2023年2月1日，复宏汉霖（2696.HK）宣布，公司自主开发的达雷妥尤单抗生物类似药HLX15（重组抗CD38全人单克隆抗体注射液）的I期临床研究（NCT05679258）于中国完成首例受试者给药。HLX15是复宏汉霖自主开发的一款全人源抗CD38 IgG1κ单克隆抗体，有望用于治疗多发性骨髓瘤（Multiple myeloma，MM）。多发性骨髓瘤是一种克隆浆细胞异常增殖的恶性疾病，多发于老年，在很多国家是血液系统第2位常见的恶性肿瘤[1]。根据2020年世界卫生组织（World Health Organization，WHO）披露的流行病学数据显示，全球5年现患率45万余，2020年新发病例约17.6万，死亡11.7万余；中国5年现患5.1万余，2020年新发病例2.1万余，死亡1.6万余[2-4]。CD38又名环状二磷酸腺苷（Adenosine diphosphate，ADP）核糖水解酶，通常表达于浆细胞、淋巴样和髓样细胞。它是一种多功能酶，能够降解烟酰胺腺嘌呤二核苷酸（Nicotinamide adenine dinucleotide，NAD），以及调节细胞内NAD的稳态，在多种生物学过程中发挥着非常重要的作用，包括正常生理水平下的代谢调节以及参与病理条件下的疾病发生等，疾病类型包括衰老、肥胖、糖尿病、心脏病等[5]。同时研究发现，CD38在大量恶性血液癌症特别是多发性骨髓瘤等癌症中高度表达，是血液瘤的细胞表面标志物，被认为是多发性骨髓瘤治疗性抗体药物的理想开发靶点[6-7]。HLX15一方面可直接与肿瘤细胞表面表达的CD38结合，通过补体依赖的细胞毒作用（Complement dependent cytotoxicity，CDC）、抗体依赖的细胞毒作用（Antibody dependent cellular cytotoxicity，ADCC）、抗体依赖的细胞吞噬作用（Antibody dependent cellular phagocytosis，ADCP）、以及Fc介导的交联作用等多重反应诱导骨髓瘤细胞凋亡和溶解，达到快速缓解；此外，HLX15还可通过降低髓源性抑制细胞和消耗CD38表达阳性的免疫调节性T、B细胞来调节免疫微环境，增强免疫系统对肿瘤细胞的抑制作用。参照NMPA发布的《生物类似药研发与评价技术指导原则（试行）》和EMA发布的Guideline on Similar Biological Medicinal Products的要求，复宏汉霖采用逐步递进、比对及相似性评价原则，对HLX15与原研达雷妥尤单抗进行了头对头的药学分析和体内外药理学比对研究。临床前研究结果显示，HLX15和原研达雷妥尤单抗在具有高度相似性。复宏汉霖从临床需求出发，目前已打造出多元化的创新产品管线，在PD-1/L1、LAG-3、TIGIT、BRAF等极具市场潜力的靶点全面布局。同时，公司将持续加码创新，加强优质创新资产的引进和合作，“内外兼修”，不断扩充创新潜力靶点，为全球患者带去更多质高价优的生物药，以造福全球病患。关于NCT05679258本研究为一项在中国男性健康受试者中比较HLX15和达雷妥尤单抗注射液的药代动力学特征、安全性、耐受性和免疫原性的1期临床研究。此研究分为两个部分。第一部分为单中心、随机、开放、双臂1a期研究，将纳入24例受试者，按1:1的比例随机分配接受静脉输注单剂量（8 mg/kg）的HLX15或中国市售达雷妥尤单抗（兆珂®）。此外在第一部分的早期阶段将设置安全导入期，额外纳入3–6例受试者接受静脉输注HLX15，并进行为期1周的安全性观察。第二部分为多中心、随机、双盲、三臂1b期研究，将纳入204例受试者，按1:1:1的比例随机分配接受静脉输注单剂量（8 mg/kg）的HLX15、美国市售达雷妥尤单抗（DARZALEX®）或中国市售达雷妥尤单抗（兆珂®）。本研究的主要终点为从0至无穷大时间血药浓度-时间曲线下面积（AUC0-inf）。次要终点包含其他药代动力学参数、安全性、和免疫原性。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5款产品，在国际上市1款产品，18项适应症获批，1个上市注册申请获得中国药监局受理。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创新中心，按照国际药品生产质量管理规范（GMP）标准进行生产和质量管控，不断夯实一体化综合生产平台，其中，上海徐汇基地已获得中国和欧盟GMP认证，松江基地（一）也已获得中国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H药汉斯状®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，欧洲商品名：Zercepac®，澳大利亚商品名：Tuzucip®和Trastucip®）、汉达远®（阿达木单抗）和汉贝泰®（贝伐珠单抗）相继获批上市，创新产品汉斯状®（斯鲁利单抗）已获批用于治疗微卫星高度不稳定（MSI-H）实体瘤、鳞状非小细胞肺癌和广泛期小细胞肺癌，成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗，其食管鳞状细胞癌适应症的上市注册申请也正在审评中。公司亦同步就15个产品、12个免疫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市场。First Subject Dosed for Phase 1 Clinical Trial of Henlius’ Daratumumab Biosimilar HLX15Shanghai, China, February 1st, 2023 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the first subject was dosed for a phase 1 clinical trial of the company's independently developed daratumumab biosimilar HLX15 (recombinant anti-CD38 fully human monoclonal antibody injection) in China.HLX15 is a fully human anti-CD38 IgG1κ monoclonal antibody independently developed by Henlius. The indication to be developed for HLX15 is multiple myeloma (MM), which is an incurable clonal plasma cell dysplasia, the second most hematological malignancy which mainly develops in elderly population[1]. According to the epidemiologic data disclosed by World Health Organization (WHO) in 2020, for MM, the second most common hematological malignancy, more than 450,000 patients in 5 years as of 2020, more than 176,000 new patients and more than 117,000 deaths have been reported worldwide in 2020. In China, there are more than 51,000 patients in 5 years as of 2020, more than 21,000 new patients and more than 16,000 deaths have been reported[2-4].CD38, also known as cyclic adenosine diphosphate (ADP) ribose hydrolase, is usually expressed in plasma cells, lymphoid cells, and myeloid cells. CD38 is a multifunctional enzyme that can degrade nicotinamide adenine dinucleotide (NAD) and regulate intracellular NAD homeostasis. It plays a very important role in a variety of biological processes, including the regulation of metabolism under normal physiological levels and the cause of diseases under pathological conditions, including ageing, obesity, diabetes mellitus, heart disease, etc[5]. High expression of CD38 is present in varied of hematologic malignancies and all stages along disease progression of multiple myeloma. Considering the expression profile of CD38, it is thought to be a cell surface marker of hematological malignancies and an ideal target for the treatment of multiple myeloma[6-7].On one hand, HLX15 can directly bind to CD38 expressed on the surface of tumour cells, inducing tumour cell lysis and apoptosis through complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), and several other pathways such as Fc mediated cross linking to achieve a quick response of tumour cells. In addition, HLX15 can also reduce multiple myeloma cells by reducing myeloid-derived suppressor cells and depleting CD38-positive immunomodulatory T and B cells. In accordance with the Technical Guidelines of Development and Evaluation of Biosimilar Drugs and EMA Guideline on Similar Biological Medicinal Products, HLX15 has been developed strictly following the principles of stepwise development, comparability and similarity assessment and has been compared head to head with reference daratumumab via analytical studies and preclinical studies. The results of these preclinical studies showed that HLX15 is highly similar to reference daratumumab.Underpinned by the patient-centric strategy, Henlius has built an innovative product pipeline with high market potential targets, including PD-1/L1, LAG-3, TIGIT, BRAF, etc., and has been pushing its early R&D research capabilities further while also upgrading the technology platform. Looking forward, Henlius will preserve its momentum for innovation by further strengthening the in-licensing and collaboration on external innovative assets and will continue strive for breakthroughs to bring more affordable and quality biologics to patients around the globe.About NCT05679258This phase 1 clinical study compares the pharmacokinetics, safety, tolerability, and immunogenicity between HLX15 and daratumumab injection in healthy Chinese male subjects. The study consists of two parts. Part 1 is a single-centre, randomised, open-label, two-arm phase 1a study. 24 subjects will be enrolled and randomly assigned (1:1) to receive single intravenous infusion of 8 mg/kg of HLX15 or China-sourced daratumumab (trade name Zhaoke). A safety run-in period is included in the early phase of part 1, during which an additional 3–6 subjects will be enrolled to receive HLX15 intravenous infusion and followed up for 1 week for safety observation. Part 2 is a multi-centre, randomised, double-blind, three-arm phase 1b study. A total of 204 subjects will be randomly assigned (1:1:1) to receive single intravenous infusion of 8 mg/kg of HLX15, US-sourced daratumumab (trade name DARZALEX®), or China-sourced daratumumab (trade name Zhaoke). The primary endpoint is the area under the serum drug concentration-time curve from time 0 to infinity (AUC0-inf). Secondary endpoints include other pharmacokinetic parameters, safety, and immunogenicity.About HenliusHenlius (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, 5 products have been launched in China, 1 approved for marketing in overseas markets, 18 indications approved worldwide, and 1 New Drug Application (NDA) 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 commercialization. It has established global innovation centers and Shanghai-based manufacturing facilities in line with global Good Manufacturing Practice (GMP), including Xuhui Plant certificated by China and the EU GMP and Songjiang First Plant certificated by China 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 HANSIZHUANG (anti-PD-1 mAb) as backbone. Apart from the launched products HANLIKANG (rituximab), the first China-developed biosimilar, HANQUYOU (trastuzumab, trade name in Europe: Zercepac®; trade names in Australia: Tuzucip® and Trastucip®, the first China-developed mAb biosimilar approved both in China and Europe, HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumors, squamous non-small cell lung cancer (sqNSCLC) and extensive-stage small cell lung cancer (ES-SCLC) , making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. Its NDA for the treatment of esophageal squamous cell carcinoma (ESCC) is under review. What's more, Henlius has conducted over 20 clinical studies for 15 products and 12 immuno-oncology combination therapies, expanding its presence in major markets as well as emerging markets.【参考文献】[1] 中国医师协会血液科医师分会, 中华医学会血液学分会. 中国多发性骨髓瘤诊治指南（2022年修订） [J] . 中华内科杂志, 2022, 61(5) : 480-487. DOI: 10.3760/cma.j.cn112138-20220309-00165.[2] Wang, S., et al., Prevalence and Incidence of Multiple Myeloma in Urban Area in China: A National Population-Based Analysis. Frontiers in Oncology, 2020. 9.[3] WHO-Multiple myeloma - Global Cancer Observatory-2020.[4] Cowan AJ, Green DJ, Kwok M, et al. Diagnosis and Management of Multiple Myeloma: A Review. JAMA. 2022;327(5):464-477.[5] Chini, E.N., et al., The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging. Trends Pharmacol Sci, 2018. 39(4): p. 424-436.[6] Bonello, F., M. D'Agostino, M. Moscvin, C. Cerrato, M. Boccadoro, and F. Gay. 2018. 'CD38 as an immunotherapeutic target in multiple myeloma', Expert Opin Biol Ther, 18: 1209-21.[7] Morandi, F., A. L. Horenstein, F. Costa, N. Giuliani, V. Pistoia, and F. Malavasi. 2018. 'CD38: A Target for Immunotherapeutic Approaches in Multiple Myeloma', Front Immunol, 9: 2722.
