Dasiglucagon Effects on QTc in Healthy Volunteers: A Randomized, Placebo-Controlled, Dose-Escalation, Double-Blind Study

Abstract

Background: Dasiglucagon is a novel glucagon analog that is stable in aqueous formulation and approved for use in severe hypoglycemia. Concentration QTc analyses are critical for assessing risk of drug-induced QTc prolongation and potential for fatal cardiac arrhythmias such as torsades de pointes.

Objective: The aim of this study was to determine whether dasiglucagon treatment resulted in any clinically relevant effect on cardiac repolarization in healthy volunteers.

Methods: This double-blind, placebo-controlled, dose-escalation Phase I trial was conducted at a single center in Germany between November 2018 and June 2019. Sixty healthy volunteers aged 18 to 45 years were randomized within dose cohorts to receive intravenous dasiglucagon, intravenous placebo, or subcutaneous dasiglucagon. In the intravenous administration cohorts, doses ranged from 0.03 mg to 1.5 mg. The subcutaneous administration cohort received the approved 0.6 mg dose. In the intravenous administration cohorts, serial electrocardiograms were extracted from continuous Holter monitors at prespecified time points beginning the day before dosing and through 24 hours postdose. Heart rate, PR interval, and QRS duration were evaluated. Concentration-QT analyses corrected by Fridericia's formula (QTcF) were performed using both a linear mixed-effects and a maximum estimated effect (Emax) model.

Results: At the doses studied, dasiglucagon did not have any clinically relevant effect on heart rate, PR interval, or QRS duration. A minor prolongation of the QTcF interval was observed without any clear dose or concentration dependency. Both the linear and Emax models predicted mean and 90% CIs of placebo-corrected change in QTcF remained below 10 ms (the threshold of regulatory concern), although the linear model did not fit the data well at low dasiglucagon plasma concentrations. In the Emax model, the Emax of dasiglucagon was 3.6 ms (90% CI, 1.23-5.95 ms), and the amount to produce half the effect of Emax) was 426.0 pmol/L (90% CI, -48.8 to 900.71 pmol/L). The treatment effect-specific intercept was -0.44 ms (90% CI, -2.37 to 1.49 ms). The most frequently observed treatment-emergent adverse events reported in the trial were gastrointestinal disorders such as nausea and vomiting.

Conclusions: Dasiglucagon does not cause clinically relevant QTc prolongation in concentrations up to ≈30,000 pmol/L, a level 5-fold higher than the highest observed plasma concentrations in clinical trials investigating use of the approved 0.6 mg SC dose. ClinicalTrials.gov Identifier: NCT03735225; EudraCT identifier: 2018-002025-32. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX).

Keywords: Cardiac repolarization; Concentration-QTc analysis; Dasiglucagon; Pharmacokinetics.

Conflict of interest statement

This study was funded by Zealand Pharma (Søborg, Denmark). R. Tehranchi, S. J. Maarbjerg, J. Pettersson, A. E. Melgaard, and A. Valeur are employees of Zealand Pharma. As authors, employees of Zealand Pharma were involved in the study design; collection, analysis, and interpretation of data; the writing of the manuscript; and the decision to submit the manuscript for publication. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

© 2022 Published by Elsevier Inc.

Figures

Figure 1

Pharmacokinetic (PK) and pharmacodynamic response to intravenous (IV) and subcutaneous (SC) dasiglucagon. (A) Log-transformed dasiglucagon plasma concentrations over time in healthy volunteers (n = 34) with typical PK profiles receiving dasiglucagon SC 0.6 mg or IV 0.03 to 1.5 mg. Data are presented as geometric mean and 95% CI. (B) Plasma glucose concentrations over time in healthy volunteers with typical PK profiles (n = 52) receiving placebo or dasiglucagon SC 0.6 mg or IV 0.03 to 1.5 mg. Data are presented as mean and 95% CI.

Figure 2

Placebo-corrected change from baseline in heart rate (ΔΔHR) over time. ΔΔHR across prespecified ECG time points in healthy volunteers with typical pharmacokinetic (PK) profiles receiving either placebo or dasiglucagon IV 0.03 to 1.5 mg (n = 46) is shown. Least squares mean and 90% CI based on a linear mixed-effects model: ΔHR = time + treatment + time * treatment + baseline HR is reported. A compound symmetry covariance structure was used to specify the repeated measures (time within participant).

Figure 3

Placebo-corrected change from baseline in QTcF (ΔΔQTcF) over time. ΔΔQTcF across prespecified ECG time points in healthy volunteers with typical pharmacokinetic (PK) profiles receiving either placebo or dasiglucagon IV 0.03 to 1.5 mg (n = 46) is shown. Least squares mean and 90% CI based on a linear mixed-effects model: ΔQTcF = time + treatment + time  × treatment + baseline QTcF is reported. A compound symmetry covariance structure was used to specify the repeated measures (time within participant).

Figure 4

Scatterplot of observed dasiglucagon plasma concentrations and placebo-adjusted change from baseline in QTc by Fridericia's formula (ΔQTcF) from the estimated maximum effect (Emax) model. The relationship between the individually observed dasiglucagon plasma concentrations and estimated placebo-adjusted ΔQTcF is shown. Data are from all participants receiving either placebo or dasiglucagon IV 0.03-1.5 mg (N = 54). The solid red line with dashed red lines denotes the model-predicted mean ΔΔQTcF with 90% CI. The blue squares, red triangles, green diamonds, brown homedowns, purple stars, and black circles denote the pairs of observed dasiglucagon plasma concentrations and estimated placebo-adjusted ΔQTcF by participants for the 0.03 mg IV dasiglucagon, 0.1 mg IV dasiglucagon, 0.3 mg IV dasiglucagon, 0.6 mg IV dasiglucagon, 1.5 mg IV dasiglucagon, and placebo treatment groups, respectively. The individually estimated placebo-adjusted ΔQTcFi,j equals the individual ΔQTcFi,j for participanti administered with dasiglucagon at time pointj minus the estimation of time effect at time pointj.