Current Status and Strategic Considerations of Biosimilar Drug Development in China

Editor’s Note: This article is reprinted from Pharmadl, authored by Sanqi. Republished with permission by VCBeat.

The Chinese government has provided substantial support for the development of the pharmaceutical industry, leading to an upward trend in the development of domestic biosimilars. However, compared with developed countries in Europe and the United States, there remains a significant gap in China’s R&D capabilities for biosimilars. To address this disparity, the state has implemented robust policy measures to promote the research and development of domestic biosimilars. In February 2015, the China Food and Drug Administration (CFDA) issued the “Technical Guidelines for the Research and Evaluation of Biosimilars (Trial),” aiming to foster the healthy development of the biopharmaceutical industry. This document provides detailed specifications on the application procedures, registration requirements, and classifications for biosimilars.

Biosimilars possess several unique characteristics. First, they entail stringent technical requirements; because they are produced in living cells, the efficacy and safety of biosimilars may vary between batches. Therefore, key quality control technologies are critical during the development process. Many manufacturing steps, including cell culture, product processing and purification, and storage, can affect the quality of the final product. Consequently, regulatory authorities, particularly those in Europe and the United States, undoubtedly require extensive clinical data analysis on biosimilars prior to approval. This ultimately translates into relatively high production costs.

Rising production costs introduce a new challenge: investment risk. The longer the development cycle for biosimilars, the higher the costs, leading to greater investment risk. Generally, successful development of a biosimilar takes 8 to 10 years or even longer, with investments potentially reaching up to $250 million. In contrast, generic small-molecule drugs may require only 3–5 years, with investment costs ranging from $2 million to $3 million.

Currently, a large number of biologic patents have expired or are about to expire, including those for adalimumab, infliximab, etanercept, rituximab, bevacizumab, and trastuzumab. This article focuses on the research and development status of domestic biosimilars for these agents in China.

Rituximab, originally developed by Roche under the brand name Rituxan, received approval from the FDA and EMA in 1997 and 1998, respectively. Its primary indications include non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, and rheumatoid arthritis. Currently, rituximab is one of the most effective CD20-targeted therapies for non-Hodgkin lymphoma. Clinical results demonstrate that combining rituximab with CHOP chemotherapy increases the overall response rate to 83% and the complete response rate to 76% in patients with aggressive NHL.

To date, the European Union has approved two rituximab biosimilars: Celltrion Healthcare’s Truxima and Sandoz’s Rixathon and Riximyo.

On April 21, 2008, Roche’s Rituxan officially entered the Chinese market. Meanwhile, a large number of Chinese biopharmaceutical companies were intensifying their competitive efforts. Most notably, Henlius Biotech, a subsidiary of Fosun Pharma, developed a recombinant chimeric anti-CD20 monoclonal antibody injection, primarily indicated for the treatment of non-Hodgkin’s lymphoma and rheumatoid arthritis. On January 29, 2018, it was included in the priority review program by the Center for Drug Evaluation (CDE), positioning it to potentially become China’s first biosimilar drug.

Furthermore, Innovent Biologics is co-developing IBI301 with the U.S. pharmaceutical giant Eli Lilly. Preclinical data indicate that IBI301 is highly similar to Rituxan across all key attributes, including primary and higher-order structures, heterogeneity, biological activity, and process-related impurities. In preclinical pharmacological studies, its pharmacokinetic and toxicity profiles also demonstrated substantial similarity to those of Rituxan. On November 13, Innovent Biologics announced that the National Medical Products Administration (NMPA) had accepted its new drug application for marketing approval of IBI-301.

Sinocelltech Ltd. and Hisun Pharmaceutical have also advanced their products to Phase III clinical trials.

Adalimumab, with the originator drug Humira as AbbVie’s flagship product, has been a top-selling medication for several consecutive years. It received FDA approval on December 31, 2002, and EMA approval on September 8, 2003. Currently, its primary indications are rheumatoid arthritis and ankylosing spondylitis.

Currently, the U.S. FDA has approved two adalimumab biosimilars, including Amgen’s Amjevita and Boehringer Ingelheim’s Cyltezo. Meanwhile, four have been approved in the European Union; in addition to Amgevita and Cyltezo, Amgen’s Solymbic and Samsung Bioepis’ Imraldi have also been accepted.

On February 26, 2012, Humira entered the Chinese market. Currently, nearly 20 Chinese pharmaceutical companies are developing this product. Among them, Innovent Biologics, Bio-Thera Solutions, and Hisun Pharmaceutical have advanced to the marketing application stage.

On August 17, Bio-Thera Solutions’ marketing application for its adalimumab injection (BAT1406) was accepted by the Center for Drug Evaluation (CDE). On September 14, Hisun Pharmaceutical announced that its marketing application for adalimumab (HS016) had been accepted by the National Medical Products Administration (NMPA) under the special review procedure. On November 12, Innovent Biologics announced that the NMPA had accepted its New Drug Application (NDA) for the investigational drug IBI303.

On April 29, 2017, Henlius announced that its adalimumab biosimilar had also been approved for clinical trials in China. Notably, Henlius did not target the indication of ankylosing spondylitis; instead, it focused on psoriasis. Other candidates include Junshi Biosciences’ UBP1211 and Chia Tai Tianqing’s TQ-Z2301. More than 20 companies, including Tonghua Dongbao, Biostar Pharmaceuticals, Alphamab Oncology, Huahai Pharmaceutical, and Qilu Pharmaceutical, have products in stages ranging from preclinical to Phase II clinical trials.

Humira’s global sales reached $18.43 billion in 2017. However, its total revenue in the Chinese market was only $31 million, accounting for less than 0.01% of the global market. This is primarily due to its relatively high cost. Nevertheless, with the emergence of domestic biosimilar manufacturers, a surge in the utilization of adalimumab is expected in the near future.

Infliximab, marketed under the brand name Remicade and developed by Janssen, is another widely used anti-TNF-α monoclonal antibody. It was approved by the FDA in August 1998 and by the EMA in August 1999. Currently, it is primarily indicated for the treatment of inflammatory conditions, including Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis.

To date, the United States has approved only two infliximab biosimilars: Pfizer’s Inflectra and Samsung Bioepis’ Renflexis. The EMA has approved three, including Pfizer’s Inflectra, Celltrion’s Remsima, and Samsung’s Flixabi.

On May 17, 2017, Remicade was officially approved for marketing by the China Food and Drug Administration (CFDA). Since then, the development of biosimilars for this product in China has been playing catch-up. Shanghai Biomab Pharmaceutical’s CMAB-008 has filed for production approval and obtained the license. Hisun Pharmaceutical’s HS626 is in Phase III clinical trials, taking a relatively leading position in this race, while the others remain in early-stage clinical development.

Etanercept, with the originator drug Enbrel initially developed by Amgen, is a fusion protein of recombinant human TNF-α receptor and human IgG-Fc. It was approved by the FDA in November 1998 and by the EMA in February 2000. It is primarily indicated for rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, and ankylosing spondylitis.

Currently, the FDA has approved Sandoz’s biosimilar Erelzi, and the EMA has approved Samsung Bioepis’s Erelzi and Benepali.

Etanercept entered the Chinese market on February 26, 2010, which was relatively late compared to other biologics discussed in this article. However, its domestic counterparts actually emerged much earlier. Yisaipu (Shanghai CP Guojian Pharmaceutical Co., Ltd.) was launched in 2005, while Qiangke (Shanghai Saijin Biopharmaceutical Co., Ltd.) and Anbinuo (Hisun Pharmaceutical Co., Ltd.) subsequently received approval. From this perspective, these domestic products are not biosimilars in the true sense.

Trastuzumab, marketed under the brand name Herceptin, was originally developed by Genentech, a member of the Roche Group. It received its initial approvals from the U.S. Food and Drug Administration (FDA) in September 1998 and from the European Medicines Agency (EMA) in August 2000.

It is an anti-HER2 monoclonal antibody that binds to HER2, thereby blocking the interaction between human epidermal growth factor and HER2 and inhibiting cancer cell proliferation. Currently, its main indications include breast cancer, metastatic gastric cancer, and metastatic esophageal and gastric cancers with HER2 overexpression.

To date, only two trastuzumab biosimilars have entered the market: Ogivri, jointly developed by Mylan and Biocon, and Ontruzant from Samsung Bioepis, which has been approved by the EMA.

Trastuzumab was approved by the China Food and Drug Administration (CFDA) on September 5, 2002. Currently, a large number of Chinese pharmaceutical companies are racing to be the first to launch domestic versions onto the market. In September, the National Medical Products Administration (NMPA) accepted the marketing application for Recombinant Humanized Anti-HER2 Monoclonal Antibody for Injection (Saiputing) submitted by 3SBio Inc. Henlius’s HLX02, under Fosun Pharma, is leading in Phase III clinical trials domestically and is aggressively expanding into overseas markets by conducting international clinical trials. Both Genor Biopharma Co., Ltd. and Anke Biotechnology have also entered Phase III clinical studies.

Herceptin’s total sales in 2017 amounted to $7.441 billion, ranking it fifth among the top 15 best-selling drugs globally last year. Meanwhile, it is the best-selling anticancer drug in China, with revenues of $159 million in 2016, accounting for approximately 2.8% of its global market.

Bevacizumab, marketed under the brand name Avastin, is a humanized monoclonal antibody against human vascular endothelial growth factor (VEGF) developed by Roche. It received approval from the FDA on February 26, 2004, and from the EMA on January 12, 2005. By inhibiting tumor angiogenesis, it disrupts the nutrient supply to tumors, thereby suppressing tumor growth. Currently, this drug is primarily used to treat metastatic colorectal cancer, non-small cell lung cancer, and other metastatic cancers.

To date, there is only one biosimilar for this product on the market: Mvasi (bevacizumab-awwb), jointly developed by Amgen and Allergan, and marketed in the United States and the European Union.

Avastin entered the Chinese market on February 26, 2010. Currently, Qilu Pharmaceutical and Innovent Biologics are leading the development of bevacizumab biosimilars in China. Qilu Pharmaceutical’s marketing application for QL1101 has been accepted, while Innovent’s IBI305 is undergoing Phase III clinical trials. Fosun Pharma, Hengrui Medicine, and Beijing Tianshi also have products in Phase III clinical trials.

The increasing return of overseas-educated talent has accelerated the maturation of domestic biologic drug development. Meanwhile, a series of supportive national policies have further promoted the growth of biosimilars in China.

"The road is long and fraught with obstacles, but perseverance will lead to success. To achieve breakthroughs in the development of biosimilars, Chinese pharmaceutical companies must address a series of new challenges."

The first issue that urgently needs to be discussed is pricing and sales strategy. Unlike chemical generic drugs, biosimilars typically do not experience significant price reductions. Therefore, determining how to boost sales volume through pricing has become a critical issue in the biopharmaceutical market.

Another critical issue is how to compete with originator drugs. Since biosimilars differ from small-molecule drugs, they are not generally interchangeable. Inclusion in the National Reimbursement Drug List (NRDL) will become a key factor influencing the development of biosimilars.

Finally, on April 12, 2018, China implemented zero tariffs on imported anticancer drugs. It is foreseeable that the prices of foreign originator drugs in the domestic market will further decline. Under such circumstances, whether Chinese pharmaceutical companies can sustain their enthusiasm for investing in biosimilars remains to be seen.