Clinical presentation

Novo Nordisk Clinical presentation of insulin detemir 1 Insulin detemir: Agenda Rationale: The need for a new basal insulin Pharmacology Clinical efficacy in type 1 and type 2 diabetes Variability Hypoglycaemia Body weight Summary

Novo Nordisk Clinical presentation of insulin detemir 2 Rationale: The need for a new basal insulin

Novo Nordisk Clinical presentation of insulin detemir 3 The physiological insulin profile Adapted from Polonsky et al. 1988

Novo Nordisk Clinical presentation of insulin detemir 4 Basal-bolus therapy attempts to recreate the physiological insulin profile

Novo Nordisk Clinical presentation of insulin detemir 5 Insulin analogues: desired properties Meal-related analogues (e.g. insulin aspart) designed to give: Rapid absorption Peak action coinciding with peak carbohydrate absorption Basal insulin analogue should provide: Slow and steady rate of absorption Protracted action Low within-subject variability in action

Novo Nordisk Clinical presentation of insulin detemir 6 Therapeutic potential of intensive analogue-based insulin therapy Achievement and maintenance of glycaemic targets: HbA 1c Postprandial plasma glucose Fasting plasma glucose Low within-subject variability Reduced risk of hypoglycaemia Minimal weight gain Enhanced convenience and improved quality of life

Novo Nordisk Clinical presentation of insulin detemir 7 NPH insulinImproved basal insulin Pharmacokinetic limitations of subcutaneous exogenous basal insulin

Novo Nordisk Clinical presentation of insulin detemir 8 Variability in glucose infusion rate (GIR) profiles for 3 patients with type 1 diabetes following NPH injection Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

Novo Nordisk Clinical presentation of insulin detemir 9 Variability in GIR profiles for 3 patients with type 1 diabetes following insulin glargine injection Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

Novo Nordisk Clinical presentation of insulin detemir 10 The balance between control and tolerability: data from DCCT New Engl J Med 1993;328:977

Novo Nordisk Clinical presentation of insulin detemir 11 Factors influencing insulin absorption Insulin preparation Dose, concentration and volume Physical status (solution or suspension) Mechanism of protraction Self association Precipitation Albumin binding Injection site factors Region of injection Depth of injection Lipodystrophy Blood flow changes e.g. temperature, exercise, hypoglycaemia, ketoacidosis

Novo Nordisk Clinical presentation of insulin detemir 12 Insulin receptor affinity Metabolic potency IGF-I receptor affinity IGF-IR/IR affinity Mitogenic potency (Saos/B10 cells) Human insulin B10 Asp 205 ± ± ± ± 173 Insulin lispro 84 ± 682 ± 3156 ± ± 10 Insulin aspart 92 ± 6101 ± 281 ± ± 22 Insulin glargine 86 ± 360 ± 3641 ± ± 13 Insulin detemir   ± 10.9  11 Adapted from P. Kurtzhals et al. Diabetes 2000;49:999 Receptor binding, metabolic and mitogenic potency of insulin analogues

Novo Nordisk Clinical presentation of insulin detemir 13 Pharmacology Return to Agenda

Novo Nordisk Clinical presentation of insulin detemir 14 Strategies for engineering basal insulins Modification of isoelectric point: precipitation at pH 7.4 NovoSol Basal Insulin glargine Strengthening of hexamer association, e.g. Co(III)-hexamer Acylation with hydrophobic residues, e.g. Insulin detemir

Novo Nordisk Clinical presentation of insulin detemir 15 Structure of insulin detemir

Novo Nordisk Clinical presentation of insulin detemir 16 3-Dimensional structure of hexameric insulin Human insulinInsulin detemir

Novo Nordisk Clinical presentation of insulin detemir 17 Potential sites of protraction In the subcutaneous depot In the circulation In the interstitial space Subcutaneous depot Plasma compartment Interstitial compartment

Novo Nordisk Clinical presentation of insulin detemir 18 Self association (hexameric) Fatty acid side chains bind to albumin in injection depot Albumin binding in circulation Protracted absorption Insulin detemir Mode of protraction ‘Buffering’ effect and minor contribution to protraction

Novo Nordisk Clinical presentation of insulin detemir 19 Albumin binding buffers against changes in absorption rate Duration Calculated effect of a 60-minute doubling of absorption rate on the interstitial concentrations of NPH insulin and insulin detemir Absorption and relative change in periphery (%) Absorption rate from subcutaneous depot Interstitial human insulin (muscle/fat) Interstitial detemir (muscle/fat) Data on file: Novo Nordisk

Novo Nordisk Clinical presentation of insulin detemir 20 Safety of albumin binding (1) Plasma concentration of HSA ~600 x M FFA binding sites/HSA molecule at least 8 Plasma concentration of FFA ~300 x M Insulin detemir conc. at therapeutic dose <0.01 x M Therefore, insulin detemir occupies only a minute fraction of available albumin binding sites HSA: human serum albumin FFA: free fatty acid

Novo Nordisk Clinical presentation of insulin detemir 21 Safety of albumin binding (2) No drug–drug interactions observed in in vitro studies with drugs at clinically relevant concentrations. Compounds investigated: FFA (C8 FA, C12 FA, C16 FA) phenylbutazone, warfarin ibuprofen, diazepam Sulphonylureas (tolbutamide, glibenclamide) aspirin, valproate P. Kurtzhals et al. Journal of Pharmaceutical Sciences 1997;86(12)

Novo Nordisk Clinical presentation of insulin detemir 22 Pharmacodynamic profile of insulin detemir - subjects with type 1 diabetes Pharmacodynamic parameters for insulin detemir and NPH Insulin detemirNPH 0.2 U/kg0.4 U/kg0.3 IU/kg Duration of action (hr) GIR max (mg/kg/min) Adapted from T. Pieber et al. Diabetes 2002;51(Suppl. 2):A53 Insulin detemir 0.2 U/kg Insulin detemir 0.3 U/kg Insulin detemir 0.4 U/kg

Novo Nordisk Clinical presentation of insulin detemir 23 Variability in time-action profile of basal insulins GIR profiles following four non-consecutive injections of identical doses (0.4U/kg, thigh) in three patients Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

Novo Nordisk Clinical presentation of insulin detemir 24 D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51 Clinical efficacy in type 1 and type 2 diabetes Return to Agenda

Novo Nordisk Clinical presentation of insulin detemir 25 9-point blood glucose profiles after 6 months’ therapy with once-daily insulin detemir or NPH insulin D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51 Type 1 diabetes *

Novo Nordisk Clinical presentation of insulin detemir 26 FPG at baseline and after 16 weeks in subjects with type 1 diabetes Data from 1448 study (P. Home et al. Diabetes 2003;52(Suppl. 1):A122) p = 0.004

Novo Nordisk Clinical presentation of insulin detemir 27 Glycaemia results Baseline HbA 1c = 8.60% Insulin detemir q 12 hour Insulin detemir am + bed NPH insulin am + bed p-value HbA 1C (%) = 0.08 Office FPG (mM) < Home FBG (mM) = 0.005

Novo Nordisk Clinical presentation of insulin detemir 28 Insulin detemir consistently achieves lower FPG values than NPH insulin Insulin detemirNPH insulinDifference TrialNmmol/l endpoint N Insulin detemir – NPH mmol/l (95% CI) –1.2 (–1.8, –0.5) –1.6 (–2.5, –0.8) –1.9 (–2.8, –1.0) 1336* (–0.4, 0.5) Meta-analysis of five 4- and 6-month trials in type 1 diabetes † –1.1 p < *Study in type 2 diabetes † Meta-analysis of trials 1181, 1205, 1335, 1447, 1448

Novo Nordisk Clinical presentation of insulin detemir 29 HbA 1c : Meta-analysis of phase 3 trials in type 1 diabetes Insulin detemir (a) NPH insulin (b) Difference (a-b) after 4–6 months NMean (SE)N Mean, p % (0.01%) % (0.11%) –0.11% p < 0.05 Endpoint data from three trials (1335, 1447, 1448) comparing insulin detemir with NPH insulin in basal-bolus therapy

Novo Nordisk Clinical presentation of insulin detemir 30 Variability Return to Agenda

Novo Nordisk Clinical presentation of insulin detemir 31 Variability in time-action profile of basal insulins Glucose infusion rate profiles following four non-consecutive injections of identical doses (0.4U/kg, thigh) in three patients Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

Novo Nordisk Clinical presentation of insulin detemir 32 Reproducibility: Probability ranges for blood glucose lowering effect of repeated injections 95% probability ranges for individual pharmacodynamic responses relative to the mean T. Heise et al. Diabetes 2003;52(Suppl.1):A121 Average GIR over 24 hours

Novo Nordisk Clinical presentation of insulin detemir 33 Insulin detemirInsulin glargineNPH insulin The subject’s risk of experiencing less than half their mean overall insulin effect (hyperglycaemic risk) 0.5%7.5%15.5% The subject’s risk of experiencing more than twice their mean maximal insulin effect (hypoglycaemic risk) 0.1%2.7%6.5% Implications of within-subject pharmacodynamic variability Data from study1450 (T. Heise et al. Diabetes 2003;52 (Suppl.1): A121)

Novo Nordisk Clinical presentation of insulin detemir Mean fluctuation from individual average blood glucose (mmol/L) 0 –1 – Time (hours) Insulin detemir NPH insulin DaytimeNocturnal Mean fluctuation from average blood glucose level across the day in monitored type 1 patients D. Russell-Jones et al. Diabetologia 2002;45(Suppl. 2):A51

Novo Nordisk Clinical presentation of insulin detemir 35 Within-subject variability of self-monitored pre-breakfast glucose concentrations Insulin detemir NPH insulin TrialMean (mmol/l)SDMean (mmol/l)SDp (SD) < < < * < ** < *Type 2 diabetes **Analogue vs. HI

Novo Nordisk Clinical presentation of insulin detemir 36 Hypoglycaemia Return to Agenda

Novo Nordisk Clinical presentation of insulin detemir 37 Overall hypoglycaemic event rate by study 12 months 6 months

Novo Nordisk Clinical presentation of insulin detemir 38 Nocturnal hypoglycaemic event rate by study in type 1 diabetes 12 months 6 months

Novo Nordisk Clinical presentation of insulin detemir 39 Monthly rate of hypoglycaemic events in type 1 diabetes P. Vague et al. Diabetes Care 2003;26(3):

Novo Nordisk Clinical presentation of insulin detemir 40 Risk of all nocturnal hypoglycaemic events in type 1 diabetes I. De Leeuw et al. Diabetologia 2002;45(Suppl. 2):A257

Novo Nordisk Clinical presentation of insulin detemir 41 Relative risk for all hypoglycaemic events: Insulin detemir vs. NPH insulin Data on file: Novo Nordisk Type 1 diabetes Relative risk (ID/NPH) 95% CI P HbA 1c adjustedInsulin aspart as bolus * – Human soluble insulin as bolus * – Type 2 diabetes Relative risk (ID/NPH) 95% CI P HbA 1c adjustedInsulin aspart as bolus – *Meta-analyses of trials comparing insulin detemir with NPH insulin in type 1 diabetes

Novo Nordisk Clinical presentation of insulin detemir 42 Body weight Return to Agenda

Novo Nordisk Clinical presentation of insulin detemir 43 Weight gain with insulin therapy Seen in both type 1 and type 2 diabetes May worsen underlying defect in type 2 diabetes Barrier to starting insulin therapy in type 2 diabetes May decrease compliance with insulin regimens May lower self-esteem

Novo Nordisk Clinical presentation of insulin detemir 44 Weight gain in type 1 diabetes: DCCT data DCCT. Diabetes Care 1988;11: and Purnell et al. JAMA 1998;280: Initial 12 months Quartile of weight gain at mean follow up, 6.1 years

Novo Nordisk Clinical presentation of insulin detemir 45 Weight change in comparative trials in type 1 diabetes

Novo Nordisk Clinical presentation of insulin detemir Change in weight (kg) Intensive (Insulin) Conventional Years from randomisation 10.0 Weight gain in type 2 diabetes: UKPDS data UKPDS Group (33). Lancet 1998;352:

Novo Nordisk Clinical presentation of insulin detemir 47 Weight change over 6 months in type 2 diabetes Data from study (T. Haak et al. Diabetes 2003;52( Suppl.1):A120

Novo Nordisk Clinical presentation of insulin detemir 48 Mean body weight (kg) and between- group difference at end of trials Trial IDInsulin detemir N Mean NPH insulin N Mean Difference: Insulin detemir – NPH [95% C.I.] –1.12 [–1.68, –0.56]* –1.58 [–2.61, –0.56]* –1.01 [–1.57, –0.45]* –1.44 [–2.19, –0.68]* –0.61 [–1.05, –0.17]* –0.95 [–1.46, –0.44]* –0.73 [–1.26, –0.21]* –0.77 [–1.41, –0.13]* –1.01 [–1.37, –0. 66]*

Novo Nordisk Clinical presentation of insulin detemir 49 Analogue versus human insulin-based basal- bolus therapy: 8-point blood glucose profiles K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510

Novo Nordisk Clinical presentation of insulin detemir 50 Analogue versus human insulin-based basal-bolus therapy: HbA 1c Data from study 1374 (K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510)

Novo Nordisk Clinical presentation of insulin detemir 51 Analogue versus human insulin-based basal-bolus therapy: Hypoglycaemia Data from study 1374 (K. Hermansen et al. ADS/ADEA Annual Scientific Meeting: Abstract 510)

Novo Nordisk Clinical presentation of insulin detemir 52 Summary Insulin detemir provides: A protracted and reproducible time-action profile Lower FPG than NPH insulin Reduced variability in comparison to NPH insulin and insulin glargine A risk reduction for nocturnal hypoglycaemia compared with NPH insulin A reduced risk of weight gain compared with NPH insulin Return to Agenda