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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
• 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
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 – 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
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 – 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
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
18
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)
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
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
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
24
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
25
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
• 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
• 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
• 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
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
Analogue-2 – 25 nM
Analogue-3 – 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