Zegalogue (Page 3 of 7)

12.3 Pharmacokinetics

Absorption

ZEGALOGUE absorption following subcutaneous injection of 0.6 mg resulted in a mean peak plasma concentration of 5110 pg/mL (1510 pmol/L) at around 35 minutes.

Distribution

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

Elimination

The half-life was approximately 30 minutes.

Metabolism

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

Specific Populations

After administration of ZEGALOGUE in pediatric patients with type 1 diabetes, the mean peak plasma concentration of 3920 pg/mL occurred at around 21 minutes.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Long-term studies in animals to evaluate carcinogenicity of dasiglucagon have not been performed.

Mutagenesis

Dasiglucagon was not mutagenic or clastogenic in a standard battery of genotoxicity tests: bacterial mutagenicity (Ames), human lymphocyte chromosome aberration, and rat bone marrow micronucleus.

Impairment of Fertility

In a fertility and early embryofetal development study in rats, dasiglucagon administered by subcutaneous injection (0.5, 2, and 8 mg/kg/day) did not impair fertility in male and female rats at exposures 179 and 269 times the human dose of 0.6 mg (based on AUC), respectively.

14 CLINICAL STUDIES

Three randomized, double-blind, placebo-controlled, multicenter trials were conducted in patients with type 1 diabetes. Two trials (Trial A and Trial B) were conducted in adult patients, and one trial (Trial C) was conducted in pediatric patients aged 6 to 17 years. In all 3 trials, patients were randomized to ZEGALOGUE 0.6 mg, placebo, or (in Trials A and C) glucagon for injection 1.0 mg. ZEGALOGUE and the comparators were administered as single subcutaneous injections following a controlled induction of hypoglycemia using intravenous administration of insulin. During this procedure, a plasma glucose concentration of <60 mg/dL was targeted in Trials A and B, whereas the target was <80 mg/dL in Trial C.

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. In Trials A and B, plasma glucose values were collected and assessed at pre-dose, and at 4, 6, 8, 10, 12, 15, 17, 20, 25, 30, 40, 45, 50, 60, 75, 90 minutes after treatment. Trial C assessed plasma glucose at the same timepoints as did Trials A and B, with the exception of the 25, 40, 50, 75 and 90-minute post-treatment timepoints. The primary hypothesis test was superiority of ZEGALOGUE versus placebo. There was no formal hypothesis test of ZEGALOGUE versus glucagon for injection.

14.1 Adult Patients

Trial A, NCT03378635: A total of 170 patients were randomized 2:1:1 to ZEGALOGUE, placebo, and glucagon for injection, stratified by injection sites (abdominal region, buttocks, thigh). 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 ZEGALOGUE (10 minutes) versus placebo (40 minutes) (Table 4). Figure 3 shows the cumulative proportions of patients achieving plasma glucose recovery over time. The median time to plasma glucose recovery was numerically similar between ZEGALOGUE (10 minutes) and glucagon for injection (12 minutes).

Trial B, NCT03688711: A total of 45 patients were randomized 3:1 to ZEGALOGUE and placebo stratified by injection sites (buttocks, deltoid). 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 ZEGALOGUE (10 minutes) versus placebo (35 minutes) (Table 4).

Table 4 Plasma Glucose Recovery in Adult Patients
Trial ATrial B
ZEGALOGUE N=82 Placebo N=43 ZEGALOGUE N=34 Placebo N=10
N is the number of patients who were randomized and treated.
*
log-log confidence interval
p < 0.001 versus placebo (log-rank test stratified by injection sites)
Median time to recovery [95% CI *] 10 min [10; 10] 40 min [30; 40] 10 min [8; 12] 35 min [20; -)
Figure 3
(click image for full-size original)

Figure 3 Time to plasma glucose recovery in Trial A

14.2 Pediatric Patients

Trial C, NCT03667053: Pediatric patients aged 6 to 17 years and weighing ≥20 kg, were randomized 2:1:1 to ZEGALOGUE, placebo, and glucagon for injection, stratified by injection sites (abdominal region, thigh) and age groups (6-11 years and 12-17 years). A total of 42 patients were randomized. The mean age 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 ZEGALOGUE (10 minutes) versus placebo (30 minutes) (Table 5). Figure 4 shows the cumulative proportions of pediatric patients achieving plasma glucose recovery over time. The median time to plasma glucose recovery was numerically similar between ZEGALOGUE (10 minutes) and glucagon for injection (10 minutes).

Table 5 Plasma Glucose Recovery in Pediatric Patients
Trial C
ZEGALOGUE N=20 Placebo N=11
N is the number of patients who were randomized and treated.
*
log-log confidence interval
p < 0.001 versus placebo (log-rank test stratified by injection site and age group)
Median time to recovery [95% CI *] 10 min [8; 12] 30 min [20; -)
Figure 4
(click image for full-size original)

Figure 4 Time to plasma glucose recovery in Trial C

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