复宏汉霖贝伐珠单抗 HLX04 临床研究数据发表于国际知名期刊 BioDrugs 和 CCP
近日，复宏汉霖（2696.HK）宣布公司自主开发的贝伐珠单抗生物类似药HLX04与原研贝伐珠单抗相似性比较的I期临床研究结果[1]及联合化疗用于治疗转移性结直肠癌患者的III期临床研究结果[2]分别在国际知名期刊Cancer Chemotherapy and Pharmacology（CCP）和BioDrugs上发表。
HLX04为复宏汉霖按照《生物类似药研发与评价技术指导原则（试行）》自主开发的贝伐珠单抗生物类似药，可用于晚期、转移性或复发性非小细胞肺癌以及转移性结直肠癌等疾病的治疗。通过特异性结合血管内皮生长因子（vascular endothelial growth factor, VEGF），贝伐珠单抗可阻断VEGF与受体的结合，抑制异常血管的新生，进而防止肿瘤生长和扩散[3]。公司针对HLX04与原研贝伐珠单抗开展了多项头对头比对研究，包括质量对比研究、非临床相似性研究、临床I期和临床III期研究等。研究结果证明HLX04在质量、安全性和有效性方面与原研贝伐珠单抗均高度相似。
HLX04多中心、随机、双盲、4臂、平行对照的I期临床研究的主要研究者为吉林大学第一医院丁艳华教授。该研究数据于2018年9月在全国临床肿瘤学大会（CSCO）上首次发表，结果表明HLX04与原研贝伐珠单抗（美国市售、欧盟市售和中国市售）的药代动力学生物等效，安全性和原研药也基本一致，为HLX04 III期临床研究的顺利开展奠定了良好的基础。
区别于目前国内已上市的贝伐珠单抗生物类似药，HLX04在III期临床研究的设计上选择了转移性结直肠癌适应症，成为国内目前唯一拥有转移性结直肠癌临床数据的贝伐珠单抗生物类似药，为贝伐珠单抗在中国结直肠癌患者人群中的应用积累了更多临床证据与经验。该研究由中国人民解放军南京八一医院秦叔逵教授、上海东方医院李进教授担任联合主要研究者。2020年8月，该项III期临床研究达到了主要和次要研究终点，研究结果在第23届CSCO学术年会上首次发布并获评优秀论文，李进教授在会上就研究结果进行了口头报告。
HLX04-mCRC03（NCT03511963）为一项多中心、随机、双盲、平行对照的III期临床试验（临床试验号：NCT03511963），旨在比较HLX04或原研贝伐珠单抗联合化疗方案（XELOX方案或mFOLFOX6方案）一线治疗转移性结直肠癌的疗效、安全性和免疫原性。主要疗效终点为依据RECIST v1.1标准评估的36周的无进展生存率（PFSR36wk）。次要疗效终点包括对疗效、安全性、免疫原性和药代动力学特征的评估。该试验共入组了677例病患（HLX04组，n=340；原研组，n=337）。HLX04组和原研组的PFSR36wk分别为46.4%（95%置信区间：41.1%，51.8%）和50.7%（95%置信区间：45.4%，56.1%）。两组率差为-4.2%（90%置信区间：-10.6%，2.1%），率比为0.92（90%置信区间：0.8，1.05），皆落在预先设定的等效界值范围之内。研究结果表明，HLX04用于一线治疗转移性结直肠癌的疗效与原研药等效，其安全性、耐受性及免疫原性与原研药相似，作为生物类似药候选药将为复发、转移性结直肠癌患者带来更多治疗选择。
本次HLX04两项研究结果的发表，再度为HLX04与原研贝伐珠单抗相似的疗效与安全性提供了有力证据。目前，复宏汉霖已就HLX04用于晚期、转移性或复发性非小细胞肺癌以及转移性结直肠癌患者的治疗向国家药品监督管理局（NMPA）递交了上市注册申请（NDA）并正式获得NMPA受理。期待HLX04早日惠及更多癌症患者，带来质高价优的治疗选择。
关于BioDrugs
BioDrugs为生物药领域老牌权威期刊，主要围绕基于生物技术的药物和诊断产品的开发和应用，覆盖生物医学、药学、生物技术、肿瘤与血液学、金融、商业和银行业等领域，是生物疗法领域科学家、专业研发人员和临床医生的重要参考资源。
关于Cancer Chemotherapy and Pharmacology
Cancer Chemotherapy and Pharmacology主要聚焦于抗癌新药的实验筛选、临床前毒理学及药理学研究、单药和药物联合给药方式，以及药物的临床I、II和III期试验结果。作为领域内的权威杂志，在实验和临床研究水平上解决了广泛的药理学和肿瘤学问题。
关于复宏汉霖
复宏汉霖（2696.HK）是一家国际化的创新生物制药公司，致力于为全球患者提供可负担的高品质生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域，已在中国上市3款产品，在欧盟上市1款产品，3款产品获得中国上市注册申请受理。自2010年成立以来，复宏汉霖已建成一体化生物制药平台，高效及创新的自主核心能力贯穿研发、生产及商业运营全产业链。公司已建立完善高效的全球研发中心，按照国际GMP标准进行生产和质量管控，位于上海徐汇的生产基地已获得中国和欧盟GMP认证。
复宏汉霖前瞻性布局了一个多元化、高质量的产品管线，涵盖20多种创新单克隆抗体，并全面推进基于自有抗PD-1单抗斯鲁利单抗的肿瘤免疫联合疗法。继国内首个生物类似药汉利康®（利妥昔单抗）、中国首个自主研发的中欧双批单抗药物汉曲优®（曲妥珠单抗，欧盟商品名：Zercepac®）、公司首个自身免疫疾病治疗产品汉达远®（阿达木单抗）相继获批上市，创新产品斯鲁利单抗MSI-H实体瘤的上市注册申请已纳入优先审评审批程序，HLX04贝伐珠单抗及HLX01利妥昔单抗类风湿关节炎新适应症的上市注册申请也正在审评中。公司亦同步就10个产品、8个联合治疗方案在全球范围内开展20多项临床试验，对外授权全面覆盖欧美主流生物药市场和众多新兴国家市场。
Clinical Results of Henlius HLX04, a Bevacizumab Biosimilar, Published in International Well-known Journals
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 (PFSR36wk) 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). PFSR36wk 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.
About BioDrugs
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.
About Cancer Chemotherapy and Pharmacology
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.
About Henlius
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.