Safety, pharmacokinetics, and immunogenicity of HLX6018, a monoclonal antibody targeting the GARP/TGF-β1 complex, in healthy subjects: A randomized, double-blind, placebo-controlled, phase I clinical study.

2526 Background: HLX6018 is a novel anti-GARP/TGF-β1 monoclonal antibody that inhibits TGF-β1 release and suppresses the activation, proliferation, and extracellular matrix secretion of fibroblasts. Preclinical studies have shown its efficacy in improving pulmonary fibrosis with a manageable safety profile. A phase 1 first-in-human study was conducted to evaluate the safety and tolerability of single-dose HLX6018 in healthy Chinese subjects. Methods: In this dose escalation phase 1 study, healthy subjects of age 18 to 55 were randomized to receive intravenous, single dose of either HLX6018 or placebo at 0.25 mg/kg, 1.0 mg/kg, 4.0 mg/kg, 12 mg/kg, 25 mg/kg, 50 mg/kg, and 70 mg/kg. A sentinel dosing approach was adopted: each dose group initially enrolled 2 subjects, with 1 receiving HLX6018 and the other receiving placebo in a blinded manner. These 2 subjects then entered a safety observation period after the infusion before the enrolment of remaining subjects for that dose group. The primary endpoint was safety. Secondary endpoints included pharmacokinetics (PK) and immunogenicity. Results: A total of 180 subjects were screened and 66 were randomized. 52 subjects received HLX6018 (0.25 mg/kg, 6; 1.0 mg/kg, 6; 4.0 mg/kg, 8; 12 mg/kg, 8; 25 mg/kg, 8; 50 mg/kg, 8; 70 mg/kg, 8) while 14 received placebo (2 subjects in each dose group). The median age was 42.0; 93.9% of the subjects were of Han ethnicity, 50.0% were male. Overall, 46 subjects (69.7%) experienced treatment-emergent adverse events (TEAEs), with 1 subject (1.5%) receiving HLX6018 at 25 mg/kg reporting a serious TEAE of osteonecrosis that was unrelated to HLX6018. 39 subjects (59.1%) experienced treatment-related adverse events (TRAEs). Most common TRAEs (≥ 10% in any dose group) included neutrophil count decreased (HLX6018 vs placebo group: 11.5% vs. 21.4%), injection site pain (11.5% vs. 21.4%), blood corticotrophin decreased (9.6% vs. 14.3%), blood triglycerides increased (9.6% vs. 14.3%) and blood follicle stimulating hormone increased (5.8% vs. 14.3%). There were no TEAEs leading to death, TRAEs leading to drug discontinuation, TRAEs of grade 3 or more in severity, or serious TRAEs. The incidence of TEAEs and TRAEs across the HLX6018 dose groups showed no clear dose-related pattern and was comparable to the placebo group. HLX6018 exhibited approximately linear PK characteristics after single intravenous infusion with the dose range of 0.25–70 mg/kg. Anti-drug antibody was detected in 3 subjects (5.8%) who received HLX6018; no neutralizing antibody was detected. Conclusions: HLX6018 is safe and well tolerated across the investigated doses. Further clinical investigation of its efficacy is warranted. Clinical trial information: NCT06310746 .