ULTRA-LONG ACTING BASAL INSULIN

Insulin degludec (Tresiba®)

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Andre McMahonPharmD Candidate, University of Florida College of

Pharmacy

Overview

Approval statusPharmacologyEfficacy

Type 1 DM Type 2 DM

Safety

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Approval Status

Japan: ApprovedUSA: Pending Approval (projected early 2013

launch) Nov 8 – Advisory panel to the U.S. FDA voted to

recommend approval 1

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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’

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Pharmacology – Kinetics2

T1/2 : 25 hoursGlucose-lowering duration : > 42 hoursTime to steady-state : 3 days of once-daily

dosingPeak : peakless

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Recent Trial Highlights – BEGIN Type 1

Type 1 DMinsulin 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 -0.14 to 0.11]; p<0.0001 for non-inferiority testing

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BEGIN Type 1 - Hypoglycemia

25 % less nocturnal hypoglycemia

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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]; p=0.21

Recent Trial Highlights – BEGIN Type 2

Type 2 DMinsulin 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 -0.05 to 0.21], confirming non-inferiority

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BEGIN Type 2 - Hypoglycemia9

(A) Overall confirmed hypoglycemic episodes. (B) Nocturnal confirmed hypoglycemic episodes. (C) DiurnalConfirmed hypoglycemic episodes. (D) Cumulative # of hypoglycemic episodes per participant during 24 h

Lower rates of hypoglycemia: overall and nocturnal

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

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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 riskPost-approval studies planned

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Insulin degludec (Tresiba®)13

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

Notes14

1. Pierson, Ransdell. "FDA Panel Recommends Approval of Novo Degludec Insulin."Reuters. Thomson Reuters, 08 Nov. 2012. <http://www.reuters.com/article/2012/11/08/us-novo-vote-idUSBRE8A71HP20121108>.

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. 2012;379(9825):1489–1497.

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. 2012;379(9825):1498–1507.

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. <http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM327017.pdf>.