复宏汉霖首款产品汉利康®获批 开启中国生物类似药新时代

• 汉利康®为中国首个获批的生物类似药。

• 复宏汉霖旗下首款产品——自主研发的首个单抗药物汉利康®获国家药监局批准，用于1）复发或耐药的滤泡性中央型淋巴瘤；2）先前未经治疗的CD20 阳性III-IV 期滤泡性非霍奇金淋巴瘤；3）CD20 阳性弥漫大B细胞性非霍奇金淋巴瘤 (DLBCL)的治疗。

•  汉利康®丰富了淋巴瘤患者的治疗选择，增强了高品质生物药的可及性，惠及更多淋巴瘤患者。

•  国产利妥昔单抗汉利康®填补了中国生物类似药市场的空白，承载着属于中国生物医药行业的民族自豪。

2019年2月25日，上海——复宏汉霖于今日宣布，旗下首款产品——自主研发的首个单抗药物汉利康®（利妥昔单抗注射液）已获国家药品监督管理局（NMPA）批准，用于1）复发或耐药的滤泡性中央型淋巴瘤；2）先前未经治疗的CD20 阳性III-IV 期滤泡性非霍奇金淋巴瘤；3）CD20 阳性弥漫大B细胞淋巴瘤 (DLBCL)的治疗，即获批原研利妥昔单抗在中国的所有适应症1。作为中国首个生物类似药，汉利康®的获批填补了我国生物类似药市场的空白，增强了高品质生物药的可及性，从而惠及更多淋巴瘤患者。

一直以来，非霍奇金淋巴瘤患者及家属承受着极为沉重的经济负担，他们始终期待着具有价格优势，同时质量、安全性和有效性有所保障的药物。利妥昔单抗是首个用于治疗癌症的单克隆抗体药物，其联合化疗是非霍奇金淋巴瘤的治疗金标准。我们相信，中国自主研发的利妥昔单抗的获批将为市场提供更多优质的治疗选择，也能降低患者的经济负担，提高药物可及性。

复宏汉霖联合创始人、总裁兼首席执行官刘世高博士表示：“今天，对于复宏汉霖来说，是个极具纪念意义的日子。汉利康®不仅是复宏汉霖获批的第一个产品，也是中国自主研发的第一个真正意义上以生物类似药路径申报上市的单抗生物药，对于这样一款里程碑式的产品的获批，我们深感自豪。接下来，我们将全力推进汉利康®的上市计划，希望可以尽快纳入医保，让更多患者尽快用上、用得起高质量的生物类似药。”

复宏汉霖联合创始人、首席科学官姜伟东博士表示：“坚守质量，从患者的需求出发，这是复宏汉霖从成立之初就开始做并将一直做下去的事情。在汉利康®早期开发时，发现氨基酸序列与原研药不一致，我们马上决定修改序列，重新进行细胞株构建，直至做出与原研高度相似的汉利康®。”

近年来，为了大力发展生物类似药，国家出台了《生物类似药研发与评价技术指导原则（试行）》等一系列政策，对这类药品的研发、申报注册、疗效安全性等方面进行了规范。生物类似药是指在质量、安全性和有效性方面与已获批准注册的参照药具有相似性的治疗用生物制品。与化学仿制药100%复制原研药不同，生物药分子量大、结构与理化性质复杂，对环境敏感度高，因此研发人员需要通过反向工程来探索生物类似药的生产工艺，找出适合细胞的培养环境，再通过与原研药的头对头对比研究来证明生物类似药与原研药的药代动力学、疗效和安全性都是高度类似的。

汉利康®的批准是基于对该产品一系列研发数据的审查，包括广泛的功能表征，临床前研究，以及人体药代动力学、免疫原性、安全性和有效性的三个临床试验（1a、1b和3期临床试验）数据都证明了其与原研产品在疗效和安全性等方面没有临床意义上的差异。其中3期治疗弥漫大B细胞淋巴瘤的多中心、随机、双盲、头对头与原研对比临床试验结果表明，汉利康®与原研利妥昔单抗联合化疗CHOP的6周期最佳总缓解率分别为92.5%和92.1%，疗效等效性获得证实2。

此次汉利康®的获批打破了中国单抗市场被外资药企垄断的格局，承载着属于中国生物医药行业的民族自豪。目前，汉利康®对类风湿关节炎治疗的3期临床试验也已启动，将造福更多疾病领域的患者。作为一家创新型生物医药企业，复宏汉霖致力于开发更多优质生物药，兑现“可负担的创新”的企业承诺，服务中国乃至全球更多患者，引领中国高品质生物药产业的创新发展。

淋巴瘤及其治疗

淋巴瘤是最常见的血液系统恶性肿瘤之一，我国淋巴瘤的发病率约为5.94/10万人3，其中非霍奇金淋巴瘤约占所有淋巴瘤病例的90%，且发病率逐年升高。非霍奇金淋巴瘤的病理类型繁杂，治疗方式多样4，但利妥昔单抗联合化疗（免疫化疗）已成为国内外治疗非霍奇金淋巴瘤的首选标准方案。无论是CHOP（环磷酰胺、阿霉素、长春新碱、强的松）还是CVP（环磷酰胺、长春新碱和强的松）联合利妥昔单抗，均明显改善患者的近期和远期疗效包括总生存期^{5, 6}。

关于复宏汉霖

上海复宏汉霖生物技术股份有限公司由复星医药与海外科学家团队于2010年2月合资组建，公司主要致力于应用前沿技术进行生物类似药、生物改良药以及创新型单抗的研发及产业化，在中国上海、台北和美国加州均设有研发中心，产品覆盖肿瘤、自身免疫性疾病等领域。

截至2019年2月25日，复宏汉霖13个产品、1个联合治疗方案已完成22项适应症的临床试验申请，累计获得全球范围内29个临床试验许可（中国大陆19个，中国台湾3个，美国3个，欧盟、澳大利亚、乌克兰和菲律宾各1个）。

参考文献：

1. 汉利康®获批说明书

2. 石远凯. HLX01的研究历程：从第1期临床试验有望成为中国首个上市的美罗华®生物类似药. 2018 CSCO口头报告.

3. 陈万青，李贺，孙可欣，郑荣寿，张思维，曾红梅，邹小农，顾秀瑛，赫捷. 2014年中国恶性肿瘤发病和死亡分析. 中华肿瘤杂志, 2018,40(1) : 5-13. DOI: 10.3760/cma.j.issn.0253-3766.2018.01.002

4. 中国临床肿瘤学会指南工作委员会.中国临床肿瘤学会（CSCO）淋巴瘤诊疗指南 2018.V1. 北京，人民卫生出版社，2018

5. Marcus R1, Imrie K, Solal-Celigny P, et al. Phases III study of R-CVP compared with cyclophosphamide, vincristine and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol, 2008, 26(28): 4579-4586

6. Hiddemann W1, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood, 2005, 106(12): 3725-3732

Henlius Receives NMPA Approval for Its First Product HLX01 –The Beginning of a New Era for Biosimilar in China

• HLX01 is the first biosimilar approved in China

• China National Medical Products Administration (NMPA) approves HLX01, the first product lead developed by Henlius, for the treatment of adult patients in three indications:

1. Relapsed or refractory, follicular lymphoma;

2. Previously untreated stages III-IV follicular, non-Hodgkin’s lymphoma; and

3. CD20-positive, diffuse large B-cell, non-Hodgkin’s lymphoma (DLBCL)

• HLX01 provides an alternative treatment option for patients with lymphoma, may improve accessibility to high-quality biological medicine, and has the potential to help many patients with CD20-positive non-Hodgkin’s lymphoma (NHL)

• HLX01 has filled the gap in China’s market for biosimilar and represented a notable achievement in the China biopharmaceutical industry

Shanghai, China, February 25, 2019 –Henlius announced today that its first product HLX01 (rituximab injection) has granted approval by the China National Medical Products Administration (NMPA) for the treatment of adult patients in three indications: 1) relapsed or refractory, follicle lymphoma; 2) previously untreated stages III-IV follicular, non-Hodgkin’s lymphoma; and 3) CD20-positive, diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL) which are the approved indications of the originator rituximab (MabThera®) in China¹. HLX01 being the first approved biosimilar in China has filled the gap in China’s market for biosimilar, may improve accessibility to high-quality biological medicine and has the potential to help many patients with lymphoma.

Over many years, non-Hodgkin’s lymphoma (NHL) patients and their families have borne extremely high financial burdens, and they are always looking for drugs that have a price advantage while offering guaranteed quality, safety and effectiveness. Rituixmab is the first monoclonal antibody (mAb) for the treatment of cancer, and rituximab in combination with chemotherapy is currently the gold standard of the treatment of NHL. We believe the approval of China’s rituximab will not only provide an alternative treatment option, but may reduce the financial burden on patients and expand their access to treatments².

“Today is a memorable day for Henlius because HLX01 is our first approved product which is also our first independently researched and developed mAb drug in China,” said Scott Liu, Ph.D., Co-founder, President and Chief Executive Officer at Henlius. “We are proud to receive approval for the first China biosimilar product. We have been working diligently on the HLX01 launch plan to ensure HLX01 will be covered by the public health insurance as soon as possible; therefore, many patients will be able to afford and have access to this high-quality biosimilar drug.”

“Henlius is dedicated to increasing access to high-quality biologics for patients suffering from serious illnesses and helping create a more sustainable healthcare system,” said Weidong Jiang, Ph.D., Co-founder, Chief Scientific Officer at Henlius. “During the early development of HLX01, we immediately decided to modify the amino acid (A.A.) sequence and rebuild the cell line until we got it as similar to the originator rituximab as possible when the A.A. sequence was different from the originator rituximab.”

To encourage the development of biosimilars, the China government has drafted and published a series of policies including the Technical Guideline for the Development and Evaluation of Biosimilars (draft) to regulate the development, registration, efficacy and safety of such drugs in recent years. Biosimilars are biological products with similar therapeutic effects to an already-approved reference drug in terms of quality, safety and efficacy. Unlike generic drugs that can reproduce identical to the originator drug, biological drugs have larger molecule weight with complex structures and physical/chemical properties which are more sensitive to the environment. Therefore, researchers need to explore the production process of biosimilars through reverse engineering to find the right cultivation environment for cells, and prove through head-to-head comparative studies that the biosimilars are highly similar to the originator products in terms of clinical pharmacology, efficacy and safety.

The NMPA approval is based on a comprehensive submission data package of extensive analytical characterization, non-clinical data and three clinical trials (Phase 1a, 1b and 3) evaluating clinical pharmacology, immunogenicity, clinical safety and efficacy data which demonstrated a high degree of similarity for HLX01 and the originator product. The totality of evidence submitted for HLX01 demonstrated that there were no clinically meaningful differences in efficacy and safety between HLX01 and the originator rituximab. The data included results from the multi-center, randomized, double-blind, parallel active-controlled phase 3 HLX01-NHL03 clinical comparative study for the treatment of previously untreated CD20-positive DLBCL, which showed clinical equivalence of best overall response rate (ORR) between intravenous infusion of HLX01 and the originator product in combination with chemotherapy within 6 cycles was 92.5% and 92.1%, respectively.2

The approval of HLX01 has broken the foreign pharmaceuticals’ monopoly in China mAb market, which is a notable achievement on the part of China’s biopharmaceutical industry. Currently, the ongoing Phase 3 clinical trial of HLX01 for the treatment of rheumatoid arthritis is conducted for the patients with auto-immune disease. With the commitment to “affordable innovation”, Henlius is investing in developing and launching a range of high-quality biological products both in China and throughout the globe which can help to reduce healthcare costs and increase patient access to important medicines.

Lymphoma and Treatment

Lymphoma is one of the most common form of hematological malignancy. The incidence rate of lymphoma in China is about 5.94 out of every 100,000 people,³ and about 90% of the cases are non-Hodgkin's lymphoma (NHL), of which the incidence is growing every year. There are complex pathological types for NHL, and there are also various therapies available,⁴ but rituximab in combination with chemotherapy (immuno-chemotherapy) has become the first-line therapy for the treatment of NHL both in China and abroad. Either CHOP or CVP chemotherapy in combination with rituximab can significantly improve patient's short- and long-term outcomes, including overall survival.5,6

About Henlius

Shanghai Henlius Biotech, Inc., a joint venture company co-founded by Fosun Pharma and a team of overseas scientists in February 2010, with its R&D footprint in Shanghai, Taipei and California, USA, specializes in the discovery, development, manufacturing and commercialization of high-quality biologics including biosimilar, bio-better and novel monoclonal antibody, to treat tumor and auto-immune disease.

Until now, Henlius has completed IND/CTA filings of 13 products and 1 combination therapy with 22 indications and obtained 29 successful IND/CTA approvals (19 approvals from China; 3 from the United States; 3 from Taiwan; each 1 from the European Union, Ukraine, Philippines and Australia).

References:

1. Product Information of approved HLX01

2. Shi Yuankai et al., The Clinical Journey of HLX01: From Phase 1 Clinical Trial to Potentially First MabThera Biosimilar in China. Oral presentation at CSCO 2018.

3. Chen Wanqing, Li He, Sun Kexin, Zheng Rongshou, Zhang Siwei, Zeng Hongmei, Zou Xiaonong, Gu Xiuying, and He Jie. Analysis of the Incidence of Malignancies in China and the Death Caused by Them in 2014. Chinese Journal of Oncology, 2018,40(1): 5-13. DOI: 10.3760/cma.j.issn.0253-3766.2018.01.002

4. The Committee for Guidelines, the Chinese Society of Clinical Oncology: CSCO Guidelines for the Treatment of Lymphoma 2018 (V1), Beijing: People's Medical Publishing House, 2018

5. Marcus R1, Imrie K, Solal-Celigny P, et al. Phases III study of R-CVP compared with cyclophosphamide, vincristine and prednisone alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol, 2008, 26(28): 4579-4586

6. Hiddemann W1, Kneba M, Dreyling M, et al. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood, 2005, 106(12): 3725-3732

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