Avexitide

Summary

Avexitide (exendin‑9‑39) is a synthetic peptide that blocks the glucagon‑like peptide‑1 receptor (GLP‑1R). It is being investigated as a treatment for conditions marked by excessive insulin secretion, notably post‑bariatric hypoglycaemia (PBH) and congenital hyperinsulinism (HI). By antagonising GLP‑1R, avexitide aims to raise blood glucose nadirs and reduce hypoglycaemic episodes in patients who have limited therapeutic options.

Mechanism of Action

Avexitide is a competitive antagonist of the GLP‑1 receptor, a G‑protein‑coupled receptor expressed on pancreatic β‑cells. Under normal physiology, GLP‑1 binding enhances glucose‑dependent insulin secretion. Avexitide binds the same receptor without activating it, thereby attenuating the GLP‑1‑mediated amplification of insulin release. This reduces post‑prandial insulin peaks and helps maintain higher plasma glucose levels, counteracting hypoglycaemia caused by overstimulation of the entero‑insular axis.

What the Research Shows

Preclinical work demonstrated that GLP‑1R antagonism with avexitide reduces insulin secretion in mouse models of hyperinsulinism and in human islets from an infant with congenital hyperinsulinism. Clinical investigations have focused on post‑bariatric hypoglycaemia. A phase‑2, randomised, placebo‑controlled crossover trial (PREVENT) in 18 women with PBH showed that avexitide 30 mg twice daily or 60 mg once daily raised glucose nadir by 21‑26% and lowered insulin peaks by about 20%, while halving the need for rescue interventions and reducing CGM‑detected hypoglycaemia. A separate dose‑escalation study of subcutaneous lyophilised and liquid formulations in 19 participants reported dose‑dependent improvements in glucose nadir, insulin peak, and symptom scores, with no rescue needed at higher doses. Both studies noted good tolerability and no increase in adverse events.

Reported Benefits

Evidence from two phase‑2 studies suggests avexitide can reliably increase the lowest glucose values during mixed‑meal testing, lower insulin peaks, and reduce the frequency of clinically significant hypoglycaemic events in patients with PBH. The drug also demonstrated dose‑dependent efficacy across formulations, and the antibody optimisation study highlighted its utility as a benchmark for GLP‑1R antagonism in congenital hyperinsulinism, indicating broader potential for disorders of excessive insulin secretion.

Limitations of the Evidence

The clinical data are limited to small, short‑term studies (19 participants in a 3‑day dosing study and 18 participants in a 28‑day crossover trial) and involve only female subjects with PBH, restricting generalisability. Long‑term safety, optimal dosing regimens, and efficacy in congenital hyperinsulinism have not been established. Avexitide remains investigational with no regulatory approval for any indication, and comparative effectiveness versus other therapies has not been formally evaluated.

Safety Considerations

Both the phase‑2 crossover trial and the repeat‑dose study reported that avexitide was well tolerated, with no increase in adverse events compared with placebo and no serious safety signals identified over the study periods. No specific adverse reactions were described in the abstracts. As an investigational peptide, caution is warranted pending larger, longer‑duration trials to fully characterise potential risks, especially with chronic use.

How It Is Administered

Avexitide is administered by injection, either subcutaneously or intravenously. Clinical studies have used subcutaneous lyophilised powder reconstituted for injection and a liquid formulation, both given twice daily (e.g., 30 mg per dose) or once daily (e.g., 60 mg). The drug is supplied as a peptide solution for parenteral use; oral administration is not reported.

Routes of Administration

Goals & Uses

• Treatment of post-bariatric hypoglycemiaMetabolic / EndocrineModerate
• Reduction of postprandial insulin secretionMetabolic / EndocrineModerate
• Management of congenital hyperinsulinismGeneticModerate
• Post‑bariatric hypoglycaemia therapyPost‑surgicalModerate
• Research tool for GLP-1 physiologyResearchHigh
• Congenital hyperinsulinismMetabolic / EndocrineLow
• Control of hypoglycaemiaMetabolicModerate

Contraindications

• Known hypersensitivity to avexitide or any excipientsAllergyHigh
• Type 2 diabetes mellitusEndocrineModerate
• Type 1 diabetes mellitusEndocrineModerate
• Hypersensitivity to exendin-based peptidesAllergyHigh

Adverse Effects

• HyperglycemiaMetabolicUncommonAbnormally high blood glucose
• Injection site reactionsLocalCommon
• HeadacheNeurologicUncommonPain in the head or upper neck
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• VomitingGastrointestinalCommonForceful expulsion of stomach contents

Drug Interactions

• Insulin and insulin secretagoguesModerate
• DPP‑4 inhibitorsModerate
• GLP‑1 receptor agonists (e.g., exenatide, liraglutide)High
• GLP-1 receptor agonists (e.g., semaglutide, liraglutide, exenatide)High
• SulfonylureasLowMay increase risk of low blood sugar

Population Constraints

• PregnancyReproductive SafetyRelative
• Renal impairmentOrgan ImpairmentRelative
• Pediatric patientsAgeRelative
• Pregnant womenReproductiveRelative

Regulatory Status

• European UnionInvestigationalClinical study under EMA oversight; not approved
• United StatesInvestigationalPhase 2 trials for hypoglycaemia; not FDA‑approved
• United KingdomInvestigationalNot approved by MHRA; no UK-specific authorization as of knowledge cutoff

Not approved in any jurisdiction; currently in Phase 2 clinical trials in the US and EU. Received Fast‑Track designation from the FDA for hypoglycaemia indications.

Evidence & Sources

• Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism
  Journal ArticleLowPeterson SM, et al.2023-01-01T00:00:00.000000Z
• Hypoglycemia post bariatric surgery: drugs with different mechanisms of action to treat a unique disorder
  Journal ArticleModerateCarpentieri GB, et al.2023-01-01T00:00:00.000000Z
• A New Potential Treatment for Postprandial Hypoglycemia Following Bariatric Surgery
  Journal ArticleUngradedRössner SM, Andersson DP2021-01-01T00:00:00.000000Z
• Beyond diabetes remission a step further: Post bariatric surgery hypoglycemia
  Journal ArticleLowLath D, et al.2022-01-01T00:00:00.000000Z
• Safety, efficacy and pharmacokinetics of repeat subcutaneous dosing of avexitide (exendin 9-39) for treatment of post-bariatric hypoglycaemia
  Journal ArticleLowTan M, et al.2020-01-01T00:00:00.000000Z
• PREVENT: A Randomized, Placebo-controlled Crossover Trial of Avexitide for Treatment of Postbariatric Hypoglycemia
  Journal ArticleModerateCraig CM, et al.2021-01-01T00:00:00.000000Z

Frequently Asked Questions