Novo Nordisk A/s Class B · OMXCOP:NOVO_B

Novo Nordisk A/s Class B — Technical Presentation (January 2004)

104 slides from Novo Nordisk A/s Class B's technical presentation, January 2004

1. Slide 1: The dual-release insulin preparation

   The dual-release insulin preparation Overview of published studies

2. Slide 2: Contents

   Contents NovoMix® 30 – the dual release insulin Contents Slides Insulin aspart 34 Dual-release kinetics 512 Postprandial glycaemic control 1336 Hypoglycaemia 3750 Combination with oral medications 5176 Convenience & flexibility 7794 Use in adolescents 9596

3. Slide 3: Insulin aspart – a rapid acting analogue

   Insulin aspart – a rapid acting analogue Brange J et al. Nature Clinical proof of concept 1988;333:679–682 study for insulin aspart Return to contents slide

4. Slide 4: Insulin aspart: preclinical proof-of-concept

   Insulin aspart: preclinical proof- of-concept 4.5 IRI (10-10 M) Insulin aspart 3.0 Human insulin 1.5 0 Plasma glucose (mM) 5 4 3 Injection 2 0 1 2 3 4 5 hours Adapted from Brange J et al. Nature 1988;333:679–682

5. Slide 5: Dual-release kinetics

   Dual-release kinetics Jacobsen L et al. Eur J PK studies in healthy Clin Pharm 2000;56: volunteers 399–403 Weyer C et al. Diabetes PD studies in healthy Care 1997;10:1612–1614 volunteers Return to contents slide

6. Slide 6: The dual-release insulin concept

   The dual-release insulin concept • Physiological insulin profile: basal component meal-related peaks • Soluble insulin fails to match normal insulin peak • Intermediate-acting insulin provides basal insulin replacement but… • …together these fail to re-create the physiological insulin profile

7. Slide 7: The dual-release insulin concept

   The dual-release insulin concept • Physiological insulin profile: basal component meal-related peaks • Rapid-acting insulin analogues together with a basal insulin provide physiological insulin replacement • Analogue premixes such as NovoMix® 30 replace both meal- related and basal insulin

8. Slide 8: Benefits of dual-release insulin replacement

   Benefits of dual-release insulin replacement 1. Mimics physiological insulin release – Early release of rapid-acting insulin targets postprandial glucose – Delayed release of intermediate-acting insulin fulfils basal insulin requirement 2. Reduces hypoglycaemic risk – < Conventional premix 3. Improv

9. Slide 9: NovoMix 30: PK/PD studies in healthy volunteers

   NovoMix® 30: PK/PD studies in healthy volunteers Comparison PK and PD profiles of NovoMix® 30 vs. BHI 30 Design 1. Randomised, double-blind, two-way single dose crossover1 2. Randomised, double-blind, crossover single dose euglycaemic clamp2 1. Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403 2. W

10. Slide 10: Proof of concept: rapid absorption and higher peak concentration

    Proof of concept: rapid absorption and higher peak concentration NovoMix® 30 25 *** BHI 30 20 ***p < 0.0001 Serum insulin (mU/l) n = 24 15 10 5 0 8:00 11:00 14:00 17:00 20:00 23:00 2:00 5:00 8:00 Time of day Jacobsen L et al. Eur J Clin Pharm 2000;56:399–403

11. Slide 11: Proof of concept: faster onset and more effective

    Proof of concept: faster onset and more effective n = 24, dose = 0.3 U/kg 12 Glucose infusion rate (mg/kg/min) NovoMix® 30 10 BHI 30 (Actraphane) 8 6 4 2 0 0 240 480 720 960 1200 1400 Time (min) Weyer C et al. Diabetes Care 1997;10:1612–1614

12. Slide 12: PK/PD conclusions: NovoMix vs. BHI

    PK/PD conclusions: NovoMix® 30 vs. BHI 30 • Faster absorption1,2 • Higher peak concentrations1,2 • More rapid and pronounced glucose-lowering effect1,2 • Similar duration of action of basal component1,2 Faster onset and greater glucose-lowering effect of insulin aspart are retained in dual-release N

13. Slide 13: Improved postprandial glycaemic control

    Improved postprandial glycaemic control McSorley PT et al. ClinTher Meal study in type 2 patients vs. 2002;24(4):530–539 BHI 30 Hermansen K et al. Metabolism Comparison vs. BHI 30 in type 1 2002;51(7):896–900 patients Hermansen K et al. Diabetes Care Comparison vs. BHI 30 and lispro 2002;25:883–888

14. Slide 14: Twice-daily NovoMix in patients with type 2 diabetes

    Twice-daily NovoMix® 30 in patients with type 2 diabetes Screening visit (n = 13) NovoMix® 30 ® Follow-up NovoMix 30 BHI 30 BHI 30 –3 to14 +3 to 7 days days 0 2 4 Weeks McSorley PT et al. Clin Ther 2002;24(4):530–539

15. Slide 15: NovoMix is rapidly absorbed

    NovoMix® 30 is rapidly absorbed * * NovoMix® 30 120 Biphasic human insulin Total serum insulin (mU/l) 100 n = 13 * p < 0.05 in favour of NovoMix® 30 for 80 mean serum insulin level and insulin Cmax after dinner and breakfast 60 40 20 0 18:00 22:00 08:00 13:00 18:00 Time McSorley PT et al. Clin Ther

16. Slide 16: Improved postprandial glucose control with NovoMix

    Improved postprandial glucose control with NovoMix® 30 NovoMix® 30 20 Biphasic human insulin * * n = 13 Blood glucose (mmol/l) 15 10 5 * p < 0.05 in favour of NovoMix® 30 for lower PPG levels after dinner and breakfast 0 18:00 22:00 08:00 13:00 18:00 Time McSorley PT et al. Clin Ther 2002;24(4):530–

17. Slide 17: NovoMix is well tolerated

    NovoMix® 30 is well tolerated • Both insulins were well tolerated • Both insulins had comparable adverse-event profiles • No major hypoglycaemic episodes or serious adverse events were reported • No other safety concerns McSorley PT et al. Clin Ther 2002;24(4):530–539

18. Slide 18: NovoMix twice daily improves postprandial glucose control

    NovoMix® 30 twice daily improves postprandial glucose control Compared with BHI 30, NovoMix® 30 given immediately before a meal (twice daily) in type 2 diabetic patients resulted in: • Significantly faster absorption • Significantly higher peak concentrations 2 hours after injection • Smaller postpr

19. Slide 19: Type 1 diabetes: single dose crossover

    Type 1 diabetes: single dose crossover NovoMix® 30 at meal Screening BHI 30 at meal Follow-up (n = 50) BHI 30 at –30 minutes Study day 1 Study day 2 Study day 3 3–21 days 5–21 days 5–21 days 7–14 days Hermansen K et al. Metabolism 2002;51(7):896–900

20. Slide 20: Reduced glucose exposure in type 1 patients after a meal

    Reduced glucose exposure in type 1 patients after a meal NovoMix® 30 ( t = 0) BHI 30 (t = 0) 20 Max glucose concn * BHI 30 (t = –30) 15% lower at t = 0 Blood glucose (mmol/l) 15 * p < 0.001 n = 50 10 5 * 23% lower glucose Max glucose conc n exposure * 20 min earlier than BHI at t = 0 0 –30 0 30 60 9

21. Slide 21: Reduced glucose excursion irrespective of timing of BHI injection

    Reduced glucose excursion irrespective of timing of BHI 30 injection p < 0.0001 p = 0.013 Blood glucose excursion 4 h after 3000 BHI 30 2800 injection (mmol.min.l-1) 23% 9% NovoMix® 30 2600 2400 2200 2000 0 t=0 t=0 t = –30 Injection time in relation to meal Hermansen K et al. Metabolism 2002;51(7):8

22. Slide 22: NovoMix is more effective than BHI

    NovoMix® 30 is more effective than BHI 30 • Superior efficacy in controlling postprandial glucose levels • Higher reduction in blood glucose concentrations when injected immediately before meals • Significantly larger insulin concentrations achieved regardless of the time of BHI 30 administration He

23. Slide 23: Comparison of NovoMix 30, Humalog Mix25 and BHI 30

    Comparison of NovoMix® 30, Humalog® Mix25TM and BHI 30 NovoMix® 30 at meal Humalog® Mix25TM at meal (n = 45) BHI 30 at –15 min • Objective To compare the postprandial blood glucose excursion between treatment groups • Design Randomised, open-labelled, three-period crossover trial • Method Single dos

24. Slide 24: Reduced glucose excursions vs. Humalog Mix25 and BHI

    Reduced glucose excursions vs. Humalog® Mix25TM and BHI 30 p < 0.001 Blood glucose excursion0– 5h(mmol/l h) 21 p < 0.05 –17% 20 19 –10% 18 17 16 15 14 13 0 Humalog® Mix 25TM NovoMix® 30 BHI 30 Hermansen K et al. Diabetes Care 2002;25:883–888

25. Slide 25: Improved postprandial control vs. Humalog Mix25 and BHI

    Improved postprandial control vs. Humalog® Mix25TM and BHI 30 Glucose parameter EXC0–5h Cmax tmax (mmol/l h) (mmol/l h) (min) NovoMix® 30 16.6  4.4a,b 15.9  2.7c 75.1  22.2c,d Humalog® 18.9  6.1 16.4  3.2 86.5  26.9 Mix25TM BHI 30 20.1  4.9 16.7  2.6 88.0  26.4 a NovoMix® 30 significantly l

26. Slide 26: Larger and more rapid increase in serum insulin with NovoMix 30

    Larger and more rapid increase in serum insulin with NovoMix® 30 Insulin parameter AUC (ins0–5h) Cmax(ins) Tmax(ins) (pmol/l h) (pmol/l h) (min) NovoMix® 30 1079  535a 415  244a 115  59a Humalog® 1031  621 360  211 100  41 Mix25TM BHI 30 741  426 237  156 169  71 a Values for NovoMix® 30 ar

27. Slide 27: Improved postprandial glucose vs. BHI and Humalog Mix25

    Improved postprandial glucose vs. BHI 30 and Humalog® Mix25TM • Superior postprandial glucose control to BHI 30 and Humalog® Mix25TM in type 2 patients • Higher maximum serum insulin with BHI and Humalog® Mix25TM • Well tolerated with no serious adverse events occurring related to treatment Hermanse

28. Slide 28: Comparison of efficacy and safety of NovoMix vs. BHI 30: study design

    Comparison of efficacy and safety of NovoMix® 30 vs. BHI 30: study design NovoMix® 30 (n = 140) Insulin-using type 1 and type 2 diabetic patients (n = 294) One screening visit; patients already using a twice-daily insulin regimen BHI 30 (n = 151) 12 weeks Boehm B et al. Diabet Med 2002;19(5):393–399

29. Slide 29: Improved postprandial glucose after 12 months

    Improved postprandial glucose after 3 months NovoMix® 30 12 * BHI 30 * p < 0.05 * Blood glucose (mmol/l) 10 * 8 * 6 0 Pre- Post- Pre- Post- Pre- Post- Bedtime 0200 h Breakfast Lunch Dinner Boehm B et al. Diabet Med 2002;19(5):393–399

30. Slide 30: Significantly lower prandial glucose increment with NovoMix 30

    Significantly lower prandial glucose increment with NovoMix® 30 3 p < 0.02 between treatment groups Mean prandial glucose increment 2.5 2 (mmol/l) 1.5 1 0.5 0 NovoMix® 30 BHI 30 (n = 128) (n = 141) Boehm B et al. Diabet Med 2002;19(5):393–399

31. Slide 31: Improved postprandial control with NovoMix

    Improved postprandial control with NovoMix® 30 • Superior postprandial glycaemic control achieved compared with BHI 30 • No increased risk of hypoglycaemia with NovoMix® 30 • Trend for reduction in nocturnal hypoglycaemic episodes with NovoMix® 30 Boehm B et al. Diabet Med 2002;19(5):393–399

32. Slide 32: NovoMix vs. NPH in type 2 patients

    NovoMix® 30 vs. NPH in type 2 patients • OHA only Twice-daily NovoMix® 30 • NPH + OHA (n = 201) • NPH monotherapy • No treatment Original treatment Twice-daily NPH insulin (n = 202) 7–14 days 16 weeks 2 weeks Screening Randomisation Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):445

33. Slide 33: NovoMix vs. NPH: lower prandial glucose increment

    NovoMix® 30 vs. NPH: lower prandial glucose increment * Difference in prandial glucose increment 1 0.56 * between treatment groups (mmol/l) p < 0.005 0.5 ** p < 0.0001 Favours NPH 0 -0.5 Favours NovoMix® 30 -1 -0.69 ** -1.5 -1.26 -1.33 Mean prandial ** ** glucose increment -2 Breakfast Lunch Dinner

34. Slide 34: Greater HbA1c reduction with NovoMix vs. NPH

    Greater HbA1c reduction with NovoMix® 30 vs. NPH NovoMix® 30 NPH (n = 66) (n = 66) 0.0 -0.2 Change in HbA1c (%) -0.4 -0.6 -0.8 p = 0.03 -1.0 Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):445-452

35. Slide 35: NovoMix offers better glycaemic control than NPH

    NovoMix® 30 offers better glycaemic control than NPH • Mean prandial glucose increment lower in NovoMix® 30 group (p < 0.0001) • Patients receiving NPH monotherapy benefit from switching to NovoMix® 30 (bid) Christiansen JS et al. Diabetes, Obesity & Metabolism 2003;5(6):445-452

36. Slide 36: Superior postprandial control

    Superior postprandial control • Higher plasma insulin levels with NovoMix® 30 vs. BHI 30 • Improved postprandial control vs. BHI 30 • Superior postprandial control vs. Humalog® Mix25TM • Lower postprandial increment and HbA1c vs. NPH • No safety concerns

37. Slide 37: Superior hypoglycaemia profile

    Superior hypoglycaemia profile Boehm B et al. Diabet Med Safety comparison vs. BHI 30 in 2002;19(5):393–399 type 1 and type 2 patients 2-year safety data in type 2 patients Boehm et al. Submitted to Eur vs. BHI 30 J Int Med 4-year safety data in type 2 patients Boehm B et al. Diabetologia vs. BHI 30

38. Slide 38: Comparison of efficacy and safety of NovoMix vs. BHI 30: study design

    Comparison of efficacy and safety of NovoMix® 30 vs. BHI 30: study design NovoMix® 30 (n = 140, 39% type 1) Insulin-using type 1 and type 2 diabetic patients (n = 294) One screening visit; patients already using a twice-daily insulin regimen BHI 30 (n = 151, 32% type 1) 12 weeks Boehm B et al. Diabe

39. Slide 39: Improved postprandial glucose after 12 months

    Improved postprandial glucose after 3 months NovoMix® 30 12 * BHI 30 * p < 0.05 * Blood glucose (mmol/l) 10 * 8 * 6 0 Pre- Post- Pre- Post- Pre- Post- Bedtime 0200 h Breakfast Lunch Dinner Boehm B et al. Diabet Med 2002;19(5):393–399

40. Slide 40: Significantly lower prandial glucose increment with NovoMix 30

    Significantly lower prandial glucose increment with NovoMix® 30 3 p < 0.02 between treatment groups Mean prandial glucose increment 2.5 2 (mmol/l) 1.5 1 0.5 0 NovoMix® 30 BHI 30 (n = 128) (n = 141) Boehm B et al. Diabet Med 2002;19(5):393–399

41. Slide 41: Reduced major hypoglycaemia after 12 months

    Reduced major hypoglycaemia after 3 months 50% relative 45 risk reduction 40 hypoglycaemic episodes 35 30 Number of 25 42 20 events 15 20 10 events 5 0 NovoMix® 30 BHI 30 (n = 138) (n = 153) Boehm B et al. Diabet Med 2002;19(5):393–399

42. Slide 42: Trend towards reduced minor nocturnal hypoglycaemic episodes

    Trend towards reduced minor nocturnal hypoglycaemic episodes p = 0.06 60 55 50 hypoglycaemic episodes 45 40 Number of 35 30 58 25 events 20 39 15 events 10 5 0 NovoMix® 30 BHI 30 Boehm B et al. Diabet Med 2002;19(5):393–399

43. Slide 43: Reduced hypoglycaemic profile with NovoMix

    Reduced hypoglycaemic profile with NovoMix® 30 • Superior postprandial glycaemic control achieved compared with BHI 30 • No increased risk of hypoglycaemia with NovoMix® 30 • Trend for reduction in nocturnal hypoglycaemic episodes with NovoMix® 30 Boehm B et al. Diabet Med 2002;19(5):393–399

44. Slide 44: NovoMix vs. BHI 30: 2-year safety in type 2 diabetes

    NovoMix® 30 vs. BHI 30: 2-year safety in type 2 diabetes NovoMix® 30 bid (n = 58) Insulin-using type 2 diabetic patients (n = 125) BHI 30 bid (n = 67) 0 24 Months Boehm et al. Submitted to Eur J Int Med

45. Slide 45: Reduced major hypoglycaemia after 2 years

    Reduced major hypoglycaemia after 2 years 12 p = 0.04 Patients with at least one major p = NS NovoMix® 30 10 BHI 30 8 episode (%) 6 4 2 0 1st year 2nd year Year of study Boehm et al. Submitted to Eur J Int Med

46. Slide 46: 2-year efficacy and tolerability of NovoMix in type 2 diabetes

    2-year efficacy and tolerability of NovoMix® 30 in type 2 diabetes Compared with BHI 30, NovoMix® 30 is associated with: • A reduced risk of major hypoglycaemia • An equivalent level of efficacy • More favourable balance between hypoglycaemia and hyperglycaemia in insulin-treated type 2 diabetes Boe

47. Slide 47: NovoMix vs. BHI 30: 4-year safety in type 2 diabetes

    NovoMix® 30 vs. BHI 30: 4-year safety in type 2 diabetes Insulin-using type 2 patients (n = 73) NovoMix® 30 bid (n = 32) BHI 30 bid (n = 41) 0 24 42 48 Months Boehm B et al. Diabetologia 2003;46(Suppl 2):A269

48. Slide 48: Twice-daily NovoMix and BHI gives stable metabolic control

    Twice-daily NovoMix® 30 and BHI 30 gives stable metabolic control NovoMix® 30 9.0 BHI 30 8.5 HbA1c (%) 8.0 7.5 7.0 0 0 3 6 12 18 24 30 36 42 Months Boehm B et al. Diabetologia 2003;46(Suppl 2):A269

49. Slide 49: Hypoglycaemic episodes in patients completing the 4-year trial

    Hypoglycaemic episodes in patients completing the 4-year trial NovoMix® 30 BHI 30 p-value (n = 32) (n = 41) People with major episodes First 2 years 1 7 0.04 Entire period 4 11 0.08 People with nocturnal episodes Entire period 0 6 0.02 Boehm B et al. Diabetologia 2003;46(Suppl 2):A269

50. Slide 50: Superior hypoglycaemic profile vs. BHI

    Superior hypoglycaemic profile vs. BHI 30 • No major hypoglycaemic episodes during second year of treatment • No nocturnal hypoglycaemic events during 4 years’ treatment

51. Slide 51: Superior HbA1c control with oral medication

    Superior HbA1c control with oral medication Kvapil M et al. Diabetes 2002;51(Suppl Addition of twice-daily NovoMix ® 30 to 2):A104 metformin vs. addition of SU Kilo C et al. J Diabetes Complications Addition of once-daily NovoMix ® 30 to 2003;17(6):30713 metformin Raz I et al. Submitted to Diabetes

52. Slide 52: NovoMix in combination with metformin

    NovoMix® 30 in combination with metformin NovoMix® 30 bid + metformin (n = 108) (n = 329) NovoMix® 30 bid (n = 107) Metformin failures (HbA1c 7.5–13.0%) glibenclamide + metformin (n = 114) 0 16 Weeks Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

53. Slide 53: NovoMix plus metformin in type 2 diabetes: Demographic characteristics

    NovoMix® 30 plus metformin in type 2 diabetes Demographic characteristics (total population) NovoMix® 30 NovoMix® 30 Met + met + SU No of patients 107 108 114 Mean age (yrs ± SD) 55.2 ± 10.3 56.4 ± 9.0 58.1 ± 8.8 Male/Female 50/57 53/55 52/62 BMI (kg/m2 ± SD) 30.9 ± 4.5 30.4 ± 4.0 30.5 ± 4.4 Kvapil

54. Slide 54: Improved HbA1c with NovoMix combination in total population

    Improved HbA1c with NovoMix® 30 combination in total population 8.5 p = 0.004 HbA 1c (%) following 16 weeks' HbA1c difference 8 of 0.6% treament 7.5 0 7 NM NM+met Met+su Treatment group Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

55. Slide 55: Superior glycaemic control with NovoMix + metformin in poorly controlled patients

    Superior glycaemic control with NovoMix® 30 + metformin in poorly controlled patients (HbA1c > 9%) 8.5 p = 0.037 p = 0.033 8 HbA 1c (%) 7.5 0 7 NM NM+met Met+SU Treatment group Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

56. Slide 56: Lower insulin dose when used with metformin

    Lower insulin dose when used with metformin NovoMix® 30 NovoMix® + met Met + SU NovoMix® 30 dose (IU/mg/day) 0.6 7 6 SU dose (mg/day) 5 0.4 4 3 0.2 2 1 0 0 0 1 2 3 4 0 1 2 3 4 Time (months) Time (months) Kvapil M et al. Diabetes 2002;51(Suppl 2):A104

57. Slide 57: Significantly lower body weight for NovoMix + met vs. NovoMix 30

    Significantly lower body weight* for NovoMix® 30 + met vs. NovoMix® 30 p = 0.0004 120 p = 0.05 100 End of trial mean body 80 weight (kg) 60 40 * Mean body 20 weights adjusted for 0 baseline NovoMix® 30 NovoMix® 30 + met Met + SU Kvapil M et al. Diabetologia 2002;45(Suppl 2):A18

58. Slide 58: NovoMix plus metformin is well tolerated

    NovoMix® 30 plus metformin is well tolerated • There were no reports of major hypoglycaemia during the trial • The total number of minor hypoglycaemic episodes was similar between groups: • NovoMix® 30 + met 23 • NovoMix® 30 alone 20 • Met + SU 28 • No other safety concerns were raised Kvapil M et a

59. Slide 59: Improved glycaemic control with NovoMix combination

    Improved glycaemic control with NovoMix® 30 combination • In poorly controlled patients: NovoMix® 30 plus metformin achieved better glycaemic control than NovoMix® 30 alone or sulphonylurea plus metformin • The end of trial mean weight was not different between the NovoMix® 30 plus metformin group a

60. Slide 60: Once-daily (dinnertime) NovoMix with metformin

    Once-daily (dinnertime) NovoMix® 30 with metformin Metformin + NovoMix® 30 od (n = 45) Run-in period – metformin (up to 2550 mg/day) Metformin + human insulin NPH od (n = 47) Follow-up Metformin + BHI 30 od (n = 46) Eligible patients: FPG  126 mg/dl –4 0 12 14 Weeks Kilo C et al. J Diabetes Complic

61. Slide 61: Addition of insulin to metformin improves glycaemic control

    Addition of insulin to metformin improves glycaemic control Treatment group (+metformin) NovoMix® 30 NPH BHI 30 -1 Reduction in HbA 1c (%) -1.2 -1.4 Kilo C et al. J Diabetes Complications 2003;17(6):307-13

62. Slide 62: Benefits of reaching fasting glycaemic targets with NovoMix 30

    Benefits of reaching fasting glycaemic targets with NovoMix® 30 FPG (mmol/l) 5–8 (n = 54) Treatment (+metformin) Change in HbA1c from baseline (%) NovoMix® 30 NPH BHI 30 0 -0.5 -1 -1.5 -2 -2.5 -3 Kilo C et al. J Diabetes Complications 2003;17(6):307-13

63. Slide 63: Fewer nocturnal hypoglycaemic events with NovoMix combination

    Fewer nocturnal hypoglycaemic events with NovoMix® 30 combination NovoMix® 30 NPH BHI 30 Patients (n) 45 46 47 Major events 0 0 0 Symptomatic 9 18 14 nocturnal events Minor nocturnal 1 6 9 events There were no major hypoglycaemic events reported during the study. There were numerically fewer nocturn

64. Slide 64: Once-daily NovoMix with metformin is effective and well tolerated

    Once-daily (dinnertime) NovoMix® 30 with metformin is effective and well tolerated • With metformin non-responders, starting NovoMix® 30 once-daily and continuing metformin is effective and well tolerated. • Reaching FPG target with NovoMix® 30 plus metformin achieves greater benefits than NPH or BH

65. Slide 65: Addition of second therapy when glibenclamide fails (I)

    Addition of second therapy when glibenclamide fails (I) NovoMix® 30 (BID) + glibenclamide (n = 22) Glibenclamide (7.5–15 mg/day) Type 2 patients, HbA1c 813% Metformin (850 mg OD) + glibenclamide (n = 24) 0 Weeks 6 Raz I et al. Submitted to Diabetes, Obesity and Metabolism

66. Slide 66: Improved glycaemic control with addition of NovoMix vs. metformin

    Improved glycaemic control with addition of NovoMix® 30 vs. metformin GLI+ GLI+ GLI+MET NovoMix® 30 GLI+MET NovoMix® 30 0.0 0.0 Mean glucose reduction –0.5 HbA1c reduction (%) –0.3 –1.0 (mmol/l) –1.5 –0.6 –2.0 –2.5 –0.9 –3.0 –1.2 –3.5 * p < 0.05 –4.0 –1.5 Raz I et al. Submitted to Diabetes, Obesity

67. Slide 67: Addition of second therapy when glibenclamide fails (II)

    Addition of second therapy when glibenclamide fails (II) NovoMix® 30 (BID) + rosiglitazone (4 mg OD) (n = 26) Glibenclamide (7–15 mg) Type 2 patients, HbA1c (813%) Glibenclamide + rosiglitazone (4mg OD) (n = 23) Weeks 0 6 Raz I et al. Clin Ther 2003;25:3109-3123

68. Slide 68: Improved glycaemic control with NovoMix combination

    Improved glycaemic control with NovoMix® 30 combination ROS+ ROS+ ROS+GLI NovoMix® 30 ROS+GLI 0.0 NovoMix® 30 0.0 Mean glucose reduction –0.5 HbA1c reduction (%) –0.3 –1.0 (mmol/l) –1.5 –0.6 –2.0 –2.5 –0.9 –3.0 –3.5 –1.2 –4.0 –1.5 * p < 0.05 Raz I et al. Clin Ther 2003;25:3109-3123

69. Slide 69: Treatment options when metformin fails

    Treatment options when metformin fails NovoMix® 30 (BID) + metformin (OD) (n = 23) Metformin NovoMix® 30 (BID) + repaglinide 1 mg (OD) (1700–2550 mg) + metformin (OD) (n = 24) Glibenclamide 5 mg (OD) + metformin (OD) (n = 23) Weeks 0 6 Raz I et al. Manuscript in preparation

70. Slide 70: Reduction in HbA1c after 6 weeks' treatment

    Reduction in HbA1c after 6 weeks’ treatment MET+ MET+ MET+ MET+ REP+ MET+ MET+ REP+ GLI NovoMix 30 NovoMix® 30 ® NovoMix ® 30 Mean glucose reduction GLI NovoMix® 30 0.0 0.0 HbA1c reduction (%) –0.5 –1.0 –0.3 (mmol/l) –1.5 –0.6 –2.0 –2.5 –0.9 –3.0 –1.2 –3.5 –4.0 –1.5 Raz I et al. Manuscript in prepar

71. Slide 71: NovoMix + oral agent is preferable to a second oral agent

    NovoMix® 30 + oral agent is preferable to a second oral agent • The addition of NovoMix® 30 to an oral agent was more effective in lowering average glucose than when a second oral agent was added • Addition of NovoMix® 30 also showed a trend to decrease HbA1c • All treatment therapies showed improve

72. Slide 72: Treatment options with NovoMix when SU therapy fails

    Treatment options with NovoMix® 30 when SU therapy fails NovoMix® 30 (BID) + pioglitazone (30 mg OD) SU mono or combination therapy NovoMix® (BID) (HbA1c 7.513.0%) Glibenclamide (515 mg, OD) + pioglitazone (30 mg OD) 0 1 2 4 8 12 18 Time (weeks) Screening Randomisation Discontinuation of (SU thera

73. Slide 73: Lower HbA1c with NovoMix combination treatment

    Lower HbA1c with NovoMix® 30 combination treatment 11.0 NovoMix® 30 10.5 NovoMix® 30 + pioglitazone 10.0 Glibenclamide + pioglitazone HbA1c (%) 9.5 9.0 * * 8.5 8.0 7.5 *p < 0.01 7.0 Screening Visit 6 End of Trial Raz I et al. Diabetologia 2003;46(Suppl 2):A8

74. Slide 74: Superior glycaemic control with NovoMix combination therapy

    Superior glycaemic control with NovoMix® 30 combination therapy • At end of trial, NovoMix® 30 + pioglitazone was superior to glibenclamide + pioglitazone on almost all measures of blood glucose (p < 0.05–p < 0.001) • Significantly lower prandial BG increment for NovoMix® 30 + pioglitazone versus gl

75. Slide 75: NovoMix + pioglitazone is effective in type 2 diabetes

    NovoMix® 30 + pioglitazone is effective in type 2 diabetes • NovoMix® 30 and pioglitazone is an effective treatment combination in type 2 diabetic patients • The combination of NovoMix® 30 and pioglitazone offers better glycaemic control than the combination of glibenclamide and pioglitazone and Nov

76. Slide 76: NovoMix is an effective add-on therapy

    NovoMix® 30 is an effective add-on therapy • Superior glycaemic improvements when NovoMix® 30 added to metformin vs. addition of SU • Adding NovoMix® 30 (once-daily) to metformin is more effective for controlling blood glucose levels compared with adding NPH or BHI 30 • Overall, adding NovoMix® 30 t

77. Slide 77: Convenience and flexibility

    Convenience and flexibility Kapitza C et al. In press Diabet Postprandial dosing vs. BHI 30 Med Warren et al. Submitted to Diabet Postprandial dosing vs. BHI 30 in Res Clin Prac the elderly Vora JP et al. Diabetologia NovoMix® 30 FlexPen® vs. 2002;45(Suppl 2):A255 Humalog® Mix25TM Pen Asakura T & Se

78. Slide 78: Postprandial dosing with NovoMix

    Postprandial dosing with NovoMix® 30 NovoMix® 30, 0 min NovoMix® 30, +15 min BHI 30, –15 min BHI 30, 0 min Visit 1 2 3 4 5 6 (Screening) (Randomisation) (Follow-up) Days 5–21 3–21 3–21 3–21 1–14 between visits Kapitza C et al. In press Diabet Med

79. Slide 79: Postprandial dosing efficacy with NovoMix

    Postprandial dosing efficacy with NovoMix® 30 BHI 30(t = –15 min) 6 BHI 30(t = 0 min) NovoMix® 30(t = 0 min) Blood glucose (mmol/l) 4 NovoMix® 30( t= +15 min) 2 0 –2 –4 0 60 120 180 240 300 Time (min) Kapitza C et al. In press Diabet Med

80. Slide 80: Postprandial dosing with NovoMix

    Postprandial dosing with NovoMix® 30 NovoMix® 30 NovoMix® 30 BHI 30 BHI 30 (t = 0 min) (t = +15 min) (t = –15 min) (t = 0 min) *AUC (0–240mins) 2563a 2864 2958 2777 (mM/min) *Cmax 13.47b 15.28 15.08 14.42 (mM) Tmax (median, 75 75 90 90 min) * Values are expressed as geometric means a AUC for NovoMix

81. Slide 81: NovoMix allows flexible dosing

    NovoMix® 30 allows flexible dosing • Superior postprandial blood glucose control compared with either of BHI 30 injection regimens • Comparable postprandial blood glucose control when injected after meal to BHI 30 (either injection regimen) • Gives advantage of increased flexibility in injection tim

82. Slide 82: Postprandial NovoMix dosing in elderly patients

    Postprandial NovoMix® 30 dosing in elderly patients Run-in Preprandial Preprandial (n = 91) dosing dosing Postprandial Postprandial NovoMix 30, ® dosing dosing bid, preprandial 0 4 8 12 Weeks Warren et al. Submitted to Diabet Res Clin Prac

83. Slide 83: Blood glucose levels did not differ between treatment groups

    Blood glucose levels did not differ between treatment groups 200 Preprandial dosing 180 (NovoMix® 30, bid) Blood glucose levels (mg/dl) Postprandial dosing 160 (NovoMix® 30, bid) 140 120 n = 91 100 p = NS in all cases 80 60 40 20 0 Before Before 2 hrs after 2 hrs after breakfast dinner breakfast din

84. Slide 84: Postprandial NovoMix is effective in elderly type 2 patients

    Postprandial NovoMix® 30 is effective in elderly type 2 patients • Postprandial NovoMix® 30 offers acceptable alternative to standard preprandial injections • No significant difference in hypoglycaemic episodes between treatment groups • Postprandial injections appear to be well tolerated Warren et

85. Slide 85: Comparison of NovoMix FlexPen with Humalog Mix25 Pen

    Comparison of NovoMix® 30 FlexPen® with Humalog® Mix25TM Pen Run-in NovoMix® 30 NovoMix® 30 (n = 133) FlexPen® FlexPen® Humalog® Humalog® Mix25TM Pen Mix25TM Pen –3 0 12 24 Weeks Vora JP et al. Submitted to Diabetes, Obesity and Metabolism

86. Slide 86: NovoMix FlexPen is simple to use

    NovoMix® 30 FlexPen® is simple to use • Device specific, and comparative questionnaires assessed patients’ opinion about attributes of the devices • Features included: – confidence in setting and injecting the correct dose – readability of the dose scale – confidence in managing daily insulin inject

87. Slide 87: NovoMix FlexPen is preferred over Humalog Mix25 Pen

    NovoMix® 30 FlexPen® is preferred over Humalog® Mix25TM Pen Equally easy/ NovoMix® 30 Humalog® Equally difficult/ 100 either FlexPen® Mix25TM neither 90 80 * * 70 % of patients 60 50 40 30 20 10 0 Overall, which pen device do Overall, which pen device would you find easiest to use? you prefer to con

88. Slide 88: Comparable efficacy and safety vs. Humalog Mix25

    Comparable efficacy and safety vs. Humalog® Mix25TM • A similar reduction in HbA1c was seen in the NovoMix® 30 and Humalog® Mix25TM treatment groups • Both treatments lowered postprandial glucose to a similar extent • The number of hypoglycaemic events did not differ significantly between treatment

89. Slide 89: Higher patient satisfaction with NovoMix FlexPen

    Higher patient satisfaction with NovoMix® 30 FlexPen® • Patients were more satisfied and experienced fewer problems than with the Humalog® Mix25TM Pen • More patients found the NovoMix® 30 FlexPen® the easiest device to use • More patients (75%) would continue to use the NovoMix® 30 FlexPen® while o

90. Slide 90: Comparison of FlexPen with Humalog Kit

    Comparison of FlexPen® with Humalog® KitTM ”Device-naïve” patients Run-in FlexPen® FlexPen® (n = 58) Humalog® KitTM Humalog® KitTM 0 2 4 Days Both pens contained rapid-acting analogues, however, no insulin was injected during the testing procedure Asakura T & Seino H Diabetes Metab 2003;29:4S236

91. Slide 91: FlexPen is more user-friendly than Humalog Kit

    FlexPen® is more user-friendly than Humalog® Kit 250 ** ** * * * FlexPen® 200 Humalog® Kit 150 * p < 0.01 Total score ** p < 0.001 100 50 0 Number Ease of Ease of Simplicity Injection legibility dose setting pressing confirmation release button Pen feature Asakura T & Seino H Diabetes Metab 2003;29:

92. Slide 92: More patients prefer FlexPen to Humalog Kit

    More patients prefer FlexPen® to Humalog® Kit * p < 0.01 90 80 70 Patients (%) 60 50 40 30 20 10 0 FlexPen® Humalog® Kit No preference Device preference Asakura T & Seino H Diabetes Metab 2003;29:4S236

93. Slide 93: FlexPen is simple to use

    FlexPen® is simple to use Patients preferred FlexPen® to Humalog® Kit for: • Readability of the dosing scale • Ease of dose setting • Ease of pressing the release button • Stability during injection • Simplicity • Confirmation of injection • No difference between the devices regarding grip and porta

94. Slide 94: Comparison of FlexPen vs vial/syringe

    Comparison of FlexPen® vs vial/syringe Run-in FlexPen® FlexPen® Type 1 and type 2 patients (using vial/syringe) Vial/syringe Vial/syringe Randomisation (n = 108) 0 4 8 12 Weeks Korytkowski M et al. Clinical Therapeutics 2003;25(11):2836-48

95. Slide 95: Patients prefer FlexPen to vial/syringe

    Patients prefer FlexPen® to vial/syringe 6% FlexPen 20 Vial/syringe Q: Overall, which % No difference device would you prefer to continue using? * Significantly more patients (p<0.05) preferred to continue 74%* using FlexPen® vs. vial/syringe Korytkowski M et al. Clinical Therapeutics 2003;25(11):28

96. Slide 96: FlexPen is preferred to vial/syringe in a number of injection parameters

    FlexPen® is preferred to vial/syringe in a number of injection parameters Easier to read dose Confidence in FlexPen® setting dose Vial/syringe Confidence in No preference injecting correct dose Injection More discreet in public parameters More stable Easier to handle Confidence in glycaemic control

97. Slide 97: Reduction in HbA1c with NovoMix

    Reduction in HbA1c with NovoMix® 30 9.5 * p<0.05 9 Absolute HbA 1c (%) 8.5 8 7.5 7 6.5 0 Baseline (week 0) End of trial (week 12) Time point Korytkowski M et al. Clinical Therapeutics 2003;25(11):2836-48

98. Slide 98: FlexPen is preferred to vial/syringe

    FlexPen® is preferred to vial/syringe • Both injection devices demonstrated high acceptance by the patients according to the Diabetes Treatment Satisfaction Questionnaire (DTSQ) • Efficacy and safety profiles were similar between treatment groups • Given the choice, more patients expressed a prefere

99. Slide 99: Health care professionals' opinion

    Health care professionals’ opinion 82% of healthcare professionals preferred FlexPen® compared with two other prefilled pens 100 * p<0.01 vs. Humalog® pen and OptiSet® (n=102) 82%* 80 Proportion of patients (%) 60 40 20 14% 3% 0 FlexPen® Humalog® Pen** OptiSet® ** Same device as Humalog® Mix 25 pen

100. Slide 100: Convenient and flexible dosing with NovoMix FlexPen

     Convenient and flexible dosing with NovoMix® 30 FlexPen® • NovoMix® 30 offers flexible dosing times while maintaining good postprandial glycaemic control • Patients prefer NovoMix® 30 FlexPen® to Humalog® Mix25TM • Patients with impaired manual dexterity and vision prefer FlexPen® to Humalog® Kit

101. Slide 101: Efficacy and safety of NovoMix in type 1 adolescents

     Efficacy and safety of NovoMix® 30 in type 1 adolescents NovoMix® 30 (TID) (n = male 37 female 49) Type 1 patients, 10-17 yrs HI + BHI (n = male 43 female 38) 0 2 weeks 16 weeks (Time) Mortensen H et al. Diabetes Metab 2003;29:4S227

102. Slide 102: Efficacy of NovoMix in adolescents

     Efficacy of NovoMix® 30 in adolescents • NovoMix® 30 significantly improved BMI in boys, but not in girls • Both treatments improved glycaemic control during the 16- week period : HbA1c decreased by ~0.2% • NovoMix® 30 tended to improve prandial glucose control more in boys than in girls • There was

103. Slide 103: NovoMix 30 summary

     NovoMix® 30: • NovoMix® 30 provides improved postprandial glycaemic control compared to biphasic human insulin and Humalog® Mix25TM • NovoMix® 30 provides a superior hypoglycaemic profile to biphasic human insulin • NovoMix® 30 improves HbA1c when used in combination with oral medications • NovoMix®

104. Slide 104: Publications/abstracts used in this slide kit

     Publications/abstracts used in this slide kit • • Kvapil M et al. Diabetes 2002;51(Suppl 2):A104 Brange J et al. Nature 1988;333:679–682 • Kilo C et al. J Diabetes Complications • Jacobsen L et al. Eur J Clin Pharm 2003;17(6):307-13 2000;56:399–403 • Raz I et al. Submitted to Diabetes, Obesity and •

Novo Nordisk — Technical Presentation (January 2004) on 6ix