产品速递|靶向+免疫,BRAF V600E抑制剂HLX208联合H药用于BRAF V600突变实体瘤的Ib/II期研究IND获批

复宏汉霖 · 公众号 · · 2022-11-11 18:31

正文

2022年11月11日，复宏汉霖（2696.HK）宣布，公司从润新生物引进的创新BRAF V600E小分子抑制剂HLX208联合H药汉斯状^®（斯鲁利单抗注射液）及其相关联合疗法（+/-西妥昔单抗或曲美替尼）用于BRAF V600E或BRAF V600突变阳性晚期实体瘤治疗的Ib/II期临床试验申请（IND）获国家药品监督管理局（NMPA）批准。

BRAF蛋白是RAF家族成员之一，位于EGFR下游，为RAS-RAF-MEK-ERK信号通路中上游调节因子，在MAPK/ERK信号通路中起着举足轻重的作用，其基因突变可传导并激活下游MEK和ERK蛋白，从而引起肿瘤细胞生长、增殖和侵袭^[1]，其中BRAF V600E突变是最常见的BRAF突变类型。BRAF突变易发生于结直肠癌、甲状腺癌、黑色素瘤等多个癌种中，该类患者往往预后较差。当前，以BRAF抑制剂为代表的靶向联合疗法在多种BRAF突变阳性实体瘤中成为主要治疗手段之一^[2,3]。近年来，随着肿瘤免疫疗法的发展，免疫检查点抑制剂在多种实体瘤如非小细胞肺癌、黑色素瘤中展现出了较好的治疗效果，也有多项研究表明BRAF抑制剂联合免疫治疗药物具有协同抗肿瘤作用^[4,5]。

HLX208具有全新的化学母核结构，是具备“同类最佳”潜力的BRAF V600E小分子抑制剂。临床前研究结果表明，HLX208具有单一稳定晶型，良好的口服生物利用度及显著的肿瘤抑制活性。早期临床研究也展现出HLX208具有良好的安全性、耐受性和有效性。2022年1月，HLX208单药或联合治疗BRAF V600突变阳性的晚期实体瘤的Ib/II期IND获NMPA批准，此外，该药在BRAF V600E突变的成人朗格汉斯细胞组织细胞增生症（LCH）和Erdheim-Chester病（ECD）治疗的II期临床研究也已完成首例患者给药。复宏汉霖期望将自有免疫治疗产品抗PD-1单抗H药与靶向药联用，为BRAF V600突变阳性的实体瘤患者探索出更优质的治疗方案。

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、GARP、TIGIT、BRAF等创新靶点全面布局。未来，复宏汉霖也将推动更多创新产品的临床研究，以抗体技术为核心，积极开展联合治疗方案、创新靶点双特异性抗体、抗体偶联药物（ADC）、融合蛋白等产品的布局，期待早日为更多患者带来可负担的高品质生物药。

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，11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11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，其治疗小细胞肺癌（SCLC）也已获得美国FDA孤儿药资格认定。

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，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13个产品、11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。

The IND Application of Phase 1b/2 Clinical Trial of BARF V600E Inhibitor HLX208 in Combination with HANSIZHUANG for the Treatment of BARF V600 Mutation-Positive Solid Tumours was Approved by the NMPA

Shanghai, China, November 11, 2022, - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the investigational new drug (IND) application for phase 1b/2 clinical trial of HLX208, a BRAF V600E inhibitor, in combination with anti-PD-1 monoclonal antibody (mAb) HANSIZHUANG (serplulimab injection) and its related combination therapies (HLX208 in combination with HANSIZHUANG +/- cetuximab or trametinib) for the treatment of BRAF V600E or BRAF V600 mutation-positive advanced solid tumours was approved by the National Medical Products Administration (NMPA).

BRAF is a member of the RAF kinase family and a critical upstream regulator in the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) cell signaling pathway downstream of EGFR. Its mutation can activate the downstream MEK and ERK protein, which induces the proliferation and invasion of tumour cells^[1]. Among all BRAF mutation types, BRAF V600E mutation is the most common one. The BRAF mutation frequently occurs in colorectal cancer, thyroid cancer, melanoma and other types of cancers, which often predicts poor prognosis. Currently, targeted combination therapy represented by BRAF inhibitors has become one of the main treatments in different kinds of BRAF mutation-positive solid tumours^[2,3]. With the development of immuno-oncology therapy, immune checkpoint inhibitors have shown good therapeutic effects in solid tumours, such as non-small cell lung cancer and melanoma, and a number of studies have shown that BRAF inhibitors combined with immunotherapy antibodies demonstrating a synergistic effect in inhibiting tumour growth^[4,5].

HLX208 is a potential “best-in-class” BRAF inhibitor with a proprietary novel chemical structure that is different from other marketed BRAF inhibitors. It exhibited a single crystal morph, high bioavailability, and excellent anti-tumour efficacy in preclinical studies. Subsequent early clinical data also demonstrated preliminary efficacy and good safety and tolerability in patients with cancer, warranting further clinical development. In January 2022, the IND of Phase 1b/2 clinical trials of HLX208 as monotherapy or in combination therapy for the treatment of BRAF V600 mutation-positive advanced solid tumours has been approved by NMPA, and the first patient has been dosed in the phase 2 clinical trial of HLX208 in adult patients with BRAF V600E mutation Langerhans Cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD). And the combination of immuno-oncology therapy HANSIZHUANG and targeted therapy will enable Henlius to explore more effective treatment options for patients with BRAF V600 mutation-positive solid tumours.

Underpinned by the patient-centric strategy, Henlius has built an innovative product pipeline with many emerging targets, including PD-1/L1, LAG-3, GARP, TIGIT, and BRAF. Regarding antibody technology as a core, Henlius will continue conducting clinical studies for more innovative products in bispecific antibodies, antibody-drug conjugates (ADC), and fusion proteins and exploring combination therapies with improved efficacy to provide patients with quality and affordable biologics.

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 11 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 forging ahead. It has successively obtained clinical trial licenses in China, the United States, the European Union and other countries and regions to initiate 11 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 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 small cell lung cancer (SCLC). Furthermore, HANSIZHUANG was recommended by the 2022 CSCO Guidelines for Diagnosis and Treatment of Small Cell Lung Cancer (SCLC) for the treatment of ES-SCLC, and the related clinical trial has also become the first study published in JAMA on SCLC immunotherapy. Serplulimab was also granted orphan drug designation by the FDA for treatment of 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 tumours 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 13 products and 11 combination therapies, expanding its presence in major markets as well as emerging markets.

【参考文献】

[1] Huang Z, Wu Y. Huang Z, Wu Y. Mutation of the BRAF genes in non-small cell lung cancer. Zhongguo Fei Ai Za Zhi. 2012;15(3):183-186.

[2] 《黑色素瘤治疗指南（2022年版）》, 国家卫生健康委办公厅.

[3] 《中国临床肿瘤学会（CSCO）结直肠癌诊疗指南2022》[M]. 人民卫生出版社.

[4] Sanlorenzo M, Vujic I, Floris A, et al. BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti–PD-1 AntibodyBRAF and MEK Inhibitors Increase PD-1–Positive Melanoma[J]. Clinical Cancer Research, 2018, 24(14): 3377-3385.

[5] Trojaniello C, Vitale M G, Ascierto P A. Triplet combination of BRAF, MEK and PD-1/PD-L1 blockade in melanoma: the more the better?[J]. Current Opinion in Oncology, 2021, 33(2): 133-138.

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