ZEGALOGUE Solution for injection Ref.[115117] Active ingredients: Dasiglucagon

Pharmacotherapeutic group: Pancreatic hormones, glycogenolytic hormones
ATC code: H04AA02

Mechanism of action

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 (see section 4.4).

Pharmacodynamic effects

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.

Clinical efficacy and safety

Three randomised, double-blind, placebo-controlled, multicenter trials were conducted in patients with type 1 diabetes. Two trials (Trial 16137 and Trial 17145) were conducted in adult patients, and one trial (Trial 17086) was conducted in paediatric patients aged 6 to 17 years. In all 3 trials, patients were randomised to dasiglucagon 0.6 mg, placebo, or (in Trials 16137 and 17086) glucagon for injection 1.0 mg. Dasiglucagon and the comparators were administered as single subcutaneous injections following a controlled induction of hypoglycaemia using intravenous administration of insulin. During this procedure, a plasma glucose concentration of <60 mg/dL was targeted in Trials 16137 and 17145, whereas the target was <80 mg/dL in Trial 17086. The primary efficacy endpoint for all 3 trials was time to plasma glucose recovery (treatment success), defined as an increase in blood glucose of ≥20 mg/dL from time of administration, without additional intervention within 45 minutes. The primary hypothesis test was superiority of dasiglucagon versus placebo. There was no formal hypothesis test of dasiglucagon versus glucagon for injection.

Trial 16137 randomised a total of 170 patients 2:1:1 to dasiglucagon, placebo, and glucagon for injection. The mean age of the patients was 39.1 years (96% were <65 years), and the mean duration of diabetes was 20.0 years; 63% were male; 92% were White. The mean baseline plasma glucose was 58.8 mg/dL. The median time to plasma glucose recovery was statistically significantly shorter for dasiglucagon (10 minutes) versus placebo (40 minutes) (Table 2). The median time to plasma glucose recovery was numerically similar between dasiglucagon (10 minutes) and glucagon for injection (12 minutes).

Trial 17145 randomised a total of 45 patients 3:1 to dasiglucagon and placebo. The mean age of the patients was 41.0 years (95% were <65 years), and the mean duration of diabetes was 22.5 years; 57% were male; 93% were White. The mean baseline plasma glucose was 55.0 mg/dL. The median time to plasma glucose recovery was statistically significantly shorter for dasiglucagon (10 minutes) versus placebo (35 minutes) (Table 2).

Table 2. Plasma glucose recovery in adult patients:

N is the number of patients who were randomized and treated
^a log-log confidence interval
^b P<0.001 versus placebo (log-rank test stratified by injection sites)

Paediatric population

Trial 17086 randomised a total of 42 patients 2:1:1 to dasiglucagon, placebo, and glucagon for injection. Patients were stratified by age (6-11 years and 12-17 years). The mean age of the patients was 12.5 years (range 7 to 17 years), and the mean duration of diabetes was 5.9 years; 56% were male; 95% were White. The mean baseline plasma glucose was 72.0 mg/dL. The median time to plasma glucose recovery was statistically significantly shorter for dasiglucagon (10 minutes) versus placebo (30 minutes) (Table 3). The median time to plasma glucose recovery was numerically similar between dasiglucagon (10 minutes) and glucagon for injection (10 minutes).

Table 3. Plasma glucose recovery in paediatric patients:

N is the number of patients who were randomized and treated.
^a log-log confidence interval
^b P<0.001 versus placebo (log-rank test stratified by injection site and age group)

The European Medicines Agency has deferred the obligation to submit the results of studies with Zegalogue in one or more subsets of the paediatric population in the treatment of severe hypoglycaemia (see section 4.2 for information on paediatric use).