Ultra-long acting basal insulin

1
Insulin degludec (Tresiba)

• Ultra-long acting basal insulin

Andre McMahonPharmD Candidate, University of
Florida College of Pharmacy
2
Overview

• Approval status
• Pharmacology
• Efficacy
• Type 1 DM
• Type 2 DM
• Safety

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 gt 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 gt 1 year, basal insulin use for gt 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 -0.14 to 0.11 plt0.0001 for non-inferiority testing
7
BEGIN Type 1 - Hypoglycemia

• 25 less nocturnal hypoglycemia

• Rates of nocturnal hypoglycemia
• 4.41 (deg) vs. 5.86 (gla) episodes per
  patient-year of exposure 0.75 95 CI 0.59 to
  0.96 p0.21

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 gt 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 -0.05 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. 1.44 comparator group
• Estimated hazard ratio
• 1.097 95 CI 0.681 1.768

11
Cardiovascular Safety

• FDA Requested Post Hoc Analyses of MACE
• Excluded UAP from MACE composite
• Estimated hazard ratio
• 1.393 95 CI 0.757 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
• Estimated hazard ratio
• 1.614 95 CI 0.999 2.609

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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

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Notes

1. Pierson, Ransdell. "FDA Panel Recommends Approval
   of Novo Degludec Insulin."Reuters. Thomson
   Reuters, 08 Nov. 2012. lthttp//www.reuters.com/art
   icle/2012/11/08/us-novo-vote-idUSBRE8A71HP20121108
   gt.
2. 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.
3. 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. 2012379(9825)14891497.
4. Garber AJ, King AB, Del Prato S, et
   al NN1250-3582 (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. 2012379(9825)14981507.
5. "Insulin Degludec and Insulin Degludec/Insulin
   Aspart Treatment to Improve Glycemic Control in
   Patients with Diabetes Mellitus - Briefing
   Document." FDA, 8 Nov. 2012. Web.
   lthttp//www.fda.gov/downloads/AdvisoryCommittees/C
   ommitteesMeetingMaterials/Drugs/EndocrinologicandM
   etabolicDrugsAdvisoryCommittee/UCM327017.pdfgt.