Recently, Henlius announced that the results of the phase 1[1]and phase 3[2]

clinical trials of HLX04, an independently developed bevacizumab biosimilar were published in two well-known journals, Cancer Chemotherapy and Pharmacology (CCP) and BioDrugs, respectively.

HLX04 is a bevacizumab biosimilar developed by Henlius independently in accordance with Technical Guidelines for the Development and Evaluation of Biosimilars (Tentative), which can be used in the treatment of advanced, metastatic or recurrent non-small cell lung cancer(NSCLC) and metastatic colorectal cancer(mCRC). HLX04 can block the interaction between vascular endothelial growth factor (VEGF) and its receptors by binding with VEGF specifically, which then inhibits tumour angiogenesis and thus suppressing the growth and metastases of tumours[3]. Henlius has conducted multiple head-to-head comparisons between HLX04 and the reference bevacizumab including the analytical and preclinical study, phase 1 and phase 3 clinical studies. The results showed that HLX04 was highly similar to the reference bevacizumab in terms of quality, safety and efficacy.

The leading principal investigator of this muti-centre, randomised, double-blind, four-arm, parallel-controlled phase 1 study was Yanhua Ding, M.D. from the First Hospital of Jilin University. The clinical data were first presented at the 21st annual meeting of Chinese Society of Clinical Oncology (CSCO) in 2018.  The results demonstrated that HLX04 had similar pharmacokinetic and safety profiles to the reference bevacizumab sourced from the United States (bevacizumab-US), the European Union (bevacizumab-EU) and China (bevacizumab-CN), supporting the confirmatory phase 3 study investigating the efficacy and safety equivalence between HLX04 and bevacizumab in patients with mCRC.

Different from currently approved bevacizumab biosimilars in China, the phase 3 study of HLX04 was conducted among Chinese patients with mCRC, which helps to accumulate more clinical evidence and experience of bevacizumab in this patient population. Shukui Qin from Nanjing Bayi Hospital of Chinese People's Liberation Army and Jin Li from Shanghai East Hospital are co-leading principal investigators of this study. This study had reached its primary and secondary endpoints in August 2020. The study results were presented  by Professor Jin Li as an oral presentation at the CSCO 23rd annual meeting, which won the outstanding award. 

HLX04-mCRC03(NCT03511963) is a multi-centre, randomised, double-blind, parallel-controlled phase 3 study aimed to compare the efficacy, safety and immunogenicity of HLX04 to the reference bevacizumab in combination with chemotherapy (XELOX or mFOLFOX6) as a first-line treatment in patients with mCRC. The primary endpoint was progression-free survival rate at week 36 (PFSR_36wk) per RECIST v1.1. Secondary endpoints included the evaluations of efficacy, safety, immunogenicity, and pharmacokinetics. A total of 677 patients were randomised in this study (HLX04, n = 340; bevacizumab, n = 337). PFSR_36wk was 46.4% (95% confidence interval [CI]: 41.1%, 51.8%) in the HLX04 group and 50.7% (95% CI:  45.4%, 56.1%) in the bevacizumab group. The rate difference (−4.2%, 90% CI: -10.6% to 2.1%) and rate ratio (0.92, 90% CI: 0.8, 1.05) both fell within the prespecified equivalence margins. The results of the phase 3 study demonstrated the efficacy equivalence between HLX04 and the reference bevacizumab with similar safety and immunogenicity profiles as a first-line treatment for mCRC patients. HLX04 will provide an alternative treatment option for mCRC patients as a potential biosimilar candidate.

Publication of the results from the two HLX04 clinical trials again provided strong evidence for the efficacy and safety similarity between HLX04 and the reference bevacizumab. As of now, Henlius has submitted the New Drug Application (NDA) of HLX04 to the National Medical Products Administration (NMPA) for the use of HLX04 in advanced, metastatic or recurrent NSCLC and mCRC patients, and has received NDA acceptance notification from the NMPA. We expect that HLX04 will benefit more tumour patients as soon as possible as a high-quality and affordable treatment option.

As an essential resource for R&D professionals and clinicians with an interest in biologic therapies, BioDrugs covers the development and therapeutic application of biotechnology-based pharmaceuticals and diagnostic products for the treatment of human disease.

Cancer Chemotherapy and Pharmacology addresses a wide range of pharmacologic and oncologic concerns on both experimental and clinical levels. The primary focus of this rapid publication medium is on new anticancer agents, their experimental screening, preclinical toxicology and pharmacology, single and combined drug administration modalities, and clinical phase 1, 2 and 3 trials.

Henlius (2696.HK) is a global biopharmaceutical company with the vision to offer high-quality, affordable and innovative biologic medicines for patients worldwide with a focus on oncology, autoimmune diseases and ophthalmic diseases. Up to date, 3 products have been launched in China, 1 in the European Union (EU), the New Drug Applications (NDA) of 3 products accepted for review in China. Since its inception in 2010, Henlius has built an integrated biopharmaceutical platform with core capabilities of high-efficiency and innovation embedded throughout the whole product life cycle including R&D, manufacturing and commercialisation. It has established global R&D centers and a Shanghai-based manufacturing facility certificated by China and the EU Good Manufacturing Practice (GMP).

Henlius has pro-actively built a diversified and high-quality product pipeline covering over 20 innovative monoclonal antibodies (mAbs) and has continued to explore immuno-oncology combination therapies with proprietary serplulimab (anti-PD-1 mAb) as backbone. Apart from the launched products 汉利康^® (rituximab), the first China-developed biosimilar, 汉曲优^® (trastuzumab, Zercepac^® in the EU), the first China-developed mAb biosimilar approved both in China and in the EU and 汉达远^® (adalimumab), the Company's first product indicated for autoimmune diseases, the NDA of HLX04 (bevacizumab) and the two innovative mAbs HLX01 (rituximab) for the treatment of rheumatoid arthritis and serplulimab indicated for MSI-H solid tumors are under review. What's more, Henlius has conducted over 20 clinical studies for 10 products and 8 combination therapies worldwide, expanding its presence in major market as well as emerging market.

参考文献

[1] Zhu X, Qian H, Sun J, et al. A phase 1 randomized study compare the pharmacokinetics, safety and immunogenicity of HLX04 to reference bevacizumab sourced from the United States, the European Union, and China in healthy Chinese male volunteers. Cancer Chemotherapy andPharmacology. 2021:1-10.

[2] Qin S, Li J, Bai Y, et al. Efficacy, Safety, and Immunogenicity of HLX04 Versus Reference Bevacizumab in Combination with XELOX or mFOLFOX6 as First-Line Treatment for Metastatic Colorectal Cancer: Results of a Randomized, Double-Blind Phase III Study. BioDrugs. 2021:1-14.

[3] Kazazi-Hyseni F, Beijnen JH, Schellens JH. Bevacizumab. Oncologist. 2010;15(8):819‐825.