Dasiglucagon

Dasiglucagon is a glucagon receptor agonist analogue, which increases blood glucose concentration by activating hepatic glucagon receptors, thereby stimulating glycogen breakdown and release of glucose from the liver. Hepatic stores of glycogen are necessary for dasiglucagon to produce an antihypoglycaemic effect.

Gender and injection site had no clinically meaningful effect on the pharmacodynamics of dasiglucagon.

After administration of dasiglucagon in adult patients with type 1 diabetes (Trial 16137), the time course of glucose is shown, with a mean glucose increase from baseline to 90 minutes of 9.3 mmol/L (168 mg/dL) (Figure 1).

Figure 1. Mean plasma glucose over time in adults with type 1 diabetes administered 0.6 mg dasiglucagon in Trial 16137:

In paediatric patients (7 to 17 years) with type 1 diabetes (Trial 17086), the time course of glucose is shown for children and adolescents, with a mean glucose increase at 60 minutes after administration of dasiglucagon of 9.0 mmol/L (162 mg/dL) (Figure 2).

Figure 2. Mean plasma glucose over time in paediatric patients with type 1 diabetes administered 0.6 mg dasiglucagon in Trial 17086:

Immunogenicity

Anti-drug antibodies (ADA) were uncommonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed, however, data are still limited.

Absorption

Dasiglucagon absorption following subcutaneous injection of 0.6 mg in adults resulted in a mean peak plasma concentration of 1 510 pmol/L at around 35 minutes.

Distribution

The mean apparent volume of distribution was 47 L to 57 L following subcutaneous administration.

Biotransformation

Metabolism data indicated that dasiglucagon is cleared like native glucagon through proteolytic degradation pathways in blood, liver, and kidney.

Elimination

The half-life of dasiglucagon was approximately 30 minutes.

Hepatic impairment

No formal studies have been performed to evaluate hepatic impairment.

Paediatric population

Data from one trial (Trial 17086) conducted in paediatric patients aged 7 to 17 years with type 1 diabetes showed that after administration of dasiglucagon, the mean peak plasma concentration of 1 160 pmol/L occurred at around 21 minutes.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.

Reproductive and developmental toxicity

In rats administered subcutaneously daily with dasiglucagon for 12 days, maternal toxicity, in terms of decreased body weight gain, lower fetal body weight, and delayed bone ossification, was observed at ≥10 mg/kg/day (≥475 times the human dose based on the Area Under the Curve (AUC)).

In rabbits administered subcutaneously daily with dasiglucagon for 14 days, lower fetal body weight and delayed bone ossification were observed at 1 mg/kg/day (100 times the human dose based on AUC), a dose that also induced maternal toxicity in terms of decreased body weight gain. At ≥0.3 mg/kg/day (≥20 times the human dose based on AUC), dasiglucagon caused fetal skeletal and visceral malformations with no maternal toxicity observed.