AstraZeneca PLC · LSE:AZN
AstraZeneca — Technical Presentation (September 1999)
27 slides from AstraZeneca's technical presentation, Sep 22, 1999
Slide 1: AstraZeneca Cardiovascular
AstraZeneca Cardiovascular Hamish Cameron Vice President & Head of Cardiovascular TA Causes of death The burden of cardiovascular disease Infectious and Chronic obstructive parasitic diseases lung diseases Other and Injury and poisoning unknown causes Maternal and perinatal causes Cancer Cardiovascu
Slide 2: AstraZeneca Cardiovascular - making the most of our marketed products
AstraZeneca Cardiovascular - making the most of our marketed products AstraZeneca marketed cardiovascular products h Atacand® h Sular® h Zestril® h Canef® h Zestoretic® h Niften® h Seloken ZOK® /Toprol XL™ h Sorbitrat® h Tenormin® h Suscard® h Inderal® h Bamycor® h Plendil® h Xylocard® h Logimax® h
Slide 3: Zestril
Blockade of the renin-angiotensin system – a rational approach to antihypertensive treatment Angiotensinogen Renin Zestril® Non-ACE pathways Angiotensin I Kinins ACE Inactive Angiotensin II fragments AT1-receptor Atacand® Vaso- Cell Sodium and fluid Sympathetic constriction growth retention activati
Slide 4: Atacand - superior BP reduction
Atacand® h AT1 receptor blocker h Early growth to challenge class leadership h Better efficacy, longer duration, tighter binding and clear dose response relationship h US superiority claim h Strong lifecycle plan Atacand® - superior BP reduction Sitting DBP 0 losartan irbesartan Atacand® -2 -4 -6 -8
Slide 5: Atacand in hypertension: more effective than losartan
Atacand® in hypertension More effective than losartan Placebo Atacand ® Losartan losartan 8 mg Week 8 Hour after dose 2 16 mg 50 mg n=85 n=82 n=84 n=83 0 4 8 12 16 20 24 28 32 36 0 0 -2 -2 -4 -6 -4 -8 P=0.004 -10 -6 -12 -14 -8 -16 -18 Change in SBP Atacand ® 16 mg -10 p=0.013 mm Hg Losartan losartan
Slide 6: Heart failure - a very high cost
Heart failure - a very high cost h 5 million with CHF in the USA h 400,000 new cases every year h 1 million hospitalisations every year h Commonest discharge diagnosis in patients over 65 years h Estimated annual cost in the US - $40bn MERIT - HF h 4000 patients, 14 countries h Moderate to severe he
Slide 7: MERIT-HF - improved survival, reduced hospitalisations
MERIT - HF - improved survival Total Mortality Per cent 20 Placebo 15 p = 0.0062 (adjusted) p = 0.00009 (nominal) 10 Metoprolol CR/XL Sudden Death 5 Risk reduction = 34% Per cent 12 0 Placebo 0 3 6 9 12 15 18 21 9 Months of follow-up p = 0.0002 The MERIT-HF Study Group, Lancet 1999;353:2001-07 6 Met
Slide 8: Developing and launching the superstatin
AstraZeneca Cardiovascular - developing and launching the superstatin ZD4522 - the superstatin opportunity US market data 7000 6000 Total Prescriptions (000) 5000 atorvastatin 4000 3000 2000 First generation statins 1000 0 Q1/95 Q2/95 Q3/95 Q4/95 Q1/96 Q2/96 Q3/96 Q4/96 Q1/97 Q2/97 Q3/97 Q4/97 Q1/98
Slide 9: Global hyperlipidemia market
Global hyperlipidemia market h $10bn market in 1998 h Double digit growth ($16bn by 2003) h Statins 88% of the market (18% growth) h Many patients remain untreated h Only 11/39 million Americans outside guidelines are treated h Desire for more patients into guidelines with starter dose Source: IMF H
Slide 10: ZD4522 - AstraZeneca's superstatin
ZD4522 - AstraZeneca’s superstatin h Midway through phase III - NDA 2Q01 h Over 2000 patients randomised h Profile as the next generation superstatin h Indications of beneficial effect on TG and HDL h Safety and tolerability equivalent to the best in the statin class h Associated science package wit
Slide 11: Thrombosis
Thrombosis Thrombosis The single largest cause of death and disability Acute/ Arterial Venous treatment UA/ A-fib/ “Prevention and AMI stroke treatment of thromboembolism” In/post hospital care Chronic/ prevention More than 2 million deaths per year in the US* * Bick R.L, Kaplan H. Med Clin North Am
Slide 12: The antithrombotic market is a large and growing market
The antithrombotic market is a large and growing market PAOD 1.5% Average annual growth rates Ischemic stroke 2% Congestive heart failure 1.7% Post myocardial infarction 1.4% Unstable angina 2.6% Atrial fibrillation 1.9% Venous thromboembolism 2.1% Hip/knee surgery 3.4% 0 2 4 6 8 10 12 14 16 18 Mill
Slide 13: Drawbacks with current therapies; H 376/95 oral direct thrombin inhibitor
Drawbacks with current therapies Vitamin K antagonists (VKA/warfarin) h Routine monitoring required h Significant food and drug interactions h Slow onset and offset of effect h Narrow therapeutic index h Variable response Low molecular weight heparins (LMWH) h Subcutaneous injections - inconvenient
Slide 14: Predictable kinetics H 376/95
Predictable kinetics H 376/95, 25 mg orally 0.4 Healthy male volunteers n=20, melagatran levels - CV 20 % Plasma conc, uM 0.3 0.2 0.1 0.0 0 3 6 9 12 Time, h Consistent kinetics - H 376/95 repeat dosing Total variability: CV of 15% Intraindividual variability: CV of 8% Plasma conc (µmol/L) 0.25 0.20
Slide 15: METHRO II - proof of concept established
METHRO II Study design low dose low medium high medium high dose LMWH Phase II dose ranging study Patients with hip or knee replacement surgery (n = 1916) 60 centres in 13 European Countries DVT rates measured 10 days post operatively Proof of concept established METHRO II - prevention of venous thr
Slide 16: H 376/95 - current status and plans
H 376/95 – current status and plans h Proof of concept/ phase III dose established h Indication plans – prevention of venous thromboembolism in hip and knee replacement – treatment of venous thromboembolism – prevention of stroke in atrial fibrillation h Regulatory authority interactions h Entering
Slide 17: H 376/95 summary; antithrombotic R&D portfolio
H 376/95 – summary The first oral direct thrombin inhibitor h The first new oral anticoagulant agent in 50 years h Meets a large unmet medical need h No need for routine monitoring h Dynamic and kinetic profile offering significant benefits over VKA and LMWH h Clinical trials – promising results h S
Slide 18: P2T Antagonists
P2T Antagonists Intravenous Oral AR-C69931MX ADP AR-C126532XX Platelet P2T receptors Platelet Platelet activation & Arterial adhesion aggregation thrombosis P2T Antagonist A new and novel class of antiplatelet h For prevention and treatment of arterial thrombosis h Blocks platelet aggregation by ADP
Slide 19: AR-C69931MX compared with GpIIb/IIIa in man
AR-C69931MX – compared with GpIIb/IIIa in man lamifiban AR-C69931MX (patients) (volunteers) ADP aggn (% inhibition) ADP aggn (% inhibition) 100 6 100 aggregation 6 bleeding time BT (fold increase) BT (fold increase) 80 5 80 5 60 4 60 4 40 3 40 3 20 2 20 2 recovery 0 +15 min 1 0 1 1 10 100 1000 10000
Slide 20: AstraZeneca Cardiovascular - future development pipeline
AstraZeneca Cardiovascular - future development pipeline Fundamental changes in the cardiovascular disease areas h Focusing on metabolic disorders and their complications rather than the traditional targets of blood pressure and circulatory dynamics h Modifying underlying disease processes rather th
Slide 21: Defining the AstraZeneca CV TA; diabetes - a growing challenge
Defining the AstraZeneca CV TA Discovery Astra Zeneca TA n entio ism olism / IRS synd coronary r is bol m ia prev sion angi tomatc ecto lure l emb s s boem II DM thmia rome id a e n ular rt fai na p throm s erte ity u ia e p lip Veno Obes Arrhy Acut Sym T yp e Vasc Arter He a H yp Dys Prescribers, p
Slide 22: Manifestations of the insulin resistance syndrome
Manifestations of the insulin resistance syndrome h Hyperinsulinemia h Hyperglycemia/ type 2 diabetes h Dyslipidemia/hypertriglyceridemia h Abdominal obesity h Hypertension h Impaired fibrinolysis The syndrome is associated with markedly increased risk of cardiovascular morbidity and mortality Combi
Slide 23: Activation of PPARs
Activation of PPAR’s AR-H039242XX Fibrates Thiazolidinediones PPARα PPARγ liver, kidney fat Regulation of genes involved in lipid metabolism Effects of AR-H039242 in Zucker Rats Normalisation of whole body insulin sensitivity 14 h Normalisation of insulin Insulin sensitivity index. 12 10 sensitivity
Slide 24: Effective doses in obese insulin resistant diabetic mice
Effective doses in obese insulin resistant diabetic mice Compared with untreated controls Compound ED25(µmol*kg-1) Relative potency AR-H039242 0.069 1/1 rosiglitazone 0.50 1/7 pioglitazone 17 1/250 troglitazone 167 1/2400 A complementary approach to treat dyslipidaemias Superstatins - Hyperlipidaemi
Slide 25: Cardiac arrhythmias - unmet need
Cardiac arrhythmias – unmet need h Atrial fibrillation – 3 million in USA – prevalence increasing by 7% per year – doubles mortality rate – five fold increase in stroke – only 10% treated AstraZeneca compounds with minimised TdP incidence identified (anaesthetised animal model) Number with TdP Dofet
Slide 26: New developments in CV; key brand filing dates to 2005
New developments in CV h PPAR agonists (AR-H039242XX) for type II diabetes/ insulin resistance and dyslipidemia (concept testing) h Novel antiarrhythmic (AR-H050642) for atrial fibrillation (concept testing) h NPY antagonist (H409/22) for ischaemic heart disease (concept testing) h Immunomodulator (
Slide 27: AstraZeneca - by 2010
AstraZeneca - by 2010 Key brand filing dates to 2005 Sales potential Atacand® ZD4522 Thrombin Oral P2T global superiority global NDA Inhibitor (AF) NDA claim in US US NDA 99 00 01 02 03 04 05 06 07 08 Atacand® + Seloken® PPAR agonist HCTZ US ZOK in CHF global NDA NDA US NDA Oral antiarrhythmic Throm
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