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Malcolm Skingle CBE DSc PhD Director – Academic Liaison Drug Discovery

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1 Malcolm Skingle CBE DSc PhD Director – Academic Liaison Drug Discovery
Innovation in the Pharmaceutical Industry through Partnerships with Academia & Industry Malcolm Skingle CBE DSc PhD Director – Academic Liaison Drug Discovery Annual Icelandic Medical Conference Venue: The Reykjavik Hilton Hotel Clinical Research – looking towards the future Wednesday January 26th 2011 January 26th 2011 Annual Icelandic Medical Conference Medical Research Symposium

2 Talk Plan Changing Landscape in the Pharma Industry
Innovation in Pharmaceuticals The Future for Pharma & Healthcare Discovery Partnerships in Academia (DPAc) Concluding remarks I am going to break my talk down into 4 sections over the next minutes. First I am going to describe the changing Landscape in the Pharma Industry before going on to talk about Innovation in Pharmaceuticals I will then share a few thoughts on the Future for Pharma & Healthcare Before describing one of my companies new initiatives which has been designed to accelerate translational research from bench to bedside and to improve links between clinical academics and scientists within GSK. This initiative has been labelled DPAc or Discovery Partnerships in Academia (DPAc) I will then finish with a few concluding remarks

3 Changing Landscape in the Pharma Industry

4 Drug Development is a costly & risky business
It takes up to15 years to develop a new drug Estimated full cost of bringing a new chemical or biological entity to market ($ million – year 2005 $) Source: J.A. Di Masi and H.G. Grabowski, ‘The Cost of Biopharmaceutical R&D: Is biotech Different? Managerial and Decision Economics 28 (2007): For every 5-10,000 molecules synthesised & screened for activity, only 250 reach pre-clinical development, only 5 reach clinical trials and only one reaches the market Cost to develop a drug in 2006: $ billion Only 2 of 10 marketed drugs ever produce revenues that match or exceed R&D costs. Pharmaceuticals are generally cheap and easy to copy – generic companies enter mature markets developed by innovator with low entry costs The Pharmaceutical industry, like many other businesses, is currently under tremendous pressure to deliver value to its shareholders. Year on year the costs of developing a medicine are going up and up. Inflation in research costs are far higher than regular inflation and the regulatory hurdles for Pharma companies are getting higher and higher. It can take up to15 years to develop a new drug, with the average being around 11 to 12 years For every 5-10,000 molecules synthesised and subsequently screened for activity, only 250 reach pre-clinical development, only 5 reach clinical trials and only one reaches the market The cost estimate to develop a drug in 2006 was $ billion dollars Only 2 of 10 marketed drugs ever produce revenues that match or exceed R&D costs. Pharmaceuticals are generally cheap and easy to copy – generic companies enter mature markets developed by innovator with low entry costs These features are probably unique to the pharmaceutical industry These features are probably unique to the pharmaceutical industry

5 R&D Productivity decreases the innovation gap is getting wider
This is the slide that all Pharma people show at talks like this showing that Pharma companies are suffering from a decline in productivity. The costs to develop a drug are increasing more and more but productivity is at best flat. Many top selling drugs are coming off patent at the same time as companies are finding it increasingly difficult to identify new drug approvals. This is causing pharma companies to re-evaluate their therapeutic area strategies and to re-organise their workforces. Pharma companies are increasingly turning to externalise parts of their R&D activities in order to diversify the science that they can access and in order to strip costs out of their businesses. Source: Burrill & Company; US Food and Drug Administration. Note: NMEs do not include BLAs

6 Pressures on the Pharma Industry
R&D spend continues to rise The blockbuster model is unsustainable Drugs not being reimbursed in some countries if they are not sufficiently differentiated There are higher regulatory risks post-launch Pricing discussions continue The pressures on the industry are causing them to re-think their innovation strategies. So as the R&D spend continues to rise the blockbuster model is unsustainable. Drugs not being reimbursed in some countries if they are not sufficiently differentiated. All clinical trials now compare the new investigational drug against the gold standard medicine for the disease rather than comparing the new drug against placebo as we would have done in the past. There are higher regulatory risks post-launch Pricing discussions continue with various regulatory agencies and governments around the world

7 Over 6,000 compounds in development
It is really competitive in the pharmaceutical industry which is a highly fragmented sector; And at the end of 2007 there were more than 6,000 compounds in development. The US leads the way in developing new medicines but the rest of the world is catching up Source: Adis R&D Insight Database, customized run (December 2007)

8 Competition in Therapeutic Innovation
Many scientists seeking to solve same problems in different or similar ways from similar starting points at the same time The first to market is generally quickly followed by several others >15 beta blockers 9 protease inhibitors 15 NSAIDs >10 statins The first mover is rarely the most successful The period of exclusivity for first movers is shrinking & Pharma are becoming more conservative Many scientists, from different organisations, seeking to solve same problems in different or similar ways from similar starting points at the same time. They all have access to the same literature and many have access to the same experimental models and platform technologies. So it is perhaps not surprising that different groups come up with similar innovations. The first drug to market is generally quickly followed by several others and if you look at the EU market at the moment you will see many different versions of molecules that treat the same therapeutic area. So for example there are more than 15 beta blockers and more than 10 statins on the market. The first to market is very rarely the most successful as often there are fast followers who improve on the original medication. This competition is healthy and good for patients. The period of exclusivity for the first to market companies is getting shorter and shorter.

9 Source: DiMasi & Paquette (2004)
The period of exclusivity for first entrants to a therapeutic class is decreasing (US data) This is the US data showing that the period of exclusivity for first entrants to a therapeutic class is decreasing. You have the mean number of years in blue, and the median in orange, and in the 1960’s and 1970’s the first to market therapeutics benefitted from a period of between 8 and 10 years exclusivity before followers entered the market. In the period from 1995 to date this period of exclusivity was between 1 and 2 years. The fast followers very quickly start nibbling into the profits of the companies who were first to market. Source: DiMasi & Paquette (2004)

10 Compound differentiation
New drugs tested against “gold standards” Patent competition drives improvements: Increased Efficacy Decreased Side-effects Decreased ADRs Decreased drug-drug interactions Decreased dosing Specialised drug delivery systems Patients benefit from a range of products with differing characteristics This level of competition leads to compound differentiation and better medicines for patients. We now have to benchmark new drugs against the gold standard treatment for the disease and have to show that our molecule has a competitive advantage over the gold standard. It is not enough to merely test your molecule against placebo as used to be the case. Patent competition drives improvement, this might be through… Increased Efficacy , Decreased Side-effects, Decreased adverse drug reactions, Decreased drug-drug interactions Decreased dosing regimens – say for example a move to once a day dosing, or depot sustained release formulations for non compliance say with schizophrenics or manic depressives who do not want to take their medication Specialised drug delivery systems Patients benefit from a range of products with differing characteristics

11 Quarterly Enalapril sales in the UK
If ever you wanted convincing that patents were important to our business you just need to look at the sales of a pharmaceutical product once it comes off patent: This is an old example now but it highlights perfectly the need for patents in the Pharma business. This is the sales curve for an ACE inhibitor, Enalapril, that was on market in the UK, it showed steady growth, sales flattened out, it came off patent and, bang, the generic companies had gobbled up their market in less than a year. Enalapril sales in the UK decreased by 70% in the first quarter once it came off patent. Source: IMS Health MIDAS database

12 The patent cliff: Pfizer will lose $13bn of income when the Lipitor patent expires in 2011. Eli Lilly will lose up to 75% of its revenue over the next 8 years unless it has new drugs to make up this loss. Forcing risk averse Pharma companies to diversify their approaches to R&D Several large pharma companies have very successful medicines that are about to come off patent and the amount of revenues that they are likely to lose are absolutely staggering. So for example Pfizer will lose $13 billion with the Lipitor patent expires this year. It has been calculated by the analysts that Eli Lilly will lose up to 75% of its revenue over the next 8 years if it does not develop new molecules to make up this shortfall.

13 Innovations in the Pharma Industry

14 Step Change Therapeutic Innovations
penicillins sulphonamides aspirin psychotropics NSAIDS H2-antagonists beta blockers lipid lowerers ACE-inhibitors Biotech drugs chronic degenerative disease associated with ageing, inflammation, cancer drugs against targets identified from disease genes 1900 2030 1950 1960 1970 1980 1990 2000 2010 2020 2040 New Therapeutic Cycles 1st generation 2nd generation 3rd generation natural products and derivatives serendipity receptors enzyme genetic engineering cell pharmacology/ molecular biology genomics / proteomics Medicine has advanced dramatically over the last 100 years and we have seen several waves of new therapeutic innovations resulting in a step change in how we practice medicine. In the first generation of this era we had the penicillins and aspirin being used to treat infection and inflammation. These were identified from natural products. We had the development of several psychotropic drugs; and the effects of these molecules, like several other classes of medicine, were identified through serendipity. In the 60’s and 70’s we had the 2nd generation therapeutics coming through as we developed a greater understanding of drug receptors and physiological enzymes. This was one of the most productive times for the pharmaceutical industry and several major classes of medicine were developed over this period. These included the NSAIDs and then slightly later the H2 antagonists and β-blockers. The lipid lowering drugs and ACE-inhibitors were developed 20 years or more ago – so many of these now off, or close to coming off, patent. Genetic engineering lead to the development of Biotech drugs and the growth of companies such as Genentech and Amgen. And around this time we developed a greater understanding of cell pharmacology and molecular biology. With the regular use of antibiotics and CV drugs we are now keeping people alive longer and, as a result, we are seeing an increased incidence of the chronic degenerative diseases associated with ageing; inflammation and cancer. We are now getting into a particularly exciting area where 3rd generation therapeutics are using genomics and proteomics to identify drugs against targets identified from disease genes. With some of the excellent Icelandic resources in deCODE, and the Icelandic health record system, Iceland is ideally placed to capitalise on this 3rd generation wave of therapeutics. I will come back this point.

15 Rapidly Changing Market
You can track the fact that the market is changing and the biologicals are gaining market share if you look at the top 10 products by sales. In 2000 the proton pump inhibitor, Losec, topped the sales charts and there was just one biological product in the top 10, namely Epogen, used to boost red blood cells. In 2008, Lipitor, Pfizers statin was the top drug but by 2008 half of the top ten were biologicals. These included biologicals such as Enbrel, Rituxan, Remicade and Avastin which all have anti-inflammatory effects. The forecast for the sales by 2014 shows that biologicals will have an even greater share of the market as we move forward with 7 of the top 10 selling pharmaceuticals will be biologicals. So all major pharmaceutical companies have expanded their biopharmaceutical research capabilities in recent years. Enbrel (Amgen/Pfizer) vs psoriasis and RA TNF inhibitor Entanercept. Rituxan (Novartis) vs RA and non-Hodgkins lymphoma anti CD20 B-cells. Remicade (Centocor) vs inflammatory disorders – psoriasis, RA Grohns; Mab vs TNF. Epogen (Amgen) EPO is a glycoprotein hormone which stimulated rbc’s. Avastin (Genentech/Roche) humanised Mab which blocks VEGF-A. Humira (Abbott Labs) 3rd anti-TNF inhibitor vs RA and ankylosing spondylitis. Lantus (Sanofi-Aventis) insulin glargine (r DNA origin). Herceptin (Genentech) Ab vs HER2 to treat breast cancer. Gleevec (Novartis) Benzamide NCE vs tyrosine kinase to treat SML chronic myelogenous leukaemia and GI stromal tumours. Crestor (AZ) another statin to reduce cholesterol. Spiriva (Boehringer-Ingelheim and Pfizer) anticholinergic bronchodilator vs COPD. Rapidly Changing Market Biologicals gaining market share

16 New drug product sales growth (2007-12)
% Sales Growth: CAGR Market Share % anti-hyperlipidaemics anti-psychotics anti-bacterials anti-hypertensives anti-virals anti-diabetics anti-rheumatics vaccines bronchodilators oncology This is a plot of % sales growth for the period 2007 projected through to 2012 against percentage market share. Everything to the left of this line is negative sales growth; so the cholesterol lowering drugs and the anti-psychotic sales are decreasing as some of the blockbuster drugs come off patent and the market is taken up by generic companies. The anti-hypertensives and anti-bacterials have flat sales growth with the anti-bacterials accounting for a very small amount of the total pharmaceutical market, again because many of these very effective medicines are now off patent. However, with antibiotic resistance and infections such as MRSA on the increase, several pharma companies are now working hard in a bid to develop the next generation antibiotics. There is a small but sustained growth with bronchodilators and anti-diabetics but the largest increases in sales growth are with anti-rheumatics, vaccines and top of the pile, oncology medicines. Many of the molecules in these 3 therapeutic areas are biopharmaceuticals rather than small chemical entities. (Compound annual growth rate)

17 Emergent science drives new disease opportunities
Where science and unmet need converge Core diseases Opportunities in “new” diseases featured in the business plan Cystic Fibrosis OSA ARDS Infant RDS IPF Idiopathic Fibrotic NSIP Fibrotic ILD Assoc RA Fibrotic ILD Assoc SLE Fibrotic ILD Assoc Sys Scl Sarcoidosis Idiopathic BOOP Chronic Cough PAH AAT Deficiency Bronchitis - acute Bronchiectasis BPD HPS Histoplasmosis Influenza Legionellosis LAM Silicosis Berylliosis HP - Farmer's Lung Pneumonia PE RSV Bronchiolitis SIDS Chronic sinusitis Nasal polyposis AR NAR - Pure AR - Pure + Mixed Peanut Allergy Atopic dermatitis COPD Asthma 1 2 3 4 5 100 1,000 10,000 100,000 1,000,000 10,000,000 100,000,000 US Population Prevalence/Incidence (Log Scale) Unmet Need Index Progressive, Fibrotic ILD (inc. IPF, NSIP, ILD Assoc CTDs - RA / SLE / Sys Scl) Key emergent areas of science Lung repair COPD, fibrotic lung diseases (IPF, ILD, CF) Neuronal mechanisms Rhinitis, asthma, COPD, cough As we use genetics and biomarkers to get a better handle on the underlying causes of some diseases we are re-classifying some diseases and often fragmenting our own markets in doing so. So companies will put data together such as these, plotting the level of unmet clinical need against the prevalence of the disease. Most large Pharma companies now also have groups of scientists focussing on rare diseases as they know that it will be easier to test potential medicines in this cohort of patients as often there are few if any effective medicines for some of these rare diseases. We also know that we are going to learn more about the aberrant physiology in these rare diseases and that this information may be transferable to other more common diseases. So many pharma companies will have projects attempting to re-purpose molecules that have perhaps been designed with another disease state in mind. Allergic Rhinitis Includes: AR-Pure, Mixed & NAR Progressive Fibrotic ILD Includes: IPF, ILD-RA Estimates of progressive fibrotic element to disease included: split out estimates. Immunomodulation Asthma, allergic rhinitis

18 Changing Trends in Pharma/Biotech
Management consultants, automation and HR: In the ’90s consulting companies offered their services to Pharma. Robotics for screening 1,000,000 compounds/week. Combinatorial Chemistry. “me too” compounds. The rise of Biotech: Antibodies were validated as drugs, small innovative companies cash starved therefore ripe for take over (could solve Pharma’s pipeline problem). How do you copy a biotech product (no generics). Health Budgets are finite: The amount paid for healthcare is no more than 15% of GDP Drugs must offer value (NICE). So the picture I am trying to paint here is one of massive change in our industry. Pharmaceutical companies have dramatically changed their drug development strategies over the last 10 to 20 years. In the 90’s we attempted to scale up our technology platforms in order to fill our innovation gap. So we had robotics where we would routinely screen a million compounds a week. We had combinatorial chemistry where we could generate millions of compounds but this did little to improve our success in developing new drugs. In parallel to this activity the biotechs were busily validating humanised Abs as drugs. Several of these small and innovative companies were cash starved and ripe for takeover and several were acquired by large pharma. So for example AZ acquired Cambridge Antibody Technology and GSK acquired Domantis. This was a smart strategic move for 2 reasons: Firstly, the biotech products helped to fill the development pipeline and secondly, unlike small chemical entities, the biologicals could not be copied as readily by the generic companies unless they made a massive investment in manufacturing technology and they acquired new know-how.

19 Biomedical innovation: The last 50 years
new technologies: applied pharmacology – agonists and antagonists genetic engineering – therapeutic proteins, imaging, arrays and antibodies bioengineering advances – hips and pacemakers but… economic model is unsustainable lacking productivity US health reforms starting to bite & we cannot focus only on “developed nations” Innovation over the last 50 years has driven enormous improvement in the quality of life and in longevity. The model has pretty much been focused on the rich nations. These innovations came at a cost to the healthcare services and in the US the percent of GDP spent on healthcare rose from around 6% in the early 60’s to around 16% by This economic model is clearly unsustainable and has been challenged; With the first attack on the Pharma industry coming from the Hillary Clinton Commission in the early 90s looking at U.S. healthcare costs and this has subsequently been taken up by the Obama legislation as they seek to force down the price of medicines. We are also entering new markets and addressing diseases in these developing countries. This is not completely altruistic……. BACKGROUND ONLY a new breed of pharmacologists with the agonists and antagonists delivered Beta Blockers for cardiac control and H2 antagonists for the control of peptic ulcers. with the breakthrough of enzymes in 1976, genetic engineering transformed our ability to re-administer therapeutic proteins and later humanised antibodies. biomedical engineering made giant strides to deliver hips and knee joints and cardiac stents and imaging moved on from x-ray to functional MRI and CT scanning – and not forgetting the cardiac pacemaker. Society continued to put little value on vaccines until Hepatitis B – patent protected - commanded a larger market and a good price. But, and it is a big BUT, the economic model that society built for healthcare was not and is not sustainable. In addition the flow of NDAs (New Drug Admissions) has rapidly declined so that even the mega merger corporation – Pfizer, GSK – can no longer afford their R&D batallions. Finally the payback from our knowledge based society in terms of jobs, profits and unmet clinical need is insufficient – THE MODEL HAS TO CHANGE Beyond GDP let’s look at some of the other failures of todays healthcare and some of the opportunities.

20 Emerging Markets will outgrow Developed Markets by 2020
2020 Growth Profile: BRIC countries, Mexico, South Korea & Turkey 12-13% growth p.a Total sales $400billion by 2020 Cf Mature markets (USA & Europe) low single digit growth $400B Assuming 2% growth per year Emerging Markets The Emerging Markets are outgrowing growing the US and the EU and they present a great opportunity for the pharmaceutical industry The emerging markets are predicted to outgrow developed markets by 2020 and IMS forecasts growth of 12-13% per year in countries including the BRIC countries (Brazil, Russia, India, China) and also Mexico, South Korea and Turkey, while mature markets are expected to grow only at low single digit rates Annual pharmaceutical sales in Emerging Markets is expected to reach $400 billion by 2020, equivalent to current sales in the US and the five major European markets combined $55B Source: IMS MIDAS 2006 sales data, Total Pharmaceutical Market * Extrapolations from 2006 to 2020 based on IMS projection and % of 2006 sales Year: 2006 Year: 2020* 20 20

21 GSK turnover growth in 2009 despite decline in US Pharma
+7% -13% +19% Consumer £4.7bn US growth rate impacted by losses to generics Rest of Pharma £2.2bn +22% Japan Ph £1.6bn US Pharma £9.2bn Emerging Markets Ph £3.0bn +20% Europe Pharma £7.7bn We can already see early signs of this with our own sales figures……..This is GSKs turnover growth in 2009 in the various markets GSK growth in 2009 was just 3% last year. This was primarily due to US sales going down 13% due to some of our drugs coming off US patents and the market being eroded by generics. Whereas all other parts of the GSK business were up. So the GSK European market was up 9%, emerging markets were up 20%, Japan was up 22% and Consumer Healthcare was up 7%. Consumer healthcare will be an increasingly important part of the GSK portfolio as we diversify our product range. +9% 2009 Turnover £28.4bn (+3%) CER growth rates Rest of Pharma includes Stiefel sales of £248m 21

22 The Future for Pharma & Healthcare
Changing Landscape in the Pharma Industry

23 The population challenge
The world today: The population challenge 60% of the worlds population is in Asia Cf. 5% of the world population in N.America N.America currently purchase almost 40% of the worlds Pharmaceuticals. This is unsustainable So what of the future of the pharmaceutical industry and healthcare – well we have a triple whammy, not only are healthcare costs per person on the increase but we are keeping people alive for longer and we have more people to care for. The population has grown almost 4 billion since I was born. The current world population is 6.9 billion with a forecast of 9.1 billion by From a pharmaceutical company perspective this is both a threat and an opportunity. Inevitably there will be a large increase in patient market size – in terms of those societies that have enough money to pay for their healthcare. 60% of the worlds population is in Asia and there economy and science base continue to grow. Only 5% of the world population is in North America and yet they currently purchase almost 40% of the worlds Pharmaceuticals. This is unsustainable. This balance has got to change in the coming years.

24 Possible game changers looking out 20 years
genomic medicine & epidemiology companion diagnostics pharmacogentics stem cell therapeutics synthetic biology nanotechnology bioengineering computational sciences digital pathology decision support systems medical imaging neurology infectious disease The development of new areas of science and new technologies will undoubtedly change how we think about healthcare in the future. With the advent of the next generation sequencing, genomic medicine & companion diagnostics will become commonplace. Companies such as decode will help us to unravel the causes of many diseases. Various platforms will allow us to determine, with greater clinical certainty, What our patients are suffering from as we work towards personalised medicine. And pharmaceutical companies will diversify their markets and product ranges as they expand from just prescription medicines to looking at the whole diagnosis and wellness spectrum.

25 The changing face of biological innovation
population (prevention) longevity (diabetes, neurological diseases, cancer) cost of healthcare (price, volume, companion diagnostics, efficacy) infectious disease (re-emergence of TB, influenza, potential for vaccines and therapeutics, drug resistance) counterfeiting understanding of genetics critical to human medicine. There will be a greater focus on prevention rather than treatment and the vaccines market will continue to grow. People will live even longer as we find better treatments for the commonest diseases. The cost of healthcare will be scrutinised yet further by payors and companies alike. In the past innovation has always been associated with a large price premium. With a new global market innovation, companies will now start to target volume and market leadership rather than price leadership. The economnics of the Pharma indusrty is likely to change. We thought that we had cracked infectious diseases but with the emergence of drug resistant strains of bacteria we are having to re-visit this area of research Counterfeiting is increasingly becoming an issue for our premium medicines Next generation sequencing is changing how we go about our research. I think that we oversold genetics in the industry for a number of years but we are now rapidly approaching the era where we are going to reap the benefit of the next generation technology.

26 Iceland’s Unique Offering:
   “Genetic correction of Prostate Specific Antigen values using sequence variants associated with PSA levels” Gudmundsson et al, Science Translational Medicine 15th December 2010 Icelandic Heart Association The Icelandic Cancer Society Iceland is fortunate in that it has a unique resource linking genotype and phenotype data. I would expect that with the excellent medical records and phenotype data collated via organisations such as the Icelandic Heart Association and the Icelandic Cancer Society; coupled with the genotyping and data analysis capability of decode……that Iceland would be able to generate new medical knowledge and make clinical advances from these datasets. With the university hospital ideally placed to capitalise and to tap into this unique data warehouse to test new clinical hypotheses. There are of course potential barriers; some potential legal issues relating to Personally Identifiable information issues but I am sure that these can be overcome with the right mindset and political will. There was an excellent example of an Icelandic genetic linkage study resulting in a potential change in clinical practice late last year. Decode published a paper in Science last December where they described several SNPs that made the PSA test for prostate cancer far more predictive such that it can now be used to determine whether a man should be subjected to a prostate biopsy. It is through careful analysis of combined phenotype and genotype information that we will make clinical advances. and the genotyping resource at decode, Iceland is in a unique position to capitalise on will give researchers a unique dataset About the Icelandic Heart Association The Icelandic Heart Association was founded in The Icelandic Heart Association Research Institute began in 1967 with very broad epidemiological research, the Reykjavik Study, where the focus was on identifying the main risk factors in cardiovascular diseases in Iceland. This research has been ongoing for nearly 40 years now and has involved more than 30,000 Icelanders. It has included a large number of new research projects, which have become the basis for expertise in Iceland on the main risk factors behind cardiovascular disease. From the very beginning the Icelandic Heart Association has placed great emphasis on getting the results of its research across to the general public and people in the health sector. In order to fulfill its educational role, the Icelandic Heart Association has published a series of information booklets on risk factors in coronary heart disease and has published its Magazine for 38 years. There is also the disease risk calculator which works out an individual’s risk of coronary heart disease over the next ten years.  The latest stage of the Reykjavik Study is the AGES Reykjavik Study.  The Icelandic Heart Association has more than 40 employees, bringing together a wide range of people with different educational backgrounds, who together conduct research as scientifically and accurately as possible. The Icelandic Heart Association employs doctors, biomedical scientists, biologists, radiologists, nurses and other people in a variety of fields. The association’s employees work on a variety of projects, such as the AGES Reykjavik Study, risk assessment, laboratory research, medical imaging, administration, education, data processing, quality management, financial management and other collaborative projects in which the Icelandic Heart Association is involved. University Hospital

27 The Future: Increased emphasis on in silico analysis
Pulling disparate datasets together to create new knowledge Genetic information Species linkages – mouse, zebra fish, human Spatial information – protein structures Epidemiology Screening data Imaging data In the future there will be an increased emphasis on in silico analysis Pulling disparate datasets together to create new knowledge This will not only include genetic information in humans But we will link data from different species and develop predictive models in different species such as mouse and zebra fish We will also increasingly use spatial information – for example modelling protein structures and how they interact with other proteins or indeed small chemical therapeutic agents. We will mine epidemiology data, screening data and imaging data to yield new knowledge.

28 Genomic medicine: Treatment of metastatic malignant melanoma with selective inhibitor of BRAF V600E (Plexxicon 4032) Here is one spectacular example of what can be achieved when you combine genetic information and high end imaging modalities. The cancer genome was released in The Cancer Genome Project identified that the BRAF gene is mutated in about 70% of all malignant melanomas. A small molecule PLX4032 was found to inhibit the mutant kinase. Phase 1 clinical trials have shown significant partial remissions and two complete remissions of the melanoma. In this case a PET scan after 15 days has been used to monitor this. This would not have been possible a decade ago and this one example provides a strong indication of where we can go with genomic medicine and advanced imaging. Before 15 days after Courtesy of Dr Grant McArthur

29 Academic - Pharma Partnerships
Finally I would like to spend a few minutes talking about how we actively attempt to work with academic and external clinical scientists to collaborate on basic underpinning science and drug development programmes. We have many different types of interaction but I particularly want to focus on one as I think it captures the spirit of what we are attempting to do in this space.

30 Innovation through Partnership
Pharma Specific agonists & antagonists - Biological reagents Clinical academics Deeper understanding of physiological & pathological control mechanisms The basic underlying principle is that the Pharma industry would normally have more specific agonists and antagonists and indeed biological reagents than most academic groups. If we share more of these selective tools with academia, particularly clinical academics with an interest in drug discovery, then we are likely to gain a deeper understanding of physiological and pathological control mechanisms. This would lead to publications which the whole of the science base would access. Other research groups would then pick up on these publications and we would all benefit from a deeper understanding of these control mechanisms. Publications

31 Q:. Why place Chemical Probes in the Public Domain. A:
Q: Why place Chemical Probes in the Public Domain? A: Potent and selective small molecules provide complimentary (if not better) target validation to genetic methods as evidenced by their scientific impact Compound Receptor Papers Citations Years h-index g-index GW1929 PPARg 317 11063 14 47 100 GW0742 PPARd 392 7212 10 41 78 GW4064 FXR 250 4482 8 37 61 SR12813 PXR 127 4628 33 67 GW9662 528 4513 32 50 GW3965 LXR 181 3073 7 29 53 GW7647 PPARa 118 2312 22 CITCO CAR 73 711 5 24 We have tangible evidence that this approach works. Some years ago we put some of our nuclear receptor Chemical Probes into the Public Domain by publishing on them and then allowing Sigma to hold them in their catalogue such that they were readily available. A couple of years ago we did an analysis of the publications relating to these nuclear receptor ligands and the science base had rapidly expanded. Once our selective molecules were available through a commercial supplier the literature exploded and we, and others, tapped into this rich vein of literature. Data compiled from Google Scholar, October 5, 2007 All compounds were made available by GSK to the Public Domain through commercial suppliers (Sigma-Aldrich and Tocris) h-index: a metric of scientific impact, combining quality and quantity of citations g index: a modification of the h-index with more weight on highly-cited articles

32 Discovery Partnerships in Academia (DPAc)
This is last topic I want to touch on briefly is to tell you about a new team that has recently been set up within GSK called Discovery Partnerships in Academia (DPAc). We have extended our model for partnerships by opening up many of our R&D resources to selected academic groups.

33 DPAc aims to leverage the unique expertise of both academia and industry...
In depth biological insight Target and pathway expertise In vivo disease models Clinical disease insight Key opinion leaders Industry Hit generation & assay development Medicinal chemistry Quantitative biology Preclinical development Integrated discovery & development Regulatory & commercial infrastructure DPAc aims to leverage the unique expertise of both academia and industry... From academia we need to access your in depth biological insight and target expertise. We may also need to access your in vivo models and to get clinical disease insight from your KOLs. From a GSK perspective we will provide a way into the development muscle of GSKs R&D and depending on the needs of the individual project, we will provide the academic with access to our facilities and expertise.

34 GSK resource and expertise to progress project
Medicinal chemistry and computational molecular design Large scale protein production HTS capacity 2 million compound set Selectivity screening PK-PD modelling Target Feasibility Assay Development Lead Identification Early Lead Optimisation Late Lead Optimisation It is our intention to open up our full resources to drive these projects. We are likely to do between 6 and 10 of these in the first instance. We are starting talking to partners we respect and think that we can work with. We have already had a couple of meetings with Dundee University and we are meeting with KCL next Monday. Preclinical development (safety assessment, pharmacy, chemical development, DMPK) Encoded Library technology >10million compounds Synthetic & analytical chemistry Flexible, high tech assay platforms

35 DPAc focus on early drug discovery and future pathway options to launch
Target validation data Some assays in place Early molecules identified Advanced assets identified DPAc Shared Project Target Feasibility Assay Dev Lead ID Early LO Late LO DPAc project can transition at any stage but likely around CS Drug Discovery Initiated Screen Initiated Lead Identified In vitro Lead Identified In vivo Candidate Selection GSK Internal Project The academic project can enter the drug discovery process at various points in the drug development pipeline. The DPAc team will actually take projects all the way through to candidate selection. Once CS has been achieved our academic discovery performance unit take over the development but importantly, we still want the academic to be involved as the molecule progresses. CS to FTIH Phase I Phase IIa Phase IIb Phase III Registr- ation AcDPU Shared Project First dose human P III start Launch

36 Activities shared between academics and GSK
3-6 mths 9-12 mths 9-12 mths 9-12 mths 9-12 mths Target Feasibility Assay Development Lead Identification Early Lead Optimisation Late Lead Optimisation Drug Discovery Initiated Screen Initiated Lead identified in vitro Lead identified in vivo Candidate Selection Typical GSK activities Chemistry DMPK Safety Pharmacy Screening Chemistry DMPK Screening Chemistry Assay development Assay feasibility Tool generation Value of GSK contribution ££ £££ £££ Value research support & reward The activities will be shared between the academic and company research teams. Payments will be made when scientific milestones have been met and will obviously be dependent on the stage that the academic project is submitted into the programme. Royalties will be paid should a molecule go all the way to market. ££ + downstream development milestones and/or royalty Reagent generation Assay development Physiological assays Physiological assays In vitro and in vivo Physiological assays In vivo models Typical academic activities

37 DPAc looks for leading academics working on a target or pathway with high therapeutic potential
DPAc Partnership Criteria Therapeutic hypothesis Coherent and supportable hypothesis that modulation of target will produce an effect expected to be of therapeutic benefit Target defined Specific drug target identified, with some understanding of type of pharmacology desired (Exclusive) enabling expertise Academic partner has know-how, experience, expertise essential to progressing the target which is not (readily) found elsewhere Tractability A path to identification of a drug molecule can be defined Target knowledge suggests that a drug-like molecule can be generated Requirement for GSK contribution GSK has capability which will help progress to the next milestone We are looking for leading academics working on a target or pathway with high therapeutic potential. We are seeking projects with a therapeutic hypothesis and a well defined target. We are looking for a competitive angle, so we would expect the academic partner to have something that is not readily available elsewhere. We need tractability ie a gameplan as to how we might develop a therapeutic And, GSK must have a capability which will help you get to the next milestone. If you have all of the pieces to the jigsaw you might as well do it yourself and then come to us with the finished product and we will licence it from you.

38 Conclusions: GSK are keen to promote a more open culture for sharing ideas & data Traditional relationships between Academia and Industry are being re-defined Access to public funding will drive areas of science underpinning the Pharma industry Innovative partnership models allow both GSK & academics better access to science & technology So in conclusion - GSK are keen to promote a more open culture for sharing ideas & data Traditional relationships between Academia and Industry are being re-defined Access to public funding will drive areas of science underpinning the Pharma industry Innovative partnership models allow both GSK & academics better access to science & technology

39 Thanks for listening

40 We are looking for innovation wherever it may originate

41 DPAc is a differentiated approach to translating innovative academic research
What DPAc is……… What DPAc is not…… Access to GSK’s expertise and resource in early drug discovery Funding of exploratory research The opportunity for academics to collaborate in drug discovery Pulling projects into industry away from academics DPAc will be a differentiated approach to translating innovative academic research. So for the academic it is Access to GSK’s expertise and resource in early drug discovery, the opportunity for an academic to take their molecule forward and it will be milestone aligned as I said. What its not is funding for exploratory research, its not GSK grabbing your project and running with it and its not fixed term funding. Milestone aligned resourcing Fixed term research funding

42 DPAc offers a new approach to collaborative drug discovery
Discovery Partnerships with Academia…….. ...looks for innovative academic science …that may ultimately deliver differentiated medicines from across multiple therapeutic areas ...integrates with academic groups …to provide resource and expertise to undertake early drug discovery in partnership with academics ...delivers quality development candidates …through milestone driven collaborations, that can then progress through the GSK organisation We, DPAc, are offering a new approach to collaborative drug discovery. We are looking for innovative academic science that may ultimately deliver a new medicine. We are aiming to fully integrate with academic groups such that they are a single team where the academic makes a real input into the R&D decision making process. This is not just another collaborative grant. We hope to deliver quality candidates through scientific milestone driven collaborations.

43 GSK profile of current global collaborations
GSK have more academic collaborations than any other UK company (all sectors)

44 GSK – UK Academic Research Partners
Birmingham Cambridge Southampton Edinburgh Glasgow Cardiff Dundee Sheffield Leicester GSK currently has >500 active research collaborations ongoing with UK Universities. Two way exchange of knowledge & technology Newcastle Ulster Durham Belfast Leeds York Bradford Hull Lancaster We are very active in this space. In the UK alone GSK have more than 500 academic collaborations. We tap into a diverse range of skills and technologies in more than 50 academic institutions in the UK. These collaborations are very much a two way exchange of knowledge and technology. We learn a lot from our academic colleagues but just as importantly they learn a lot from the industrial science base. (As a very rough figure (and depending on database accuracy) there are at least 600 active agreements (collab / stud / MTAs) with UK insititutions currently, and there are bound to be alot more that don't come through our team or aren't properly entered into Verticali. Plus we don't capture consultancies, Compound MTAs, any of the clinical type agreements... ) Manchester Liverpool Nottingham Loughborough Warwick Cranfield Ipswich Hertfordshire Buckingham Essex Oxford Reading Bath Surrey Canterbury Bristol Brighton Exeter Portsmouth

45 EUROPEAN ACTIVE AGREEMENTS BY COUNTRY
No. Austria 1 Belgium 4 Denmark France 16 Germany 21 Greece Ireland 10 Italy Netherlands Norway 2 Spain Sweden Switzerland 15 Iceland 2 Finland 4 Russia Norway Estonia 4 Sweden Latvia 10 Denmark Lithuania 4 Russia Belarus Ireland 4 UK 21 Poland Holland Ukraine Belgium Lux Germany 1 Czech R. Slovakia Moldova 15 16 Austria Hungary We have around 90 to 100 collaborations in mainland Europe. The key countries being Germany, France, Switzerland and to a lesser extent, Ireland. Switzerland Romania Slovenia France 4 Croatia Italy Bosnia & Herz Serbia Bulgaria 4 Macedonia 1 Corsica Portugal Albania Turkey Spain Sardinia Greece EUROPEAN ACTIVE AGREEMENTS BY COUNTRY Sicily Crete

46 GSK Agreements by State
WA(3) MA (15) MI (6) OR North Carolina NC Maryland MD Pennsylvania PA Massachusetts MA New York NY California CA Texas TX Michigan MI Missouri MO Colorado CO Connecticut CT Virginia VA Washington WA Georgia GA New Jersey NJ Alabama AL Arizona AZ Delaware DE Florida FL Iowa IA Nebraska NE Oregon OR Tennessee TN CT(3) NE IA NJ(2) CO(3) DE PA (19) VA(3) NY (10) CA (9) AZ TN AL GA( 2) MD (19) NC (20) FL We will have a couple of hundred collaborative research agreements in the US and these are concentrated around Boston, RTP and Philadelphia where GSK have a research presence. I haven’t mapped out our collaborations in India and China but as you might expect, they are on the increase. MO (4) 1 Agreement 2-3 Agreements TX (7) 4-9 Agreements 10-18 Agreements 19-20 Agreements January 2008-April 2010

47 GSK Academic Spend 2009 I thought that you might like to see how much funding Kings College receive relative to other universities in the UK and elsewhere. So this is just a snapshot of the number of pounds spent by GSK, the ordinate, on external research last year. So Duke University received £2.5m last year from GSK, next is Imperial College at a little under £2m. The blue histobars are UK institutions – Imperial, UCL, Cambridge, Dundee and Oxford and then in 6th place in the UK spend - KCL. This is 23rd globally and there were more than 400 academic institutuions on the GSK funded list. in the £600,000 and the SGC at around £560,000. There is a gap here as I have left the top academic institution off this graph because if I included it was difficult to differentiate at the lower end of the graph. If you add the 2009 spend up for these institutions it comes to around £20m……….

48 GSK funding to Harvard in 2009 was >£9m
Immune Disease Institute, Harvard Stem Cell Institute, MGH, Dana Farber Cancer Institute, Brighams & Womens, MIT Just to put it into context, last year we spent in excess of £9m with Harvard alone when you total all of the various institutes in Boston affiliated to Harvard- i.e Immune Disease Institute, MGH, Dana Farber Cancer Institute, Brighams & Womens, MIT. Why have they fared so much better in attracting GSK funding – they have the critical mass of scientists, who are comfortable working across the disciplines to the tackle the very large scientific problems.

49 How large Corporates are changing their business models to embrace Open Innovation
I now want to quickly move on to how large Corporates are changing their business models to embrace Open Innovation. There are many examples from GSK that I could mention but I want to tell you about just 2 examples.

50 Data Sharing Agreements
GSK have collected bloods from clinical trials for more than a decade Genetic analysis on cohorts of >20,000 patients Need to combine datasets with other well phenotyped collections to find significant trends e.g MRC £500k + GSK £500k Nick Wareham (University of Cambridge) Obesity/Diabetes Peter McGuffin (KCL) Bipolar disorder Here for me, is one of the simplest forms of Open Innovation. OI to me and in practical terms, means putting more information and/or technology out there to selected partners in order to get more back into your own organisation. So for example, GSK have collected bloods from well phenotyped cohorts of patients in clinical trials for more than a decade. Some of these cohorts have more than 20,000 patients. We used to think that these sample sizes were large enough to extract all of the information that we required. We now know of course, that they are not. And we are having to pool datasets with other well phenotyped collections to find significant trends and rare phenotypes. A couple of years ago we entered into a collaboration with the MRC where we both put £0.5 million into a programme and we solicited genetic proposals from academics. Two projects were funded. Your own Peter McGuffin had a a project on bipolar disorder and the other project was with Nick Wareham from Cambridge who had a project on obesity and diabetes. Nick Wareham pooled the data with the GSK data but also went out to other scientists who had large collections with the same phenotype and massively leveraged on our combined dataset. This leveraging resulted in a dozen quality publications over the course of the grant, 9 or 10 of them were in Nature journals. We could not possibly have done this on our own.

51 Developing Chemical Probes for Epigenetics
No structures disclosed Structures disclosed GSK Oxford Public Domain Oxford Chemical Probe * Sigma make probe available Data to GSK The second example I want to share with you is in the rapidly developing field of epigenetics. We are co-funding the project with the Wellcome Trust and Ontario Innovation Fund to develop chemical probes to better understand the field of epigenetics. GSK are providing the services of 7 chemists for 4 years, so 28 man years, to make non-druggable probes to be used by scientists around the world. So the GSK chemists make the molecules and send them to the Universities of Oxford and Toronto for screening. This is done blind i.e the screeners do not at this stage know the structure of the molecule. The Wellcome Trust and Ontario Innovation Fund pay for the screening operation to the tune of several million pounds. If the chemical probes achieve certain pre-agreed criteria we release the structure to the collaborators. The same day we also tell Sigma how to make the compound and they have 6 months to get the molecule into their catalogue. We publish the results for the non-druggable probe on the structural genomics consortium website and academics can access the data and they can also order the molecule from Sigma for their own studies. 1–5 Compounds meeting probe criteria for potency and selectivity: e.g. Potency <100nM, Selectivity >100, Cellular activity <1uM Only GSK scientists can view data with compound structures *

52 Proprietary Target Validation
A future model for Drug Discovery? Wellcome Trust Epigenetics Collaboration GSK-WT-SGC Partnership Public Domain Pharmaceutical Industry Chemical Tractability Chemistry (GSK) Screening (WT-NIH) Structure (SGC) Chemical Probes No restrictions on use or publication Enable Academic Target Validation Drug Discovery Proprietary Target Validation (Re)Screening Lead optimization Pharmacology DMPK Toxicology Chemical development Clinical development There will be no IP or restrictions on publications for any scientists using these probes. We want the academic world to use these molecules and to expand the general science base so that we, and others, can tap into it. We, GSK, see everything to the left of this dotted line being pre-competitive and we would actively encourage others to work in this space to expand the science base. We see our expertise as everything to the right of this dotted line and we would consider our internal studies to be proprietary. For the most part, Academia will not be good at this package of activities required to take a drug through late stage development. Open Access Proprietary

53 While we are on the subject of publications I cannot resist sharing this slide with you. I meet a lot of academics who are quite snobby about the quality of academic publications relative to those from industry. This slide was sent to me by a Masters level student from Cambridge and I didn’t even pay for the study. Here is a plot of average impact factor on the ordinate against average citations along the abcissa. Ie all the things you academics get excited about. This is in the field of clinical medicine, biomedical research and biology; and the size of the bubble is relative to the number of publications. So Harvard are right up there top right, great big football of high impact and highly cited publications. At the other end of the spectrum you have a couple of research intensive universities, namely Newcastle and Southampton and in the middle here we have Oxford, Cambridge and Imperial. But on par with Cambridge, albeit with fewer publications, is GSK publishing some pretty high impact science.

54 The realities of having the best pipeline
Pipeline renews 60% of sales GlaxoSmithKline Merck Bristol Myers Squibb Novartis Johnson & Johnson Sanofi-Aventis AstraZeneca Pfizer Wyeth Eli Lilly Roche Abbott Labs Schering Plough AVERAGE This is a slide showing the replacement power of drugs in the R&D pipeline which is a measure used by analysts Use this slide (or updated version) to make the point that phama has not been productive enough and has tended to focus on blockbusters We must earn our right to exist Society expects us to do more to address healthcare issues We must earn the right by meeting the expectations of society When you think like this, you see the world differently Lehman Brothers PharmaPipelines (Sept 2007) Pharma Replacement Power – NPV LB Method: [NPV of recent launches (06-07) + NPV of pipeline opportunities from ‘08-’13] / NPV of products marketed before 2006. 54

55 Science base attracts R&D spend
Global Pharma sector R&D spend usually follows the commercial markets but in the UK the quality of the science base has attracted a higher proportion of the Pharma R&D spend. So the UK prescription market accounts for just 2.46% of the worlds total prescription market and yet pharmaceutical companies in the UK are currently undertaking 9% of the global pharma i.e we are already punching more than 3X above our weight. However we cannot be complacent. About 5 years ago the US market share for prescription medicines was approximately half of world sales, however with generic erosion and greater regulatory hurdles the US share of the prescription market is now down to 37.6%. Interestingly they are still undertaking half of the global R&D but I do not think that this is sustainable and they will be challenged by developing world science bases. This is evident in GSK sales figures….

56 MRC

57 MRC translational activities
TSB Developmental Pathway Funding Scheme Developmental Clinical Studies Translational Research Support Translational Stem Cell Research Programme NIHR Basic research Prototype discovery and design Pre-clinical development Early clinical trials Late clinical trials Targeted initiatives to alleviate bottlenecks Slide demonstrates MRC’s translational activities Next few slides describe where we’ve got to in implementing the strategy – we’ve done a lot in a short period of time to make a step change in the UK translational research activity Continued commitment to basic lab, clinical and population research Infrastructure/Resources Capacity building Methodology Training

58 Developmental Pathway Funding Scheme (DPFS)
Cornerstone of the MRC’s Translational Strategy Launched at end of April 2008 Planned expenditure of at least £25m over next 3 years Guidance of £250k-750k; 1-2 years per project Will consider larger scale proposals where justified Projects do not need to originate from MRC funded research Goal oriented rather than hypothesis-led Funding is milestone-based Projects will be required to submit quarterly and milestones progress reports Failure to meet a milestone may result in funding being terminated

59 Scope of the DPFS Examples of proposals:
validating an association between a fundamental discovery & a preventive, diagnostic or disease process (target validation) developing candidate therapeutic entities - from discovery up to early evaluation in humans developing candidate diagnostics or medical devices - from prototype design up to early evaluation in humans developing a new research tool to overcome a bottleneck in the development of therapies or diagnostics

60 Drug Development Costs Escalate

61 MRC

62 MRC translational activities
TSB Developmental Pathway Funding Scheme Developmental Clinical Studies Translational Research Support Translational Stem Cell Research Programme NIHR Basic research Prototype discovery and design Pre-clinical development Early clinical trials Late clinical trials Targeted initiatives to alleviate bottlenecks Slide demonstrates MRC’s translational activities Next few slides describe where we’ve got to in implementing the strategy – we’ve done a lot in a short period of time to make a step change in the UK translational research activity Continued commitment to basic lab, clinical and population research Infrastructure/Resources Capacity building Methodology Training

63 Developmental Pathway Funding Scheme (DPFS)
Cornerstone of the MRC’s Translational Strategy Launched at end of April 2008 Planned expenditure of at least £25m over next 3 years Guidance of £250k-750k; 1-2 years per project Will consider larger scale proposals where justified Projects do not need to originate from MRC funded research Goal oriented rather than hypothesis-led Funding is milestone-based Projects will be required to submit quarterly and milestones progress reports Failure to meet a milestone may result in funding being terminated

64 Scope of the DPFS validating an association between a fundamental discovery & a preventive, diagnostic or disease process (target validation) developing candidate therapeutic entities - from discovery up to early evaluation in humans developing candidate diagnostics or medical devices from prototype design up to early evaluation in humans developing a new research tool to overcome a bottleneck in the development of therapies or diagnostics

65 MRC Industrial Collaboration Applications (MICAs)
MICAs are aimed at encouraging & supporting collaborative research projects between academic researchers & industry The key feature of this scheme is its flexibility, especially the level & nature of the industry contribution

66 MRC Industrial Collaboration Applications (MICAs)
MICAs are aimed at encouraging & supporting collaborative research projects between academic researchers & industry The key feature of this scheme is its flexibility, especially the level & nature of the industry contribution

67 Without patents there would be no innovation
Given the costs & risks of drug development, without a period of exclusivity against copyists there would be no investment in pharmaceutical innovation Pharma do not seek therapeutic area exclusivity (anti-virals, antibiotics) Patent protection promotes therapeutic & innovative competition So the take home message is that “Without patents there would be no innovation” Patent protection promotes therapeutic & innovative competition Given the costs & risks of drug development, without this period of exclusivity against copyists there would be no investment in pharmaceutical innovation and no new medicines. This should not be confused with a period of therapeutic exclusivity. We do not want therapeutic exclusivity, indeed in some areas it is of paramount importance that there are multiple approaches to address the same disease. For example, drug resistance is an issue with anti-viral HIV drugs and also many anti-bacterials. In order to overcome these issues you need different drug types to reduce the development of drug resistance

68 Changing Landscape of I.P
More small companies owning & licensing basic IP Many companies not in manufacturing, only generating technology/IP More patent aggregators, who take on patents from universities & small companies Patents used as bargaining chips The IP landscape is also changing, There are more small companies owning & licensing basic IP, some of which will be acquired by large Pharma. Many companies are not in manufacturing, only generating technology/IP with a mind to a trade sale or licence deal More patent aggregators, who take on patents from universities & small companies. Companies such as And increasingly Patents are used as bargaining chips – particularly in fields such as vaccine development and other biopharm activities So the landscape is constantly changing and evolving and only companies that are versatile and open minded will continue to grow. Universities will play a part in this continuing evolution but they, also, will have to be versatile and change their business plans.


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