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Minimum clear space Minimum clear space Last text line A focused healthcare company SG Cowen & Co. 25 th Annual Health Care Conference Boston, March 15.

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Presentation on theme: "Minimum clear space Minimum clear space Last text line A focused healthcare company SG Cowen & Co. 25 th Annual Health Care Conference Boston, March 15."— Presentation transcript:

1 Minimum clear space Minimum clear space Last text line A focused healthcare company SG Cowen & Co. 25 th Annual Health Care Conference Boston, March

2 Minimum clear space Minimum clear space Last text line 2 This presentation contains forward-looking statements as the term is defined in the US Private Securities Litigation Reform Act of Forward-looking statements provide our expectations or forecasts of future events such as new product introductions, product approvals and financial performance. You can identify these statements by the fact that they do not relate strictly to historical or current facts. They use words such as ‘anticipate’, ‘estimate’, ‘expect’, ‘project’, ‘intend’, ‘plan’, ’believe’ and other words and terms of similar meaning in connection with a discussion of future operating or financial performance. Such forward-looking statements are subject to risks, uncertainties and inaccurate assumptions. This may cause actual results to differ materially from expectations and it may cause any or all of our forward-looking statements here or in other publications to be wrong. Factors that may affect future results include interest rate and currency exchange rate fluctuations, delay or failure of development projects, production problems, unexpected contract breaches or terminations, government-mandated or market-driven price decreases for Novo Nordisk's products, introduction of competing products, Novo Nordisk's ability to successfully market both new and existing products, exposure to product liability and other lawsuits, changes in reimbursement rules and governmental laws and related interpretation thereof, and unexpected growth in costs and expenses. Risks and uncertainties are further described in reports filed by Novo Nordisk with the US Securities and Exchange Commission (SEC) including the company's Form 20-F, which was filed on 23 February Please also refer to the section Risk Management' in the Annual Report Novo Nordisk is under no duty to update any of the forward-looking statements or to conform such statements to actual results, unless required by law. Novo Nordisk has the copyright on the information contained in this presentation. © 2005 Novo Nordisk A/S. Forward-looking statements

3 Minimum clear space Minimum clear space Last text line 3 Agenda Novo Nordisk – a focused healthcare company Novo Nordisk in diabetes The metabolic syndrome Liraglutide - The first and only once daily human GLP-1 derivative New treatment modalities Insulin - the ultimate therapy NovoSeven® going forward

4 Minimum clear space Minimum clear space Last text line 4 Agenda Novo Nordisk – a focused healthcare company Novo Nordisk in diabetes The metabolic syndrome Liraglutide - The first and only once daily human GLP-1 derivative New treatment modalities Insulin - the ultimate therapy NovoSeven® going forward

5 Minimum clear space Minimum clear space Last text line Expected % CAGR % CAGR Diabetes care CNS Infectious disease Cancer Respiratory GI Cardiovascular Arthritis Growth hormone 5Y CAGR 31% Million USD … and NovoSeven® is on its way to becoming a blockbuster Source: SG Cowen, IMS/BW and Novo Nordisk A focused healthcare company within attractive therapy areas Existing and new focus areas continue to offer attractive growth rates … ,

6 Minimum clear space Minimum clear space Last text line 6 Agenda Novo Nordisk – a focused healthcare company Novo Nordisk in diabetes The metabolic syndrome Liraglutide - The first and only once daily human GLP-1 derivative New treatment modalities Insulin - the ultimate therapy NovoSeven® going forward

7 Minimum clear space Minimum clear space Last text line 7 The evolution of mankind 2.5 mn years50 years

8 Minimum clear space Minimum clear space Last text line 8 Causes of the metabolic syndrome Overweight/obesity Physical inactivity Genetics Closely associated with insulin resistance Underlying cause of diabetes Reduced HDL-C Elevated triglycerides Hypertension Abdominal obesity NCEP ATP III. Circulation. 2002;106: Dyslipidemia Hyper- glycaemia Obesity

9 Minimum clear space Minimum clear space Last text line 9 Glucose-induced insulin secretion Tissue response to insulin Hepatic glucose production Glucose uptake Impaired beta cell function Basal hyper- insulinemia Post receptor defect Glucose transport Insulin binding Insulin deficiency Insulin resistance Hyperglycemia Genetic Acquired Obesity Age Genetic Acquired Glucotoxicity Lipotoxicity Incl Type 2 diabetes – a complex disease

10 Minimum clear space Minimum clear space Last text line 10 Shortcomings of available treatments Progressive b-cell failure not counteracted Efficacy of available drugs is not sustained Treatment-related trade-offs Weight gain Hypoglycaemia Complexity of regimens Tolerability issues

11 Minimum clear space Minimum clear space Last text line 11 Agenda Novo Nordisk – a focused healthcare company Novo Nordisk in diabetes The metabolic syndrome Liraglutide - The first and only once daily human GLP-1 derivative New treatment modalities Insulin - the ultimate therapy NovoSeven® going forward

12 Minimum clear space Minimum clear space Last text line 12 What is GLP-1? Insulin response to oral glucose load (50 g/400 ml, ●) and during isoglycaemic i.v. glucose infusion (●) IR-insulin (mU/l) –10– * * * * * * * Time (min) Incretin effect A 31 amino acid peptide Cleaved from proglucagon in L-cells in the GI-tract (and neurons in hindbrain/hypothalamus) Secreted in response to meal ingestion (direct luminal and indirect neuronal stimulation) Member of incretin family (GIP, GLP-1 and others) GLP-1 has following effects: Nauck et al. Diabetologia 1986;29: 46–52, *p ≤ Increased insulin response Key observations Glucose-dependently stimulates insulin secretion and decreases glucagon secretion Delays gastric emptying Decreases food intake and induces satiety Stimulates -cell function and preserves or increases -cell mass in animal models

13 Minimum clear space Minimum clear space Last text line 13 Because of its short half-life, native GLP-1 has limited clinical value Lys DPP-IV HisAlaThr Ser PheGluGly Asp Val Ser TyrLeuGluGlyAla GlnLys Phe Glu IleAlaTrp LeuGly ValGlyArg Type 2 diabetes Healthy individuals i.v. bolus GLP-1 (15 nmol/l) Intact GLP-1 (pmol/l) Time (min) – t ½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l) Enzymatic cleavage High clearance (4–9 l/min) Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.

14 Minimum clear space Minimum clear space Last text line 14 Liraglutide is a long-acting GLP-1 analogue Knudsen et al. J Med Chem 2000;43: Improved pharmacokinetics: Self-association Albumin binding Slow absorption from subcutis Metabolic stability Long plasma half-life Stability against DPP-IV Based on natural GLP-1 (97% homology) HisAlaThr Ser PheGluGly Asp Val Ser TyrLeuGluGlyAla GlnLys Phe Glu IleAlaTrp LeuGly ValGlyArg Glu Arg C-16 fatty acid (palmitoyl)

15 Minimum clear space Minimum clear space Last text line 15 Once-daily injection of Liraglutide covers 24-h BG profile in type 2 diabetes Adapted from: Degn et al. Diabetes 2004;53: h glucose AUC (mmol/l/h, mean ± SE) ± ± 14.0 (p = 0.01) Plasma glucose (mmol/l) Injection (08.00) Time after injection (hours) Placebo Liraglutide (6 µg/kg OD) n=13

16 Minimum clear space Minimum clear space Last text line 16 Liraglutide – a significant effect on both glucose regulation and weight Fasting serum glucose mMmM Note: Data from the double-blind, double-dummy, randomised, parallel group dose titration phase 2 study including a total of 144 patients with an average HbA1c of %. All changes are from baseline; that is, FSG of mM and an average weight of kg. p<0.015 Liraglutide and metformin Glimepiride and metformin Mean change in body weight from baseline (%) Time (weeks) Significant effect on glucose regulationContinuing weight loss A reduction of HbA1c of more than 1%-points despite this being only a 5 week trial

17 Minimum clear space Minimum clear space Last text line 17 Effect on body weight and food intake in rats compared with DPP-IV inhibitor LAF-237 Total cumulated caloric intake was reduced with liraglutide (p=0.009) and unchanged with LAF237 12w treatment in obese candy fed rats ns LAF237, obese n = 9 Liraglutide, obese n = 10 Vehicle, obese n = 14 ***p = Body weight gain (g) Data are mean ± SEM Adapted from: Knudsen et al. Diabetes 2004;52(suppl 2):A339. Liraglutide selectively reduced calories obtained from candy

18 Minimum clear space Minimum clear space Last text line 18 Effect on -cell glucose sensitivity after a single dose Adapted from: Chang et al. Diabetes 2003;52: 1786–1791. n=10 Data are mean ± SEM.

19 Minimum clear space Minimum clear space Last text line 19 Summary of results from preclinical and clinical studies with liraglutide A 24-hour pharmacodynamic profile –Once-daily injection Multiple anti-diabetic actions –Increases insulin and lowers glucagon secretion –Rapid and sustained glycaemic effect –Weight control –-cell mass increased in animal models –-cell function improved in type 2 diabetes Strictly glucose-dependent actions –Very low hypoglycaemia risk (no major and few minor events) –Counter-regulatory response to hypoglycaemia not impaired Well-tolerated –Mild, transient GI-symptoms; no antibodies (12-week data)

20 Minimum clear space Minimum clear space Last text line 20 Key observations from two concepts Liraglutide Once daily Peakless Good effect on HbA1c and FBG Weight loss No antibodies No injection site reactions Exendin-4 Twice daily Peak Good effect on HbA1c Weight loss Antibodies Historical attempts to prolong GLP-1 action have led to injection site reactions

21 Minimum clear space Minimum clear space Last text line 21 Agenda Novo Nordisk – a focused healthcare company Novo Nordisk in diabetes The metabolic syndrome Liraglutide - The first and only once daily human GLP-1 derivative New treatment modalities Insulin - the ultimate therapy NovoSeven® going forward

22 Minimum clear space Minimum clear space Last text line 22 Muscle/Fat: PPARγ Protein tyrosine phosphatase-1b (PTP-1b) PPARδ IkB Kinase AMPK 1) 11bHSD1 2) Hormone Sensitive Lipase Adiponectin 3) ß-cell: GLP-1 Brain: GLP-1 Appetite regulators Liver: Hepatic enzyme inhibitors PPARα Glukokinase Glucagon antagonists PPARδ Gut: DPP-IV 1) AMPK: Adenosine 5’-MonoPhosphate activated protein Kinase 2) 11bHSD1: 11b-hydroxysteroid dehydrogenase-1 3) Adiponectin: One of the adipocyte-expressed proteins that function in the homeostatic control of glucose, lipid, and energy metabolism. Potential future targets for Type 2 diabetes Cure Disease prevention Stop disease progression Symptomatic treatment Possible targetsTreatment aspiration

23 Minimum clear space Minimum clear space Last text line 23 Examples of potential future type 2 diabetes drug candidates at Novo Nordisk Glucose lowering e.g. Glucagon receptor antagonists Obesity e.g. Histamine H3 receptor antagonists Beta-cell regeneration e.g. Transition Therapeutics, Islet neogenesis therapy

24 Minimum clear space Minimum clear space Last text line 24 Gluconeogenesis Glycerol Lactate Amino acids fructose Glucose-6-Phosphate Glucose Glucokinase Glucose-6- Phosphatase PEPCK Fructose 1-6-bisphosphatase Glycogenolysis Glycogen Glycogen Synthase Glycogen phosphorylase Glucagon Inappropriate hepatic glucose production in type 2 diabetes                               

25 Minimum clear space Minimum clear space Last text line 25 Hyperglucagonemia through-out the day in people with type 2 diabetes Reaven et al. J. Clin. Endo. & Metab Time Glucagon (pg/ml)

26 Minimum clear space Minimum clear space Last text line 26 Lowered glucose in glucagon receptor knockout mice GR-/- GR+/+ RW Gelling et al. PNAS 100: , 2003 Blood glucose (ad lib fed)

27 Minimum clear space Minimum clear space Last text line 27 Decreased fat mass in glucagon receptor KO mice +/+ -/- RW Gelling et al. PNAS 100: , 2003

28 Minimum clear space Minimum clear space Last text line 28 Glucagon receptor antagonists activities Discovery: Potent, selective, competitive and reversible glucagon receptors antagonists with acceptable pharmacokinetics have been identified The glucagon receptor antagonists improve glucose handling in animal models of type 2 diabetes Development: The glucagon receptor antagonist NN2501 is currently in phase 1 with the aim of evaluating the concept in humans

29 Minimum clear space Minimum clear space Last text line 29 Islet Neogenesis Therapy Regeneration of beta cells in animal models of type 1 and type 2 diabetes following Islet Neogenesis Therapy (INT): a combination of the growth factors EGF and Gastrin –In a type 2 diabetes animal model Psammomys obesus (Sand rat) –In a type 1 diabetes animal model: Non obese diabetic mouse (NOD)

30 Minimum clear space Minimum clear space Last text line 30 Islet Neogenesis Therapy: proposed mechanism of action Regeneration of islet cells in the body using two growth factors, Epidermal Growth Factor (EGF) and Gastrin that reproduces fetal development Islet Precursor Stem Cell Nesidioblast proliferation Mature Islet Low level Insulin Expression New islet budding from duct EGF + Gastrin Fetal Development BIRTH

31 Minimum clear space Minimum clear space Last text line 31 Morning blood glucose in Psammomys obesus before, during and after treatment with INT or vehicle HE LE INT Follow-up Vehicle, N=8 INT, N=6 Days after start of HE diet Blood glucose in mmol/l

32 Minimum clear space Minimum clear space Last text line 32 Psammomys obesus pancreas after 2 weeks INT BetaNon Beta cell mass mg/kg Vehicle INT Vehicle INT Islet cell mass

33 Minimum clear space Minimum clear space Last text line 33 Agenda Novo Nordisk – a focused healthcare company Novo Nordisk in diabetes The metabolic syndrome Liraglutide - The first and only once daily human GLP-1 derivative New treatment modalities Insulin - the ultimate therapy NovoSeven® going forward

34 Minimum clear space Minimum clear space Last text line 34 Restore postprandial insulin response and improve basal insulin levels to near normal Improve insulin sensitivity in peripheral tissues and reverse insulin resistance Spare beta cells and preserve beta-cell function Prevent development of microvascular complications Insulin is the ultimate treatment for type 2 diabetes… Benefits of the addition of insulin therapy in type2 diabetes Insulin is the ultimate treatment Source: UKPDS Study Group 1998, Daily G; Clinical Therapeutics/vol 26, no -Cell function Time from diagnosis Diet and exercise OADs Insulin

35 Minimum clear space Minimum clear space Last text line 35 Type 2 - slope Out of ‘guideline’ control HbA 1c 10% 9% 8% 7% 6% Recommended insulin initiation Guideline control ADA IDF ADA EASD/AACE Note: ADA is American Diabetes Association, IDF is International Diabetes Federation, EASD is European Association for the Study of Diabetes, AACE is American Association of Clinical Endocrinologists Source: Novo Nordisk type 2 diabetes market research, Roper Starch, ADA, EASD, IDF, AACE, Wright A., Burden et al, Diabetes Care 2002; 25:330–336, Turner RC, Cull et al, JAMA 1999; 281:2005–2012 It is estimated that more than 2/3 of the patients are not in control Real-life insulin initiation  -cell function Time from diagnosis Type 1 – immediate need for insulin 50%

36 Minimum clear space Minimum clear space Last text line 36 Hypoglycaemia in UKPDS: a problem, also in type 2 diabetes % patients reporting hypo- glycaemia during treatment with Per yearSUInsulinMetf. Any event Major event*) UKPDS 16. Diabetes 1995;44:1249– Riddle et al. Diabetes Care 2003;26:3080– Alberti. Pract Diab Int 2002;19:22– Korytowski. Int J Obesity 2002;26(Suppl 3)18– Hunt et al. Diabetes Care 1997;20:292– Leslie et al. Diabetes Spectrum 1994;7:52. *) Requiring 3rd party help Around 50% of patients are very worried about the risk of hypoglycaemic events Fear of hypoglycaemia and need for careful blood glucose monitoring contributes to psychological insulin resistance Concerns regarding hypoglycaemia is a barrier to intensifying treatment

37 Minimum clear space Minimum clear space Last text line 37 Weight HbA1c Hypos The Levemir® puzzle: - It all comes together Change in Hb1Ac p < p < Hypoglycaemia all p < Nocturnal hypoglycaemia Levemir®/NovoRapid® Human insulin Source: Diabetologia (2004) 47: Study design: 18-week study, 1:1 randomised, open-labelled, parallel trial, 595 patients with type 1 diabetes mellitus received insulin detemir or NPH insulin in the morning and at bedtime in combination with mealtime insulin aspart or regular human insulin respectively ±2.4 kg 0.1 ±2.0 kg 1 0 p < Change in body weight Predictable

38 Minimum clear space Minimum clear space Last text line 38 Levemir® vs. NPH in treat-to-target trial: HbA1c and hypoglycaemia HbA 1c (%) Weeks NPH + OAD Insulin detemir + OAD Hermansen et al. EASD 2004 Poster 754:PS % risk reduction p < % risk reduction p < Events per patient per year Overall Nocturnal Hypoglycaemia

39 Minimum clear space Minimum clear space Last text line 39 Levemir® vs. NPH insulin Treat-to-target trial: HbA1c and weight HbA 1c (%) Weeks Insulin detemir + OAD NPH + OAD Insulin detemir + OAD NPH + OAD p < kg kg Change in weight from baseline to endpoint (kg) Hermansen et al. EASD 2004 Poster 754:PS 64.

40 Minimum clear space Minimum clear space Last text line 40 Clamp-profiles for NPH insulin, insulin glargine and Levemir® Adapted from T. Heise, et al. Diabetes The reasoning behind the superior Levemir® profile NPHInsulin glargine Levemir

41 Minimum clear space Minimum clear space Last text line 41 Novo Nordisk is the only company offering the full range of analogues Convenience Meeting physiological need for control Analogue s supported by strong device portfolio

42 Minimum clear space Minimum clear space Last text line 42 CompoundTypeIndicationPhase Levemir® (insulin detemir)InsulinType 1+2 diabetes Being rolled out in EU Filed US Phase 3 JP NovoMix® 50 and 70InsulinType 1+2 diabetesFiled EU+JP AERx® iDMS (NN1998)InsulinType 1+2 diabetesPhase 2 Liraglutide (NN2211) GLP-1 analogue Type 2 diabetesPhase 2 NN344InsulinType 1+2 diabetesPhase 1 NN2501OADType 2 diabetesPhase 1 Diabetes care pipeline

43 Minimum clear space Minimum clear space Last text line 43 Agenda Novo Nordisk – a focused healthcare company Novo Nordisk in diabetes The metabolic syndrome Liraglutide - The first and only once daily human GLP-1 derivative New treatment modalities Insulin - the ultimate therapy NovoSeven® going forward

44 Minimum clear space Minimum clear space Last text line 44 Critical bleedings in elective surgery Bleedings in emergencies Intracerebral haemorrhage Trauma UGI Prophylaxis High single-dose Liver transplantation Spinal surgery Hepatectomy Glanzmann’s FVII deficiency Orthopaedic surgery Acquired haemophilia Variceal bleedings TBI Cardiac surgery NovoSeven® - expanding into general haemostasis Congenital clotting disorders Key observations Trauma Regulatory dossier for blunt trauma submitted to EMEA early January 2005 Trial targeting the US to be initiated in Q Current activities ICH data published in NEJM in February 2005 Trauma data to be published in medical journals during 2005 Several studies ongoing ICH Regulatory dossier expected to be submitted to EMEA by mid-2005 A global phase 3 trial to be initiated in Q2 2005

45 Minimum clear space Minimum clear space Last text line 45 NovoSeven® - Novo Nordisk keeps expanding the IP rights Factor VII first filings of patent applications by Novo Nordisk Key observations More than 80 patent filings so far Major patent expirations are US end 2010 EU early 2011 Japan 2008

46 Minimum clear space Minimum clear space Last text line 46 Taking NovoSeven® beyond patent expiration - an example Clot Firmness Build on rFVIIa mechanism of action to provide fast and efficient local haemostasis Same activity as rFVIIa when bound to tissue factor Increased activity when bound to the activated platelet Time (s) FVIIa – 25 nM (90 µg/kg) FVIIa – 200 nM (720 µg/kg) Analogue-1 – 25 nM Analogue-2 – 25 nM Analogue-3 – 25 nM

47 Minimum clear space Minimum clear space Last text line 47 Taking NovoSeven® beyond patent expiration Formulations Ready-to-use device Alternative formulation Heat stable Analogues Various analogues Derivatives Long-acting derivative Combinations FXIII combination therapy Extensive preclinical activities ongoing

48 Minimum clear space Minimum clear space Last text line 48 Investor information Investor Relations contacts Novo Nordisk A/S Investor Relations Novo Allé, DK­2880 Bagsværd Fax (+45) Mogens Thorsager Jensen Tel (direct): (+45) Palle Holm Olesen Tel (direct): (+45) In North America: Christian Kanstrup Tel (direct): (+1) Share information Novo Nordisk’s B shares are listed on the stock exchanges in Copenhagen and London. Its ADRs are listed on the New York Stock Exchange under the symbol ‘NVO’. For further company information, visit Novo Nordisk on the internet at


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