2022年12月15日，复宏汉霖（2696.HK）宣布，公司自主研发的PD-1抑制剂 H药 汉斯状®（斯鲁利单抗）用于治疗小细胞肺癌（SCLC）获得欧盟委员会（EC）授予的孤儿药资格认定，这是H药用于治疗SCLC继获美国食品和药品监督管理局（FDA）孤儿药资格认定后的第二项孤儿药认证。目前全球尚无一线治疗SCLC的抗PD-1单抗获批，H药有望成为首个一线治疗SCLC的抗PD-1单抗，填补未来五年PD-1抑制剂一线治疗SCLC的临床空白。

全面推进中美欧上市，加速惠及全球患者

基于复宏汉霖在中国、欧盟波兰、土耳其、格鲁吉亚等多个国家开展一项国际多中心III期临床研究全球（ASTRUM-005），H药一线治疗广泛期小细胞肺癌（ES-SCLC）在适应症的上市申请已获得中国国家药品监督管理局（NMPA）受理。复宏汉霖亦计划后续于欧盟递交该适应症的上市注册申请。此外，公司在美国启动了一项H药对比一线标准治疗阿替利珠单抗用于广泛期小细胞肺癌的头对头桥接试验并于近期完成首例患者入组，拟招募200名美国受试者参与此项桥接临床试验，以评估H药在美国ES-SCLC患者中的疗效。

此次H药获得欧盟孤儿药认定基于欧洲药品管理局（EMA）孤儿药委员会（COMP）的积极意见。根据EC的定义，孤儿药(Orphan Medicinal Product)被用于诊断、预防或治疗那些危及生命或者非常严重的疾病，并且患者比例不超过欧盟人口总数万分之五。欧盟《孤儿药法规》确立了孤儿药资格认定的集中审批程序，并为孤儿药的研发和上市制定了激励措施，包括但不限于 (1)获得临床研究方案协助(EMA为获得认定的孤儿药提供专门的科学建议)；(2)可享受药品集中审批程序（企业可直接向EMA提交上市/有条件批准申请，由此获得的欧盟委员会建议或决议在所有欧盟国家均有效）；(3)上市后享有10年市场独占权；(4)监管活动费用减免(涉及方案协助、上市许可申请与核查、上市后变更申请和年费)。

持续创新，引领SCLC免疫治疗新时代

据GLOBOCAN数据显示，肺癌是全球发病率第二大高发癌种，2020年全球肺癌新发病例220万例，新发肺癌死亡病例180万例，位居癌症死亡人数第一[1]。SCLC占肺癌总数的15%-20%，是肺癌中侵袭性最强的亚型，分为局限期小细胞肺癌（LS-SCLC）和ES-SCLC，二者共同点是恶性程度高、转移早、疾病进展迅速，总体预后不良。对于ES-SCLC而言，免疫检查点抑制剂的出现为临床提供了新的治疗选择，目前抗PD-L1单抗联合化疗已陆续被最新版NCCN指南和CSCO指南推荐为ES-SCLC一线治疗方案，但近年来多款PD-1产品在ES-SCLC领域接连折戟，未使ES-SCLC患者真正获益。另一方面，手术、化疗同步放疗仍是治疗LS-SCLC的标准治疗手段，但大多数患者容易出现对药物产生耐药性或疾病迅速复发，传统化疗药物在LS-SCLC中无明显进展[2-4]。

基于未满足的临床需求，复宏汉霖在SCLC领域推动免疫疗法的一系列探索，希望为该领域患者提供更有效的治疗方法。针对H药用于一线治疗ES-SCLC，ASTRUM-005临床试验结果于2022年美国临床肿瘤学会（ASCO）年会以口头报告方式首次发布，并于全球四大顶级医学期刊之一的《美国医学会杂志》（JAMA，影响因子：157.3）在线发表，成为全球首个登上JAMA主刊的小细胞肺癌免疫治疗临床研究。近期，ASTRUM-005研究的更新数据在欧洲肿瘤学会亚洲分会（ESMO Asia）年会发布，截至2022年6月13日，该试验总人群中斯鲁利单抗组的中位总生存期（OS）达到15.8个月，进一步刷新全球一线广泛期小细胞肺癌总生存期纪录的研究成果，并显示出良好的疗效和安全性。针对H药用于一线治疗LS-SCLC，复宏汉霖开展了一项国际多中心III期临床研究（NCT05353257），该研究已于中国完成首例受试者给药，并于澳大利亚和欧盟等地获批开展临床研究。

未来公司也将继续以患者需求为核心，积极推进H药的免疫联合疗法和产品的国际临床注册，为全球更多患者带去福音。

关于H药 汉斯状®

H药 汉斯状®为重组人源化抗PD-1单抗注射液（通用名：斯鲁利单抗注射液），是复宏汉霖首个自主研发的创新型单抗，目前2项适应症获批上市，2项适应症上市申请获受理，10余项临床试验同步在全球开展。

2022年3月，H药正式获批上市，目前可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（sqNSCLC)。围绕H药，复宏汉霖积极推进其与公司其他产品的协同以及与创新疗法的联合，相继获得中国、美国、欧盟等国家及地区的临床试验许可，在全球同步开展12项肿瘤免疫联合疗法临床试验，广泛覆盖肺癌、食管癌、头颈鳞癌和胃癌等适应症，全面覆盖肺癌一线治疗。截至目前，H药已于中国、土耳其、波兰、格鲁吉亚等国家和地区累计入组超3100人，其中2项国际多中心临床试验入组白人的比例超过30%，是拥有国际临床数据较多的抗PD-1单抗之一。H药联合化疗一线治疗广泛期小细胞肺癌（ES-SCLC）和食管鳞状细胞癌（ESCC）的NDA已获得NMPA受理，H药有望成为全球首个一线治疗小细胞肺癌（SCLC）的抗PD-1单抗。此外，该药入选《2022 CSCO小细胞肺癌诊疗指南》作为ES-SCLC治疗推荐，针对ES-SCLC的国际多中心临床研究ASTRUM-005成为全球首个登上JAMA的小细胞肺癌免疫治疗临床研究。H药治疗SCLC也已获得美国FDA和欧盟EC的孤儿药资格认定，并在美国启动了一项H药对比一线标准治疗阿替利珠单抗的头对头桥接试验。

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，在欧洲上市1款产品，15项适应症获批，4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药品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，其广泛期小细胞肺癌和食管鳞状细胞癌2项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。

HANSIZHUANG Granted Orphan Drug Designation in the European Union for Small Cell Lung Cancer

Shanghai, China, December 15th, 2022 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the European Commission (EC) has granted Orphan Drug Designation (ODD) for HANSIZHUANG (serplulimab) for the treatment of small cell lung cancer (SCLC). This is the second ODD that HANSIZHUANG has been granted for the treatment of SCLC following the one granted by the United States Food and Drug Administration (FDA). At present, there is no anti-PD-1 mAb approved for the first-line treatment of SCLC worldwide. HANSIZHUANG is expected to become the world's first anti-PD-1 mAb for the first-line treatment of SCLC and to fill the clinical gap in the next five years.

Based on the results of ASTRUM-005, an international multi-centre phase 3 study conducted in various countries including China, Poland, Turkey, and Georgia, the New Drug Application (NDA) of HANSIZHUANG in combination with chemotherapy for the first-line treatment of extensive stage small cell lung cancer (ES-SCLC) has been accepted by the National Medical Products Administration (NMPA). Henlius also plans to file marketing authorisation applications (MAA) on ES-SCLC in the EU. Moreover, the first patient has been dosed in a bridging head-to-head trial in the United States to comparing HANSIZHUANG to standard of care Atezolizumab (anti-PD-L1 mAb) for the first-line treatment of ES-SCLC. Henlius plans to recruit 100 pairs of US patients with ES-SCLC to further evaluate the efficacy of HANSIZHUANG.

This ODD granted by EC follows the positive opinion from the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA). According to the EC, orphan medicinal products are intended for the diagnosis, prevention or treatment of life-threatening or very serious conditions that affect no more than 5 in 10,000 people in the EU. The EU Regulation on orphan medicinal products establishes a centralised procedure for the designation of orphan medicinal products and puts in place incentives for their research, development and marketing, certain policy support, including but not limited to 1) protocol assistance for clinical studies; 2) access to the centralised authorization procedure; 3) ten years of protection from market exclusivity once approved for marketing; 4) fee reductions for regulatory activities.

According to GLOBOCAN 2020, lung cancer (LC) is the second most common cancer around the world. There were 2.2 million new LC cases and 1.8 million new deaths in 2020 worldwide, and LC is the leading cause of cancer deaths [1]. SCLC accounts for 15%–20% of all cases and is the most aggressive type of LC. It is classified into two stages: limited stage (LS-SCLC) and ES-SCLC, with both exhibiting high malignancy, strong invasiveness, early metastasis, fast disease progression, and a poor prognosis. The advent of immune checkpoint inhibitors has been proved to bring hope to patients and anti-PD-L1 mAb has been recommended by the latest NCCN guidelines and CSCO guidelines as the first-line treatment for ES-SCLC. In recent years, however, a number of PD-1 mAbs have failed in this indication. On the other hand, the standard treatment regimens for LS-SCLC are surgery, chemotherapy, and concurrent radiotherapy. Traditional chemotherapeutic drugs did not exhibit significant progress in patients with LS-SCLC, and most patients tend to develop drug resistance or rapid relapse [2-4].

Based on the unmet clinical needs, Henlius promotes a series of immunotherapy studies in the field of SCLC, with the goal of providing more effective treatment approaches for patients. As for the first-line treatment of ES-SCLC with HANSIZHUANG, the results of ASTRUM-005 were presented for the first time in an oral report at the 2022 ASCO annual meeting, and ASTRUM-005 went on to become the first immunotherapy clinical study of SCLC to be published in The Journal of the American Medical Association (JAMA, impact factor of 157.3), one of the top four medical journals in the world. Recently, the updated results of ASTRUM-005 has released in the European Society for Medical Oncology Asia (ESMO Asia) Congress. As of data cutoff date (June 13, 2022), median overall survival (OS) was significantly longer in the serplulimab group (15.8 months) than in the placebo group (11.1 months), forming a new world record with good safety and consistent efficacy over time. For the first-line treatment of LS-SCLC with HANSIZHUANG, the company has carried out an international multi-centre phase 3 study with the first patient dosed in China and has obtained clinical approvals in countries and regions including Australia and Spain.

In the future, Henlius will continue to emphasize unmet clinical needs and actively promote the combination immunotherapy of HANSIZHUANG and international regulatory registration to benefit more patients around the world.

About HANSIZHUANG

HANSIZHUANG (recombinant humanised anti-PD-1 monoclonal antibody injection, generic name: serplulimab injection) is the first innovative monoclonal antibody developed by Henlius. Up to date, 2 indications are approved for marketing in China, 2 NDAs have been accepted by the NMPA, and more than 10 clinical trials are ongoing across the world.

HANSIZHUANG was launched in March 2022 and has been approved by the NMPA for the treatment of MSI-H solid tumours and squamous non-small cell lung cancer (sqNSCLC). Its synergy with in-house products of the company and innovative therapies are being actively promoted. It has successively obtained clinical trial licenses in China, the United States, the European Union and other countries and regions to initiate 12 clinical trials on immuno-oncology combination therapies in a wide variety of indications, such as lung cancer, esophageal carcinoma, head and neck squamous cell carcinoma and gastric cancer, etc., and covering the full range of first-line treatments of lung cancers. As of now, the company has enrolled more than 3,100 subjects in China, Turkey, Poland, Georgia and other countries and regions, and the proportion of White is over 30% in two MRCTs, making HANSIZHUANG an anti-PD-1 mAb with one of the largest global clinical data pools. The NDAs of the first-line treatment for squamous non-small cell lung cancer (sqNSCLC), extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC) have been accepted by the NMPA, which makes HANSIZHUANG potentially the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. Furthermore, HANSIZHUANG was recommended for the treatment of ES-SCLC in the 2022 CSCO Guidelines for Diagnosis and Treatment of Small Cell Lung Cancer (SCLC), and the associated clinical trial became the first study published in JAMA on SCLC immunotherapy. Serplulimab was also granted orphan drug designations by the FDA and EC for the treatment of SCLC, and the first patient has been dosed in a bridging head-to-head trial in the United States to comparing HANSIZHUANG to standard of care Atezolizumab (anti-PD-L1 mAb) for the first-line treatment of ES-SCLC.

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, 5 products have been launched in China, 1 approved for marketing in overseas markets, 15 indications approved worldwide, and 4 New Drug Applications (NDAs) 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 and squamous non-small cell lung cancer (sqNSCLC). Its NDAs for the treatment of extensive-stage small cell lung cancer (ES-SCLC) and esophageal squamous cell carcinoma (ESCC) are 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] Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and MortalityWorldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249.

[2] Faivre-Finn C, Snee M, Ashcroft L, Appel W, Barlesi F, Bhatnagar A, Bezjak A, Cardenal F, Fournel P, Harden S, Le Pechoux C, McMenemin R, Mohammed N, O'Brien M, Pantarotto J, Surmont V, Van Meerbeeck JP, Woll PJ, Lorigan P, Blackhall F; CONVERT Study Team. Concurrent once-daily versus twice-daily chemoradiotherapy in patients with limited-stage small-cell lung cancer (CONVERT): an open-label, phase 3, randomised, superiority trial. Lancet Oncol. 2017 Aug;18(8):1116-1125.

[3] Wang Z, Wan J, Liu C, Li L, Dong X, Geng H. Sequential Versus Concurrent Thoracic Radiotherapy in Combination With Cisplatin and Etoposide for N3 Limited-Stage Small-Cell Lung Cancer. Cancer Control. 2020 Jan-Dec;27(1):1073274820956619.

[4] Ha IB, Jeong BK, Jeong H, Choi HS, Chai GY, Kang MH, Kim HG, Lee GW, Na JB, Kang KM. Effect of early chemoradiotherapy in patients with limited stage small cell lung cancer. Radiat Oncol J. 2013 Dec;31(4):185-90.