Domestic Biopharma Firms Race to Develop Cetuximab Biosimilars as CDE Issues Clinical Trial Guidance

On September 8, the Center for Drug Evaluation (CDE) issued a notice soliciting public comments on the 《Guiding Principles for Clinical Trial Design of Cetuximab Injection Biosimilars (Draft for Comments)》. It is reported that cetuximab is a chimeric human-mouse monoclonal antibody of the IgG1 isotype targeting the human epidermal growth factor receptor (EGFR). Developed and marketed by Merck KGaA, it was approved for marketing in mainland China in 2007 under the trade name Erbitux. Its currently approved indications include colorectal cancer and squamous cell carcinoma of the head and neck.

 

The global patent for cetuximab expired in 2017. Currently, many pharmaceutical companies in China, including Kelun Pharmaceutical, Qilu Pharmaceutical, Sansheng Guojian, and Sinocelltech,CompanyBiosimilars are currently under development, but none have yet received approval. To further clarify technical principles, the CDE has organized the drafting of this guidance document, releasing it as a draft for public consultation. From an industry perspective, this initiative is clearly aimed at helping to improve companies' R&D efficiency and providing reference guidance for the development of such drugs.

 

 

 

As the first anti-EGFR monoclonal antibody approved globally, cetuximab injection achieved global sales of nearly USD 1.5 billion in 2019. In the Chinese market, cetuximab injection, which was included in the 2018 National Reimbursement Drug List (NRDL) through price negotiations with a price reduction exceeding 65%, witnessed remarkable sales growth. According to MENET data, terminal sales of cetuximab in China's public medical institutions reached RMB 1.576 billion in 2019, with a year-on-year growth rate as high as 117.23%.

 

　　Sales of Cetuximab at the Public Medical Institution Terminal in China (RMB billion)

 

In March 2020, the National Medical Products Administration (NMPA) approved cetuximab injection in combination with platinum- and fluorouracil-based chemotherapy for the first-line treatment of recurrent and/or metastatic head and neck squamous cell carcinoma. Following its successful renewal in the updated National Reimbursement Drug List (NRDL) and the inclusion of new indications, cetuximab injection is poised to achieve a new peak in market sales. This substantial market potential has also attracted domestic pharmaceutical companies, including Kelun Pharmaceutical, Qilu Pharmaceutical, 3SBio, and SinoCellTech, to compete aggressively for market positioning.

 

According to incomplete statistics compiled by a reporter at 《Pharmaceutical Economic Daily》, to date, over 10 domestic enterprises have entered the cetuximab biosimilar space, though none have yet submitted a marketing authorization application. Leading the field are Kelun Pharmaceutical, Mabpharm, and Apuze Biopharma, whose respective candidate products have all advanced to Phase III clinical trials. Following closely are 3SBio with GPGJ602 and Sinocelltech with SCT200, both of which have entered Phase II clinical trials. Other pharmaceutical companies, including Jinmente Biopharma, Guilin Sanjin/Baochuan Biopharma, Henlius, and Qilu Pharmaceutical, are also accelerating their development pipelines.

 

According to the recently disclosed semi-annual report, Kelun Pharmaceutical stated that the Phase III head-to-head study of A140 versus the originator cetuximab completed pre-initiation preparations last year and has completed the activation of the first clinical site and the enrollment of the first patient in February this year; Mabspace is currently conducting a Phase III clinical trial of CMAB009 for colorectal cancer and expects to submit a New Drug Application (NDA) to the National Medical Products Administration (NMPA) in the third quarter of 2022; while Sinocelltech has completed the Phase I clinical study of SCT200 for colorectal cancer, is currently preparing for the database lock and clinical study report for its Phase II trial, and has also initiated exploratory Phase I or Phase II clinical studies for six other projects.

 

No.	Drug Name	Manufacturer	Indications	R&D Progress
1	CMAB009	Mabwell / Shanghai Zhangjiang Biotech	Colorectal Cancer	Phase III Clinical Trial
2	A140	Kelun Pharmaceutical	`Colorectal Cancer`	Phase III Clinical Trial
3	APZ001	Ampure Biopharma	Colorectal Cancer	Phase III Clinical Trial
4	GPGJ602	3SBio Inc.	Colorectal cancer	Phase II clinical trial
5	SCT200	SinoCellTech	Colorectal cancer	Phase II Clinical Trial
6	JMT-101	GeneMate Biotech	Solid tumor	Phase I Clinical Trial
7	CDP1	Guilin Sanjin / Baochuan Biotech Substance	Colorectal Cancer	Phase I Clinical Trial
8	HLX07	Henlius	Advanced solid tumor	Phase I Clinical Trial
9	QL1105	Qilu Pharmaceutical	Solid tumor	Phase I Clinical

According to statistics and forecasts by Frost & Sullivan, the sales revenue of China’s EGFR monoclonal antibody market for colorectal and nasopharyngeal cancers was RMB 1.28 billion in 2018. By 2023 and 2030, market sales for these indications are projected to reach RMB 3.85 billion and RMB 6.62 billion, respectively. Furthermore, should EGFR monoclonal antibodies gain approval for additional tumor indications in the future, the market size is expected to expand further. Under the new guidelines for clinical trial design, it remains to be seen which domestic pharmaceutical company will be the first to cross the finish line.

 

 

 

Against the industrial backdrop where the consistency evaluation of generic chemical drugs has entered a deepening phase, the promotion of biosimilar development has also been placed on the agenda. In February this year, the CDE issued the *Technical Guideline for Similarity Assessment and Indication Extrapolation of Biosimilars*. Building upon the previous *Technical Guideline for Research and Evaluation of Biosimilars (Trial)*, this document further supplements it with guiding recommendations on similarity assessment and indication extrapolation, thereby providing more in-depth standardization and guidance for the development and evaluation of biosimilars.

 

Meanwhile, the CDE has successively issued clinical guidelines for biosimilars of individual products such as liraglutide, trastuzumab, rituximab, adalimumab, and bevacizumab. These guidelines specify the clinical trial design and endpoints for evaluation parameters including pharmacokinetics, comparative efficacy, safety, and immunogenicity, and recommend primary study endpoints for each respective drug. For the cetuximab injection biosimilar, the CDE has similarly taken into account the specific characteristics of this product and provided numerous targeted recommendations to guide pharmaceutical companies in conducting comparative clinical studies.

 

According to relevant statistics, by the end of 2020, approximately 270 biosimilars were under research and development in China, with more than half still in the preclinical research stage and 65 having submitted clinical trial applications. Currently, biosimilars for blockbuster biologics such as rituximab, adalimumab, bevacizumab, trastuzumab, and infliximab have all received marketing approval, and competition for certain products has already become a "red ocean." Industry insiders point out that the series of product-specific guidelines issued by the CDE will largely prevent pharmaceutical companies from flocking to the biosimilar sector and pursuing identical development tracks, thereby significantly reducing redundant investment and construction.

 

　　Monoclonal Antibody Biosimilars Approved in China and Their Reference Products

　　

 

Menet Network data shows that in recent years, anti-TumorThe biologics market continues to expand, with terminal sales in China's public medical institutions surpassing RMB 100 billion in 2020, as multiple blockbuster biologics dominate hospital sales rankings. Under the top-level policy of comprehensive centralized procurement, insulin is poised as the pilot for biologics procurement, making the inclusion of remaining eligible products merely a matter of time. Currently, leading players such as Henlius, Innovent Biologics, and Qilu Pharmaceutical have already solidified their market positions. Large-scale production capacity and low costs will become the key to success in the biosimilars market in China going forward.