477 READY-TO-USE DASIGLUCAGON INJECTION AS A FAST AND EFFECTIVE TREATMENT FOR SEVERE HYPOGLYCEMIA T. Pieber1; R. Tehranchi2; U. Hövelmann3; J. Willard4; L. Plum-Moerschel5; R. Aronson6 1Medical University of Graz, Division of Endocrinology and Diabetology, Graz, Austria, 2Zealand Pharma AS, Clinical & Medical Affairs, Copenhagen, Denmark, 3Profil, Profil, Neuss, Germany, 4ProSciento, Inc., Diabetes, Chula Vista, United States of America, 5Profil, Profil, Mainz, Germany, 6LMC Healthcare, LMC, Toronto, Canada Introduction Primary and All Secondary Endpoints Were Met (continued) • At the present time, glucagon is a first-line treatment option for severe hypoglycemia in patients Dasiglucagon Placebo GlucaGen® Dasiglucagon with insulin-treated diabetes1,2,3 (n = 82) (n = 43) (n = 43) vs Placebo • Overall, patients with type 1 diabetes mellitus (T1DM) do not receive adequate prescription for, Mean increase in plasma glucose from baseline (mg/dL) or education and proper training regarding the use of glucagon kits to treat or prevent severe hypoglycemia1-5 10 minutes 23.9 -0.1 22.0 < 0.001**** • Presently available glucagon kits have required user training and multiple preparation steps that 15 minutes 43.5 5.1 44.1 < 0.001**** are barriers to their prescription and utilization, especially under emergent circumstances1,2 20 minutes 59.7 8.7 58.4 < 0.001**** Dasiglucagon 30 minutes 90.9 19.1 88.5 < 0.001**** • Is a peptide analogue of glucagon, with 7 amino acid substitutions designed to eliminate peptide *Distribution-free. aggregation and fibril formation6 **Log-rank test. • Is physically and chemically stable in aqueous solution, making it a good candidate for use in ****Analysis of Covariance model including treatment group and baseline plasma glucose. 7 single-injection pen applicators Plasma Glucose Concentrations Rapidly and Consistently Increased • Is a specific agonist at the glucagon receptor6 • Dasiglucagon is presented in a ready-to-use formulation With Dasiglucagon • Allows for easy-to-use, simple, auto-injector or pre-filled safety syringe administration • Allows for refrigerated and room temperature storage Mean Plasma Glucose Mean (95% CI) Plasma Glucose, mmol/L 180 Dasiglucagon 0.6 mg 10 Aib A R ® A E E GlucaGen 1.0 mg F K V 160 9 W E S Placebo L T 8 HSQGTFTSDYSKYLD 140 7 120 Substitution 6 Hot-spots 100 5 80 Dasiglucagon Phase 3 Clinical Trial Design 4 Study of dasiglucagon versus placebo for treatment of insulin-induced hypoglycemia in T1DM using 60 3 GlucaGen® as reference* Mean (95% CI) Plasma Glucose, mg/dL 40 0 10 20 30 40 Randomization Dosing Time (min) Dasiglucagon 0.6 mg (n = 82) Median True Time to 20 mg/dL (1.1 mmol/L) Increase in Plasma Glucose Patients ® T1DM; insulin ≥ 1 year; 1-month Plasma Glucose Dasiglucagon Placebo GlucaGen HbA1c < 10%; Placebo (n = 43) safety Recovery* (n = 82) (n = 43) (n = 43) Age: ≥ 18 y to ≤ 70 y follow-up (n = 170) Induction Median (min) 9.0 33.7 10.0 Hypoglycemia GlucaGen® 1.0 mg (n = 43) [95% CI] [8.4, 9.7] [26.1, 36.1] [8.4, 10.6] *Estimated true time to recovery (interpolated between sampling times). 0 4 6 8 10 12 15 17 20 25 30 40 50 60 300 Summary of Adverse Events (AEs) Minutes From Injection (Time points for blood sampling and/or safety assessment) Dasiglucagon 0.6 mg Placebo GlucaGen® 1.0 mg (n = 82) (n = 43) (n = 43) * NCT03378635: A phase 3, randomized, double-blind, parallel trial to confirm the clinical efficacy and safety of dasiglucagon in the rescue treatment of hypoglycemia in subjects with T1DM compared to placebo and with reference to GlucaGen®. Number of pts (%) GlucaGen® is a registered trademark of Novo Nordisk A/S. All 66 (80%) 14 (33%) 32 (74%) Primary and Secondary Endpoints Serious 0 0 0 • Primary endpoint Severe 0 0 1 (2%)** – Time to plasma glucose recovery defined as first increase in plasma glucose of ≥ 20 mg/dL Drug related 52 (63%) 3 (7%) 27 (63%) (1.1 mmol/L) from time of SC injection* • Secondary endpoints** Most-frequent ≥ 10% drug related*** – Plasma glucose recovery within 10, 15, 20, and 30 min from time of injection* – Plasma glucose change from baseline at 10, 15, 20, and 30 min from time of injection* Nausea 45 (55%) 1 (2%) 23 (53%) *Without administration of rescue intravenous glucose. Vomiting 19 (23%) 1 (2%) 8 (19%) **Multiplicity adjusted. Headache 8 (10%) 1 (2%) 4 (9%) Baseline Characteristics Were Balanced Between Treatment Groups Leading to discontinuation 0 0 0 ® Dasiglucagon Placebo GlucaGen Total *Treatment-emergent AEs presented. (n = 82) (n = 43) (n = 43) (n = 168) **Severe, and transient AEs of nausea and vomiting. ***All AEs were mild/moderate and transient, except nausea and vomiting reported in one patient in GlucaGen® group. Age (years) Median (range) 37 (18-71) 36 (18-65) 38 (23-66) 38 (18-71) 2 BMI (kg/m ) Median (range) 25 (19-38) 26 (20-34) 26 (19-35) 26 (19-38) Conclusions Gender Female 32 (39%) 16 (37%) 15 (35%) 63 (38%) • Primary and all secondary endpoints were met HbA1c (%) Median (range) 7.4 (5.2-9.7) 7.1 (6.0-9.2) 7.4 (5.4-8.9) 7.3 (5.2-9.7) – Median time to plasma glucose recovery of 10 min with dasiglucagon (placebo 40 min, GlucaGen® 12 min) Diabetes (years) Median (range) 22 (2-56) 18 (3-42) 18 (3-57) 19 (2-57) – 65% of dasiglucagon patients recovered within 10 min (placebo 0%, GlucaGen® 49%) BMI: Body Mass Index. – 99% of dasiglucagon patients recovered within 15 min (placebo 2%, GlucaGen® 95%) • Similar rates of nausea and vomiting were reported for both dasiglucagon and GlucaGen® Primary and All Secondary Endpoints Were Met • Dasiglucagon has the potential to be a fast and effective treatment for severe hypoglycemia Dasiglucagon Placebo GlucaGen® Dasiglucagon (n = 82) (n = 43) (n = 43) vs Placebo References 1. Harris G, Diment A, Sulway M, Wilkinson M. Glucagon administration–underevaluated and undertaught. Pract Diabetes Int. Time to plasma glucose recovery (minutes) 2001;18(1):22-25. 2. Kedia N. Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. Diabetes Metab Syndr Median (95% CI)* 10 (10, 10) 40 (30, 40) 12 (10, 12) P < 0.001** Obes. 2011;4:337-346. 3. Glycemic Targets: Standards of Medical Care in Diabetes-2020. Diabetes Care. 2020 Jan;43(Suppl 1):S66-S76. Plasma glucose increase of 20 mg/dL (1.1 mmol/L) 4. Mitchell BD, He X, Sturdy IM, Cagle AP, Settles JA. Glucagon Prescription Patterns in Patients With Either Type 1 or 2 Diabetes With Newly Prescribed Insulin. Endocr Pract. 2016;22:123-135. 10 minutes 65% 0% 49% < 0.001*** 5. Haymond MW, Liu J, Bispham J, Hickey A, McAuliffe-Fogarty AH. Use of Glucagon in Patients With Type 1 Diabetes. Clin Diabetes. 2019;37:162-166. 15 minutes 99% 2% 95% < 0.001*** 6. Hövelmann U, Bysted BV, Mouritzen U, et al. Pharmacokinetic and Pharmacodynamic Characteristics of Dasiglucagon, a Novel Soluble and Stable Glucagon Analog. Diabetes Care. 2018;41:531-537. 7. Hövelmann U, Olsen MB, Mouritzen U, Lamers D, Kronshage B, Heise T. Low doses of dasiglucagon consistently increase plasma 20 minutes 99% 14% 98% < 0.001*** glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus. Diabetes Obes Metab. 2019;21:601-610. 30 minutes 100% 47% 100% < 0.001*** Disclosures and Acknowledgements *Distribution-free. Zealand Pharma • Is the developer of dasiglucagon, and the sponsor of this clinical trial **Log-rank test. ***Fisher’s Exact test. Medical writing services provided by José L. Walewski, PhD of rareLife solutions, S. Norwalk, CT, USA were funded by Zealand Pharma A/S of Søborg, Denmark. Presented at the ATTD 2020 Congress, Madrid, Spain February 19 – 22, 2020.