Apraglutide

Apraglutide differs from native human GLP-2 by four amino acid substitutions that simultaneously block DPP-4 cleavage and greatly increase plasma protein binding, which reduces renal clearance and stretches the terminal half-life to roughly 30 hours in short bowel patients and around 72 hours in healthy volunteers. Downstream biology is the same as teduglutide — GLP-2 receptor activation on subepithelial myofibroblasts, IGF-1 and KGF release, villus hypertrophy, slower transit and increased mesenteric blood flow — but the sustained receptor exposure produced by weekly dosing may drive a somewhat different adaptation profile. It has also been explored in steroid-refractory gastrointestinal acute graft-versus-host disease, where the gut epithelium is the target tissue.

Targets: GLP-2 receptor, Intestinal subepithelial myofibroblasts, IGF-1 / KGF downstream signalling

• · 5 mg weekly for body weight 50 kg or above, 2.5 mg weekly below 50 kg — the lower band exists because exposure rises non-linearly as weight falls. The STARS Extend long-term extension used 3.5 mg and 1.4 mg. The FDA flagged lower-than-expected exposure in STARS as part of its request for a confirmatory trial, so the final approved dose may end up higher.

Work out your exact syringe units →

• very commonAbdominal pain, distension and nausea— The GLP-2 class signature, driven by the growth and transit effects.
• commonPeripheral oedema and fluid overload— Improved absorption without a matching reduction in parenteral fluid causes overload.
• commonStoma complications— Stomal tissue hypertrophies along with the rest of the bowel.
• commonInjection-site reactions— Once weekly, so far less cumulative than daily GLP-2 dosing.
• uncommonColonic polyps and theoretical neoplastic risk— Class effect of chronic intestinal growth signalling; colonoscopy surveillance applies.

• Active gastrointestinal malignancy — class contraindication for all GLP-2 agonists.
• Not available outside clinical trials; anything sold as apraglutide on the grey market is unverified.

• redundantteduglutide — Same receptor; a straight substitute, never a combination.
• redundantglepaglutide — Same receptor and same indication.
• cautionoral-medications — Increased absorptive surface and slowed transit can raise systemic exposure to oral drugs, a class effect shared with teduglutide.

• · Colonoscopy before initiation and on the same class schedule as teduglutide.
• · Fluid balance, weight and electrolytes weekly during parenteral support weaning.
• · Liver enzymes, bilirubin, lipase and amylase periodically.

Investigational. Not approved by the FDA or EMA. Orphan drug designation for short bowel syndrome; a confirmatory phase 3 is required before US approval.

• STARS phase 3 trial of once-weekly apraglutide in SBS-IF (NCT04627025) (trial)
• Ironwood Pharmaceuticals clinical and regulatory update on apraglutide, April 2025 (other)
• Eliasson et al. 2022, apraglutide phase 2 metabolic balance trial, JPEN (trial)
• STARGAZE phase 2 trial of apraglutide in steroid-refractory GI acute GVHD (trial)

Downstream of the receptor, apraglutide does exactly what teduglutide does: GLP-2 receptor agonism on subepithelial myofibroblasts and enteric neurons, paracrine IGF-1 and KGF release, crypt cell proliferation, increased villus height, slowed gastric emptying and transit, increased mesenteric blood flow. There is no novel biology here and nobody claims otherwise. The interesting question is whether continuous receptor exposure from weekly dosing produces the same adaptation as the daily peak-and-trough pattern of teduglutide. Nobody knows. There is a reasonable argument in either direction: sustained exposure might drive more complete mucosal growth, or it might promote receptor desensitisation in a way that intermittent exposure avoids. The trials have measured clinical endpoints, not receptor kinetics, so this remains open. What is genuinely distinctive is the pharmacokinetic engineering. Teduglutide extends half-life with a single Gly2 substitution and clears at roughly glomerular filtration rate. Apraglutide instead makes the molecule stick to plasma proteins, which keeps it out of the glomerulus entirely — clearance drops to 16.5-20.7 L/day and half-life stretches to roughly 30 hours in short bowel patients and around 72 hours in healthy volunteers. The interesting consequence is that exposure rises non-linearly as body weight falls, which is why the dose is weight-banded rather than weight-proportional: 5 mg weekly at 50 kg and above, 2.5 mg below. One finding worth knowing: in the healthy-volunteer study the 5 mg dose produced maximal pharmacodynamic effects on enterocyte mass markers, with 10 mg adding nothing. The dose-response for the biomarker plateaus. Yet the FDA's complaint about STARS was insufficient exposure. Those two facts sit uneasily together and the confirmatory trial is where that gets resolved.

The headline problem with apraglutide is regulatory, not clinical. It met its phase 3 primary endpoint and the FDA still asked for a confirmatory trial, citing lower-than-expected drug exposure. That is an unusual position: a drug with a positive phase 3 that may be under-dosed. If it is eventually approved, the dose may well be higher than the 5 mg used in STARS, which makes any grey-market self-dosing based on STARS numbers doubly unwise. Clinically, the failure modes are the class ones: fluid overload from failing to wean parenteral support, abdominal pain and distension in the early weeks, stoma hypertrophy in ostomy patients, and the polyp surveillance burden. The specific risk of weekly dosing is monitoring drift. With a daily injection, a patient is engaged with their therapy every day. With a weekly injection, and clinic visits every few months, a slow fluid accumulation can run a long way before anyone notices. Weekly weights are not optional on this drug. And the practical one: apraglutide is investigational and supplied only through trials. There is no legitimate vial. Anything sold as apraglutide on the grey market is unverified material with no reference standard to check it against.

1. 5 mgWeek 1 onward, body weight 50 kg or above — 5 mg once weekly. No titration — the dose is set by weight band from the first injection.
2. 2.5 mgWeek 1 onward, body weight below 50 kg — 2.5 mg once weekly. The lower band exists because exposure rises non-linearly as weight falls, so a proportional dose would overshoot.
3. 3.5 mgLong-term extension dosing — The STARS Extend long-term extension used 3.5 mg and 1.4 mg rather than 5 mg and 2.5 mg. This is not a step in a ladder so much as evidence that the correct maintenance dose was still being worked out.
4. —From week 4 — As with every GLP-2, the thing that actually gets titrated is parenteral support volume, downward, in 10-20% steps guided by urine output, weight and electrolytes. Primary endpoint in STARS was measured at week 24.

• GLP-2 receptor (GLP2R), human — pEC50 10.5 (EC50 approximately 3 x 10^-11 M, i.e. 30 pM), per the IUPHAR/BPS Guide to Pharmacology. Essentially the same potency as teduglutide — the difference between these drugs is pharmacokinetic, not pharmacodynamic.

  Selective Gs-coupled agonism raising cAMP in GLP-2R-bearing subepithelial myofibroblasts and enteric neurons.

• IGF-1 / KGF paracrine axis — Not a direct target.

  The effector arm, identical to teduglutide: crypt cell proliferation, increased villus height and crypt depth, increased absorptive surface.

• Plasma proteins (albumin and others) — High, though I could not resolve a published percentage.

  Not a therapeutic target but the central design feature. Binding sequesters the peptide from glomerular filtration and from proteolysis, cutting clearance roughly tenfold versus teduglutide and creating the weekly dosing interval.

• STARS — A multicenter, double-blind, randomised, placebo-controlled trial to evaluate the efficacy and safety of apraglutide in adult subjects with short bowel syndrome and intestinal failure (NCT04627025) Phase 3 · n=164 · 24 weeks · 2024

  Change in weekly parenteral support volume from baseline through week 24, expressed as a relative percentage. ClinicalTrials.gov records the study as Completed. The sponsor has reported that the primary endpoint was met; a peer-reviewed results publication was not indexed in PubMed at the time of writing, so the effect size here is not independently verifiable.

• Characterization of the pharmacokinetic and pharmacodynamic profile of apraglutide in healthy volunteers Phase 1 · n=24 · 6 weeks · 2023

  Pharmacokinetics and pharmacodynamics of six weekly subcutaneous doses of 1, 5 or 10 mg apraglutide versus placebo. Clearance 16.5-20.7 L/day, volume of distribution 55.4-105.0 L. The 5 mg dose produced maximal pharmacodynamic effect on enterocyte mass markers.

• Phase 1 open-label trial of single-dose apraglutide in renal impairment Phase 1 · 2024

  Pharmacokinetics and tolerability of a single dose of apraglutide in individuals with impaired renal function.

• Phase 1 open-label trial of single-dose apraglutide in hepatic impairment Phase 1 · 2026

  Pharmacokinetics and safety of a single dose of apraglutide in individuals with normal and impaired hepatic function.

• STARGAZE — phase 2 trial of apraglutide in steroid-refractory gastrointestinal acute graft-versus-host disease Phase 2

  Response in steroid-refractory GI acute GVHD. Referenced in the Core record; I did not resolve a registration record or publication for it in this session.

Same tissue-growth timescale as the rest of the class. Nothing meaningful in the first two weeks beyond side effects. Parenteral support reductions accrue over 12-24 weeks, and the STARS primary endpoint was measured at week 24. Long-term extension dosing continued beyond that, which is the usual pattern — adaptation is not finished at six months.

Never with teduglutide or glepaglutide. Same receptor, same indication, purely additive risk. The oral drug absorption interaction is a class effect and applies identically here: more surface area plus slower transit means oral medications that were previously under-absorbed in a short bowel start being absorbed properly. Reassess doses of psychotropics, benzodiazepines, anticoagulants and antiepileptics in the first month. Because dosing is weekly rather than daily, one practical stacking point is worth noting: any interacting oral drug will see its absorption change on a weekly rhythm in the early phase, not a flat one. Whether that matters clinically is unstudied. Do not combine with a GLP-1 agonist without a specific reason — both slow transit, and in a very short bowel the combination risks functional obstruction.

Apraglutide and glepaglutide are both attempts to solve teduglutide's real weakness, which is a daily reconstituted injection for life. They solve it in different ways. Apraglutide uses plasma protein binding to slow renal clearance, giving a genuinely long half-life and weekly dosing. Glepaglutide uses a hexalysine tail to create a slow-release subcutaneous depot, and needs twice-weekly dosing but arrives as a ready-to-use liquid autoinjector with no reconstitution at all. On patient burden, one injection a week beats two; on preparation burden, an autoinjector beats a vial. Neither is available. On receptor pharmacology the three drugs are near-identical: teduglutide pEC50 10.7, apraglutide pEC50 10.5. The differences are entirely in duration and delivery. Direct efficacy comparison is not possible. STARS measured relative percentage change in weekly parenteral volume; STEPS measured a responder rate at weeks 20 and 24; EASE-1 measured absolute change in litres per week. Different endpoints in different populations. Anybody presenting a league table of these three is fabricating a comparison the trials do not support.

No commercial price exists because the drug is not approved anywhere. If it reaches market it will be priced as a specialty orphan biologic in the same territory as teduglutide.

• ?The STARS results have not been published in a peer-reviewed journal indexed in PubMed as far as I could determine, so the effect size is not independently verifiable — only the trial's existence, design, enrolment and completion status are confirmed.
• ?The half-life figures in the Core record (about 30 hours in SBS patients, about 72 hours in healthy volunteers) were not independently confirmed in this session; the PK paper I did resolve gives clearance and volume of distribution but I did not verify a terminal half-life number.
• ?Protein binding percentage is described qualitatively as high in the literature; I could not resolve a published figure, so the field is null.
• ?Volume of distribution is entered as 80 L, the approximate midpoint of the published 55.4-105.0 L range in healthy volunteers. It is a midpoint, not a measured population value.
• ?The amino acid sequence is not published in the sources I could reach, so the sequence fields are empty and verified is false. Molecular formula and weight are from PubChem CID 155559189 and are reliable; the residue string is not.
• ?The exact nature of the four amino acid substitutions relative to native GLP-2 is described in the literature but I did not resolve the specific positions.
• ?The STARGAZE GVHD trial could not be verified in this session.
• ?The FDA's April 2025 request for a confirmatory trial is reported in the Core record; I did not independently verify that announcement in this session, though the drug's continued unapproved status is consistent with it.

• Characterization of the Pharmacokinetic and Pharmacodynamic Profile of Apraglutide, a Glucagon-Like Peptide-2 Analog, in Healthy Volunteers Bolognani F, et al., The Journal of Pharmacology and Experimental Therapeutics, 2023 · PMID 37316329

  Source for clearance (16.5-20.7 L/day), volume of distribution (55.4-105.0 L), and the finding that 5 mg produces maximal pharmacodynamic effect with 10 mg adding nothing.

• Pharmacokinetics and Tolerability of a Single Dose of Apraglutide in Individuals With Impaired Renal Function Greig G, et al., Journal of Clinical Pharmacology, 2024 · PMID 38465515

  Renal impairment PK — relevant because short bowel patients frequently have chronic kidney disease from years of dehydration and oxalate nephropathy.

• Pharmacokinetics and Safety of Single-Dose Apraglutide in Individuals with Normal and Impaired Hepatic Function: A Phase 1, Open-Label Trial Greig G, et al., Clinical Pharmacology in Drug Development, 2026 · PMID 41545784

  Hepatic impairment PK — relevant given the high rate of parenteral-nutrition-associated liver disease in this population.

• Early ecological changes in intestinal microbiota with the long-acting GLP-2 analog apraglutide in short bowel syndrome Ekhlas D, et al., Clinical Nutrition ESPEN, 2026 · PMID 41903849

  One of the few pieces of work looking at what GLP-2 therapy does to the microbiome rather than to the mucosa.

• NCT04627025 — STARS trial registration record ClinicalTrials.gov

  Confirms phase 3, 164 participants, Completed status, and the primary outcome definition — relative percentage change in weekly parenteral support volume through week 24.

• Apraglutide, IUPHAR/BPS Guide to Pharmacology ligand 10685 — GLP-2 receptor pEC50 10.5 IUPHAR/BPS Guide to Pharmacology

  Receptor potency: EC50 approximately 30 pM at the human GLP-2 receptor, essentially matching teduglutide.