Sustained Action of Imapextide, A Glucagon-Like Peptide-1 Receptor Antagonist, in Healthy Volunteers

Clinical Snapshot

Key Findings

• P Value: Not reported

• Effect Size: Dose-proportional exposure with median time to maximum concentration 24-48 hours

• Primary Outcome: Treatment-emergent adverse events ranged from 33.3% to 50.0% (single doses), 33.3% to 100% (multiple doses), and 14.3% (drug interaction cohort)

• Nnt Or Sensitivity: Mean half-life approximately 90 hours supporting once-weekly dosing

• Confidence Interval: Not reported

Clinical Application

Once-weekly subcutaneous injection appears feasible. Injection site reactions were common adverse events requiring monitoring Would require TGA approval for clinical use. Post-bariatric hypoglycemia management currently relies on dietary modification and continuous glucose monitoring as per Australian clinical guidelines. PBS listing would depend on demonstrated clinical efficacy and cost-effectiveness Currently limited to research setting. Potential future application in patients with post-bariatric hypoglycemia requiring pharmacological intervention beyond dietary management

Abstract

CONTEXT: After weight-loss surgery, some patients experience postbariatric hypoglycemia (PBH). Although PBH is customarily managed by dietary modifications with continuous glucose monitoring, advanced treatment options are needed. Imapextide is a sustained-action, selective, reversible glucagon-like peptide-1 (GLP-1) receptor antagonist designed for once-weekly administration for PBH treatment. OBJECTIVE: This work aimed to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending doses (SAD/MAD) of imapextide in healthy volunteers (HVs). METHODS: This 3-part, phase 1, double-blind study enrolled healthy adults. In the SAD/MAD parts, randomly assigned participants (3:1) received subcutaneous imapextide (SAD, 10-200 mg; MAD, 10-30 mg once weekly, 4 doses) or placebo. The primary end point was safety/tolerability (treatment-emergent adverse events [TEAEs]). PK (SAD/MAD; time-to-maximal concentration [tmax] and half-life [t1/2]) and PD (MAD; GLP-1 and glycemic parameters during a mixed meal tolerance test [MMTT]) were assessed. Imapextide drug-drug interactions (DDIs) of OATP1B1/OATP1B3 inhibition and accelerated gastric emptying were evaluated with coproporphyrin-I, rosuvastatin, and acetaminophen. RESULTS: Overall, 69 HVs were randomly assigned (32 SAD, 23 MAD, 14 DDIs). Imapextide TEAE rates ranged from 33.3% to 50.0% (SAD), 33.3% to 100% (MAD), and 14.3% (DDIs) across cohorts. The most common TEAEs included injection site erythema (SAD, MAD) and injection site swelling (MAD). Imapextide exposure was dose proportional (median tmax 24-48 hours; mean t1/2 ∼90 hours). During the MMTT, imapextide increased GLP-1 concentrations at early time points, while effects on other glycemic parameters were variable. Minimal nonclinically relevant DDIs occurred with rosuvastatin. Imapextide slightly accelerated gastric emptying. CONCLUSION: Imapextide was generally well tolerated in HVs. PK findings supported weekly dosing. PD showed consistent effects on GLP-1 levels, supporting a potential role for imapextide in modulating PBH pathophysiology.