1. Insulin degludec (Tresiba®)
Ultra-long acting basal insulin
Andre McMahon PharmD Candidate, University of Florida College of Pharmacy

2. Overview Approval status Pharmacology Efficacy Safety Type 1 DM

3. Approval Status Japan: Approved
USA: Pending Approval (projected early 2013 launch)
Nov 8 – Advisory panel to the U.S. FDA voted to recommend approval 1

4. Pharmacology – Structure
Retained sequence of human insulin
Depletion of B30 residue
No amino acid substitutions
Fatty acid (hexadecanedioic acid) coupled to lysine at B29 position via glutamic acid ‘spacer’

5. Pharmacology – Kinetics2
T1/2 : 25 hours
Glucose-lowering duration : > 42 hours
Time to steady-state : 3 days of once-daily dosing
Peak : peakless

6. Recent Trial Highlights – BEGIN Type 1
Type 1 DM insulin degludec vs. glargine
Study
Trial design & Treatment arms
Trial population
Results
BEGIN Basal-Bolus Type 1 3
52 weeks, randomized, controlled, open-label, multinational, parallel design, treat-to-target, non-inferiority trial
Basal insulin: insulin degludec or insulin glargine
Bolus insulin: insulin aspart
629 patients with type 1 DM
Diabetes duration for > 1 year, basal insulin use for > 1 year, HbA1c of 10% or less, and BMI of 35 kg/m2 or less
472 patients to degludec
157 patients to glargine
HbA1c fall at year 1
0.40% degludec
0.39% glargine
Treatment difference: -0.01% [95% CI to 0.11]; p< for non-inferiority testing

7. BEGIN Type 1 - Hypoglycemia
25 % less nocturnal hypoglycemia
Rates of nocturnal hypoglycemia:
4.41 (deg) vs (gla) episodes per patient-year of exposure; 0.75 [95% CI 0.59 to 0.96]; p=0.21

8. Recent Trial Highlights – BEGIN Type 2
Type 2 DM insulin degludec vs. glargine
Study
Trial design & Treatment arms
Trial population
Results
BEGIN Basal-Bolus Type 2 4
52 weeks, randomized, controlled, open-label, treat-to-target, multinational, non-inferiority trial
1006 patients with type 2 DM
Diabetes duration for > 6 months, any insulin use for at least 3 months, HbA1c of 7.0 – 10.0%, and BMI of 40.0 kg/m2 or less, with or without oral antidiabetic drugs
744 patients to degludec
248 patients to glargine
Excluded: glp-1 agonist or rosiglitazone use within previous 3 months
HbA1c fall at year 1
1.1 % degludec
1.2 % glargine
Treatment difference: 0.08% [95% CI to 0.21], confirming non-inferiority

9. BEGIN Type 2 - Hypoglycemia
Lower rates of hypoglycemia: overall and nocturnal
(A) Overall confirmed hypoglycemic episodes. (B) Nocturnal confirmed hypoglycemic episodes. (C) Diurnal
Confirmed hypoglycemic episodes. (D) Cumulative # of hypoglycemic episodes per participant during 24 h

10. Cardiovascular Safety
MACE (Major Adverse Cardiovascular Events)
Composite of CV death, stroke, myocardial infarction (MI), and unstable angina pectoris (UAP)
In the 16 phase 3 trials included in the NDA
80 patients experienced a MACE (76/80 patients Type 2 DM)
53 In the degludec group vs. 27 in comparator group
Similar incidence rates
1.48 degludec vs comparator group
Estimated hazard ratio
1.097; 95% CI: – 1.768

11. Cardiovascular Safety
FDA Requested Post Hoc Analyses of MACE
Excluded UAP from MACE composite
Estimated hazard ratio
1.393; 95% CI: – 2.565
Additional Post Hoc Analyses of MACE
Included data from 9 additional completed trials (6 extension trials and 3 phase 3 trials)
Contributed 742 degludec 149 comparator patients
Excluded UAP and included MACE reported within 30 days after drug discontinuation
1.614; 95% CI: – 2.609

12. Cardiovascular Safety
In summary:
Data neither confirms nor excludes increased CV risk
Post-approval studies planned

13. Insulin degludec (Tresiba®)
Insulin degludec is an ultra long-acting insulin formulation with several advantages:
Lower risk of hypoglycemia
True 24 hour insulin
Allows flexibility in dosing; especially with missed doses
Can be coformulated with other proteins
Combination of degludec with insulin aspart planned to allow effective mealtime coverage

14. Notes
Pierson, Ransdell. "FDA Panel Recommends Approval of Novo Degludec Insulin."Reuters. Thomson Reuters, 08 Nov <
Jonassen I, Havelund S, ribel U, et al. Insulin degludec: Multi-hexamer formation is the underlying basis for this new generation ultra-long acting basal insulin. Paper presented at: European Association for the Study of Diabetes Annual Meeting; September 20-24, 2010; Stockholm, Sweden.
Heller S, Buse J, Fisher M, et al; BEGIN Basal-Bolus Type 1 Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 1 diabetes (BEGIN Basal-Blus Type 1): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1489–1497.
Garber AJ, King AB, Del Prato S, et al; NN (BEGIN BB T2D) Trial Investigators. Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012;379(9825):1498–1507.
"Insulin Degludec and Insulin Degludec/Insulin Aspart Treatment to Improve Glycemic Control in Patients with Diabetes Mellitus - Briefing Document." FDA, 8 Nov Web. <