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Novo NordiskNovo Nordisk
A focused global healthcare company A focused global healthcare company with biotech expertisewith biotech expertise
Diabetes Conference atDiabetes Conference at
Union Bank of SwitzerlandUnion Bank of Switzerland October 2001October 2001
Agenda
Introduction
Novo Nordisk: The futureInsulin therapy (NovoRapid®,insulin detemir, delivery systems)
Novo Nordisk diabetes commitment outside insulinOral Antidiabetics (OAD): NN622NN2211
Other conceptsIslet replacement
Metabolic abnormalities associated with Metabolic abnormalities associated with Type 1 and Type 2 diabetesType 1 and Type 2 diabetes
Type 1 Type 2
Elevated blood glucose xxx xxx
Ketosis xx 0
Insulin resistance x xxx
Hypertension x xx
Obesity x xxx
Increased LDL x/0 x/0
Increased triglycerides/FFA 0 xxx
Decreased HDL 0 xxx
Diabetes care: Treatment matters
Only a small number of Only a small number of patients are in controlpatients are in control
Intensive treatment mattersIntensive treatment matters
Dis
trib
uti
on
of
Dis
trib
uti
on
of
pat
ien
tsp
atie
nts
HbA1cHbA1c
* Measured according to Guidelines for Diabetes Care, IDF Europe
** According to epidemiological analysis of the UKPDS data, 1998
HbA1c lowering by one HbA1c lowering by one percentage point reduces percentage point reduces
micro vascular risk by 35%**micro vascular risk by 35%**
Close to 80% are exposed to
arterial or microvascular risk*
Diabetes therapy represents a growth marketDiabetes therapy represents a growth market
Number of diabetics estimated to grow 4% p.a.
Diagnosis rate will increase Some 75 million people are diabetics today without knowing it
Medicine use per diagnosed patient will increaseTreating more assertively reduces burden of late stage complications
Volume growth of at least 5% p.a. sustainableCurrent insulin market volume growth is 7-8%
Key insulin market observationsKey insulin market observations
VolumeVolume
No of people with diabetes No of people with diabetes expected to double by 2025expected to double by 2025
Increased diagnosis rateIncreased diagnosis rate
Intensified therapyIntensified therapy
Product upgradesProduct upgrades
Insulin analoguesInsulin analogues
Insulin delivery systemsInsulin delivery systems
5% annual growth5% annual growth Adding 5% to annual growthAdding 5% to annual growth++
Novo Nordisk to leverage on growthNovo Nordisk to leverage on growth
Building on more than 75 years of experience within Building on more than 75 years of experience within diabetesdiabetes
Dominant position in the European and Japanese insulin Dominant position in the European and Japanese insulin markets – solid growth in the USmarkets – solid growth in the US
More than 2,000 R&D employees dedicated to diabetes, More than 2,000 R&D employees dedicated to diabetes, representing approximately ¾ of R&D resourcesrepresenting approximately ¾ of R&D resources
Most complete portfolio of new insulinsMost complete portfolio of new insulins
Leadership in insulin delivery systems – one new device Leadership in insulin delivery systems – one new device per yearper year
Most comprehensive diabetes Type 2 pipeline in the Most comprehensive diabetes Type 2 pipeline in the industryindustry
Diabetes R&D at Novo Nordisk:Diabetes R&D at Novo Nordisk:Sources of innovationSources of innovation
Clinical researchClinical research
Steno Diabetes CentreSteno Diabetes Centre
Oxford Diabetes CentreOxford Diabetes Centre
Clinical research centres worldwideClinical research centres worldwideEvidence-based medicineEvidence-based medicine
NN disease mgt programmesNN disease mgt programmes
Outcomes data from > 100.000 Outcomes data from > 100.000 individuals with diabetesindividuals with diabetes
Molecular diversity & designMolecular diversity & design
Protein chemistry since ’23Protein chemistry since ’23
Medicinal chemistry since ’68Medicinal chemistry since ’68
Computational chemistry since ’75Computational chemistry since ’75
Rational drug design since ’83Rational drug design since ’83
Combinatorial chemistry since ’93Combinatorial chemistry since ’93 TrinomicsTrinomics
Genomics: Incyte since ’95Genomics: Incyte since ’95
Proteomics: CPA since ’97Proteomics: CPA since ’97
Metabonomics since ’99Metabonomics since ’99
Drug target & screeningDrug target & screening
Molecular biology since ’80Molecular biology since ’80
HT screening: Amersham since ’92HT screening: Amersham since ’92
Chemoinformatics since ’95Chemoinformatics since ’95
Dundee MRC consortium since ’98Dundee MRC consortium since ’98
Ultra HT Screening since ’00Ultra HT Screening since ’00
Basic researchBasic research
Hagedorn Research InstituteHagedorn Research Institute
Oxford and Steno Diabetes CentreOxford and Steno Diabetes Centre
Academic collaborationsAcademic collaborations
ConsortiaConsortia
R&D projectsR&D projects
Pharmaceutical needs in diabetes Pharmaceutical needs in diabetes
Type 1
Intervention in -cell destruction
Blood glucose regulation*
Type 2
Blood glucose regulation*
Regulation of energy balance (diabetes-associated obesity)
Reduction of triglycerides, FFA and LDL/HDL ratio (diabetic dyslipidaemia)
* Including, but not restricted to, new pharmaceuticals
Diabetes drug candidates in development Diabetes drug candidates in development at Novo Nordisk at Novo Nordisk
Genotype
Phenotype
ObesityInsulin Resistance
Dyslipidaemia
Type 2diabetes*
Failure of oral drugs
Diet and exercise:
NN education programme
Appetiteregulation:
NN2211
Sensitizers andlipid-lowering agents:
NN2344
NN622
β-cell agents: NovoNorm® NN2211, NN414
Hepatic glucose regulators:NN4201
Insulins:
NovoRapid®, NovoMixTM,
AERx, insulin detemir, LABI
• Type 2 diabetes is preceded by impaired glucose tolerance and occurs when the beta- cell fails. It may also be seen in the absence of obesity and insulin resistance.
Going forward in diabetes:Expanding leadership in insulin therapy
Innovation within insulin therapy will continue to drive the insulin market by providing more efficacious, reproducible and convenient treatment modalities
Novo Nordisk will expand leadership in insulin therapy by maintaining the world’s richest insulin therapy portfolio
Insulin analogues
Insulin formulations
Insulin delivery systems
Insulin profiles in type 1 diabetic patients Insulin profiles in type 1 diabetic patients treated with NovoRapidtreated with NovoRapid®® or human insulin or human insulin
Ser
um in
sulin
Time of day
Dinner NPHBreakfast LunchAdapted from Home et al. 1998
NovoRapid®
Soluble human insulin
(0.15 U/kg)
(mU/l) (pmol/l) 600
300
0
100
200
400
500
0
20
40
60
80
100
0600 1200 1800 2400 0600
NovoRapid® appears to have a longer post-prandial duration of action; this may contribute to
insulin coverage until next meal
lower pre-prandial blood glucose levels, comparable with human insulin
flexibility with timing of meals
NovoRapidNovoRapid®® versus insulin lispro versus insulin lispro
Home PD, et al. Diabetes Care 1998;21:1904-1909Gale EAM, et al. Diabetic Medicine 2000;17:209-214
Profile of the ideal basal insulinProfile of the ideal basal insulin
Desirable properties:
SolubilitySoluble at neutral pH
Mixable with other insulins
AbsorptionPredictable
Glucose lowering effectPeakless with low variability
Safety profileLow risk of hypoglycaemia at all times
Injection siteNo local reactions
Limitations of current insulins:
SolubilityMost current basal insulins require re-suspension
AbsorptionHighly variable
Glucose lowering effectNot predictable
Safety profileRisk of hypoglycaemia
Injection siteInjection pain with acidic insulin
Mechanism of protractionMechanism of protraction of i of insulin detemirnsulin detemir
HSA: human serum albumin
Distribution
AbsorptionReceptor
interaction
Insulin detemir versus NPH insulinInsulin detemir versus NPH insulinNight-time glucose profileInsulin detemir versus NPH insulinInsulin detemir versus NPH insulinNight-time glucose profile
Treatment: Insulin detemir NPH insulin
BG (mM)
N = 21
N = 52
5
6
7
8
9
10
11
12
11pm 3am 7am
J. L. Selam et al. :Oral presentation EASD 2001
Findings: Predictable glucose profiles over night with detemir
Insulin detemir showed reduced variability compared to NPH
Insulin detemir versus NPH insulin Insulin detemir versus NPH insulin Hypoglycaemic events:Hypoglycaemic events: reduced for insulin detemir at all timesreduced for insulin detemir at all times
Hermansen et al. Diabetes Care 2001;24:296-301
36%
39%
26%
62%
50
40
30
20
10
0
NPH insulin
Insulin detemir
Time unknown22:30-8:00 8:00-12:00 12:00-22:00
Nu
mb
er o
f ep
iso
des
Findings: Statistatically fewer hypoglycaemic events
Insulin detemir: Results presented at EASDInsulin detemir: Results presented at EASD
Soluble at neutral pH: No re-suspension required
Contributes to reproducible pharmacokinetic profile
Mixable with other insulin products
Novel mechanism of protraction:Protracted action due to albumin binding
Predictable action profile
Low intra-patient variability:Contributes to low risk of hypoglycaemia
Safety:Reduced risk of hypoglycaemic events versus NPH
Novo Nordisk devices in diabetes care
First pen (NovoPen 1) launched in 1985
In the US, launch of the first pen in 1988
Upgrading the insulin marketUpgrading the insulin market
De
vic
e p
en
etr
atio
nD
ev
ice
pe
ne
trat
ion
Insu
lin a
nal
og
ue
Insu
lin a
nal
og
ue
pe
ne
tra
tio
np
en
etr
ati
on
100%
100%
100%
100%
0%0%
(+50
% p
rem
ium
)(+
50%
pre
miu
m)
(+30
% p
rem
ium
)(+
30%
pre
miu
m)
Increasing turnover Increasing turnover per patientper patient
US
A
Jap
anE
uro
pe
AERx iDMS: Pulmonary insulin administration
Pulmonary insulin opportunityNon-invasive insulin delivery
Mainly poorly controlled Type 2 diabetes patients
Expanded insulin sales
Product requirementsAccuracy, precision, dose adjustment
Patient friendly device interface
Scaleable manufacturing
Aradigm is the ideal partnerLiquid insulin formulation
Breath control
Increment of single insulin units
Performance monitoring
Pulmonary insulin delivery: Competition
Aradigm Inhale Alkermes
Speciality Systemic + local delivery
Systemic delivery
Systemic
Device Single dose, liquid aerosol
Single dose -
Size Portable, not pocket-sized
Portable, not pocket-sized
Portable, pocket sized
Formulation Liquid, disposable unit dose
Dry powders, disposable unit dose
Dry powders
Breath Control Yes, patient training device
None Breath activated device
Comments Phase II, Novo Nordisk
Phase III, Pfizer/Aventis
Phase I, Eli Lilly
The insulin market: Overall conclusionsThe insulin market: Overall conclusions
Both Type 1 and 2 diabetes
Mainly specialist driven, but GPs very important in US
Few players, large volumes
Inexpensive and reimbursed treatment
Necessitates multiple daily injections and glucose monitoring
Patients start too late on insulin
Devices increasingly important
Need for education on importanceof treating more assertively
Insulin products Actrapid®, Insulatard®, Monotard®,
Mixtard®, Ultratard®, Velosulin®, Novolin®, NovoRapid®, NovoMix™ (registration), Insulin detemir (Phase 3), LABI (Phase 1)
Insulin delivery systems NovoPen®, NovoLet®, PenMate™,
Innovo®, InnoLet®, In-Duo™, FlexPen, AERx/NN1998 (Phase 2)
Committed to 1 new device per year
Novo Nordisk in type 2 diabetes careNovo Nordisk in type 2 diabetes care
NovoNorm®/Prandin® – the 1st prandial glucose regulator
NN622 – the dual-acting insulin sensitiser
NN2211 - a long-acting GLP-1 analogue
00
2020
4040
6060
00 11 22 33 44 55 66Years from randomisationYears from randomisation
Adapted from UK Prospective Diabetes Study (UKPDS) Adapted from UK Prospective Diabetes Study (UKPDS) Group. Group. DiabetesDiabetes. 1995; 44:1249-1258.. 1995; 44:1249-1258.
-Cell function ( % of healthy ) -Cell function ( % of healthy ) Diet and exerciseDiet and exercise Oral productsOral products
(approx 66%)(approx 66%)
Oral/insulinOral/insulin(approx 7%)(approx 7%)
InsulinInsulin(approx 27%)(approx 27%)
Type 2 diabetes disease management Type 2 diabetes disease management throughout lifethroughout life
00
5050
100100
150150
200200
250250
300300
350350
19961996 19971997 19981998 19991999 20002000 20012001
MA
TQ
1.19
96=
100
MA
TQ
1.19
96=
100
Growth within the OAD marketGrowth within the OAD market
Sales development in USDSales development in USDCAGR: 26%CAGR: 26%
No of treated patientsNo of treated patients CAGR: 13%CAGR: 13%
Growth in USD 5.8 bn OAD marketGrowth in USD 5.8 bn OAD marketKey observations Novo Nordisk
Experience in the OAD market from NovoNorm®/Prandin®
Novartis partner on NN622 for North America
Broad pipeline of innovative approaches for Type 2 diabetes
NovoNormNovoNormTMTM/Prandin/Prandin®®
NovoNormNovoNormTMTM/Prandin/Prandin®®
NN304NN304
NN1998NN1998
NN2344NN2344
Glucose-induced Glucose-induced insulin secretioninsulin secretion
Tissue response Tissue response to insulinto insulin
ImpairedImpairedbeta cellbeta cellfunctionfunction
Basal hyper- Basal hyper- insulinemiainsulinemia
Post Post receptor receptor defectdefect
GlucoseGlucosetransporttransport
Insulin Insulin bindingbinding
NN414
NN4201NN4201
Genetic
Acquired
Obesity
Age
Genetic
Acquired
Obesity
Age
Insulin deficiencyInsulin deficiency
Insulin resistanceInsulin resistance
NovoRapidNovoRapid®®
Type 2 Diabetes – the Metabolic Type 2 Diabetes – the Metabolic Syndrome Syndrome
Insulin deficiencyInsulin deficiency
Insulin resistanceInsulin resistance
HyperglycemiaHyperglycemia
NN2211NN2211
NN2211NN2211
NN622
NN622Genetic
Acquired Glucotoxicity Lipotoxicity
Genetic
Acquired Glucotoxicity Lipotoxicity
Hepatic Hepatic glucose glucose productionproduction
Glucose Glucose uptakeuptake
NN622
Elevated lipid levels are detrimental in Elevated lipid levels are detrimental in type 2 diabetestype 2 diabetes
MUSCLE
TG accumulation
Insulin resistance
B CELLS
TG accumulation
Disturbed insulinsecretion(hyperinsulinaemia)
AD
IPO
SE
TI S
SU
EA
DIP
OS
E T
ISS
UE
FFAFFA
Increasedhepatic glucose output(hyperglycaemia)
LIVER
• Increased VLDL • Decreased HDL• Increased small dense LDL Atherosclerosis
NN622: The dual acting PPARNN622: The dual acting PPAR// agonist agonist conceptconcept
insulin
Glucoseclearancerate
Glucoseproduction
+ -Inhibition of lipolysis,fat re-distribution
Fattyacids PPAR
PPAR
Triglyceride,Cholesterol
AGGTCA N AGGTCA Target gene
Transcription
PPRE
Nucleus
RXRPPAR
AGGTCA N AGGTCA Target gene
Transcription
PPRE
Nucleus
RXRPPAR
Effect on hepatic glucose productionEffect on hepatic glucose productionComparison between NN622, Avandia, Actos and a fibrateComparison between NN622, Avandia, Actos and a fibrate
Hep
atic
glu
cose
ou
tpu
t(m
g/kg
x m
in)
Vehicl
e
NN622:
3 m
g/kg
Avand
ia: 3
mg/
kg
Actos:
3 m
g/kg
Fibrat
e: 3
mg/
kg
0
1
2
3
4
5
6
7
8
NN622 shows superior efficacy in suppressing glucose production by the liver.
Source: Ye et al. Diabetes 2001; 50: A316
NN622 possesses potent lipid-lowering NN622 possesses potent lipid-lowering activity in cholesterol-fed ratsactivity in cholesterol-fed rats
HDL Cholesterol
VLDL Cholesterol
0
25
50
75
100
* *
Pla
sm
a H
DL
ch
ole
ste
rol
(mg
/dL
)
*
**
0
10
20
30
40
Pla
sm
a V
LD
L c
ho
leste
rol
(mg
/dL
)
*
**
*
Triglycerides
0
100
200
**
*
Pla
sma
Tri
gly
ceri
des
(mg
/dL
)
Source: Data on file
Triglycerides in liver and muscleTriglycerides in liver and muscleComparison between NN622, Avandia, Actos and a fibrateComparison between NN622, Avandia, Actos and a fibrate
*P < 0.05, ** P < 0.01, *** P < 0.001 vs Vehicle
Liver:mmol/g
0
10
20
30
******
Red muscle:mmol/g
Vehicle
NN62
2
Avand
ia
Fibr
ate
Actos
0
2
4
6
*******
*
00
2020
4040
6060
00 11 22 33 44 55 66Years from randomisationYears from randomisation
Adapted from UK Prospective Diabetes Study (UKPDS) Adapted from UK Prospective Diabetes Study (UKPDS) Group. Group. DiabetesDiabetes. 1995; 44:1249-1258.. 1995; 44:1249-1258.
-Cell function ( % of healthy ) -Cell function ( % of healthy ) Diet and exerciseDiet and exercise Oral productsOral products
(approx 66%)(approx 66%)
Oral/insulinOral/insulin(approx 7%)(approx 7%)
InsulinInsulin(approx 27%)(approx 27%)
Type 2 diabetes disease management Type 2 diabetes disease management throughout life: throughout life: -cell failure leads to T2D-cell failure leads to T2D
Increased insulin staining intensity after NN2211 treatment
-cell volume Proliferation0.00
0.25
0.50
0.75
1.00
(%)
NN2211 prevents diabetes in ZDF ratsNN2211 prevents diabetes in ZDF rats
Control
NN2211
NN2211 prevents the progression of diabetes in ZDF rats
Proliferation and volume of -cells are normalized
NN2211: Effect on fasting and post-prandial NN2211: Effect on fasting and post-prandial blood glucose in type 2 patientsblood glucose in type 2 patients
-2 0 2 4 6 8 10 12 14 16 18
4
5
6
7
8
9
10
11
12
NN2211Placebo
Time (hours)
Mea
n gl
ucos
e pr
ofile
s(m
mol
/l)
Dosing
Insulinpulse
analysis
Standardmeal
GLP-1 effects:
Insulin
-cell survival
Glucagon
Appetite
GI-emptying
NovoNordisk commitment to the cure of T1D : Stem cell research at Hagedorn Research Inst.
Cell type 1Cell type 2Cell type 3
Cell type 210
Beta cellZygote /ES-cell
Pancreatic Stem Cell
Islet Stem Cell
Goal: To mature or differentiate beta cells from stem-cell stages
Adult stem cell
Pancreatic islet cells
Hematopoietic cells
Cardiomyocytes
Neurons Hepatocytes
Immunologically
compatible transplant
Autologous stem cell therapyPatient
Modified from Nature Medicine 5:975-7, 1999
In Type 1 diabetes protection against autoimmune destruction will be necessary
Clinical stage diabetes pipelineClinical stage diabetes pipeline
NN2211NN2211 (GLP-1 analogue)(GLP-1 analogue)
NN1215NN1215 (LABI)(LABI)
NN1998NN1998 (AERx)(AERx)
NN4201NN4201 (Hepatic glucose regulator)(Hepatic glucose regulator)
NN304NN304 (Basal analogue) (Basal analogue)
NN414NN414 (Insulin secretion)(Insulin secretion)
NN622NN622 (Dual-acting sensitiser)(Dual-acting sensitiser)
Phase 1Phase 1 Phase 2Phase 2 Phase 3Phase 3
NN2344NN2344 (Insulin sensitiser)(Insulin sensitiser)
Forward-looking statements
This presentation contains forward-looking statements as the term is defined This presentation contains forward-looking statements as the term is defined in the US Private Securities Litigation Reform Act of 1995 in the US Private Securities Litigation Reform Act of 1995
Such forward-looking statements are subject to risk and uncertainties that Such forward-looking statements are subject to risk and uncertainties that may cause actual results to differ materially from expectations, including may cause actual results to differ materially from expectations, including unexpected developments in the international currency exchange and unexpected developments in the international currency exchange and securities markets, government-mandated or market-driven price decreases securities markets, government-mandated or market-driven price decreases for Novo Nordisk's products in the company's major markets and the for Novo Nordisk's products in the company's major markets and the introduction of competing products within Novo Nordisk's core businesses introduction of competing products within Novo Nordisk's core businesses
These and other risks and uncertainties, are further described in reports filed These and other risks and uncertainties, are further described in reports filed with the US Securities and Exchange Commission (SEC) by Novo Nordisk with the US Securities and Exchange Commission (SEC) by Novo Nordisk and readily available to the public, including the company's Form 20-F, which and readily available to the public, including the company's Form 20-F, which was filed on 2 was filed on 2 MayMay 20002000. . A Form 20-F for 2000 will be filed by the end of A Form 20-F for 2000 will be filed by the end of June 2001June 2001
Investor Information
Investor Relations Contacts:
Novo Nordisk A/S Investor Relations Novo Allé DK 2880 BagsværdDenmark Fax (+45) 4444 2314.
Peter HaahrPhone (+45) 4442 1207 E-mail: [email protected]
Palle Holm Olesen Phone (+45) 4442 6175 E-mail: [email protected]
Rasmus Holm-JørgensenPhone (+1) 212 867 0123 E-mail: [email protected]
Share information
Novo Nordisk’s B shares are listed on the stock exchanges in Copenhagen and London. Its ADSs are listed on the New York Stock Exchange under the symbol "NVO". For further company information, visit Novo Nordisk on the World Wide Web at
http://www.novonordisk.com