that the original research “has not reduced prices through tax cuts and cut prices”.

All in all, the author still sincerely hopes that the domestic biosimilar drug will do its best in the morning and be available and affordable for more patients.

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