产品速递 | 双免疫联合抗血管靶向疗法，HLX53联合H药与汉贝泰®一线治疗肝细胞癌的II期临床试验完成首例患者给药

2024年8月8日，复宏汉霖（2696.HK）宣布，公司自主开发的创新型抗TIGIT Fc融合蛋白HLX53联合H药汉斯状^®（斯鲁利单抗，HLX10）及汉贝泰^®（贝伐珠单抗，HLX04）在局部晚期或转移性肝细胞癌患者中开展的II期临床试验（NCT06349980）完成首例患者给药。

肝癌是全球范围内常见的恶性肿瘤。据GLOBOCAN统计，2022年全球肝癌发病数和死亡数分别为87万及76万例^[1]。在中国，原发性肝癌是第五大最常见的癌症，以及第二大致死癌症。2022年中国新发肝癌病例约37万例，肝癌死亡病例32万例。其中，肝细胞癌是最常见的原发性肝癌类型，约占总病例数的75-85% ^[2]。因原发性肝癌起病隐匿，早期无症状或症状不明显，进展迅速，确诊时大多数患者已经达到局部晚期或发生远处转移，治疗困难，预后很差，五年生存率仅约18%^[3]。对晚期肝癌患者来说，目前一线治疗以靶向治疗和免疫治疗为主，免疫抑制剂及抗血管生成药物的联合治疗显示出显著的临床抗肿瘤活性和生存获益 ^[2]，但仍有较大比例的患者并不能从中获益，导致肿瘤复发或进展，尚存在迫切的临床需求以扩大免疫治疗的受益人群，并提高免疫治疗的疗效。

含免疫球蛋白和ITIM结构域的T细胞免疫受体（T cell immunoglobulin and ITIM domain, TIGIT）是近年来肿瘤免疫治疗中最有前景和潜力的靶点之一。TIGIT是一种抑制性受体，在淋巴细胞中表达，包括自然杀伤（NK）细胞、活化的CD8+ T和CD4+ T细胞以及Treg（调节性T细胞）等，其重要配体为主要表达于APC（抗原提呈细胞）或肿瘤细胞表面的CD155（脊髓灰质炎病毒受体，PVR）^[4]。作为免疫检查点蛋白，TIGIT可通过多种作用机制抑制固有和适应性免疫，在肿瘤免疫抑制中的“踩刹车”作用和PD-1/PD-L1类似。多项研究数据显示，TIGIT抑制剂有望治疗多种晚期癌症，包括肺癌、胃癌、黑色素瘤和多发性骨髓瘤等多种实体瘤和淋巴瘤。且已有临床前研究表明，TIGIT靶点可能与 PD-1 通路产生协同效应，同时阻断TIGIT和PD-1/PD-L1信号通路优于单独阻断任一通路，可增强抗肿瘤活性^[5]。

HLX53是复宏汉霖自主研发的创新型抗TIGIT的Fc融合蛋白，由重链抗体的可变区（VHH）和野生型 IgG1的Fc端组成。临床前研究结果表明，HLX53具有优异的肿瘤抑制效果且安全性良好。公司亦于2022年启动了一项I期临床研究，以评估HLX53在晚期/转移性实体瘤患者中的安全性、耐受性、药代动力学特征及初步疗效。鉴于抗PD-1/PD -L1单抗等免疫抑制剂及抗血管生成药物在晚期肝细胞癌患者中取得的良好疗效，及TIGIT与PD-1/PD-L1信号通路的协同效应，复宏汉霖旨在通过开展此项研究，进一步探索抗PD-1单抗与TIGIT抑制剂的双免疫治疗与抗血管靶向疗法的组合，以期为晚期肝细胞癌患者带来更高的临床获益。

复宏汉霖从临床需求出发，目前在PD-1/L1、CTLA-4、LAG-3等免疫检查点全面布局，为免疫联合治疗的探索创造更多可能。同时，公司充分运用自有管线覆盖肿瘤特异性靶点、抗血管生成靶点和肿瘤免疫靶点等多个类别的特点，助力H药与自有单抗产品、化疗等治疗手段开展联合治疗，有助于充分挖掘免疫疗法的治疗潜力，为全球患者带去高品质、可负担的创新治疗方案。

【参考文献】

[1] Globocan 2022 (version 1.1) - 08.02.2024；https://gco.iarc.fr/today/en/dataviz/bars-compare-populations?mode=cancer&group_populations=1&cancers=11&populations=900&sort_by=value1&types=0_1&key=total

[2]原发性肝癌诊疗指南（2024年版）

[3] Asafo-Agyei KO, Samant H. Hepatocellular Carcinoma. 2023 Jun 12. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 32644603.

[4] Chauvin, Joe-Marc, and Hassane M Zarour. “TIGIT in cancer immunotherapy.” Journal for immunotherapy of cancer vol. 8,2 (2020): e000957. doi:10.1136/jitc-2020-000957.

[5] Chu, Xianjing et al. “Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials.” Molecular cancer vol. 22,1 93. 8 Jun. 2023, doi:10.1186/s12943-023-01800-3.

关于NCT06349980

本研究为一项随机、双盲、多中心的II期临床研究，旨在评估HLX53联合汉斯状®及汉贝泰®对比安慰剂联合汉斯状®及汉贝泰®在未经治疗的局部晚期或转移性肝细胞癌患者中的有效性、安全性和耐受性。研究分为两个部分：A部分为安全导入期，将采用“3+3”剂量递增设计，合格的受试者将接受每三周一次静脉输注不同剂量HLX53（1000 mg或2000 mg）联合汉斯状®（300 mg）及汉贝泰®（15 mg/kg）的治疗；B部分为初步疗效探索期，合格的受试者将按照1:1:1的比例，随机分配接受每三周一次静脉输注HLX53（1000 mg）、HLX53（2000 mg）或安慰剂分别联合汉斯状®（300 mg）及汉贝泰®（15 mg/kg）的治疗。A部分的主要终点为安全性和耐受性，评估每个剂量组中发生剂量限制毒性（DLT）事件的患者比例。B部分的主要终点为由独立影像评估委员会根据RECIST v1.1评估的客观缓解率和无进展生存期。

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，在国际获批上市3款产品，23项适应症获批，3个上市申请分别获中国药监局和欧盟EMA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，公司商业化生产基地已相继获得中国、欧盟和美国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50多个分子，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）、自主研发的中美欧三地获批单抗生物类似药汉曲优^®（曲妥珠单抗，美国商品名：HERCESSI™，欧洲商品名：Zercepac^®）、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、广泛期小细胞肺癌和食管鳞状细胞癌，并成为全球首个获批一线治疗小细胞肺癌的抗PD-1单抗。公司亦同步就16个产品在全球范围内开展30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 Patient Dosed of Phase 2 Clinical Trial of Novel Anti-TIGIT Fc Fusion Protein in Combination with Serplulimab Plus HANBEITAI for the First-line Treatment of Locally Advanced or Metastatic Hepatocellular Carcinoma Patients

Shanghai, China, August 8, 2024 - Shanghai Henlius Biotech, Inc. (2696.HK) announced that the first patient has been dosed in a phase 2 clinical trial (NCT06349980) of HLX53, an anti-TIGIT Fc fusion protein, in combination with HANSIZHUANG (serplulimab, HLX10) and HANBEITAI (bevacizumab, HLX04) for the first-line treatment of locally advanced or metastatic hepatocellular carcinoma (HCC).

Liver cancer is one of the most prevalent malignancy in the world. According to GLOBALCAN 2022, there are about 870,000 new cases diagnosed and 760,000 deaths for the tumour in the globe^[1]. Meanwhile, primary liver cancer (PLC) is the fifth most common cause and the second mortality cancer in China, with about 370,000 new cases and 320,000 deaths in 2022. From which, hepatocellular carcinoma (HCC) is the predominant pathological type of PLC, which accounts for between 75% and 85% of liver cancer cases^[2]. Due to its insidious onset, lack of symptom in its early stage, and quick progression, PLC usually has been in its locally advanced stage or develops distant metastasis when it is diagnosed. As a result, the management becomes extremely difficult and the prognosis usually is poor. The 5-year survival rate of PLC is only about 18%^[3]. For patients with advanced liver cancer, the first-line treatment is based on targeted therapy and immunotherapy. And the standard therapy (combination therapies of immune inhibitor plus anti-angiogenic treatment) have shown significant clinical anti-tumour efficacy and survival benefit^[2]. However, some patients failed to benefit from the standard therapy and suffered from recurrence or progression of the disease. Thers is still an urgent clinical need to further expand the benefit population with advanced liver cancer and improve the efficacy of immunotherapy.

T-cell immunoglobulin and ITIM domains (TIGIT) has emerged as popular inhibitory checkpoint receptor, which is mainly expressed on natural killer (NK) cells, activated CD8+ T and CD4+ T cells, and T regulatory cells. TIGIT binds to the ligand CD155 (poliovirus receptor, PVR)^[4], mainly expressed on antigen-presenting cells (APC) or the surface of tumour cells, to down-regulate T cell and NK cell functions. As an immune checkpoint protein, TIGIT can inhibit innate and adaptive responses in various mechanisms of action and act as “brakes” like PD-1/PD-L1 does to stop T cells from attacking tumours. Studies have shown that TIGIT inhibitor are effective against lung cancer, gastric cancer, melanoma, multiple myeloma, etc. Moreover, TIGIT has shown a synergistic effect with the PD-1 pathway in preclinical studies, indicating that simultaneous blocking of TIGIT and PD-1/PD-L1 signaling pathways is superior to blocking either pathway alone, which can enhance anti-tumour activity^[5].

HLX53 is an anti-TIGIT Fc fusion protein independently developed by Henlius, consisting of variable domain of heavy chain of heavy-chain antibody (VHH) and wildtype IgG1 Fc. Pre-clinical studies have demonstrated that HLX53 exhibits excellent tumour inhibition with good safety. In addition, Henlius has initiated a phase 1 study to evaluate the safety, tolerability, pharmacokinetics characteristics and preliminary efficacy of HLX53 in patients with advanced/metastatic solid tumors. Considering the good efficacy of immune checkpoint inhibitor such as anti-PD-1/PD-L1 antibody plus anti-angiogenic drug in the first-line treatment of patients with advanced HCC, as well as the synergistic effect of TIGIT and PD-1/PD-L1 signaling pathway, Henlius intends to further combine TIGIT inhibitor based on the standard therapy in order to bring greater clinical benefits to patients with advanced HCC.

Underpinned by the patient-centric strategy, Henlius has achieved an overall layout of the immune checkpoint products of PD-1/L1, CTLA-4, LAG-3, etc., proactively exploring immuno-oncology combination therapy. Meanwhile, Henlius actively promotes HANSIZHUANG in conjunction with in-house products of the company such as tumour-specific target, angiogenesis target, immunotherapeutic target, etc. and chemotherapy drugs to conduct immune combination therapies in a wide variety of indications, committing to bringing affordable and high-quality innovative biologics to patients around the world.

About NCT05483530

This randomised, double-blind, multicentre phase 2 clinical study aims to evaluate the efficacy, safety, and tolerability of HLX53 in combination with HANSIZHUANG and HANBEITAI versus placebo in combination with HANSIZHUANG and HANBEITAI in previously untreated patients with locally advanced or metastatic hepatocellular carcinoma. The study consists of two parts. Part A is the safety run-in stage, which follows a “3+3” dose-escalation design. Eligible patients will be given different doses of HLX53 (1000 mg or 2000 mg) in combination with HANSIZHUANG (300 mg) and HANBEITAI (15 mg/kg) intravenously, every three weeks. Part B is the preliminary efficacy exploration stage. Eligible patients will be randomly assigned (1:1:1) to receive intravenous HLX53 (1000 mg), HLX53 (2000 mg), or placebo in combination with HANSIZHUANG (300 mg) and HANBEITAI (15 mg/kg), every three weeks. The primary endpoints of Part A are safety and tolerance， evaluating the proportion of patients with a dose-limiting toxicity (DLT) event in each group. The primary endpoints of Part B are objective response rate and progression-free survival assessed by independent radiological review committee per RECIST v1.1.

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, 3 have been approved for marketing in overseas markets, 23 indications are approved worldwide, and 3 marketing applications have been accepted for review in China and the EU, respectively. 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 centre and Shanghai-based commercial manufacturing facilities certificated by China, the EU and U.S. GMP.

Henlius has pro-actively built a diversified and high-quality product pipeline covering over 50 molecules 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: HERCESSI™ in the U.S., Zercepac^® in Europe), a China-developed mAb biosimilar approved in China, Europe and U.S., HANDAYUAN (adalimumab) and HANBEITAI (bevacizumab), the innovative product HANSIZHUANG has been approved by the NMPA for the treatment of MSI-H solid tumours, squamous non-small cell lung cancer (sqNSCLC) and extensive-stage small cell lung cancer (ES-SCLC), and esophageal squamous cell carcinoma (ESCC), making it the world’s first anti-PD-1 mAb for the first-line treatment of SCLC. What’s more, Henlius has conducted over 30 clinical studies for 16 products, expanding its presence in major markets as well as emerging markets.

联系方式

媒体：PR@Henlius.com

投资者：IR@Henlius.com