David Brown: proteomics in drug discovery

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<ul><li><p>Was your time at Pfizer a highlight for youbecause of the success of Viagra?I have enjoyed all of the companies I haveworked for and there have been severalhighlights in addition to the drugs that made itto market.You never know whether any drug isgoing to make it, and Viagra was never easy, itwas always teetering on the edge of success orfailure. I cant complain about my career at all,Ive had a good time. I think the critical thing isthat Ive had a gradual expansion of experiencein many aspects of the pharma business. Myboss at Pfizer, Simon Campbell, was particularlyhelpful in ensuring this, as also was JonathanKnowles at Roche. I owe a lot to them. Inaddition to research, Ive been involved inclinical development and business development;the only parts of the business Ive not beeninvolved in are manufacturing, sales andmarketing. Joining Cellzome in September 2002was another highlight. Biotech really suits me.I enjoyed my time in pharma but the moresenior you get, the more committees you siton, and the more travel you do, and you startto wonder whether its what you really want todo for the rest of your career. Biotech is veryfast and stimulating and that suits me you can</p><p>see a lot of progress month-by-month, which isvery satisfying.There is less politics and morefocus on developing the business anddiscovering drugs, which is where my interestis. Another thing Ive really enjoyed is that thebiotech community is very friendly. In bigcompanies you dont know much about whatsgoing on in other companies and its quiteinward looking, but the biotech community isvery open and companies help each other.There is a tremendous camaraderie in thebiotech community and I really enjoy that.Biotechs are also far more aware of theimmediate state of the market and howimportant it is to be productive.There are a lotof good people in biotech but if I had one hopefor biotech it would be that more good peoplewould move from pharma. I especially thinkthat biotech needs more experienced drugdiscoverers, clinical development expertiseand experienced senior leaders at CEO level.There is enormous potential in this industryand it needs people with highly developed skillsfrom pharma to move in. I think as biotechmatures well see more of those peoplecoming in and more drugs will be discovered,to the benefit of patients.</p><p>Why did you decide to make the move tobiotech, and why Cellzome?I had always planned to move to biotech, butmy plan was to move in 2004.When I movedto Glaxo in the mid-1990s I bought a housenear Cambridge, UK, because Cambridge isthe biggest biotech centre in Europe. I reallyenjoyed my job at Roche and its a finecompany, but the travel 100 flights in my lastyear was exhausting. I became aware ofCellzome in 2002 and I thought it was a greatlittle biotech with enormous potential.Theywere looking for a CEO in 2002 and thereforeit was likely that the job might not be vacantin 2004. So I looked hard at the job. I alsoconsidered joining the venture capital world.However the people at Cellzome were goodand the technology that they had was reallybeginning to impress me.They had two verypowerful drug proteomics platforms and asuperb informatics platform, and I saw thatthese could have a very significant impact ondrug discovery.That was a good fit with what Iwanted to do. I did not just want to lead anybiotech, I wanted to lead one that would bothdiscover drugs and transform the efficiency ofdrug discovery. So, I took the leap and I dontregret the move at all.</p><p>What main lessons from pharma have youtaken and used in biotech?The biggest drive for me is to get drugs intothe clinic to treat sick people. My grandmotherwas dying when I was a PhD student and thathad a big impact on me in my desire to helppeople by discovering medicines.The mainlesson for me is to maintain absolute focus ongetting drugs into clinical trials.Theeffectiveness of the various companies I haveworked for correlates directly with howeffective the senior management is in keepingthe organization focused on that goal.A second lesson is the need to constantlydeepen and broaden skills. I had studiedbiochemistry as part of my chemistry degreeand continued to do so during my PhD studies.That proved very helpful to my career. Itsdifficult to make progress in this industrywithout the knowledge and confidence to takeon ever broader scientific and managerialresponsibility, which means developing anever-broader scientific base.</p><p>A third lesson is just how difficult it is todiscover drugs, a fact I think that is not fully</p><p>TARGETS Vol. 2, No. 4 August 2003</p><p>1477-3627/03/$ see front matter 2003 Elsevier Science Ltd. All rights reserved. PII: S1477-3627(03)02358-4134 www.drugdiscoverytoday.com</p><p>UPDATE</p><p>INTERVIEW</p><p>David Brown:proteomics in drugdiscovery</p><p>Interview by Joanna Owens</p><p>David Brown, Chief Executive Officer, Cellzome</p><p>David Brown has worked for four of the top ten pharmaceutical companies,beginning his 28 years in the pharma industry at ICI Pharmaceuticals (Zeneca),followed by a move to Pfizer at Sandwich, UK, where he spent a decade managingmedicinal chemistry. He was then headhunted by Glaxo just after they boughtWellcome to be responsible for a research division of 300 biologists and chemists.Most recently, he was Global Head of Drug Discovery for Roche Pharma, based in Basel,Switzerland, where he was responsible for the output of 2000 scientists across fiveresearch sites.At Roche he also served on the committee responsible for clinical drugdevelopment as well as on the business development committee responsible forin-licensing of products and for technology agreements and acquisitions. He wasclosely involved in the acquisition by Roche of Chugai.His career has included getting several drugs to market, including Viagra, of which hewas co-inventor, and he led the clinical development team to Phase II; and Relpax, Pfizersmigraine drug that was launched in 2002, and other drugs currently in clinical trials atGlaxoSmithKline. He joined Cellzome as Chief Executive Officer in September 2002and spends his time between their locations in Elstree, UK, and Heidelberg, Germany.</p><p>If I had one hope for biotech itwould be that more good peoplewould move from pharma</p></li><li><p>appreciated by many people in biotech,especially those with an academic backgroundrather than a pharma background. It has beensaid that discovering a drug and getting it tomarket is more difficult and complicated thanputting a man on the moon! I particularly valuethe years I spent at Pfizer because I learnt somuch about drug discovery and its challenges.I worked with very talented people and gainedexperience of getting drugs into developmentand then leading the development teamsthrough from Phase I to Phase II. Having hadthat experience at Pfizer, I was placed on theclinical development committees at Glaxo andRoche, which was an enormous help to me indeveloping the skills to lead a researchorganization. From the perspective of theclinical development committee you see theproblems that molecules hit in clinicaldevelopment, and you try to avoid makingthose mistakes again and try to improvethings further back in discovery. So thoseexperiences have quite an influence on theway I lead Cellzome; we will try to ensure thatwe avoid the mistakes in discovery that lead toclinical failure.</p><p>A fourth lesson from pharma is theimportance of general management skills. Ivebeen through many roles in highly professionalcompanies that invested heavily in training anddevelopment.You see good managers and poormanagers and learn from both! Those lessonsare essential as Cellzome recruits people andbuilds up the infrastructure for drug discovery.</p><p>Would you ever return to pharma?I wouldnt say absolutely not, but I think itwould feel like going backwards. Im reallyenjoying biotech so a return to pharma doesntseem an obvious move at the moment.</p><p>If you did, what have you learnt atCellzome so far that you take back topharma?Ive learnt a lot more about where genomicsand proteomics can actually impact drugdiscovery. I believe that a lot of pharmacompanies are struggling to figure how to applygenomics and proteomics technologies, withconsiderable waste of money and resources.Ive had to think very clearly over the past ninemonths about what value there is in Cellzomestechnology and what our competition is doing,and this has given me a clear view of where the</p><p>major benefits of these technologies exist indrug discovery.</p><p>How exactly is pharma wasting money ongenomics and proteomics technology?I wouldnt want to generalize about allpharma, Im sure there are some companiesdoing interesting things with this technology.But here are some of the issues. One is theuse of differential gene expression andassociated gene data from pathological versusnormal cells and tissues.That data is really justa symptomatic view of a disease, it doesntnecessarily capture the underlying diseasecause or mechanism. I think what you needto add is some mapping of individual diseasepathways. Ideally you would take hits fromdifferential display, work out from those theassociated proteins and map disease pathwaysaround those associated proteins.This allowsyou to interpret data at a functional level, andyou begin to see the disease context. Similarlywith disease-associated genes, you usually geta very weak association with a disease, whichalone isnt very convincing. However, thisassociation can be further validated, byworking out which pathways include thepredicted proteins encoded by these genes.What you will often find is that two or threegene products interact in the same pathway,and this gives you a high confidence that thepathway is relevant and youve actually got agenuine finding.Then there is the bigquestion of chemical tractability to be takeninto account, preferably right at thebeginning of thinking about the use ofgenomics and proteomics.</p><p>Why do you think the drug discovery anddevelopment process is still so slow despitethe huge advances in technology such asHTS and combichem?I dont know whether the process has gotmore efficient, because interpreting whether ithas got more efficient is confounded by thefact that its got more difficult as well.There isno doubt that we are having to tackle muchmore difficult diseases.We have to come upwith much tougher target and product profiles,and there is a demand for much safercompounds. So the clinical and regulatoryhurdles have got higher. My view is actually thatefficiency has not improved in general in the</p><p>industry, because the industry got too involvedwith industrializing processes in research andlost some thoughtfulness on the way; and therehave been precious few advances in clinicalresearch methodology.Theres no doubt thatproductivity, in terms of drugs registered, hasstalled over the past few years. But there isperhaps an indication now, looking at thenumber of drugs submitted to the FDA so farin 2003 compared with 2002, that things areimproving a bit, although its not totallyconvincing. Many of those NDAs are smallmolecules and biologicals coming from biotech.As companies get bigger it gets more difficultto manage them and maintain efficiency, and Ibelieve that the mergers are having a negativeimpact on efficiency. Once a big company goesinto a merger, it spends between 18 monthsand two years just on internally restructuringthe company, which undoubtedly impactsproductivity downstream, not to mention theimpact on morale!</p><p>How do you think small biotechs withlimited resources can impact drugdevelopment, will they be able to holdtheir own alongside big pharma?The evidence is that biotechs are producing anincreasing proportion of drugs, if only becausethere are so many biotechs probably 4000 and only 1520 pharmas of any size in researchnow. Between 25 and 50% of the drugs comingthrough late development and onto the marketnow are coming from biotechs, and if anythingthats going to increase. Pharma companies arein-licensing 2550% of their clinicaldevelopment portfolios from biotechs now.I dont think it will ever be 100%. Some peoplehave argued that pharmas will become clinicaldevelopment, manufacturing and marketingmachines. I dont believe that; no pharmacompany is going to mortgage its future bygiving away its research, because its incompetition with other companies for drugin-licensing. Pharma also needs its in-houseexpertise, it needs researchers to keep abreastof whats going on in biotech and perhaps dosome work on those molecules. It could bethat were reaching, at least for the biggercompanies, something of a point of equilibrium,where perhaps half of the compounds are frominternal research and half are from externalsources.There are some interesting modelsdeveloping. For example, Roche in-licensescompounds as other companies do but also it</p><p>TARGETS Vol. 2, No. 4 August 2003</p><p>135www.drugdiscoverytoday.com</p><p>UPDATE</p><p>INTERVIEW</p><p>A lot of pharma companies arestruggling to figure how to applygenomics and proteomics technologies</p><p>The industry got too involved with industrializing processesin research and lost somethoughtfulness on the way</p><p>I believe that the mergers are havinga negative impact on efficiency</p></li><li><p>partially acquires companies to access theirproducts yet leaves the companiesindependent. Genentech and Chugai areindependently quoted amgen with their ownmanagement, but Roche has options toco-develop and co-market drugs with thesecompanies. I hope Roche continues to developthat model because I think its a winwin forpharma and biotech.</p><p>Do you see Cellzome being acquired by apharma company in that way?Its quite possible, but at the moment theacquisitions by pharma tend to involve largerbiotechs with a lot of products, and Cellzomeisnt in that position yet.The acquisition routetoo often is not a particularly attractive onefor pharma or biotech unless there isimmediate value in the biotechs products,because it can be difficult to retain thebiotechs key staff. Again, this why Rochesmodel is attractive. It leaves the biotechsemi-autonomous and key people are morelikely to stay. Moreover Roche hasnt had topay a lot of money up front, and hasnt had totake the acquired company onto its revenuebudget, and yet Roche has access to the drugs.</p><p>How does Cellzomes proteinproteininteractions platform fit into the companysfuture in drug discovery? Since I joined weve been transformingCellzome into a drug discovery company, andthe proteinprotein pathway mapping is justone technology that is part of that mission.We are vertically integrating through to clinicaltrials as fast as we can.We have the initialpathway mapping technology, which forms thebasis of the company and enables us to mapdisease pathways in disease areas of interest tous.We then select proteins that are at pivotalpoints in these pathways, that will not lead totoxicity when modulated, and that arechemically tractable.The next step is focusedlibrary synthesis for lead generation.We do notuse HTS because our technology is a moreefficient way to generate targets and leads we can map whole pathways and paralle...</p></li></ul>

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