First Patient Dosed in Phase 2 Trial of Anti-TIGIT Protein with Serplulimab for Advanced Hepatocellular Carcinoma

SHANGHAI, China | August 8, 2024 |Shanghai Henlius Biotech, Inc. has commenced a phase 2 clinical trial (NCT06349980) involving its anti-TIGIT Fc fusion protein, HLX53. The trial is evaluating HLX53 in combination with HANSIZHUANG (serplulimab, HLX10) and HANBEITAI (bevacizumab, HLX04) for first-line treatment of locally advanced or metastatic hepatocellular carcinoma (HCC).

Liver cancer is among the most common malignancies globally. According to GLOBALCAN 2022, approximately 870,000 new cases were diagnosed and 760,000 deaths occurred worldwide. Primary liver cancer (PLC) ranks as the fifth most common cancer and the second leading cause of cancer mortality in China, with an estimated 370,000 new cases and 320,000 deaths in 2022. Hepatocellular carcinoma (HCC) makes up 75% to 85% of PLC cases. Due to its subtle onset and rapid progression, PLC is often diagnosed at an advanced stage, leading to poor prognosis and a 5-year survival rate of just 18%.

The first-line treatment for advanced liver cancer typically includes targeted therapies and immunotherapies. Standard treatments, which combine immune inhibitors with anti-angiogenic therapies, have demonstrated substantial clinical efficacy and survival benefits. Despite this, some patients do not respond to these treatments and experience disease progression or recurrence, highlighting the need for more effective treatments.

T-cell immunoglobulin and ITIM domains (TIGIT) have emerged as key inhibitory checkpoint receptors, primarily expressed on natural killer (NK) cells, activated CD8+ T, CD4+ T cells, and T regulatory cells. TIGIT interacts with the ligand CD155 (poliovirus receptor, PVR), which is expressed on antigen-presenting cells (APC) or tumor cells, to suppress T cell and NK cell functions. As an immune checkpoint protein, TIGIT acts like PD-1/PD-L1 to inhibit T cell activity against tumors. Research has shown that TIGIT inhibitors can be effective against various cancers including lung cancer, gastric cancer, melanoma, and multiple myeloma. Preclinical studies have also demonstrated that blocking both TIGIT and PD-1/PD-L1 pathways is more effective than targeting either pathway alone, enhancing antitumor activity.

HLX53, developed independently by Henlius, is an anti-TIGIT Fc fusion protein comprising a variable domain of heavy-chain antibody (VHH) and a wildtype IgG1 Fc. Preclinical studies have shown that HLX53 has strong tumor-inhibiting properties and a good safety profile. Henlius has already started a phase 1 study to assess the safety, tolerability, pharmacokinetics, and preliminary efficacy of HLX53 in patients with advanced or metastatic solid tumors. Given the effectiveness of combining immune checkpoint inhibitors with anti-angiogenic drugs in first-line treatments for advanced HCC, and the synergistic effects of blocking both TIGIT and PD-1/PD-L1 pathways, Henlius plans to integrate a TIGIT inhibitor into the standard therapy to potentially offer greater clinical benefits for patients with advanced HCC.

Henlius, driven by a patient-centric approach, has established a comprehensive lineup of immune checkpoint products, including PD-1/L1, CTLA-4, and LAG-3, and is actively exploring combination therapies in immuno-oncology. The company is also promoting HANSIZHUANG in combination with its other in-house products targeting tumors, angiogenesis, and immunotherapy, as well as chemotherapy drugs, to develop immune combination therapies for a diverse range of indications. Henlius is committed to delivering affordable, high-quality innovative biologics to patients worldwide.

This randomized, double-blind, multicenter phase 2 clinical study aims to assess the efficacy, safety, and tolerability of HLX53 with HANSIZHUANG and HANBEITAI compared to a placebo combined with the same drugs in previously untreated patients with advanced HCC. The study is divided into two parts. Part A is a safety run-in stage with a "3+3" dose-escalation design, administering varying doses of HLX53 (1000 mg or 2000 mg) along with HANSIZHUANG (300 mg) and HANBEITAI (15 mg/kg) intravenously every three weeks. Part B focuses on preliminary efficacy, with patients randomly assigned to receive either HLX53 (1000 mg or 2000 mg) or a placebo, combined with the same doses of HANSIZHUANG and HANBEITAI, every three weeks. The primary endpoints for Part A are safety and tolerance, specifically the proportion of patients experiencing dose-limiting toxicity (DLT). For Part B, the primary endpoints are objective response rate and progression-free survival, evaluated by an independent radiological review committee per RECIST v1.1.

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