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Home , Dasiglucagon, Diabetes, Diabetic hypoglycemia, Insulin (medication)

477 READY-TO-USE INJECTION AS A FAST AND EFFECTIVE TREATMENT FOR SEVERE T. Pieber1; R. Tehranchi2; U. Hövelmann3; J. Willard4; L. Plum-Moerschel5; R. Aronson6 1Medical University of Graz, Division of and Diabetology, Graz, Austria, 2Zealand Pharma AS, Clinical & Medical Affairs, Copenhagen, , 3Profil, Profil, Neuss, Germany, 4ProSciento, Inc., , Chula Vista, United States of America, 5Profil, Profil, Mainz, Germany,6 LMC Healthcare, LMC, Toronto,

Introduction Primary and All Secondary Endpoints Were Met (continued) • At the present time, is a first-line treatment option for severe hypoglycemia in patients Dasiglucagon Placebo GlucaGen® Dasiglucagon with -treated diabetes1,2,3 (n = 82) (n = 43) (n = 43) vs Placebo • Overall, patients with mellitus (T1DM) do not receive adequate prescription for, Mean increase in plasma 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 *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 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 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 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 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 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* 45 (55%) 1 (2%) 23 (53%) *Without administration of rescue intravenous glucose. Vomiting 19 (23%) 1 (2%) 8 (19%) **Multiplicity adjusted. 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: . –– 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 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