Introduction: To investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the novel synthetic peptide analog of glucagon-like peptide-2 (GLP-2) apraglutide (FE 203799) in male and female healthy volunteers following subcutaneous (SC) and intravenous (IV) injection.

Methods: A total of 40 subjects were randomized to receive a single ascending dose of either apraglutide or placebo (3:1 ratio) at doses of 2.8, 5.7, 11.4, 28.4, and 56 mg. The first cohort received the lowest dose level of apraglutide by SC injection. Subjects were enrolled into the next dose level cohort sequentially and received the next higher dose level after all subjects in the preceding dose level cohort had been assessed.

Results: Apraglutide was considered safe and well tolerated at all doses with no Serious Adverse Events (SAEs). No immunogenicity was observed. The dose comparisons performed indicated that peak concentrations and exposure were similar for most dose levels when both genders were pooled (Tukey-Kramer p-values >0.05). Dose proportionality analyses demonstrated C_max was less than dose proportional with a single ascending dose of apraglutide, whereas AUC0 t/Dose and AUC0-∞ showed no significant difference between dose levels. No gender effects were observed. The rate and exposure to apraglutide was proportional over the dose range when administered via SC injection. Following SC administration, dose-adjusted PK parameters showed dose-proportional kinetics and no accumulation. The half-life was approximately 30 hours. The single-dose administration of SC apraglutide was generally well tolerated. The AEs reported at 2.8 mg SC, 5.7 mg, and 56 mg dose levels were only mild in severity. Four (4) moderate AEs were reported for 11.4 mg and 28.4 mg dose levels and no severe AEs were reported. Increasing single doses of apraglutide did not affect heart rate or cardiac conduction and in the studied range of plasma concentration, up to approximately 1500 ng/mL, apraglutide did not have a clinically relevant effect on ECG parameters.

Conclusions: This study in healthy volunteers exposed to single ascending doses of apraglutide confirm a favorable safety profile. The long pharmacokinetic half-life of approximately 30 hours for apraglutide supports a dosing interval of one week or longer in clinical trials. Apraglutide is currently in Phase II development for patients with short bowel syndrome requiring parenteral support.