Digital Features for this Adis Drug Q&A can be found at https://doi.org/10.6084/m9.figshare.17149049

FormalPara Adis evaluation of dasiglucagon (Zegalogue®) in severe hypoglycemia

Ready-to-use aqueous formulation; no need to reconstitute

Available in convenient auto-injector and prefilled syringe forms; can be carried at room temperature

Indicated in the USA for the rescue treatment of severe hypoglycemia in patients aged ≥ 6 years with diabetes

A single dose reverses hypoglycemia within a median 10 min, without need for additional intervention

Generally well tolerated, with nausea and vomiting being the most frequent adverse reactions

What is the rationale for developing dasiglucagon in severe hypoglycemia?

Hypoglycemia is a serious, and potentially fatal, complication of glycemic management in diabetes, particularly type 1 diabetes mellitus (T1DM) [1]. Based on glucose levels, hypoglycemia is classified into level 1 (54 to < 70 mg/dL), level 2 (< 54 mg/dL) and level 3 (a severe event characterized by altered mental and/or physical status requiring assistance for hypoglycemia treatment) [1, 2]. Hypoglycemia negatively impacts emotional status and quality of life, with severe hypoglycemia also associated with an increased risk of cardiovascular and cerebrovascular events [1, 3]. Thus, rapid reversal of severe hypoglycemia is of high clinical importance.

Glucagon, a peptide hormone produced by alpha cells in the pancreas, increases blood glucose level; recombinant glucagon is a well-established rescue treatment option for severe hypoglycemia [4, 5]. As native glucagon undergoes degradation in aqueous solutions and loses its bioactivity [6], commercial glucagon emergency kits formulate glucagon as a recombinant crystalline lyophilized powder [7, 8]. However, the powder must be reconstituted in sterile water prior to subcutaneous (SC), intramuscular, or intravenous (IV) injection. The reconstitution involves multiple steps and requires detailed instruction to parents or caregiver on how to prepare and administer glucagon [7, 8]. These complexities in an emergency situation often result in delayed rescue, dosing error and potential total treatment failure [9]. Glucagon, a valuable therapy, remains underutilized [10], partly due to a lack of adequate education and training in the use of glucagon emergency kits and due to fears of improper use [11]. To overcome the limitations associated with reconstitution, ready-to-use glucagon products have become available, including a SC non-aqueous formulation using dimethyl sulfoxide as diluent (Gvoke®) [12] and an intranasal formulation (Baqsimi®) [13].

Dasiglucagon (Zegalogue®) is a next-generation, ready-to-use, SC glucagon analog in aqueous formulation that does not require reconstitution [6]. Dasiglucagon is indicated in the USA for the treatment of severe hypoglycemia in patients aged ≥ 6 years with diabetes [14]. Table 1 provides a summary of the prescribing information for dasiglucagon in the USA.

Table 1 Summary of the prescribing information for dasiglucagon (Zegalogue®) in hypoglycemia in the USA [14]
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Dasiglucagon is also being evaluated for use in dual hormone artificial pancreas systems [15] and as a potential treatment for congenital hyperinsulinism [16], both of which are outside the scope of this article.

What are the pharmacological properties of dasiglucagon?

Chemistry and mechanism of action

Dasiglucagon is a novel peptide analog of human glucagon [6]. Like native glucagon, dasiglucagon comprises 29 amino acids, but with seven substitutions to increase solubility (≥ 20 mg/mL) and physicochemical stability in aqueous solution at physiological pH relative to native glucagon [6]. Dasiglucagon did not form aggregates over 14 days in an accelerated stability assay run at 40 °C under shaking conditions; this finding was confirmed in a 1-year stability study in which dasiglucagon prefilled syringes were tested for aggregates under constant rotation at room temperature [17]. In vitro, dasiglucagon has similar potency to glucagon at the human glucagon receptors [17]. As a glucagon receptor agonist, dasiglucagon increases blood glucose levels by activating glucagon receptors in the liver, thereby stimulating glycogen breakdown and the release of glucose from the liver; the antihypoglycemic effect of dasiglucagon relies on hepatic glycogen stores [14].

Pharmacodynamic profile

In a rat model of hypoglycemia, SC injection of dasiglucagon was associated with a rapid and dose-dependent increase in blood glucose levels and this effect was similar to that achieved with glucagon [17].

Dasiglucagon rapidly and dose-dependently increased plasma glucose (PG) levels in patients with T1DM in a randomized, double-blind, single-center, phase 2 trial (n = 58) [18]. Patients in a hypoglycemic state received a single SC injection of dasiglucagon 0.1, 0.3, 0.6, or 1.0 mg or reconstituted glucagon 0.5 or 1.0 mg. Dasiglucagon 0.3 mg and 0.6 mg doses were comparable to reconstituted glucagon 0.5 mg and 1.0 mg, respectively, in terms of their effect on PG levels, as measured by PG area under the effect curves (AUE) from time zero to 30 min and PG excursions 30 min postdose. The overall effect as measured by PG AUElast was significantly (p ≤ 0.0043) higher with dasiglucagon 0.3 mg versus reconstituted glucagon 0.5 mg and with dasiglucagon 0.6 or 1 mg versus reconstituted glucagon 1.0 mg. There was no significant difference between the groups for median time to achieve PG ≥ 70 mg/dL (6 min for dasiglucagon ≥ 0.3 mg vs 6–7 min for reconstituted glucagon 0.5 or 1.0 mg) or a PG increase of ≥ 20 mg/dL from baseline (9–10 min vs 10 min) [18]. These results are supported by another randomized double-blind trial in 17 patients with T1DM, in which a more highly concentrated dasiglucagon formulation (4 mg/mL) was evaluated for use in dual-hormone artificial pancreas systems [19].

Pharmacokinetic profile

Based on population pharmacokinetic modeling, dasiglucagon pharmacokinetics can be described by a one-compartment model, with first-order absorption and elimination, including an absorption lag time and standard allometric relations to bodyweight [20]. Following SC injection, dasiglucagon plasma concentrations rapidly increased in a dose-proportional manner [18], with a tmax [time to maximum plasma concentration (Cmax)] of ≈ 35 min [14, 18]. In pediatric patients with T1DM, dasiglucagon tmax is ≈ 21 min [14]. The mean apparent volume of distribution of dasiglucagon is 47–57 L and the half-life is ≈ 30 min. Like native glucagon, dasiglucagon is metabolized and eliminated via proteolytic degradation pathways in the blood, liver, and kidney [14]. Dasiglucagon has a similar Cmax and a longer tmax (35 vs 20 min) versus reconstituted glucagon; however, the total exposure is 1.56-fold higher for dasiglucagon 0.6 mg than for reconstituted glucagon 1.0 mg [18]. Model-predicted effects of covariates (kidney function, bodyweight, injection site and age) on dasiglucagon area under the plasma concentration-time curve (AUC) generally fell within the observed AUC for the overall analysis population [20].

What is the efficacy of dasiglucagon in severe hypoglycemia?

The efficacy of dasiglucagon as rescue treatment for severe hypoglycemia was evaluated in three randomized, double-blind, placebo-controlled phase 3 trials in adult [21, 22] and pediatric [23] patients with T1DM. Both prefilled syringe [22, 23] and autoinjector [21] dasiglucagon delivery devices were tested. Eligible patients were aged 18–75 years [21, 22] or 6–17 years (bodyweight ≥ 20 kg) [23], with HbA1c < 10% and receiving stable insulin therapy. Where stated, exclusion criteria included daily use of β-blockers, indomethacin, warfarin, or anticholinergic drugs during the previous 28 days, severe hypoglycemia during the previous month and hypoglycemia with seizure during the previous year [21, 23].

Patients fasted overnight, had their regular insulin stopped within the predefined timelines (12–72 h depending on insulin type) and underwent controlled hypoglycemia induction to a target PG level of 55 mg/dL [21, 22] or 80 mg/dL [23] using a hypoglycemic clamp. Patients were randomized to a single SC injection of dasiglucagon 0.6 mg or placebo [21,22,23], administered at 5 min [22, 23] or 2 min [21] post clamp when PG reached between ≥ 45 and < 60 mg/dL [21, 22] or ≥ 54 and < 80 mg/dL [23]. Two trials included an additional randomized reference arm of reconstituted glucagon [22, 23]; efficacy data for this explorative arm are presented in Table 2 but are not discussed further. Dasiglucagon was administered via a prefilled syringe in the abdomen, buttocks or thigh in adults [22] and in the abdomen or thigh in pediatric patients [23], or via an autoinjector in the buttocks or deltoid muscle in adults [21]. Randomization was stratified by the injection site [21,22,23] and age group (6–11 and 12–17 years) [23].

Table 2 Efficacy of dasiglucagon in the rescue treatment of severe hypoglycemia in phase 3 trials
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Overall, demographic and baseline diabetes characteristics were generally similar between the treatment groups within each trial. In adult trials, at baseline, the mean age of patients was 36.0–42.4 years, mean HbA1c was 7.17–7.52%, mean duration of diabetes was 18.3–22.5 years and the mean PG levels were 54.6–58.9 mg/dL [21, 22]. In the pediatric trial, at baseline, the mean age of patients was 12.0–12.5 years, mean HbA1c was 7.5–7.8%, mean bodyweight was 53.0–53.7 kg, mean duration of diabetes was 4.64–5.59 years and the mean PG levels were 72.16–73.15 mg/dL [23].

Dasiglucagon rapidly reversed hypoglycemia when administered via a prefilled syringe or an autoinjector in adults and via a prefilled syringe in pediatric patients [21,22,23]. The primary endpoint of median time to PG recovery was significantly shorter with dasiglucagon than with placebo (10 min vs 30–40 min) (Table 2) [21,22,23]. The median true time (estimated using linear interpolation) to PG recovery was 8.7–9.3 min versus 29.3–33.7 min. In the pediatric trial, the primary analysis was confirmed by two sensitivity analyses (with or without censoring patients receiving rescue IV glucose within 45 min) [23]. The injection site in all patients [21,22,23] and age group in pediatric patients (6–11 or 12–17 years) [23] had no clinically relevant effect on PG recovery time.

A significantly higher proportion of dasiglucagon than placebo recipients achieved PG recovery at prespecified timepoints (10, 15, 20, and 30 min post injection) [21,22,23]. None of the dasiglucagon recipients required rescue IV glucose, with the exception of an adult patient in one trial [21] who received the rescue therapy due to post-clamp hypoglycemia. Consistently, mean change from baseline in PG at 10,15, 20, and 30 min was significantly (p ≤ 0.01) greater in the dasiglucagon group than in the placebo group; data for the 30 min timepoint are shown in Table 2 [21,22,23].

What is the tolerability profile of dasiglucagon?

Dasiglucagon rescue treatment for severe hypoglycemia was generally well tolerated in adult and pediatric patients with T1DM in phase 3 clinical trials, with its safety profile being consistent with that expected for glucagon treatment [21,22,23]. There were no serious or fatal adverse events (AEs) with dasiglucagon [21,22,23].

In a pooled analysis of adult patients (n = 116 for dasiglucagon and 53 for placebo), the most common (incidence ≥ 2% vs placebo) adverse reactions occurring within 12 h of dasiglucagon treatment were: nausea (57 vs 4% with placebo), vomiting (25 vs 2%), headache (11 vs 4%), diarrhea (5 vs 0%), and injection site pain (2 vs 0%) [14]. In a phase 3 trial in adults, the incidence of drug-related AEs was largely similar between dasiglucagon and glucagon groups [22]. Nausea and vomiting typically occurred 1–3 h and 2–3 h, respectively, after dasiglucagon administration, both lasting < 3 h in most cases [22].

In the phase 3 trial in pediatric patients, the most common (incidence ≥ 2% vs placebo) adverse reactions occurring within 12 h of dasiglucagon treatment were: nausea (65 vs 0% with placebo), vomiting (50 vs 0%), headache (10 vs 0%), and injection site pain (5 vs 0%) [14]. A dasiglucagon subgroup analysis revealed that incidences of these events were greater in patients aged 12–17 years than in those aged 6–11 years: nausea (92 vs 25%), vomiting (67 vs 25%), headache (17 vs 0%), and injection site pain (8 vs 0%) [14]. There was no apparent correlation between dasiglucagon exposure and nausea and/or vomiting by either age or bodyweight [23].

In pediatric patients, dasiglucagon differed from reconstituted glucagon for treatment-emergent AEs of nausea (incidence 65 vs 30%), vomiting (50 vs 10%), upper respiratory tract infection (10 vs 0%), hypoglycemia (10 vs 20%), and injection site erythema (0 vs 30%). In both dasiglucagon and reconstituted glucagon groups, nausea typically occurred 1.5–3 h post dose and lasted < 2 h, whereas vomiting had on onset around 2–3 h post dose and lasted < 5 min [23].

In both adult [21, 22] and pediatric [23] patients, injection site reactions (such as redness, edema, and pain on palpation) to dasiglucagon were generally mild and transient. The drug was not associated with any clinically significant changes in laboratory evaluations, vital signs, ECG measurements or physical examinations [21, 23].

What is the immunogenicity of dasiglucagon?

As with all therapeutic peptides, dasiglucagon can be immunogenic. In clinical trials, dasiglucagon had a low potential for immunogenicity, with < 1% of 498 dasiglucagon recipients developing treatment-emergent anti-drug antibodies (ADAs) [14]. ADAs with transient neutralizing activity and cross-reactivity against native glucagon were detected in one patient who received multiple dasiglucagon doses [14].

The immunogenicity of dasiglucagon was compared with that of reconstituted glucagon in a randomized, double-blind, phase 3 safety trial in patients with T1DM (NCT03216226) [24]. Patients received three SC injections of dasiglucagon (n = 57) or glucagon (n = 55) 1 week apart. Treatment-induced or -boosted ADA responses were not observed at any assessed timepoints (35, 60, and 104 days) after the first dose for either treatment (primary endpoint) [24].

What is the current clinical positioning of dasiglucagon in severe hypoglycemia?

Dasiglucagon is a valuable addition to ready-to-use glucagon formulations for the rescue treatment of severe hypoglycemia. It is available in convenient autoinjector and prefilled syringe forms that can be carried at a room temperature and can be administered by family members, caregivers or healthcare professionals. A single dose of dasiglucagon reverses insulin-induced hypoglycemia typically within 10 min in patients aged ≥ 6 years, without need for additional intervention. Dasiglucagon is generally well tolerated, with its safety profile consistent with that expected for glucagon treatment.

The most recent American Diabetes Association treatment guidelines recommend glucagon treatment for level 2 hypoglycemia and its administration is not limited to healthcare professionals, particularly with the availability of ready-to-use formulations [5]. It is recommended that caregivers, school personnel, or family members of the patients should know where glucagon is stored, and when and how to administer it [5]. Similarly, International Society for Pediatric and Adolescent Diabetes guidelines recommend non-IV glucagon for severe hypoglycemia for children and adolescents with diabetes in a home or ambulatory setting [4]. Thus, dasiglucagon is a guideline-recommended option for severe hypoglycemia.

Time from glucagon injection to PG recovery is critical in the emergency management of severe hypoglycemia, and it as such was the primary endpoint in dasiglucagon pivotal trials [21,22,23]. Dasiglucagon was comparable to reconstituted glucagon for this endpoint. However, as a ready-to-use formulation, dasiglucagon saves reconstitution time and prevents potential human errors associated with this step in an emergency situation. In one study, trained caregivers were able to administer dasiglucagon autoinjector more reliably and quickly than a glucagon emergency kit [25]. The mean administration time was 75 s versus 133 s, the rate of successful correct administration was 94% versus 56% (p < 0.05; primary endpoint), and the rate of successful correct administration within 2 min was 88% versus 40%. Of note, untrained bystanders were able to administer dasiglucagon autoinjector (success rate 89% vs 72% for glucagon emergency kit; mean administration time 137 vs 251 s) [25]. The ease of use and the high success rate with dasiglucagon may increase glucagon utilization in severe hypoglycemia [11].

The other ready-to-use glucagon formulations, Gvoke® [12] and Baqsimi® [13], also offer the benefit of avoiding the reconstitution step, although they have unique AE profiles, such as injection site reactions due to the use of non-aqueous solvent (Gvoke®) and nasal/ocular AEs because of intranasal administration (Baqsimi®) [Table 3]. While dasiglucagon and Gvoke® require an injection, intranasal Baqsimi® offers the practical benefit of ease of use. In simulated usability studies, trained and untrained participants preferred nasal glucagon over intramuscular glucagon [26]. On the other hand, dasiglucagon provides marginally better time to PG recovery relative to the other two products (Table 3). It must be noted that the hypoglycemic clamp technique used in clinical studies to demonstrate the effect of dasiglucagon may not closely mirror real-life scenarios. Head-to-head trials comparing dasiglucagon with other ready-to-use formulations and real-world studies of dasiglucagon are required to fully define its relative position in the management of hypoglycemia.

Table 3 Features of ready-to-use glucagon formulations in severe hypoglycemia treatment in adult and pediatric patients in USA
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Severe hypoglycemia is associated with substantial economic burden and the use of non-medical assistance reduces this burden [27]. For instance, compared with medical assistance, non-medical assistance reduces direct ($US 1161 vs 66) and indirect ($US 579 vs 176) cost per severe hypoglycemic episode in patients with type 2 diabetes mellitus in the USA [27]. As a non-medical assistance, dasiglucagon may contribute to a further reduction in the overall cost by reducing the incidence of severe and persistent hypoglycemia that requires additional medical intervention [22]. The cost effectiveness dasiglucagon versus glucagon emergency kits and other ready-to-use formulations remains to be demonstrated.