HLX-53

SHANGHAI, China I August 8, 2024 I 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. [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. 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. SOURCE: Shanghai Henlius Biotech