复宏汉霖再传喜讯！创新型PD-1抑制剂斯鲁利单抗获NMPA受理，有望成为国内首个治疗MSI-H实体瘤的抗PD-1单抗！

2021年4月22日，复宏汉霖（2696.HK）宣布，自主研制的创新型PD-1抑制剂斯鲁利单抗注射液（HLX10）针对经标准治疗失败的、不可切除或转移性高度微卫星不稳定型（Microsatellite Instability-High, MSI-H）实体瘤适应症的上市注册申请（NDA）正式获得国家药品监督管理局（NMPA）受理，并拟纳入优先审评程序，有望成为国内首个治疗MSI-H实体瘤的抗PD-1单抗。该适应症依据特定的MSI-H肿瘤标志物进行筛查，不以癌种进行区分，覆盖患者群体广泛。围绕斯鲁利单抗，公司采取了“Combo+Global”（联合治疗+国际化）的差异化开发战略，在适应症选择和联合治疗上重点发力，已于全球范围内同步开展10项临床试验。
斯鲁利单抗单药治疗高度微卫星不稳定型或错配修复缺陷型（MSI-H/dMMR）实体瘤的II期临床研究联合主要研究者，南京金陵医院肿瘤中心秦叔逵教授表示：

“

斯鲁利单抗在临床前研究和早期临床研究中已展现出优秀的抗肿瘤活性，本次针对MSI-H实体瘤的II期临床研究结果显示产品疗效及安全性优异。期待质量、疗效均有保证的国产创新型PD-1抑制剂早日上市，让更多MSI-H实体瘤患者获得高品质的免疫治疗新选择。

” 
复宏汉霖执行董事、首席执行官兼总裁张文杰先生表示：


“

斯鲁利单抗是复宏汉霖核心创新单抗产品，公司对其实施差异化开发，重点布局免疫联合疗法和国际临床研究，现各项研究正在加速推进中。斯鲁利单抗的NDA受理离不开所有受试者、研究人员的支持以及团队各位同事的努力，我们将尽快推进该产品更多适应症的上市进程，持续开拓海外市场，惠及更多患者。

” 

  适应症全面覆盖高发癌种  

多项研究进入关键临床3期

围绕“Combo+Global”的战略部署，目前公司已开展斯鲁利单抗的2项单药及8项联合疗法临床试验，积极就化疗、自有VEGF、EGFR靶点单抗等治疗方案进行免疫联合疗法，不仅全面覆盖了肺癌、食管癌、肝细胞癌、胃癌、头颈癌等高发大瘤种，并针对中国的癌症发病人群特点实施差异化临床开发。其中，胃癌新辅助/辅助领域中PD-1抑制剂相关的探索较少，复宏汉霖聚焦该适应症开展3期临床研究，在这一细分领域上处于国际领先地位，有望使胃癌患者在前线便从肿瘤免疫疗法中获益。此外，针对一线鳞状非小细胞肺癌、一线非鳞状非小细胞肺癌及一线小细胞肺癌的斯鲁利单抗联合治疗均已进入关键性3期研究阶段，在肺癌一线治疗中实现了全面布局。斯鲁利单抗联合化疗一线治疗鳞状非小细胞肺癌的上市注册申请有望于今年下半年递交。斯鲁利单抗临床研究进展

  多方位国际化布局，惠及新兴国家市场  

斯鲁利单抗的研发严格按照国际标准，该产品的生产基地已通过欧盟和中国的GMP认证。公司针对斯鲁利单抗前瞻性地进行了国际布局，已于中国、美国、欧盟等国家和地区获得批准开展临床试验，并于中国、土耳其、波兰、乌克兰、俄罗斯等国家及地区累计入组近2000名受试者，印证了国际市场对公司产品质量的信心与认可。同时，复宏汉霖也希望凭借丰富的国际临床研究数据，通过国际合作等方式惠及欧盟、美国及新兴市场的更多患者。目前，公司已与PT Kalbe Genexine Biologics（KG Bio）达成合作协议，授予其斯鲁利单抗首个单药疗法及两项联合疗法在东南亚地区10个国家的独家开发和商业化权利。

随着“Combo+Global”战略的不断深入，以斯鲁利单抗为先导，复宏汉霖持续打造丰富的创新药候选产品管线，积极加速多元化创新，提高创新效率，致力于持续为全球患者带来可负担的高品质创新生物药。

关于MSI-H实体瘤

微卫星不稳定通常由于基因的错配修复功能缺失，使DNA复制过程中微卫星序列碱基插入或错配，造成错误碱基累积所致[1]。其中，高度微卫星不稳定常发生在多个癌种中，如子宫内膜癌、结直肠癌、胃癌、肾细胞癌、卵巢癌等[2]，有研究显示MSI-H在所有癌种中的发生率约为14%[3]，该类患者通常对于免疫检查点抑制剂有较高的应答率[4-5]，MSI-H也越来越成为预测实体瘤患者免疫治疗效果的重要生物标志物。若患者被检测出这一肿瘤标志物呈阳性且符合治疗标准，即可进行相应的肿瘤免疫治疗，而不需要按照传统的肿瘤原发灶部位与病理分型对患者进行筛选，符合精准治疗的先进理念，适用癌种范围广泛。目前美国食品药品监督管理局（US FDA）已批准PD-1靶点药物用于治疗既往一线标准治疗失败的MSI-H/dMMR晚期实体瘤及一、二线MSI-H/dMMR结直肠癌等适应症，我国尚未有针对MSI-H/dMMR晚期实体瘤获批的抗PD-1单抗，治疗需求远未被满足。

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，公司HLX04贝伐珠单抗及两款创新药HLX01利妥昔单抗类风湿关节炎新适应症、斯鲁利单抗MSI-H实体瘤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。

The NDA of the Novel Anti-PD-1 mAb Serplulimab of Henlius Accepted by NMPA and Proposed to be Granted Priority Review  

Shanghai, China, April 22^th, 2021 –Shanghai Henlius Biotech, Inc. (2696.HK) announced that the New Drug Application (NDA) of serplulimab injection (HLX10), a novel anti-PD-1 monoclonal antibody (mAb), for the treatment of unresectable or metastatic microsatellite instability-high (MSI-H) solid tumors that fail to respond to the standard therapy, has been accepted by the National Medical Products Administration (NMPA) and proposed to be granted priority review. Serplulimab is potentially to be the first anti-PD-1 mAb in MSI-H solid tumors in China. For this indication, patients are screened for specific MSI-H tumor markers, rather than classifying the tumor types, covering a wide range of cancer types. Henlius adopts the “Combo+Global” development strategy for serplulimab, focusing on indication differentiation and combination therapy, with a total of 10 clinical trials conducted worldwide.

The co-leading principal investigator of serplulimab Phase 2 clinical trial in unresectable or metastatic microsatellite instability-high or mismatch repair-deficient (MSI-H/dMMR) solid tumors, Professor Shukui Qin of Cancer Center of Nanjing Jinling Hospital, said, ” Serplulimab showed excellent anti-tumor activity in preclinical and early-stage clinical studies, and the results of the Phase 2 clinical study in MSI-H solid tumors also states the favorable safety and efficacy. We hope that this China-developed novel PD-1 inhibitor will be launched as soon as possible, so that more patients with solid tumors could be accessible to high quality immunotherapy new options.”

Executive Director, Chief Executive Officer and President of Henlius, Mr. Wenjie Zhang, said, “Serplulimab is the core innovative mAb of Henlius. Focusing on combination immunotherapy and international clinical trials, we have built up a differentiation development strategy for the product. Steady progress has been made in all clinical studies. We are very grateful to all the subjects, physicians and colleagues that have contributed to the NDA acceptance of serplulimab. We will push forward the clinical process in more indications as soon as possible and look forward to benefiting more patients around the world.”

Several pivotal Phase 3 clinical trials covering comprehensive cancer types with high incidence

With the"Combo+Global" strategy, steady progress has been made in the clinical studies of 2 monotherapies and 8 combination therapies of serplulimab with chemotherapy, in-house VEGF and EGFR targets mAbs. Henlius actively carries out combination therapies that cover a wide range of tumor types with high incidence such as lung cancer, esophageal cancer, hepatocellular cancer,gastric cancer, head and neck cancer, and implements differentiation clinical development based on the Chinese cancer characteristics. Among them, while there are few explorations in the gastric cancer neoadjuvant/adjuvant area of PD-1 inhibitors, Henlius has conducted Phase 3 clinical studies in this field, leading the clinical trial progress around the globe, with the aim of enabling gastric cancer patients to benefit from the early line of immunotherapy. What’s more, the company has achieved all-around layout in the first-line of lung cancer, and has entered pivotal Phase 3 clinical trials in first-line squamous non-small cell lung cancer (sqNSCLC), first-line non-squamous non-small cell lung cancer (nsqNSCLC) and first-line small cell lung cancer (SCLC). The NDA filing of HLX10 in combination with chemotherapy for the first-line treatment of sqNSCLC in China will also be expected in the second half of 2021.

The all-around international layout to benefit emerging markets

The manufacturing and development of serplulimab is strictly in accordance with international standards and its manufacturing facility based in Shanghai has passed the European Union (EU) and China GMP certification. Henlius developed the international layout for serplulimab, which has been approved for clinical trials in China, the United States, the EU and other countries and regions. About 2000 patients have been enrolled in China, Turkey, Poland, Ukraine, Russia, etc., which shows confidence and recognition on the quality of the product in the international market. Apart from conducting international trials of HLX10, Henlius also actively seeks for international cooperation opportunities with the aim of benefiting more patients in the world, especially patients in emerging markets. Henlius has reached a collaboration agreement with PT Kalbe Genexine Biologics (KG Bio), upon which KG Bio is granted exclusive rights to develop and commercialize serplulimab in relation to its first monotherapy and two combination therapies in 10 Southeast Asian countries.

With the continuous development of the "Combo+Global" strategy, Henlius continues to build a diversified pipeline of innovative drug candidates with serplulimab as the lead, actively accelerating innovation and improving innovation efficiency, and committing to bringing affordable and high-quality innovative biologics to patients around the world.

About MSI-H solid tumors

The defect of mismatch repair (MMR) that can lead to base mismatch or insert in microsatellites during DNA replication, and the accumulation of incorrect bases usually causes microsatellite instability (MSI)^[1]. MSI-H often occurs in several cancer types, such as endometrial cancer, colorectal cancer, gastric cancer, renal cell carcinoma, ovarian cancer, etc^[2]. Studies have revealed that the prevalence of MSI-H across all tumor types is 14%^[3]. Patients who suffer from this disease usually have higher response rates for immune checkpoint inhibitors^[4-5]. Thus, MSI-H is becoming a more and more important biomarker for the immunotherapy predictions of patients with solid tumors. If the patient is MSI-H positive and meets the treatment criteria, the corresponding immunotherapy can be carried out without screening tumor sites and pathological classification, which aligns with the advanced concept of precision medicine and is applicable to a wide range of cancer types. Currently, the U.S. Food and Drug Administration (US FDA) has approved PD-1 target mAb for the treatment of second-line MSI-H/dMMR advanced solid tumors and first/second-line MSI-H/dMMR colorectal cancers. While there are still no anti-PD-1 mAb approved for MSI-H/dMMR advanced solid tumors in China, the treatment needs are far from being met.

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] Yang G, Zheng RY, Jin ZS. Correlations between microsatellite instability and the biological behaviour of tumours. J Cancer Res Clin Oncol.2019 Dec;145(12):2891-2899.[2] Hause, R., Pritchard, C., Shendure, J. et al. Classification and characterization of microsatellite instability across 18 cancer types. Nat Med22, 1342–1350 (2016).[3] Lorenzi M, Amonkar M, Zhang J, et al. Epidemiology ofMicrosatellite Instability High (MSI-H) and Deficient Mismatch Repair (dMMR) inSolid Tumors: A Structured Literature Review[J]. Journal of Oncology, 2020,2020.[4] Michael J Overman, Ray McDermott, Joseph L Leach, et al. Nivolumab in patients with metastatic DNA mismatch repair deficient/microsatelliteinstability-high colorectal cancer (CheckMate 142): results of an open-label,multicenter, phase 2 study[J]. Lancet Oncology, 2017,18(9):1182-1191.[5] Aurelien Marabelle, Dung T Le, Paolo A Asciert, et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase IIKEYNOTE-158 Study[J]. J Clin Oncol, 2020, 38(1): 1-10.

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