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

Abstract

After weight-loss surgery, some patients experience post-bariatric 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 (QW) administration for PBH treatment. To evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple ascending doses (SAD/MAD) of imapextide in healthy volunteers (HVs). This 3-part phase 1 double-blind study enrolled healthy adults. In the SAD/MAD parts, randomized participants (3:1) received subcutaneous imapextide (SAD, 10-200 mg; MAD, 10-30 mg QW, 4 doses) or placebo. The primary endpoint 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 (DDI) of OATP1B1/OATP1B3 inhibition and accelerated gastric emptying were evaluated with coproporphyrin-I, rosuvastatin, and acetaminophen. Overall, 69 HVs were randomized (32 SAD, 23 MAD, 14 DDI). Imapextide TEAE rates ranged from 33.3%-50.0% (SAD), 33.3%-100% (MAD), and 14.3% (DDI) 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 non-clinically relevant DDI occurred with rosuvastatin. Imapextide slightly accelerated gastric emptying. 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. NCT06036784; https://clinicaltrials.gov/study/NCT06036784.