Absence of QTc Prolongation with Sodium N-(8-[2-Hydroxybenzoyl] Amino) Caprylate (SNAC), an Absorption Enhancer Co-Formulated with the GLP-1 Analogue Semaglutide for Oral Administration

Jul 28, 2021Diabetes therapy : research, treatment and education of diabetes and related disorders

No QTc Heart Rhythm Changes with SNAC, an Absorption Helper Used with Oral Semaglutide

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Abstract

SNAC doses 12-fold higher than the 300 mg dose used in oral semaglutide do not cause unacceptable prolongation of the QTcF interval.

The trial involved 36 participants in Part A and 46 in Part B, all completing the study.
Adverse events reported were mild to moderate, with no correlation to SNAC dose.
SNAC 3.6 g was determined to be the maximum safe dose for assessing QTcF interval effects.
No unacceptable QTcF prolongation was observed with SNAC 3.6 g, and assay sensitivity was confirmed with moxifloxacin.
There was no significant relationship between SNAC concentration and QTcF interval changes.

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INTRODUCTION: Oral delivery of proteins, including glucagon-like peptide 1 (GLP-1) receptor agonists, is impeded by low gastrointestinal permeation. Oral semaglutide has been developed for once-daily oral administration by co-formulation of the GLP-1 analogue semaglutide with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC, 300 mg). A randomised, partially double-blind, placebo-controlled thorough QT/corrected QT (QTc) trial was conducted to confirm the absence of unacceptable prolongation with SNAC. QT is defined as interval on the electrocardiogram, measured from the start of the QRS complex to the end of the T wave.

METHODS: Part A of the study sought to identify an appropriate dose of SNAC (which was substantially higher than that used in the oral semaglutide co-formulation) for QTc assessment. Three sequential healthy volunteer cohorts were randomised to escalating single oral doses of SNAC (1.2, 2.4 or 3.6 g) or placebo. Following identification of an appropriate dose, a cross-over trial was conducted (Part B). Healthy volunteers received one of four treatment sequences, including single oral doses of SNAC, moxifloxacin (positive control) and placebo. Primary objectives were to (1) assess adverse events (AEs) with escalating SNAC doses and (2) confirm that SNAC does not cause unacceptable QTc interval prolongation versus placebo, using the Fridericia heart rate-corrected QT interval (QTcF).

RESULTS: All subjects completed Part A (N = 36) and 46 subjects completed Part B. In Part A, all AEs were mild to moderate in severity; no relationship was identified between AE incidence and SNAC dose. SNAC 3.6 g, the maximum investigated SNAC dose, was selected for Part B. There was no unacceptable prolongation of the QTcF interval with SNAC 3.6 g, and assay sensitivity was demonstrated with moxifloxacin as the positive control. There was no significant exposure-response relationship between SNAC concentration and QTcF interval, and no instances of QTc interval > 450 ms or increases > 30 ms.

CONCLUSION: This QT/QTc trial demonstrates that SNAC doses 12-fold higher than the 300 mg dose used in the oral formulation of semaglutide do not cause unacceptable prolongation of the QTcF interval.

TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02911870.

Key numbers

12×

Dose Increase

SNAC 3.6 g dose compared to the 300 mg in oral semaglutide.

< 10 ms

QTc Difference

Treatment difference between SNAC and placebo at all 14 time points.

> 5 ms

Assay Sensitivity Confirmation

Difference between moxifloxacin and placebo at predefined time points.

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Absence of QTc Prolongation with Sodium N-(8-[2-Hydroxybenzoyl] Amino) Caprylate (SNAC), an Absorption Enhancer Co-Formulated with the GLP-1 Analogue Semaglutide for Oral Administration

Abstract

Key numbers

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