Supaglutide (Supa) is a novel once-weekly, human-derived long-acting GLP-1 analogue developed for patients with type 2 diabetes. In this study, we investigated the safety, pharmacokinetics (PK) , pharmacodynamics (PD) and potential immunogenicity of single-dose subcutaneous injections of Supa in healthy subjects. In this double-blind, single dose-escalation, 14-week trial, 48 healthy subjects were randomized to subcutaneous Supa treatment (ranging from 0.375 to 9 mg) or placebo arms for 2 weeks. PK profile and safety parameters were assessed. PD parameters (glucose and insulin concentrations) were measured following an oral glucose tolerance test (OGTT) (Day 3) . The half-life of Supa was approximately 120 h with a median Tmax ranging from 48 to 72 h (Table 1) . Supa treatment significantly reduced body weight compared to placebo in a dose-dependent and time-dependent fashion. OGTT results showed that Supa at all doses investigated significantly decreased glucose levels during the test, suggesting increased glucose tolerance. Supa was safe and well-tolerated in healthy subjects with some increase in mild to moderate gastrointestinal symptoms with escalating doses. No subjects developed anti-Supa antibodies. The safety, PK and PD profiles supported Supa as a long-acting injectable medication for glycemic control and weight loss, as an alternative GLP-1 therapy. Disclosure A. Ma: None. J. Li: None. G. J. Prud’homme: None. D. Zhu: n/a. Q. Wang: None. Y. Zhou: None. Y. Lou: None. Y. Liao: None. A. Shao: None. Z. Wang: None. Y. Jiang: None. Q. Cui: None. Y. Zhao: None. Funding Ministry of Science and Technology (No. 2011ZX09102, No. 2017ZX09303001) , Shanghai Science and Technology Department (No. 2017ZX09303001)

Supaglutide, a novel GLP-1-IgG Fc fusion protein, exerts hypoglycemic effects in type 2 diabetic db/db mice and spontaneous diabetic monkeys. In this study, we investigated the pharmacokinetics and pharmacodynamics of supaglutide by single or repeated subcutaneous and intravenous injection (s) in rats and rhesus monkeys. We found that the half-life of supaglutide at 0.1 mg/kg in rhesus monkeys was 39.7 hours and 35.8 hours upon subcutaneous or intravenous administration, respectively. The plasma supaglutide peaked at 8-10 hours, while the plasma drug exposure levels increased with the increase of dose, showing approximately a linear pharmacokinetic characteristic. The elimination kinetics was similar between subcutaneous (∼0.025 in rats and ∼0.018 in monkeys) and intravenous administration (0.021 in rats and 0.020 in monkeys) , whereas the bioavailability was found to be 31.1% in rats and 63.9% in monkeys. In monkeys, the marked glucose-lowering effect of a single dose injection of supaglutide peaked at 14-16 hours and lasted for 72 hours. 125I-supaglutide distributed mainly in the serum and organs rich in blood supply. Urine was found to be the primary excretion route of supaglutide, following by feces, but the least by bile. Our results demonstrate that supaglutide has an excellent pharmacokinetic profile with prolonged hypoglycemic effects and is a potential weekly dosing therapeutic agent for the treatment of type 2 diabetes. Disclosure Y. Liao: None. A. Ma: None. Z. Wang: None. Y. Zhou: None. L. Zhang: None. L. Liu: None. N. Zhang: None. G. J. Prud’homme: None. Q. Wang: None.