TY - JOUR T1 - Pharmacological Characterization of Apraglutide a Novel Long-Acting Peptidic Glucagon-Like Peptide-2 Agonist for the Treatment of Short Bowel Syndrome JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.262238 SP - jpet.119.262238 AU - Diane M Hargrove AU - Sudarkodi Alagarsamy AU - Glenn Croston AU - Regent Laporte AU - Steve Qi AU - Karthik Srinivasan AU - Javier Sueiras-Diaz AU - Kazimierz Wisniewski AU - Jennifer Hartwig AU - Mark Lu AU - Alexander P Posch AU - Halina Wisniewski AU - Claudio D Schteingart AU - Pierre J-M Riviere AU - Violetta Dimitriadou Y1 - 2020/01/01 UR - http://jpet.aspetjournals.org/content/early/2020/02/19/jpet.119.262238.abstract N2 - Glucagon-like peptide-2 (GLP-2) agonists have therapeutic potential in clinical indications where the integrity of the intestinal mucosa or its absorptive function are compromised, such as in short bowel syndrome (SBS). Native hGLP-2, a 33-amino acid peptide secreted from the small intestine, contributes to nutritional absorption but its very short half-life due to enzymatic cleavage and renal clearance severely limits its therapeutic value. The GLP-2 analog teduglutide (Revestive®/Gattex®, Shire Inc) has been approved for use in SBS since 2012 but has a once-daily injection regimen. Pharmacokinetic (PK) and pharmacodynamic studies confirm that apraglutide, a novel GLP-2 analog, has very low clearance, long elimination half-life and high plasma protein binding compared with GLP-2 analogs teduglutide and glepaglutide. Apraglutide and teduglutide retain potency and selectivity at the GLP-2 receptor comparable to native hGLP 2 while glepaglutide was less potent and less selective. In rat intravenous PK studies, hGLP-2, teduglutide, glepaglutide and apraglutide had clearances of, 25, 9.9, 2.4 and 0.27 ml/kg/min, respectively, and elimination half-lives of 6.4, 19, 18 and 159 min, respectively. The unique PK profile of apraglutide via intravenous and subcutaneous routes was confirmed in monkey and minipig, and translated into significantly greater in vivo pharmacodynamic activity, measured as small intestinal growth in rats. Overall, apraglutide showed greater intestinotrophic activity compared with the other peptides when administered at less frequent dosing intervals because of its prolonged half-life. We postulate that apraglutide offers several advantages over existing GLP-2 analogs and is an excellent candidate for the treatment of gastrointestinal diseases such as SBS.SIGNIFICANCE STATEMENT Apraglutide is a potent and selective GLP-2 agonist with an extremely low clearance and prolonged elimination half-life, which differentiate it from teduglutide (the only approved GLP-2 agonist). The enhanced pharmacokinetics of apraglutide will benefit patients by enabling a reduced dosing frequency and removing the need for daily injections. ER -