The Future Pattern of Biosimilars in China

As patent expiration of global monoclonal antibody biological drugs peaks, the biosimilars in China have entered the fast lane of development, and CFDA is now open to and encouraging biosimilar R&D, however, China still has a gap with the U.S. and EU in terms of biosimilar development. So far, the U.S. FDA has approved 9 biosimilars (7 monoclonal antibody products) in total, and there have been 40 varieties of biosimilars in 13 categories approved by EMA (14 monoclonal antibody products) in the EU. Please read the Talks on the Future Pattern of Biosimilars—U.S. and Talks on the Future Pattern of Biosimilars—EU for the details.

CFDA issued the Technical Guideline for Development and Evaluation of Biosimilars (Interim) in February 2015 to promote the sound development of the biomedicine industry, and with this, China’s biosimilar regulations began to be gradually improved; the Guideline gives clear guideline for the definition and R&D of biosimilars. The Measures for the Administration of Drug Registration (Revised Draft) issued in July 2016 further regulates the concept of biosimilar, and proposes that "the drug review shall focus on the similarities of biosimilars and original drugs in terms of quality and efficacy", etc. The Opinions on Deepening the Reform of the Review and Approval System and Inspiring Innovation of Drugs and Medical Devices jointly issued by the General Office of the Communist Party of China Central Committee and General Office of the State Council of China on October 8, 2017 again clearly proposes to "support biosimilars". However, there is still no biosimilar in the real sense applied for approval in China.

The technical threshold and investment threshold of biosimilars are much higher compared to the chemical generic drugs. From the perspective of technology, the same raw material, process and preparation method may lead to differences in protein product safety and effectiveness due to biological drug complexity, therefore, the critical process parameters and process control are very critical in the R&D process, many steps such as cell culture conditions (temperature and nutrition), product processing, purification, storage, and packaging, etc. will affect the production, and small differences in the whole process may have big impacts on the quality, purity, biological characteristics, and clinical effects of the final products. Furthermore, the quality standard setting and control are also a vital part. From the perspective of investment, it is thought that biosimilar R&D take 8-10 years or longer, while chemical generic drug R&D take 3-5 years; and in terms of the investment cost, a typical chemical generic drug generally costs USD 2-3 million, while a biosimilar costs up to USD 75-250 million, with the difference of about 100 times.

The global biosimilar R&D currently focus on the big monoclonal antibodies of which the patents have expired or will soon expire, such as adalimumab, infliximab, etanercept, rituximab, bevacizumab, and trastuzumab, and the case is the same for China, however, there are not many products applied for as biosimilars in China. Next, let’s focus on the R&D progress of several big monoclonal antibody varieties in China:

Rituximab

Rituximab originally developed by Roche is the world’s first monoclonal antibody approved for clinical treatment of Non-Hodgkin lymphoma (NHL), and was separately approved for marketing in the U.S. and EU in 1997 and June 1998.

The EU has approved 6 biosimilars of rituximab, separately being Truxima of Celltrion Healthcare Hungary Kft., Riximyo and Rixathon of Sandoz, and Blitzima, Rituzena (formally called Tuxella) and Ritemvia of Celltrion Healthcare Hungary Kft.

Rituximab entered China on April 21, 2008, with the trade name of Rituxan, being one of the three major monoclonal antibodies of Roche (rituximab/Rituxan, bevacizumab/Avastin, and trastuzumab/Herceptin). In China, the rituximab injection of Henlius under Fosun Pharmaceutical was included in the priority review on January 29, 2018, to enter the new drug marketing stage, which is the first biosimilar applied for production by a local Chinese enterprise and expected to become the first biosimilar drug of China (see the following figure). The rituximab injection (recombinant chimeric mouse-human anti-CD20 monoclonal antibody injection) is a macromolecular biosimilar independently developed by Fosun Pharmaceutical, and mainly indicated for NHL and rheumatoid arthritis.

Besides, products of Innovent Biologics and Sinocelltech have entered Phase III clinical trials, while the application of CP Guojian Pharm has been withdrawn.

Adalimumab

Developed by AbbVie, adalimumab was approved by the U.S. FDA on December 31, 2002 and approved by the EU EMA on September 8, 2003, being a star product among the global biologics, and ranking first in terms of global biological drug sales for consecutive years.

Currently, there are 2 biosimilars of adalimumab approved in the U.S., separately being Amgen’s Amjevita (adalimumab-atto) and Boehringer Ingelheim’s Cyltezo (adalimumab-adbm); there are 4 biosimilars thereof approved in the EU, separately being Amgen’s biosimilar Amgevita and Solymbic, Samsung Bioepis’ Imraldi, and Boehringer Ingelheim’s Cyltezo.

Adalimumab entered China on February 26, 2010, with the trade name of Humira. There are currently nearly 20 enterprises developing adalimumab biosimilars in China, wherein, Innovent Biologics, Bio-Thera Solutions, Fosun Pharmaceutical’s Henlius have relevant products enter Phase III clinical trials, and Alphamab and Tonghua Dongbao Biotechnology, etc. have relevant products enter Phase I clinical trials.

Infliximab

As a monoclonal antibody drug against tumor necrosis factor alpha (TNF-α) developed by Janssen, infliximab was approved for marketing by FDA and EMA separately in August 1998 and August 1999. The drug can bind to TNF-α and exert the anti-inflammatory action by neutralizing the physiological activity of TNF-α, and is used for Crohn’s disease, ulcerative colitis, rheumatic arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.

There have been 2 biosimilars of infliximab approved so far in the U.S., separately being the biosimilar infliximab-dyyb of Pfizer and Celltrion, and Ixifi (infliximab-qbtx) of Pfizer; 3 biosimilars of infliximab have been approved by EMA, separately being Inflectra of Hospira (acquired by Pfizer), Remsima of Celltrion, and Flixabi of Samsung.

Infliximab entered China on May 17, 2007, with the trade name of Remicade. In China, Biomabs’ infliximab has been applied for production and received approval, and belongs to a variety required for clinical data self-inspection and checking. The product of Hisun Pharmaceutical has entered the Phase III clinical trial, and others are at the early phases of clinical trials.

Etanercept

Etanercept is recombinant human TNF (tumor necrosis factor) receptor Ⅱ-IgG Fc fusion protein originally developed by Amgen, and was approved for marketing by FDA and EMA separately in November 1998 and February 2000. The drug exerts the anti-inflammatory action by neutralizing the in vivo activity of TNF-α, and is indicated for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis.

Currently, the biosimilar of etanercept approved by FDA is Erelzi (etanercept-szzs) of Sandoz, and that approved for marketing in the EU includes Benepali of Samsung and Erelzi of Sandoz.

Etanercept entered China on February 26, 2010, with the trade name of Enbrel. The imitation of etanercept started early in China: the Yisaipu of CP Guojian Pharm was approved for marketing in 2005 far earlier than 2010 when Enbrel entered China; there are also two similar products of TNF-α fusion protein: Qiangke (Shanghai Celgen, marketed in 2011) and Anbainuo (Zhejiang Hisun, marketed in 2015), however, those three products are not biosimilars in the real sense, and all of them were applied for as new drugs according to the old regulation; they also have differences with etanercept in terms of structure, and their clinical trials were not designed according to head to head.

Trastuzumab

As an original product of Genentech under Roche, trastuzumab is indicated for HER2-overexpressing breast cancers and HER2-overexpressing metastatic gastric carcinoma and metastatic gastroesophageal junction adenocarcinoma.

Currently, the biosimilar of trastuzumab approved by FDA is Ogivri (trastuzumab-dkst) of Mylan and Biocon, and that approved by the EU is Ontruzant of Samsung Bioepis Co., Ltd.

Trastuzumab entered China on September 5, 2002, with the trade name of Herceptin. In China, relevant biosimilar R&D of Henlius under Fosun Pharmaceutical, Genor Biopharma, and Anke Biotechnology have entered Phase III clinical trials, that of Hualan Genetic Engineering, etc. have entered Phase I clinical trials, and the application of CP Guojian Pharm has been withdrawn.

Bevacizumab

Bevacizumab is a humanized anti-VEGF (vascular endothelial growth factor) monoclonal antibody developed by Roche (Genentech) for metastatic colorectal cancer, non-small cell lung cancer, and other metastatic cancers. It was approved for marketing by FDA and EMA separately on February 26, 2004 and January 12, 2005.

The biosimilar of bevacizumab: Mvasi (bevacizumab-awwb) of Amgen and Allergan has been separately approved for marketing in the U.S. and EU.

Bevacizumab entered China on February 26, 2010, with the trade name of Avastin. In China, relevant biosimilar R&D of Qilu Pharmaceutical and Innovent Biologics have entered Phase III clinical trials, and that of Henlius under Fosun Pharmaceutical, etc. have entered Phase I clinical trials.

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