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.

A focused healthcare company

SG Cowen & Co. 25th Annual Health Care ConferenceBoston, March 15 2005

2

This presentation contains forward-looking statements as the term is defined in the US Private Securities Litigation Reform Act of 1995. 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 2005. Please also refer to the section Risk Management' in the Annual Report 2004. 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

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

Agenda

•Novo Nordisk – a focused healthcare company




5

0

5

10

15

20

0 5 10 15 20Expected % CAGR 2003-10

% C

AG

R 1

99

9-2

00

3

Diabetes careCNS

Infectious disease

Cancer

Respiratory

GI

Cardiovascular ArthritisGrowth hormone

5Y CAGR 31%

Million

US

D

… 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 …

0

250

500

750

1,000

1999 2000 2001 2002 2003 2004

6

Agenda


•Novo Nordisk in diabetes• The metabolic syndrome• Liraglutide - The first and only once daily human GLP-1



7

The evolution of mankind

2.5 mn years 50 years

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;106:3143-3421.

Dyslipidemia

Hyper-glycaemiaObesity

9

Glucose-induced insulin secretion

Tissue response to insulin

Hepatic glucose production

Glucose uptake

Impairedbeta cellfunction

Basal hyper- insulinemia

Post receptor defect

Glucosetransport

Insulin binding

Insulin deficiency

Insulin resistance

Hyperglycemia

GeneticAcquired Obesity Age

GeneticAcquired Glucotoxicity Lipotoxicity

InclType 2 diabetes – a complex disease

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

Agenda


•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


12

What is GLP-1?

Insulin response to oral glucose load (50 g/400 ml, ●) and during isoglycaemic i.v.

glucose infusion (●)

IR-i

nsu

lin (

mU

/l)

80

60

40

20

–10 –5 60 120 1800

** * * *

**

Time (min)

Incretineffect

• A 31 amino acid peptide

• Cleaved from proglucagon inL-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 ≤ 0.05.

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

Because of its short half-life, native GLP-1 has limited clinical value

7

37

9

Lys

DPP-IV

His Ala Thr Thr SerPheGlu Gly Asp

Val

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Type 2 diabetes

Healthy individuals

i.v. bolus GLP-1 (15 nmol/l)

Inta

ct G

LP-1

(p

mol/l)

Time (min)

–5 5 15 35 45

0

500

1000

25

t½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l)

Enzymatic cleavageHigh clearance (4–9 l/min)

Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.

14

Liraglutide is a long-acting GLP-1 analogue

Knudsen et al. J Med Chem 2000;43: 1664-1669.

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)

His Ala Thr Thr SerPheGlu Gly Asp

Val

Ser

SerTyrLeuGluGlyAlaAla GlnLys

Phe

Glu

Ile Ala Trp Leu GlyVal Gly Arg

Glu

Arg

C-16 fatty acid (palmitoyl)

7 9

37

15

Once-daily injection of Liraglutide covers 24-h BG profile in type 2 diabetes

Adapted from: Degn et al. Diabetes 2004;53: 1187-1194.

24-h glucose AUC(mmol/l/h, mean ± SE)

232.3 ± 21.9 187.5 ± 14.0 (p = 0.01)

Pla

sma g

luco

se (

mm

ol/l)

Injection (08.00)

Time after injection (hours)

00 4 8 12 16 20 24

6

8

10

12

14Placebo

Liraglutide (6 µg/kg OD)

n=13

16

Liraglutide – a significant effect on both glucose regulation and weight

Fasting serum glucose

0

-1

-2

-3

-4

mM

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 9.4-9.5%. All changes are from baseline; that is, FSG of 13.0-13.2 mM and an average weight of 91-94 kg.

p<0.015

Liraglutide and metformin Glimepiride and metformin

Mean c

hange in b

ody w

eig

ht

from

base

line (

%)

Time (weeks)

-3

-2

-1

0

1

2

0 1 2 3 4 5

Significant effect on glucose regulation Continuing weight loss

A reduction of HbA1c of more than 1%-points

despite this being only a 5 week

trial

17

Effect on body weight and food intake in rats compared with DPP-IV inhibitor LAF-237

Total cumulated caloric intake was reduced withliraglutide (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 = 0.0001

***p = 0.0001

Bod

y w

eig

ht

gain

(g

)

-20

-15

-10

-50

510

1520

25

30

35

Data are mean ± SEM

Adapted from: Knudsen et al. Diabetes 2004;52(suppl 2):A339.

Liraglutide selectively reduced calories obtained from candy

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Effect on -cell glucose sensitivity after a single dose

Adapted from: Chang et al. Diabetes 2003;52: 1786–1791.

0

2

4

6

8

10

12

14

4 6 8 10 12

Glucose (mmol/l)

Insu

lin s

ecr

eti

on r

ate

(p

mol/m

in/k

g)

Placebo

Liraglutide 7.5 μg/kg

Healthy controls

n=10

Data are mean ± SEM.

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)

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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

Agenda





22

Muscle/Fat:• PPARγ• Protein tyrosine

phosphatase-1b (PTP-1b)• PPARδ• IkB Kinase• AMPK1)

• 11bHSD12)

• Hormone Sensitive Lipase• Adiponectin3)

ß-cell: • GLP-1

Brain:• GLP-1• Appetite

regulators

Liver:• Hepatic

enzymeinhibitors

• PPARα• Glukokinase • Glucagon

antagonists• PPARδ

Gut:• DPP-IV

1) AMPK: Adenosine 5’-MonoPhosphate activated protein Kinase2) 11bHSD1: 11b-hydroxysteroid dehydrogenase-13) 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 targets Treatment aspiration

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

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Gluconeogenesis

GlycerolLactate

Amino acidsfructose

Glucose-6-Phosphate

Glucose

GlucokinaseGlucose-6-

Phosphatase

PEPCK

Fructose 1-6-bisphosphatase

Glycogenolysis

Glycogen

Glycogen Synthase

Glycogen phosphorylase

Glucagon

Inappropriate hepatic glucose production in type 2 diabetes

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Hyperglucagonemia through-out the day in people with type 2 diabetes

Reaven et al. J. Clin. Endo. & Metab. 1987

Time Time

Glu

ca

go

n (

pg

/ml)

26

Lowered glucose in glucagon receptor knockout mice

700 1000 1600 2000 24000.0

2.5

5.0

7.5

10.0

******

*****

Time of Day

Blo

od

Glu

cose

(mM

)

GR-/-

GR+/+

RW Gelling et al. PNAS 100: 1438-1443, 2003

Blood glucose (ad lib fed)

0 25 50 75 100 125

0

3

6

9

12

15

18

**

********

** ** *

Time (min)B

loo

d G

luco

se(m

M) GR+/+GR-/-

0

500

1000

1500

***

AU

C

IP-GTT

27

Decreased fat mass in glucagon receptor KO mice

GR+/+ GR-/-0

10

20

30

**

Ad

ipo

se t

issu

e

(% t

ota

l b

od

y m

ass)

+/+ -/-

RW Gelling et al. PNAS 100: 1438-1443, 2003

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

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

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 PrecursorStem Cell

Nesidioblastproliferation

Mature Islet

Low levelInsulin

Expression

New isletbudding

from duct

EGF + Gastrin

Fetal DevelopmentBIRTH

31

Morning blood glucose in Psammomys obesus before, during and after treatment with INT or vehicle

-10 0 10 20 30 40 50

0

10

20

HE HELE INT Follow-up

Vehicle, N=8

INT, N=6

Days after start of HE diet

Blo

od

glu

cose in

mm

ol/

l

32

Psammomys obesus pancreas after 2 weeks INT

0

25

50

75

100

125

150

Beta Non Beta

cell m

ass m

g/k

g

VehicleINT

Vehicle

INT

Islet cell mass

33

Agenda





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 diabetesInsulin is the ultimate treatment

Source: UKPDS Study Group 1998, Daily G; Clinical Therapeutics/vol 26, no 6 2004

-C

ell

funct

ion

Time from diagnosis

Diet and exercise

OADs

Insulin

35

Type 2 - slope

Out of ‘guideline’ control

HbA1c

10%

9%

8%

7%

6%

Recommended insulin initiationGuideline control

ADAIDFADAEASD/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

-ce

ll fu

nctio

n

Time from diagnosis

Type 1 – immediate need for insulin

50%

36

Hypoglycaemia in UKPDS: a problem, also in type 2 diabetes

% patients reporting hypo-glycaemia during treatment with

Per year SU Insulin Metf.

Any event 17.0 37.0 13.0

Major event*) 0.7 2.3 0.3

1. UKPDS 16. Diabetes 1995;44:1249–1258. 2. Riddle et al. Diabetes Care 2003;26:3080–3086.1. Alberti. Pract Diab Int 2002;19:22–24. 2. Korytowski. Int J Obesity 2002;26(Suppl 3)18–24.3. Hunt et al. Diabetes Care 1997;20:292–298. 4. 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

Weight

HbA1c

Hypos

The Levemir® puzzle:- It all comes together

Change in Hb1Ac

-0.5

-0.28 -0.5

0.5

0

p < 0.001

8.611.1

5

15 10

p < 0.001

Hypoglycaemia all

0.9

2.1

1

3

2

p < 0.001

Nocturnal hypoglycaemia

Levemir®/NovoRapid®

Human insulin

Source: Diabetologia (2004) 47:622-629. 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.

-0.8 ±2.4 kg

0.1 ±2.0 kg

-1

1 0

p < 0.001

Change in body weight

Predictable

38

Levemir® vs. NPH in treat-to-target trial:HbA1c and hypoglycaemia

-2 0 12

8.5

9.0

8.0

7.5

7.0

6.5

HbA

1c (%

)

Weeks

NPH + OADInsulin detemir + OAD

Hermansen et al. EASD 2004 Poster 754:PS 64.

55% risk reduction p < 0.001

24

47% risk reduction p < 0.001

Events

per

pati

ent

per

year

0

2

4

6

8

10

12

14

16

18

Overall Nocturnal Hypoglycaemia

39

Levemir® vs. NPH insulinTreat-to-target trial: HbA1c and weight

HbA

1c (%

)

-2 0 12 24Weeks

Insulin detemir + OAD

NPH + OAD8.5

9.0

8.0

7.5

7.0

6.5

0Insulin detemir

+ OADNPH + OAD

p < 0.05

+ 1.2 kg

+ 2.8 kg

0.5

1

1.5

2

2.5

3

3.5

Change in w

eig

ht

fro

m b

ase

line t

o e

ndpoin

t (k

g)

Hermansen et al. EASD 2004 Poster 754:PS 64.

40

Clamp-profiles for NPH insulin, insulin glargine and Levemir®

Adapted from T. Heise, et al. Diabetes 2004.

The reasoning behind the superior Levemir® profile

NPH Insulin glargine Levemir

41

Novo Nordisk is the only company offering the full range of analogues

Con

ven

ien

ce

Meeting physiological need for control

Analogues

supported by

strong device

portfolio

42

Compound Type Indication Phase

Levemir® (insulin detemir) Insulin Type 1+2 diabetes Being rolled

out in EU

Filed US

Phase 3 JP

NovoMix® 50 and 70 Insulin Type 1+2 diabetes Filed EU+JP

AERx® iDMS (NN1998) Insulin Type 1+2 diabetes Phase 2

Liraglutide (NN2211) GLP-1

analogue

Type 2 diabetes Phase 2

NN344 Insulin Type 1+2 diabetes Phase 1

NN2501 OAD Type 2 diabetes Phase 1

Diabetes care pipeline

43

Agenda




•NovoSeven® going forward

44

Critical bleedings in elective surgery

Bleedings inemergencies

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 Q2 2005

• 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

NovoSeven® - Novo Nordisk keeps expanding the IP rights

0

10

20

30

40

50

60

70

80

90

1999 2000 2001 2002 2003 2004

# o

f pate

nts

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

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



47

Taking NovoSeven® beyond patent expiration

FormulationsReady-to-use device

Alternative formulationHeat stable

AnaloguesVarious analogues

DerivativesLong-acting derivative

CombinationsFXIII combination therapy

Extensive preclinical activities ongoing

48

Investor information

Investor Relations contactsNovo Nordisk A/S Investor Relations Novo Allé, DK 2880 BagsværdFax (+45) 4443 6633

Mogens Thorsager JensenTel (direct): (+45) 4442 4579 E-mail: [email protected]

Palle Holm Olesen Tel (direct): (+45) 4442 6175 E-mail: [email protected]

In North America:

Christian KanstrupTel (direct): (+1) 609 919 7937 E-mail: [email protected]

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

http://www.novonordisk.com

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.

Documents

text line

agenda novo nordisk

forwardlooking statements

novo nordisks products

novo nordisks ability

cause of diabetes

complex disease slide

metabolic syndrome liraglutide