重磅！NMPA正式受理HLX01（利妥昔单抗）类风湿关节炎新适应症的上市注册申请

2020年12月17日，复宏汉霖（香港联交所代码：2696）宣布，国家药品监督管理局（NMPA）正式受理了HLX01（利妥昔单抗注射液）用于新适应症类风湿关节炎（RA）的上市注册申请（NDA）。此前，HLX01汉利康®（利妥昔单抗注射液）已于2019年2月获NMPA 批准上市，目前可用于非霍奇金淋巴瘤和白血病适应症的治疗。截至目前，公司已成功上市了汉利康®、汉曲优®、汉达远®三款单抗生物药，商业化产品管线日渐丰富。

类风湿关节炎（Rheumatoid Arthritis，RA）是一类以关节病变为主的慢性全身自身免疫性疾病，患者约占全球人口的0.5%-1.0%^[1]。其中女性患病人数约为男性的两倍以上，该病易在任何年龄段发生，50岁左右发病风险最高^[2]。类风湿关节炎的常见临床表现为对称性、持续性的关节肿胀和疼痛，常伴有晨僵，轻者可至关节软骨和骨破坏，重者可至关节畸形及功能丧失，甚至影响患者的正常生活。由于该病不可完全治愈，只能通过治疗进行缓解，因此需要终身治疗。

治疗类风湿关节炎安全有效

此次HLX01（利妥昔单抗注射液）新适应症的上市注册申请主要基于一项I期临床试验HLX01-RA01和III期临床试验HLX01-RA03的关键研究数据。HLX01-RA01临床数据于2019年欧洲风湿病学会（EULAR）年会上发布，研究结果显示HLX01在药代/药效动力学与安全性方面均与欧盟市售的利妥昔单抗高度相似，可有效支持后续临床III期试验(HLX01-RA03)的开展。HLX01-RA03是一项在对甲氨蝶呤治疗应答不完全（MTX-IR）的中重度活动性类风湿关节炎受试者中评估HLX01（利妥昔单抗注射液）联合甲氨蝶呤（MTX）治疗的有效性和安全性的随机、双盲、安慰剂对照的III期临床研究，主要研究者为北京协和医院风湿免疫科曾小峰教授。该研究的主要终点为第24周达到美国风湿病学会20%缓解标准（ACR20）的受试者比例，次要有效性终点包括28关节疾病活动性评分（DAS28）、达到ACR20/50/70缓解标准的受试者比例等。本试验对HLX01（利妥昔单抗注射液）在RA受试者中的安全性、药代动力学、免疫原性进行了持续性观察分析。目前，该研究已达到主要终点，研究结果表明HLX01（利妥昔单抗注射液）联合MTX在MTX-IR的中重度活动性RA受试者中安全且有效。

差异化开发，覆盖更广泛患者群体

HLX01汉利康®（利妥昔单抗注射液）为复宏汉霖自主开发的首个单抗生物药，同时也是中国首个根据2015年发布的《生物类似药研发与评价技术指导原则（试行）》开发并批准上市的生物类似药，可用于非霍奇金淋巴瘤和白血病的治疗，全面覆盖原研利妥昔单抗在中国获批的所有适应症。鉴于原研利妥昔单抗的类风湿关节炎适应症仅于美国和欧盟获批，在中国尚未获批。复宏汉霖在开发血液肿瘤的基础上，针对HLX01（利妥昔单抗注射液）采取了差异化的开发策略，积极探索其在类风湿关节炎患者中的疗效，以期惠及国内更多患者群体。

增长潜力大，丰富公司自身免疫产品布局

HLX01（利妥昔单抗注射液）RA新适应症获得上市注册申请受理，标志着该产品有望更加充分地发挥其在风湿免疫领域的临床潜力。相信，凭借HLX01（利妥昔单抗注射液）给药频次低、药物有效性持续时间长等优势，有望大幅提升患者用药依从性，从而改善患者生活质量，降低患者医疗负担，惠及更多医疗需求尚未满足的患者。同时，HLX01（利妥昔单抗注射液）也将成为复宏汉霖自身免疫疾病领域的又一重要产品，丰富公司的产品布局。

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质高价优的创新生物药，产品覆盖肿瘤、自身免疫疾病、眼科疾病等领域。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。公司在全球已建立完善的研发中心，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HLX10的肿瘤免疫联合疗法。截至目前，公司已成功上市3个单抗生物药，包括国内首个生物类似药汉利康Ⓡ（利妥昔单抗）、首个中欧双批的国产生物类似药汉曲优Ⓡ（曲妥珠单抗，欧盟商品名：ZercepacⓇ）以及公司首个自身免疫疾病治疗产品汉达远Ⓡ（阿达木单抗）。此外，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正在审评中，公司亦同步就10个产品、8个联合治疗方案于全球范围内开展20多项临床试验，产品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。

NMPA Has Accepted The NDA of HLX01(Rituximab Injection) for the Treatment of Rheumatoid Arthritis

Shanghai, China, December 17th, 2020 –Shanghai Henlius Biotech, Inc. (2696.HK) announced that the National Medical Products Administration (NMPA) has accepted the New Drug Application (NDA) for a new indication of its rituximab injection HLX01 to treat rheumatoid arthritis (RA). In February 2019, HLX01汉利康®( rituximab injection) had been approved by the NMPA and currently it can be used for the treatment of Non-hodgkin’s lymphoma and leukemia. As of now, Henlius has successively launched three in-house developed monoclonal antibodies including 汉利康® (HLX01, rituximab), 汉曲优® (HLX02, trastuzumab, EU brand name Zercepac® ) and 汉达远® (HLX03, adalimumab).

Rheumatoid arthritis (RA) is the most common chronic autoimmune disease of the joints affecting close to 0.5–1.0% of the global population^[1]. It affects at least twice as many women as men, and although it can occur at any age, the peak incidence is at the age of 50 years^[2]. The common clinical symptoms of RA includes symmetrical, persistent joint swollen and ache, and are often associated with morning stiff. Most mild RA patients are facing damage of articular cartilage and bone, while patients with severe RA can even suffer from joint malformation and loss of function. It can heavily affect patients’ quality of life. Since RA is incurable and can only be alleviated through treatment, lifelong treatment is required.

Safe and effective for the treatment of RA

The new drug application (NDA) of HLX01 (rituximab injection) for RA is based on results from the Phase 1 clinical study (HLX01-RA01) and Phase 3 clinical study (HLX01-RA03). The HLX01-RA01 study data had been presented on the 2019 European Congress of Rheumatology (EULAR) and the results showed that HLX01 was bioequivalent to European-Union (EU) sourced rituximab originator in RA patients and supported the initiation of the following Phase 3 clinical study. HLX01-RA03 is a randomised, double-blind, placebo-controlled, Phase 3 study aimed to evaluate the efficacy and safety of HLX01 (rituximab injection) in combination with MTX in patients with moderate to severe active RA who have had methotrexate-inadequate response (MTX-IR). Professor Xiaofeng Zeng from Department of Rheumatology and Immunology, Peking Union Medical College Hospital is the leading principle investigator of this study. The primary endpoint of the study is the proportion of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at week 24. Secondary efficacy endpoints include Disease Activity Score based on 28 joints, proportions of patients achieving ACR20/50/70 and so on. The safety, pharmacokinetics and immunogenicity of HLX01 are observed and analysed throughout the study. Recently, this study has met the primary endpoints and demonstrated that HLX01 in combination with MTX is safe and effective in MTX-IR patients with moderate to severe active RA.

Differentiated development to cover a broader patient population

HLX01汉利康®(rituximab injection) is the first mAb biosimilar independently developed by Henlius and the first-ever China-manufactured biosimilar approved by the NMPA in accordance with Technical Guidelines for the Development and Evaluation of Biosimilars (Tentative). It has been approved for the treatment of Non-hodgkin’s lymphoma and leukemia, covering all the indications approved for the rituximab originator in Chinese Mainland. Since the NDA of the rituximab originator has not been approved for RA in China, Henlius has adopted a differentiated strategy to fully develop the potential of HLX01 (rituximab injection) in RA and to benefit a broader patient population.

Enriching the company’s products pipeline in autoimmune diseases

The acceptance of the NDA for RA of HLX01 (rituximab injection) by NMPA indicates that the product is expected to demonstrate its clinical benefit in the field of rheumatology and immunology. Considering the advantages of long half-life and low dosing frequency, HLX01 (rituximab injection) may greatly improve RA patients’ adherence to treatment, reduce patients’ burden and improve patients’ quality of life. Meanwhile, HLX01 (rituximab injection) will also become another important product of Henlius in the field of autoimmune diseases and will enrich the company’s products layout.

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 and autoimmune diseases. 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 European Union (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 HLX10 (anti-PD-1 mAb) as backbone. Up to date, Henlius has launched three mAbs developed independently: 汉利康® (HLX01, rituximab), the first China-developed biosimilar, 汉曲优® (HLX02, trastuzumab, Zercepac® in the EU), the first China-developed mAb biosimilar approved both in China and in the EU and 汉达远® (HLX03, adalimumab), the Company’s first product indicated for autoimmune diseases. In addition, the New Drug Applications of HLX04 (bevacizumab) and HLX01 (rituximab) for the treatment of rheumatoid arthritis are under review, and 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] Sharif K , Jumah F , Oskouian R , et al. Rheumatoid arthritis in review: Clinical, anatomical, cellular and molecular points of view[J]. Clinical Anatomy, 2017.

[2] Diane, van, der, et al. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis.[J]. Best Practice & Research Clinical Rheumatology, 2018.