Apraglutide

Apraglutide (FE 203799) is a synthetic 33-amino-acid peptide analog of human glucagon-like peptide-2 (GLP-2) and a potent, selective, full agonist of the GLP-2 receptor (GLP-2R), developed as a next-generation intestinotrophic agent for the treatment of short bowel syndrome with intestinal failure (SBS-IF) and under investigation for steroid-refractory gastrointestinal acute graft-versus-host disease (GI aGVHD). The compound differs from native human GLP-2(1-33) by four amino acid substitutions ([Gly2, Nle10, D-Phe11, Leu16]hGLP-2(1-33)-NH2) that confer resistance to dipeptidyl peptidase-IV (DPP-IV) degradation, very low systemic clearance, slow absorption from the subcutaneous depot, and high plasma protein binding, resulting in an elimination half-life of approximately 72 hours in healthy volunteers and enabling once-weekly subcutaneous administration [1, 2]. In head-to-head rat intravenous pharmacokinetic comparisons, apraglutide demonstrated a clearance of 0.27 mL/kg per minute versus 9.9 mL/kg per minute for teduglutide and 2.8 mL/kg per minute for glepaglutide, and an elimination half-life of 159 minutes versus 19 minutes for teduglutide and 16 minutes for glepaglutide [1]. The compound retains potency and selectivity at the human GLP-2 receptor comparable to native GLP-2 and teduglutide, with approximately two-fold greater potency than both in cell-based receptor activation assays [1]. Apraglutide was originally discovered at Ferring Pharmaceuticals (development code FE 203799) and subsequently licensed to GLyPharma Therapeutic in 2012, acquired by Therachon (a Novo Holdings-backed rare disease company), transitioned to VectivBio AG, and acquired by Ironwood Pharmaceuticals in 2023 [3, 4]. The compound received orphan drug designation from the United States Food and Drug Administration, the European Medicines Agency, and the Japanese regulatory authority for SBS-IF. The pivotal Phase 3 STARS trial (NCT04627025), a global, randomized, double-blind, placebo-controlled study in 164 adults with SBS-IF across 73 centers in 18 countries, met its primary endpoint: apraglutide-treated patients achieved a 25.5 percent relative reduction in weekly parenteral support volume at week 24 versus 12.5 percent for placebo (P = 0.001), with treatment effect evident from week 8 [5, 6]. Secondary endpoints demonstrated that 43 percent of apraglutide-treated patients gained at least one additional day off parenteral support per week (versus 27.5 percent for placebo, P = 0.04), and 6.4 percent of apraglutide-treated patients achieved complete enteral autonomy at week 24 compared to 0 percent on placebo [5]. Long-term extension data through 48 weeks showed 12.5 percent of apraglutide-treated patients achieving enteral autonomy versus 7.4 percent on placebo, with 27 patients overall achieving enteral autonomy across the development program [7]. In metabolic balance studies, once-weekly apraglutide at 5 mg subcutaneous increased wet weight absorption by 741 g/day, increased energy absorption by 1095 kJ/day, and increased sodium absorption by 38 mmol/day, making apraglutide the first GLP-2 analog to significantly improve energy absorption across the full SBS patient spectrum as measured by bomb calorimetry [8, 9]. The Phase 2 STARGAZE trial in steroid-refractory GI aGVHD demonstrated a 58.1 percent overall response rate at day 28 (versus 38.8 percent in a matched MAGIC control cohort) and a lower cumulative non-relapse mortality at day 180 (33.3 percent versus 41.9 percent) [10]. Adverse events across the clinical program have been predominantly mild to moderate gastrointestinal effects (decreased stoma output, stoma complications, nausea, flatulence, abdominal pain) consistent with the pharmacological intestinotrophic mechanism, with injection site reactions, polyuria, and edema also reported at low incidence [8, 11]. Ironwood Pharmaceuticals initiated a rolling NDA submission in January 2025; following FDA feedback requiring a confirmatory Phase 3 trial, the STARS-2 study is planned with site initiations in the second quarter of 2026 and an NDA submission target before end of 2029 [7, 12]. This monograph reviews the chemistry and peptide engineering of apraglutide; the GLP-2 receptor pharmacology and downstream intestinotrophic signaling; the comprehensive pharmacokinetic profile in healthy volunteers, SBS patients, and special populations; the preclinical intestinal growth pharmacology; the clinical evidence base across SBS-IF, metabolic balance, and GI aGVHD indications; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events and safety signal; and a comparative assessment of five GLP-2 receptor agonist candidates against apraglutide on five competency standards. The compound is not approved by any regulatory authority as of the monograph revision date.