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

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 QTc interval 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.

Keywords: Cardiac repolarisation; Drug safety; QT interval; SNAC.

© 2021. The Author(s).

Figures

Fig. 1

Trial design for Part A (a) and Part B (b). Asterisk (*) denotes trial safety group review. aTen subjects on SNAC and two subjects on placebo at each dose level. For each dose level: randomisation, dosing and pharmacokinetics sampling (visit 2). Follow-up (visit 3) occurred 7–10 days after dosing. SNAC Sodium N-(8-[2-hydroxybenzoyl] amino) caprylate

Fig. 2

Estimated mean time-matched baseline-adjusted difference between SNAC 3.6 g and placebo in the Fridericia heart rate-corrected QT interval (QTcF interval) following a single oral dose (full analysis set). Means are estimated from analysis of covariance models where the change from baseline for each of the 14 QTcF endpoints were entered as a dependent variable, with subject, period and treatment as fixed effects and treatment period-specific baseline QTcF as covariate. Bars represent the corresponding two-sided 90% confidence intervals. The broken horizontal line is the threshold for the limit of interest. SNAC Sodium N-(8-[2-hydroxy-benzoyl] amino) caprylate

Fig. 3

Arithmetic mean plasma concentration–time profile following a single oral dose of SNAC 3.6 g (full analysis set). Bars represent the standard error of the mean. The broken horizontal line is the reference line for the lower limit of quantification. SNAC Sodium N-(8-[2-hydroxy-benzoyl] amino) caprylate. SNAC Sodium N-(8-[2-hydroxy-benzoyl] amino) caprylate