BAQSIMI Nasal powder in single-dose container Ref.[115693] Active ingredients: Glucagon

Pharmacotherapeutic group: Pancreatic hormones, glycogenolytic hormones
ATC code: H04AA01

Mechanism of action

Glucagon 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 glucagon to produce an anti-hypoglycaemic effect.

Pharmacodynamic effects

Gender and body weight had no clinically meaningful effect on the pharmacodynamics of glucagon nasal powder.

After administration of 3 mg glucagon nasal powder in adult patients with type 1 diabetes, glucose levels began to rise as early as 5 minutes (see figure 1). By 10 minutes, the median glucose level was above 3.9 mmol/L (70 mg/dL). The mean maximum glucose increase was 7.8 mmol/L (140 mg/dL).

In paediatric patients with type 1 diabetes (aged 1 to <17 years), after administration of 3 mg glucagon nasal powder, glucose levels began to rise as early as 5 minutes, with a mean maximum glucose increase of 5.7 mmol/L (102 mg/dL) to 7.7 mmol/L (138 mg/dL). The mean maximum glucose increase from baseline was 7.33 mmol/L (132 mg/dL) (1 to <4 years), 7.67 mmol/L (138 mg/dL) (4 to <8 years), 7.39 mmol/L (133 mg/dL) (8 to <12 years), and 5.67 mmol/L (102 mg/dL) (12 to <17 years) (Figure 2).

Common cold with nasal congestion with or without concomitant use of a decongestant did not impact pharmacodynamics of glucagon nasal powder.

Figure 1. Mean glucose concentration over time in adult patients with type 1 diabetes:

Figure 2. Mean glucose concentration over time in paediatric patients with type 1 diabetes:

Clinical efficacy

The adult pivotal study was a randomized, multicentre, open-label, 2-period, cross-over study in adult patients with type 1 diabetes or type 2 diabetes. The primary objective was to compare the efficacy of a single 3 mg dose of glucagon nasal powder against a 1 mg dose of intramuscular glucagon in adult patients with type 1 diabetes. Insulin was used to reduce blood glucose levels to the hypoglycaemic range with a target blood glucose nadir of <2.8 mmol/L (<50 mg/dL).

The pivotal study enrolled 83 total patients aged 18 to <65 years. Seventy-seven patients had type 1 diabetes, with a mean age of 32.9 years and a mean diabetes duration of 18.1 years, and 45 (58%) patients were female. The mean age of patients with type 2 diabetes (n=6) was 47.8 years, with a mean diabetes duration of 18.8 years, and 4 (67%) patients were female.

The primary efficacy outcome measure was the proportion of patients achieving treatment success, which was defined as either an increase in blood glucose to ≥3.9 mmol/L (≥70 mg/dL) or an increase of ≥1.1 mmol/L (≥20 mg/dL) from glucose nadir within 30 minutes after receiving study glucagon, without receiving additional actions to increase the blood glucose level. Glucose nadir was defined as the minimum glucose measurement at the time of, or within 10 minutes, following glucagon administration.

For patients with type 1 diabetes, the mean nadir blood glucose was 2.5 mmol/L (44.2 mg/dL) for glucagon nasal powder and 2.7 mmol/L (48.9 mg/dL) for intramuscular glucagon. Glucagon nasal powder demonstrated non-inferiority to intramuscular glucagon in reversing insulin-induced hypoglycaemia with 98.7% of glucagon nasal powder-treated patients and 100% of intramuscular glucagon-treated patients achieving treatment success within 30 minutes (see table 2). All patients met glucose treatment success criteria within 40 minutes. All patients with type 2 diabetes (100%) achieved treatment success within 30 minutes.

The mean time to treatment success was 16.2 and 12.2 minutes in the glucagon nasal powder and intramuscular glucagon 1 mg treatment groups, respectively. Time to treatment success represents the time from glucagon administration to patient achieving treatment success; it does not include the time for reconstitution and preparation of the intra-muscular injection in the control group.

By 30 minutes post-glucagon administration, patients in both glucagon nasal powder and intramuscular glucagon groups had similar improvement in symptoms of hypoglycaemia, as evaluated by Edinburgh Hypoglycaemia Symptom Questionnaire.

Table 2. Patients meeting treatment success and other glucose criteria in pivotal study:

^a The efficacy analysis population consisted of all patients who received both doses of the study medicinal product with evaluable primary outcome.
^b Difference calculated as (percentage with success in intramuscular glucagon) – (percentage with success in glucagon nasal powder).
^c 2-sided 95% confidence interval (CI) using the unconditional profile likelihood method based on 'exact' tail areas; non-inferiority margin=10%.
^d Percentage based on number of patients meeting treatment success

In a similarly designed clinical confirmatory study, 70 patients with type 1 diabetes were enrolled with a mean age of 41.7 years (20-64 years), and a mean diabetes duration of 19.8 years. Twenty-seven (39%) were female. Insulin was used to reduce blood glucose levels to <3.3 mmol/L (<60 mg/dL).

The mean nadir blood glucose was 3.0 mmol/L (54.2 mg/dL) for glucagon nasal powder and 3.1 mmol/L (55.7 mg/dL) for intramuscular glucagon. Glucagon nasal powder demonstrated non-inferiority to intramuscular glucagon in reversing insulin-induced hypoglycaemia with 100% of glucagon nasal powder-treated patients and 100% of intramuscular glucagon-treated patients achieving treatment success (see table 3). The mean time to treatment success was 11.4 and 9.9 minutes in the glucagon nasal powder and intramuscular glucagon 1 mg treatment groups, respectively.

Table 3. Patients meeting treatment success and other glucose criteria in confirmatory study:

^a The efficacy analysis population consisted of all patients who received both doses of the study medicinal product with evaluable primary outcome.
^b Difference calculated as (percentage with success in intramuscular glucagon) – (percentage with success in glucagon nasal powder); non-inferiority margin = 10%.
^c 2-sided 95% confidence interval (CI) using the unconditional profile likelihood method based on 'exact' tail areas.

In an adult actual use study of approximately 6 months duration, 129 patients with type 1 diabetes (mean age, 46.6 years; range, 18 to 71 years) and their caregivers were dispensed glucagon nasal powder to treat moderate or severe hypoglycaemic events in the home or work setting. A total of 157 moderate or severe hypoglycaemic events reported by 69 patients were included in the efficacy analysis. An episode of severe hypoglycaemia was defined as an episode wherein the person with diabetes is clinically incapacitated (that is, unconscious, convulsions, severe mental disorientation) to the point where the person requires third-party assistance to treat the hypoglycaemia. An episode of moderate hypoglycaemia was defined as an episode wherein the person with diabetes was showing signs of neuroglycopenia (that is, weakness, difficulty speaking, double vision, drowsiness, inability to concentrate, blurred vision, anxiety, hunger, tiredness or confusion) and had a glucometer reading of approximately 60 mg/dL (3.3 mmol/L) or less. In 151 (96.2%) of these events, patients awoke or returned to normal status within 30 minutes following glucagon nasal powder administration. In all (100%) 12 severe hypoglycaemic events, patients awoke, stopped convulsions (7 events from 4 patients having presented with convulsions before glucagon nasal powder dosing) or returned to normal status within 5 to 15 minutes following glucagon nasal powder administration.

Paediatric population

The paediatric pivotal study was a randomised, multicentre, clinical study that assessed glucagon nasal powder compared to intramuscular glucagon in children and adolescents with type 1 diabetes. Glucagon was administered after glucose reached < 4.4 mmol/L (< 80 mg/dL) on the dosing day. Efficacy was assessed based on percentage of patients with a glucose increase of ≥1.1 mmol/L (≥20 mg/dL) from glucose nadir within 30 minutes following glucagon administration.

Forty-eight patients were enrolled and received at least one dose of study medicinal product. The mean age in the young children cohort (4 to < 8 years) was 6.5 years. In the children cohort (8 to < 12 years), mean age was 11.1 years and in the adolescents cohort (12 to < 17 years) mean age was 14.6 years. In all age cohorts, the population was predominantly male and white.

Across all age groups, 3 mg glucagon nasal powder and intramuscular glucagon 0.5 mg (children below 25 kg) or 1 mg (children 25 kg or above), demonstrated similar glycaemic responses. All (100%) patients in both treatment arms across all age groups achieved an increase in glucose ≥1.1 mmol/L (≥20 mg/dL) from glucose nadir within 20 minutes of glucagon administration.

The mean time to reach a glucose increase of ≥1.1 mmol/L (≥20 mg/dL) was similar between glucagon nasal powder and intramuscular glucagon for all age groups (see table 4).

Table 4. Mean time to reach glucose increase of ≥1.1 mmol/L (≥20 mg/dL) from nadir in paediatric pivotal study:

^a 0.5 mg or 1 mg of intramuscular glucagon (based upon body weight).

In a paediatric actual use study of approximately 6 months duration, 26 patients aged 4 to <18 years old with type 1 diabetes (mean age, 11.7 years; range, 5 to 17 years) and their caregivers were dispensed 3 mg glucagon nasal powder to treat moderate including major hypoglycaemic events in the home or school setting. A total of 33 moderate hypoglycaemic events reported by 14 patients were included in the efficacy analysis. An episode of major hypoglycaemia was defined as an episode with neuroglycopenia symptoms and a glucose level below 50 mg/dL (2.8 mmol/L). An episode of moderate hypoglycaemia is defined as an episode wherein the child/adolescent with diabetes has symptoms and/or signs of neuroglycopenia and has a blood glucose level of ≤70 mg/dL (3.9 mmol/L). In all events, including major hypoglycaemia (8 events from 5 patients), patients returned to normal status within 5 to 30 minutes following glucagon nasal powder administration.

In a paediatric Phase 1, open-label, multi-center study, safety and tolerability of a single 3 mg dose of nasal glucagon (NG) was assessed in paediatric patients aged 1 to <4 years with type 1 diabetes. Seven patients were enrolled, all received the planned 3-mg dose of the study drug and completed the study. Participants were recommended to fast overnight before the dosing, to achieve the target range blood glucose of 70 to 140 mg/dL (3.9 to 7.8 mmol/L) at dosing. Efficacy was assessed based on the percentage of patients with a glucose increase of ≥1.1 mmol/L (20 mg/dL) from glucose nadir within 30 minutes following Baqsimi administration. All (100%) patients achieved an increase in glucose ≥1.1 mmol/L (20 mg/dL) from glucose nadir within 30 minutes of glucagon administration. The mean time to reach a glucose increase of ≥1.1 mmol/L (20 mg/dL) for Baqsimi was 15.6 minutes (see section 4.2 for information on paediatric use).