Transcript Insulin degludec - Diabetes In Control

Insulin degludec (Tresiba®)
ULTRA-LONG ACTING BASAL INSULIN
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Andre McMahon
PharmD Candidate, University of Florida College of Pharmacy
Overview
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 Approval status
 Pharmacology
 Efficacy
 Type 1 DM
 Type 2 DM
 Safety
Approval Status
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 Japan: Approved
 USA: Pending Approval (projected early 2013
launch)

Nov 8 – Advisory panel to the U.S. FDA voted to recommend
approval 1
Pharmacology – Structure
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 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’
Pharmacology – Kinetics2
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 T1/2 : 25 hours
 Glucose-lowering duration : > 42 hours
 Time to steady-state : 3 days of once-daily dosing
 Peak : peakless
Recent Trial Highlights – BEGIN Type 1
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Type 1 DM
insulin degludec vs. glargine
Study
Trial design & Treatment
arms
Trial population
Results
BEGIN BasalBolus Type 1 3
• 52 weeks, randomized,
controlled, open-label,
multinational, parallel
design, treat-to-target,
non-inferiority trial
• 629 patients with type 1 DM
• 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
• Basal insulin: insulin
degludec or insulin
glargine
• 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
• Bolus insulin: insulin
aspart
BEGIN Type 1 - Hypoglycemia
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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]; p=0.21
Recent Trial Highlights – BEGIN Type 2
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Type 2 DM
insulin degludec vs. glargine
Study
Trial design & Treatment
arms
Trial population
Results
BEGIN BasalBolus Type 2 4
• 52 weeks, randomized,
controlled, open-label,
treat-to-target,
multinational, noninferiority trial
• 1006 patients with type 2 DM
• 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
• 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
BEGIN Type 2 - Hypoglycemia
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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
Cardiovascular Safety
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 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)


Similar incidence rates


53 In the degludec group vs. 27 in comparator group
1.48 degludec vs. 1.44 comparator group
Estimated hazard ratio
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1.097; 95% CI: 0.681 – 1.768
Cardiovascular Safety
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 FDA Requested Post Hoc Analyses of MACE
 Excluded UAP from MACE composite
 Estimated hazard ratio
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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
Cardiovascular Safety
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In summary:
Data neither confirms nor excludes increased CV risk
Post-approval studies planned
Insulin degludec (Tresiba®)
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 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
Notes
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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>.
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; NN1250-3582 (BEGIN BB T2D) Trial Investigators. Insulin degludec, an ultralongacting 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. 2012. Web.
<http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMeta
bolicDrugsAdvisoryCommittee/UCM327017.pdf>.