Pharmacodynamics, pharmacokinetics, safety, and tolerability of a ready-to-use, room temperature, liquid stable glucagon administered via an autoinjector pen to youth with type 1 diabetes.

BACKGROUND: Prompt and reliable management of hypoglycemia in youth with diabetes is important to prevent serious medical complications. OBJECTIVES: To determine efficacy, pharmacodynamics (PD), pharmacokinetics (PK), safety, and tolerability of a ready-to-use, liquid stable glucagon formulation administered subcutaneously via an autoinjector pen to youth with type 1 diabetes (T1D). METHODS: After plasma glucose concentration was < 80 mg/dL (< 4.4 mmol/L) after insulin, participants aged 2 to < 12 years with T1D were administered 0.5 mg of glucagon; participants aged 12 to < 18 years instead received 1 mg of glucagon. Then, adolescents were challenged with 0.5 mg after a 7- to 28-day washout period. Primary endpoint was mean plasma glucose concentration at 30 min after glucagon. RESULTS: Plasma glucose concentrations significantly (p < 0.001) increased from baseline to 30 min after glucagon, with mean change in plasma glucose concentration between baseline and 30 min for each age cohort as follows: 2 to < 6 years (n = 7; 81.4 mg/dL [4.5 mmol/L]); 6 to < 12 years (13; 84.2 mg/dL [4.7 mmol/L]); 12 to < 18 years (11; dose, 1 mg; 54.0 mg/dL [3.0 mmol/L]); and 12 to < 18 years (11; 0.5 mg; 52.4 mg/dL [2.9 mmol/L]). Among age cohorts, no clinically relevant differences were observed for PD and PK parameters. Common adverse events were nausea, vomiting, and hypoglycemia. CONCLUSION: Age-appropriate dosing of this glucagon formulation was effective at 30 min in reversing plasma glucose concentrations from < 80 mg/dL in youth with T1D.

Comparison of a ready-to-use liquid glucagon injection administered by autoinjector to glucagon emergency kit for the symptomatic relief of severe hypoglycemia: two randomized crossover non-inferiority studies.

INTRODUCTION: To prevent medical sequelae of severe hypoglycemic emergencies, prompt and reliable rescue intervention is critically important. A ready-to-use, liquid stable glucagon, administered subcutaneously by glucagon autoinjector (GAI), Gvoke HypoPen (glucagon injection; Xeris Pharmaceuticals), was evaluated for rescue treatment of severe hypoglycemia. RESEARCH DESIGN AND METHODS: Two phase III, randomized, controlled, blinded, non-inferiority crossover studies were conducted in 161 adults with type 1 diabetes to compare 1 mg doses of GAI versus glucagon emergency kit (GEK) for treating insulin-induced severe hypoglycemia. Efficacy was evaluated as either a return of plasma glucose to >70 mg/dL (3.9 mmol/L) or increase ≥20 mg/dL (1.1 mmol/L) from a baseline glucose of <50 mg/dL (2.9 mmol/L), within 30 min of dosing. RESULTS: For successful plasma glucose recovery within 30 min, treatment with GAI was non-inferior to GEK. Treatment with GAI was non-inferior to GEK for a plasma glucose >70 mg/dL (3.9 mmol/L) or neuroglycopenic symptom relief within 30 min. From administration of glucagon, the mean time to achieve plasma glucose >70 mg/dL (3.9 mmol/L) or increase ≥20 mg/dL (1.1 mmol/L) was 13.8±5.6 min for GAI and 10.0±3.6 min for GEK. This mean time does not account for the significantly shorter (p<0.0001) drug preparation and administration time for GAI (27.3±19.7 s) versus GEK (97.2±45.1 s). The incidence of treatment emergent adverse events was comparable in both groups. CONCLUSIONS: A ready-to-use GAI was non-inferior to GEK, with a similar tolerability profile. GAI is an effective, safe, and well-tolerated rescue treatment for severe hypoglycemia and is a viable alternative to GEK. TRIAL REGISTRATION NUMBERS: NCT02656069 and NCT03439072.

Human factors studies of a prefilled syringe with stable liquid glucagon in a simulated severe hypoglycemia rescue situation.

Background: Two human factors studies evaluated whether a stable liquid formulation of glucagon in a prefilled syringe (G-PFS) could be safely and effectively administered and evaluated the effectiveness of the product label guide and instructions-for-use (IFU). Research design and methods: In a formative study, 11 participants received orientation with the G-PFS instructional materials and performed a single unaided rescue attempt. In the validation study, 75 adult and adolescent participants received training or familiarized themselves with the G-PFS IFU, Label Guide, and device. All participants returned 1 week later to perform a single unaided rescue attempt of a simulated person with diabetes suffering from an emergency severe hypoglycemic event. Results: The formative study resulted in a 100% success rate across all rescue dose attempts. The validation study resulted in 74/75 (99%) of participants successfully using the G-PFS to administer the full glucagon rescue dose, and validated that intended users could learn from, comprehend, and recall the G-PFS instructions to successfully use the product. Conclusion: The G-PFS provides a familiar, easy-to-use alternative to currently marketed lyophilized glucagon kits for treating severe hypoglycemia. The G-PFS IFU and Label Guide enable even untrained users to successfully administer a full rescue dose of stable liquid glucagon.

Design and Clinical Evaluation of a Novel Low-Glucose Prediction Algorithm with Mini-Dose Stable Glucagon Delivery in Post-Bariatric Hypoglycemia.

BACKGROUND: Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery with limited therapeutic options. We developed an event-based system to predict and detect hypoglycemia based on continuous glucose monitor (CGM) data and recommend delivery of minidose liquid glucagon. METHODS: We performed an iterative development clinical study employing a novel glucagon delivery system: a Dexcom CGM connected to a Windows tablet running a hypoglycemia prediction algorithm and an Omnipod pump filled with an investigational stable liquid glucagon formulation. Meal tolerance testing was performed in seven participants with PBH and history of neuroglycopenia. Glucagon was administered when hypoglycemia was predicted. Primary outcome measures included the safety and feasibility of this system to predict and prevent severe hypoglycemia. Secondary outcomes included hypoglycemia prediction by the prediction algorithm, minimization of time below hypoglycemia threshold using glucagon, and prevention of rebound hyperglycemia. RESULTS: The hypoglycemia prediction algorithm alerted for impending hypoglycemia in the postmeal state, prompting delivery of glucagon (150 µg). After observations of initial incomplete efficacy to prevent hypoglycemia in the first two participants, system modifications were implemented: addition of PBH-specific detection algorithm, increased glucagon dose (300 µg), and a second glucagon dose if needed. These modifications, together with rescue carbohydrates provided to some participants, contributed to progressive improvements in glucose time above the hypoglycemia threshold (75 mg/dL). CONCLUSIONS: Preliminary results indicate that our event-based automatic monitoring algorithm successfully predicted likely hypoglycemia. Minidose glucagon therapy was well tolerated, without prolonged or severe hypoglycemia, and without rebound hyperglycemia.

Comparative Pharmacokinetic/Pharmacodynamic Study of Liquid Stable Glucagon Versus Lyophilized Glucagon in Type 1 Diabetes Subjects.

BACKGROUND: There is currently no stable liquid form of glucagon commercially available. The aim of this study is to assess the speed of absorption and onset of action of G-Pump™ glucagon at 3 doses as compared to GlucaGen®, all delivered subcutaneously via an OmniPod®. METHODS: Nineteen adult subjects with type 1 diabetes participated in this Phase 2, randomized, double-blind, cross-over, pharmacokinetic/pharmacodynamic study. Subjects were given 0.3, 1.2, and 2.0 µg/kg each of G-Pump glucagon and GlucaGen via an OmniPod. RESULTS: G-Pump glucagon effectively increased blood glucose levels in a dose-dependent fashion with a glucose Cmax of 183, 200, and 210 mg/dL at doses of 0.3, 1.2, and 2.0 µg/kg, respectively (P = ns vs GlucaGen). Mean increases in blood glucose from baseline were 29.2, 52.9, and 77.7 mg/dL for G-Pump doses of 0.3, 1.2, and 2.0 µg/kg, respectively. There were no statistically significant differences between treatments in the glucose T50%-early or glucagon T50%-early with one exception. The glucagon T50%-early was greater following G-Pump treatment at the 2.0 µg/kg dose (13.9 ± 4.7 min) compared with GlucaGen treatment at the 2.0 µg/kg dose (11.0 ± 3.1 min, P = .018). There was more pain and erythema at the infusion site with G-Pump as compared to GlucaGen. No serious adverse events were reported, and no unexpected safety issues were observed. CONCLUSIONS: G-Pump glucagon is a novel, stable glucagon formulation with similar PK/PD properties as GlucaGen, but was associated with more pain and infusion site reactions as the dose increased, as compared to GlucaGen.

Nonaqueous, Mini-Dose Glucagon for Treatment of Mild Hypoglycemia in Adults With Type 1 Diabetes: A Dose-Seeking Study.

OBJECTIVE: To evaluate mini-dose glucagon in adults with type 1 diabetes using a stable, liquid, ready-to-use preparation. RESEARCH DESIGN AND METHODS: Twelve adults with type 1 diabetes receiving treatment with insulin pumps received subcutaneous doses of 75, 150, and 300 µg of nonaqueous glucagon. Plasma glucose, glucagon, and insulin concentrations were measured. At 180 min, subjects received insulin followed in ~60 min by a second identical dose of glucagon. RESULTS: Mean (±SE) fasting glucose concentrations (mg/dL) were 110 ± 7, 110 ± 10, and 109 ± 9 for the 75-, 150-, and 300-µg doses, respectively, increasing maximally at 60 min by 33, 64, and 95 mg/dL (all P < 0.001). The post-insulin administration glucose concentrations were 70 ± 2, 74 ± 5, and 70 ± 2 mg/dL, respectively, with maximal increases of 19, 24, and 43 mg/dL post-glucagon administration (P < 0.02) at 45-60 min. CONCLUSIONS: Subcutaneous, nonaqueous, ready-to-use G-Pen Mini glucagon may provide an alternative to oral carbohydrates for the management of anticipated, impending, or mild hypoglycemia in adults with type 1 diabetes.

Development of a highly stable, nonaqueous glucagon formulation for delivery via infusion pump systems.

Despite a vigorous research effort, to date, the development of systems that achieve glucagon stability in aqueous formulations (without reconstitution) has failed to produce any clinical candidates. We have developed a novel, nonaqueous glucagon formulation based on a biocompatible pharmaceutical solvent, dimethyl sulfoxide, which demonstrates excellent physical and chemical stability at relatively high concentrations and at high temperatures. This article reports the development of a novel, biocompatible, nonaqueous native human glucagon formulation for potential use in subcutaneous infusion pump systems. Data are presented that demonstrate physical and chemical stability under presumed storage conditions (>2 years at room temperature) as well as "in use" stability and compatibility in an Insulet's OmniPod(®) infusion pump. Also presented are results of a skin irritation study in a rabbit model and pharmacokinetics/pharmacodynamics data following pump administration of glucagon in a diabetic swine model. This nonaqueous glucagon formulation is suitable for further clinical development in pump systems.

Effects of excipients on the chemical and physical stability of glucagon during freeze-drying and storage in dried formulations.

PURPOSE: To evaluate the effects of several buffers and excipients on the stability of glucagon during freeze-drying and storage as dried powder formulations. METHODS: The chemical and physical stability of glucagon in freeze-dried solid formulations was evaluated by a variety of techniques including mass spectrometry (MS), reversed phase HPLC (RP-HPLC), size exclusion HPLC (SE-HPLC), infrared (IR) spectroscopy, differential scanning calorimetry (DSC) and turbidity. RESULTS: Similar to protein drugs, maintaining the solid amorphous phase by incorporating carbohydrates as well as addition of surfactant protected lyophilized glucagon from degradation during long-term storage. However, different from proteins, maintaining/stabilizing the secondary structure of glucagon was not a prerequisite for its stability. CONCLUSIONS: The formulation lessons learned from studies of freeze-dried formulations of proteins can be applied successfully to development of stable formulations of glucagon. However, peptides may behave differently than proteins due to their small molecule size and less ordered structure.