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 can’t complain about my career at all,I’ve had a good time. I think the critical thing isthat I’ve 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, I’ve been involved inclinical development and business development;the only parts of the business I’ve 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 it’s what you really want todo for the rest of your career. Biotech is veryfast and stimulating and that suits me – you can
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 I’ve really enjoyed is that thebiotech community is very friendly. In bigcompanies you don’t know much about what’sgoing on in other companies and it’s 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 we’ll see more of those peoplecoming in and more drugs will be discovered,to the benefit of patients.
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 it’s 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 don’tregret the move at all.
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. It’sdifficult to make progress in this industrywithout the knowledge and confidence to takeon ever broader scientific and managerialresponsibility, which means developing anever-broader scientific base.
A third lesson is just how difficult it is todiscover drugs, a fact I think that is not fully
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UPDATE
INTERVIEW
David Brown:proteomics in drugdiscovery
Interview by Joanna Owens
David Brown, Chief Executive Officer, Cellzome
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®, Pfizer’smigraine 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.
‘If I had one hope for biotech itwould be that more good peoplewould move from pharma’
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.
A fourth lesson from pharma is theimportance of general management skills. I’vebeen 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.
Would you ever return to pharma?I wouldn’t say ‘absolutely not’, but I think itwould feel like going backwards. I’m reallyenjoying biotech so a return to pharma doesn’tseem an obvious move at the moment.
If you did, what have you learnt atCellzome so far that you take back topharma?I’ve 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.I’ve had to think very clearly over the past ninemonths about what value there is in Cellzome’stechnology and what our competition is doing,and this has given me a clear view of where the
major benefits of these technologies exist indrug discovery.
How exactly is pharma wasting money ongenomics and proteomics technology?I wouldn’t want to generalize about allpharma, I’m 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 doesn’tnecessarily 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 isn’t 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 you’ve 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.
Why do you think the drug discovery anddevelopment process is still so slow despitethe huge advances in technology such asHTS and combichem?I don’t know whether the process has gotmore efficient, because interpreting whether ithas got more efficient is confounded by thefact that it’s 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
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.There’s 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 it’s 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!
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 15–20 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 anythingthat’s going to increase. Pharma companies arein-licensing 25–50% of their clinicaldevelopment portfolios from biotechs now.I don’t think it will ever be 100%. Some peoplehave argued that pharmas will become clinicaldevelopment, manufacturing and marketingmachines. I don’t believe that; no pharmacompany is going to mortgage its future bygiving away its research, because it’s incompetition with other companies for drugin-licensing. Pharma also needs its in-houseexpertise, it needs researchers to keep abreastof what’s going on in biotech and perhaps dosome work on those molecules. It could bethat we’re 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
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135www.drugdiscoverytoday.com
UPDATE
INTERVIEW
‘A lot of pharma companies arestruggling to figure how to applygenomics and proteomics technologies’
‘The industry got too involved with “industrializing processes”in research and lost somethoughtfulness on the way’
‘I believe that the mergers are havinga negative impact on efficiency’
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 it’s a win–win forpharma and biotech.
Do you see Cellzome being acquired by apharma company in that way?It’s quite possible, but at the moment theacquisitions by pharma tend to involve largerbiotechs with a lot of products, and Cellzomeisn’t in that position yet.The acquisition routetoo often is not a particularly attractive onefor pharma or biotech unless there isimmediate value in the biotech’s products,because it can be difficult to retain thebiotech’s key staff. Again, this why Roche’smodel is attractive. It leaves the biotechsemi-autonomous and key people are morelikely to stay. Moreover Roche hasn’t had topay a lot of money up front, and hasn’t had totake the acquired company onto its revenuebudget, and yet Roche has access to the drugs.
How does Cellzome’s protein–proteininteractions platform fit into the company’sfuture in drug discovery? Since I joined we’ve been transformingCellzome into a drug discovery company, andthe protein–protein 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 parallelprocess targets through to focused librarysynthesis.We’ve also moved downstream todevelop a second proteomics technology,which is basically reverse HTS. Instead of takingone target and half a million compounds, wemap individual compounds back on to theentire proteome – we call this drug pulldowntechnology.To complement that, we’ve built adatabase that we call computer-assisted targetselection (CATS), which contains all of thetargets that pharma is working on, plus newtargets predicted from genomic information.
When we use drug pulldown and we hit aprotein, CATS tells us automatically whetherwe’ve got a target and a lead of interest.We’refocusing on Alzheimer’s disease and metabolicdiseases and building a portfolio based on thatboth from our own in-house drug discoveryand in-licensing.We haven’t in-licensed anythingas yet but we’re working quite aggressively onthat at the moment.We have a plan to havetransformed into a fully fledged drug discoverycompany with a clinical pipeline by 2005.
What have you done personally sincejoining Cellzome to change the directionof the company?When I came it was a proteomics companyand I’ve put the strategy in place to turn itinto a drug discovery company. I’ve raised theseries C money (US$30 million), recruitedexperienced drug discoverers into the UK site,and I’ve done some restructuring to rebalancethe organization, because as you movedownstream you need a different balance ofstaff. I’m beginning to work on acquiring moreadvanced compounds for clinical trials toaccelerate our progression downstream.
Was it your personal vision to turnCellzome into a drug discovery company orwere you appointed to do that?It was the Board of Directors’ vision.When Ijoined I asked the Board what they wantedfrom me and they said:‘Build the next Amgenby 2020’, so there was always that intentionand they brought me in to do that. It is to thecredit of my predecessor and company founderCharles Cohen and other board members thatthey had the vision to see the long termpotential in this company.
What companies are you collaboratingwith at the moment?We are in both early and mid-to-late-stagediscussions with several pharma companies.We seem to have no problem getting throughthe door of pharma companies. People haveheard of Cellzome and know that we’ve gotsomething quite interesting so there are a lotof discussions ongoing and I think we’ll drivesome of those through to collaborations in late2003 and early 2004.These collaborations willinvolve both our pathway expansion and drugpulldown technologies. For example, we’vemapped the APP processing pathway in
Alzheimer’s disease and that is generating a lotof interest from pharma.We have also mappedthe whole of the yeast proteome – 6000 ORFs– and used that as a predictive platform forantifungal research, so we can predict targetsversus Candida and Aspergillus, and there isinterest and ongoing discussions regardingpartnering in that area. Our drug pulldownplatform is also proving interesting to manypharma companies for several uses. One useis to find a second or alternative medical usefor current compounds, drugs in clinical trials,and even failed drugs. It can also be used todetermine the mode of action of drugs.Furthermore, it can be used for chemicalproteomics, for example, to systematicallymatch ligands to kinases or nuclear receptors.Finding new templates, and predicting the off-target risks of kinase or nuclear receptor leads,are key issues, and we can help with that.Weare also looking into potential partnershipswith biotechs for capability sharing, and we’vegot a number of those discussions ongoing.
Cellzome has had a very successful roundof funding recently in a difficult climate –what do you think sets you apart and whatadvice would you give to other companiesraising funding at the moment?It has been a very interesting experience, andI think we were fortunate that we finished ourround of funding just before the war with Iraq.There is no doubt that from late 2002 to early2003 the environment got tougher and tougher.I think things are easing up at the moment, butpeople who started raising funds earlier thisyear will have had a hard time.There is moneyavailable however for premier companies.Theadvice I would give is that there are two typesof investor.There are those who are productinvestors, they basically want to invest incompanies with products in clinical trials, andthey have one particular investment strategy.Then there are others who are platforminvestors, whose philosophy is that you need apowerful platform to keep generating newproducts.The first thing to do is to decide whichtype of company you are and target the righttype of investor.You are wasting your time if yougo to the wrong type.You then need to projectthat you have a credible and experiencedmanagement team, and if you’re a platformcompany then you must show that you have apowerful approach to drug discovery that reallycan generate long-term value. Finally, you needto have a strong board and strong financialbackers.We were fortunate at Cellzomebecause we met all of those requirements and Ithink that really underpinned our success. If abiotech is lacking in any of those, even though
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136 www.drugdiscoverytoday.com
UPDATE
INTERVIEW
‘I asked the [Cellzome] Board whatthey wanted from me and they said:“Build the next Amgen by 2020”’
the market is ‘freeing up’ a little, I think they’regoing to find it tough because the environmentis still very demanding.
How did you feel after the success ofViagra? Did the serendipitous nature of itsdiscovery as a treatment for erectiledysfunction change the way you thinkabout drug discovery processes?People say that it was serendipitous, butactually Pfizer set itself up for serendipity,which I think is a wise thing to do.When Iwent for interview at Pfizer in 1985, the Headof Research, Dion Butt, said to me:‘You knowDavid, at Pfizer we believe drugs arediscovered in the clinic’, which I thought was astrange thing to say. But I realised while atPfizer that they had discovered a lot of drugs inthe clinic. Some drugs had been discoveredusing a very logical process, but many drugswere redirected. Pfizer’s key principle was toget a very high quality molecule with a newmechanism and then see what it does, but havea hook to hang it on. In other words, have aninitial market you’re interested in that keepsthe drug development going.That’s what wedid with Viagra. In a way it was a strategy, andchanging indication is something Pfizer wasalways happy to do. Moreover, Pfizer hadalready thought through the potential of thetype of ‘life-style’ market Viagra would sell into,and was ahead of competitors in this respect,so Pfizer was fully prepared to recognise thepotential when the unexpected clinical findingscame in. So, yes it was serendipitous, but Pfizerset itself up for serendipity!
People often talk about focusing only ondruggable targets, but others have said thatthere are many blockbuster drugs whosetargets do not fall into a druggablecategory – what is your take on this?Over the past ten years, I believe there wasinsufficient focus on druggable targets for quitesome time, largely because people gotenamoured with HTS and thought that wouldsolve all the problems in drug discovery.What we’ve seen since is a rebalancing, withpeople focusing more now on druggabletargets, I think wiser people realise that thereis a risk:benefit trade-off associated with such astrategy.What is ‘druggable’ is beginning to beanalyzed and understood based upon the HTSexperience of the past ten years. I know from
my experience at Roche and Glaxo that thesecompanies are very advanced in doing this,and I believe that many of the top pharmaand biotech companies have a very goodunderstanding of this now. Companies arepicking targets in four or five major targetclasses and designing, using combinatorialchemistry in a very productive and focusedway, libraries that have a much higher successrate against those targets.That is a very basicand essential thing for a company to do, but Ithink they also understand that everybody cando that, and so the competitive advantage willbegin to erode.There will always be value intaking more difficult targets and screeninglarger libraries of compounds against them tomake breakthroughs.Those breakthroughs aregoing to be few and far between comparedwith hits obtained using focused libraries, butthey will provide greater competitive advantageand higher value if successful. I think the bettercompanies are balancing their portfolios for anagreed risk:benefit ratio using those twoprinciples. It’s probably not possible for acompany to survive on the high risk targetsalone. Cellzome’s drug pulldown technology is another way, besides HTS, of makingserendipitous breakthroughs to give high valueligands for previously ‘intractable’ targets.
People have been awaiting the promise ofthe human genome, but how well is thedrug discovery industry doing at turning thisinto something that will benefit healthcare?You can almost predict the phasing of therollout.The first gain is going to be indiagnostics and we’re beginning to see thatalready. For instance, Roche Diagnostics isusing the genome really effectively. Over thenext five years there will be an explosion ofvalue in the diagnostics industry comingdirectly from genomics. Sub-typing of patientswill follow with improvements in clinical trialdesign and safety margins. For research targetsit’s going to be harder and will take longer toextract full value. Personally, I would usedisease pathway mapping and genomic data inparallel.The real limitations in drug discoveryare still the problems of validating a targetand getting a chemical lead, and the genomeitself doesn’t directly help that. However, whenyou fully understand the components ofdisease pathways then you can take thechemically tractable targets in the pathwayand generate a chemical ligand by focusedlibrary synthesis.You can then use this lead tovalidate the target alongside other biochemicalassay methods, such as RNAi for example,which is proving invaluable as a validation toolin our work.
What in your view is needed to increaseproductivity in the industry?There are three things, two in discovery andone in the clinic. In discovery it’s still targetvalidation and lead generation.They willcontinue to be the bottlenecks, and I thinkpushing on these and finding ways to improveefficiency should be the key focus oftechnology development and collaborationsbetween biotech and pharma. In the clinic, weneed to be able to predict a patient’s responseto drugs, which is happening with increasingfrequency now, and also to be able to subtypepatients so that we can reduce the size, costand duration of clinical trials and reduce theside effects of drugs.The phrase ‘ the right drugfor the right patient’ is absolutely correct and Ithink clinical genetics will really help.
What professional achievement are youmost proud of?You might expect me to highlight some of thedrugs I’ve helped to get into man, but actuallyI would also highlight the help I’ve given indeveloping people’s skills and confidence.What drives me is helping people – one of theprinciples of my life is to help people as much aspossible.With the skills I have I can do this byhelping to invent drugs and by helping to developpeople. I think one of the best things you cando is train people and help to develop them.So, the work I’ve done for various companiesin that respect has given me a lot of pleasure.
What would you like to have achieved bythe end of your career?Two things. First, I would like to build a significantbusiness, such as turning Cellzome into the nextAmgen. I would like to lead Cellzome at least partof the way towards that goal. Second, I’d like to getmore drugs to patients, particularly for chronicgenetic diseases such as Alzheimer’s Disease.AD is becoming a real problem for society ashuman life-span increases.We’re focusing asignificant part of Cellzome’s research on ADand helping to find drugs for that devastatingdisease is a key goal for this stage of my career.
David BrownChief Executive Officer
CellzomeMeyerhofstrasse 169117 Heidelberg
Germanye-mail: [email protected]
TARGETS Vol. 2, No. 4 August 2003
137www.drugdiscoverytoday.com
UPDATE
INTERVIEW
‘People say [Viagra] wasserendipitous, but actually Pfizer setitself up for serendipity!’
‘The phrase “the right drug for theright patient” is absolutely correct’
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