復宏漢霖貝伐珠單抗 HLX04 臨床研究資料發表于國際知名期刊 BioDrugs 和 CCP
近日，複宏漢霖（2696.HK）宣佈公司自主開發的貝伐珠單抗生物類似藥HLX04與原研貝伐珠單抗相似性比較的I期臨床研究結果[1]及聯合化療用於治療轉移性結直腸癌患者的III期臨床研究結果[2]分別在國際知名期刊Cancer Chemotherapy and Pharmacology（CCP）和BioDrugs上發表。
HLX04為複宏漢霖按照《生物類似藥研發與評價技術指導原則（試行）》自主開發的貝伐珠單抗生物類似藥，可用於晚期、轉移性或復發性非小細胞肺癌以及轉移性結直腸癌等疾病的治療。 通過特异性結合血管內皮生長因數（vascular endothelial growth factor，VEGF），貝伐珠單抗可阻斷VEGF與受體的結合，抑制异常血管的新生，進而防止腫瘤生長和擴散[3]。 公司針對HLX04與原研貝伐珠單抗開展了多項頭對頭比對研究，包括質量對比研究、非臨床相似性研究、臨床I期和臨床III期研究等。 研究結果證明HLX04在質量、安全性和有效性方面與原研貝伐珠單抗均高度相似。
HLX04多中心、隨機、雙盲、4臂、平行對照的I期臨床研究的主要研究者為吉林大學第一醫院丁豔華教授。 該研究數據於2018年9月在全國臨床腫瘤學大會（CSCO）上首次發表，結果表明HLX04與原研貝伐珠單抗（美國市售、歐盟市售和中國市售）的藥代動力學生物等效，安全性和原研藥也基本一致，為HLX04 III期臨床研究的順利開展奠定了良好的基礎。
區別於目前國內已上市的貝伐珠單抗生物類似藥，HLX04在III期臨床研究的設計上選擇了轉移性結直腸癌適應症，成為國內現時唯一擁有轉移性結直腸癌臨床數據的貝伐珠單抗生物類似藥，為貝伐珠單抗在中國結直腸癌患者人群中的應用積累了更多臨床證據與經驗。 該研究由中國人民解放軍南京八一醫院秦叔逵教授、上海東方醫院李進教授擔任聯合主要研究者。 2020年8月，該項III期臨床研究達到了主要和次要研究終點，研究結果在第23届CSCO學術年會上首次發佈並獲評優秀論文，李進教授在會上就研究結果進行了口頭報告。
HLX04-mCRC03（NCT03511963）為一項多中心、隨機、雙盲、平行對照的III期臨床試驗（臨床試驗號：NCT03511963），旨在比較HLX04或原研貝伐珠單抗聯合化療方案（XELOX方案或mFOLFOX6方案）一線治療轉移性結直腸癌的療效、安全性和免疫原性。 主要療效終點為依據RECIST v1.1標準評估的36周的無進展生存率（PFSR36wk）。 次要療效終點包括對療效、安全性、免疫原性和藥代動力學特徵的評估。 該試驗共入組了677例病患（HLX04組，n=340；原研組，n=337）。 HLX04組和原研組的PFSR36wk分別為46.4%（95%置信區間：41.1%，51.8%）和50.7%（95%置信區間：45.4%，56.1%）。 兩組率差為-4.2%（90%置信區間：-10.6%，2.1%），率比為0.92（90%置信區間：0.8，1.05），皆落在預先設定的等效界值範圍之內。 研究結果表明，HLX04用於一線治療轉移性結直腸癌的療效與原研藥等效，其安全性、耐受性及免疫原性與原研藥相似，作為生物類似藥候選藥將為復發、轉移性結直腸癌患者帶來更多治療選擇。
本次HLX04兩項研究結果的發表，再度為HLX04與原研貝伐珠單抗相似的療效與安全性提供了有力證據。 現時，複宏漢霖已就HLX04用於晚期、轉移性或復發性非小細胞肺癌以及轉移性結直腸癌患者的治療向國家藥品監督管理局（NMPA）遞交了上市註冊申請（NDA）並正式獲得NMPA受理。 期待HLX04早日惠及更多癌症患者，帶來質高價優的治療選擇。
關於BioDrugs
BioDrugs為生物藥領域老牌權威期刊，主要圍繞基於生物技術的藥物和診斷產品的開發和應用，覆蓋生物醫學、藥學、生物技術、腫瘤與血液學、金融、商業和銀行業等領域，是生物療法領域科學家、專業研發人員和臨床醫生的重要參攷資源。
关于Cancer Chemotherapy and Pharmacology
Cancer Chemotherapy and Pharmacology主要聚焦於抗癌新藥的實驗篩選、臨床前毒理學及藥理學研究、單藥和藥物聯合給藥管道，以及藥物的臨床I、II和III期試驗結果。 作為領域內的權威雜誌，在實驗和臨床研究水准上解决了廣泛的藥理學和腫瘤學問題。
關於複宏漢霖
複宏漢霖（2696.HK）是一家國際化的創新生物製藥公司，致力於為全球患者提供可負擔的高品質生物藥，產品覆蓋腫瘤、自身免疫疾病、眼科疾病等領域，已在中國上市3款產品，在歐盟上市1款產品，3款產品獲得中國上市註冊申請受理。 自2010年成立以來，複宏漢霖已建成一體化生物製藥平臺，高效及創新的自主核心能力貫穿研發、生產及商業運營全產業鏈。 公司已建立完善高效的全球研發中心，按照國際GMP標準進行生產和質量管控，位於上海徐匯的生產基地已獲得中國和歐盟GMP認證。
複宏漢霖前瞻性佈局了一個多元化、高品質的產品管線，涵蓋20多種創新單克隆抗躰，並全面推進基於自有抗PD-1單抗斯魯利單抗的腫瘤免疫聯合療法。 繼國內首個生物類似藥漢利康（利妥昔單抗）、中國首個自主研發的中歐雙批單抗藥物漢曲優（曲妥珠單抗，歐盟商品名：Zercepac）、公司首個自身免疫疾病治療產品漢達遠（阿達木單抗）相繼獲批上市，創新產品斯魯利單抗MSI-H實體瘤的上市註冊申請已納入優先審評審批程式，HLX04貝伐珠單抗、 斯魯利單抗鱗狀非小細胞肺癌適應症、HLX01利妥昔單抗類風濕關節炎新適應症的上市註冊申請也正在審評中。 公司亦同步就11個產品、8個聯合治療方案在全球範圍內開展20多項臨床試驗，對外授權全面覆蓋歐美主流生物藥市場和眾多新興市場。
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 漢利康 ®(rituximab), the first China-developed biosimilar, 漢曲優 ® (trastuzumab, Zercepac® in the EU), the first China-developed mAb biosimilar approved both in China and in the EU and 漢達遠 ®(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.
參考文獻
[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.