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p . 3 2 T h e p a t i e n t ’ s r e s p o n s i b i l i t yp . 1 0 V i a g r a a n d t h e v a l u e o f s e r e n d i p i t yp . 4 W h e r e a r e t h e n e w d r u g s ? p . 2 2 F i r s t , d o n o h a r m05S U M M E R
Powerful techniques shed new light
Out of the shadowA PUBLICATION OF VANDERBILT UNIVERSITY MEDICAL CENTER
A N e w W a y o f L o o k i n g
a t S c i e n c e
Lens
NEW WAYS TO REFILLTHE MEDICINE CHEST
Lens – A N e w Wa y o f L o o k i n g a t S c i e n c e
SUMMER 2005
VOLUME 3, NUMBER 1
EDITOR
Bill Snyder
CONTRIBUTING WRITERS
Lisa DuBoisLeigh MacMillanMelissa MarinoBill Snyder
PHOTOGRAPHY/ILLUSTRATION
Don ButtonChristopher J. Cannistraci Dean DixonDominic DoyleDavid JohnsonSam KittnerCasey McKeeWilliam OldhamAnne RaynerAntonello Silverini
DESIGN
Diana Duren/Corporate Design, Nashville
DIRECTOR OF PUBLICATIONS
MEDICAL CENTER NEWS AND PUBLIC AFFAIRS
Wayne Wood
EDITORIAL OFFICE
Office of News and Public AffairsCCC-3312 Medical Center NorthVanderbilt University Nashville, Tennessee 37232-2390615-322-4747E-mail address: [email protected]
They are ill discoverers thatthink there is no land, whenthey can see nothing but sea.
– S I R F R A N C I S B A C O N
Cover: Mysteries within the medicine chest
Photo illustration by Dean Dixon
Lens is published three times a year by Vanderbilt University Medical Center in cooperation with
the VUMC Office of News and Public Affairs and the Office of Research. Lens® is a registered
mark of Vanderbilt University.
Our goal: to explore the frontiers of biomedical research, and the social and ethical dimensions
of the revolution that is occurring in our understanding of health and disease. Through our Lens,
we hope to provide for our readers – scientists and those who watch science alike – different
perspectives on the course of discovery, and a greater appreciation of the technological, eco-
nomic, political and social forces that guide it.
© 2005 by Vanderbilt University
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contentsT A B L E O F
2 DRUG DISCOVERY IN THE 21ST CENTURY
4 WHERE ARE THE NEW DRUGS?Despite a recent doubling in both the budget of the National Institutes ofHealth and research-and-development spending by the pharmaceutical industry,the supply of truly new drugs has been dwindling. Part of the reason: a dramaticincrease in the cost of drug development. What academic scientists and the fed-eral government are doing to help.
10 TAKING THE BLINDERS OFF
The recent withdrawal of the blockbuster painkillers Vioxx and Bextra from themarket illustrates the difficulty in predicting uncommon but serious side effects.Science may help solve this problem through the development of biomarkers,new imaging techniques and pharmacogenetics – understanding how genetic dif-ferences affect drug response. For cancer patients, this knowledge is being trans-lated into more effective therapies.
16 A CLOSER LOOK
John Oates, M.D., sees beauty in complexity – whether he’s examining the mag-nified petals of a wildflower or the intricacies of drug metabolism. The founderof Vanderbilt’s Division of Clinical Pharmacology is best known for discoveriesthat shaped the field of prostaglandin biology. Equally valuable to his far-flung
colleagues and friends: his vision, commitment to science and insatiable curiosity.
22 FIRST, DO NO HARM
Doctors are on the front line when it comes to detecting adverse drug reactions andside effects. It’s a hit-or-miss system, and efforts to improve post-marketing surveil-lance of approved pharmaceuticals have had only limited success. The creation of anindependent drug safety board may help, but nothing can replace the vigilance,imagination and persistence of our “medical sleuths.”
25 ONCE IN A LIFETIME
For decades, scientists had searched unsuccessfully for a way to treat severe sepsis, acomplication of bloodstream bacterial infections that kills 250,000 American adultsevery year. Then, in 1994, Vanderbilt sepsis researcher Gordon R. Bernard, M.D.,was asked to lead a “long-shot” clinical trial of a promising drug. How a partnershipwith industry led to a “common good.”
28 GETTING THE DRUGS WE NEED
Steven M. Paul, M.D., president of Lilly Research Laboratories, and Vanderbilt’sAlastair J.J. Wood, M.B., Ch.B., who chaired the recent FDA advisory panel onCOX-2 inhibitors, tackle some of the economic and legal challenges facing thenation’s pharmaceutical industry. Among their suggestions: improved patent protec-tion and other incentives to encourage the development of “the drugs that we need.”
32 THE PATIENT’S RESPONSIBILITYNo amount of work by the Food and Drug Administration can ensure the safety ofthe nation’s drug supply if doctors and patients don’t prescribe or take medicationresponsibly. But while medical and consumer education may improve drug safety,costs will probably continue to rise – and that may not be such a bad thing.
05S U M M E R
page 10 If you pull one lever, it will affect another
page 16 Discerning beauty in life’s complexity
Lens
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s Over the past decade, wehave witnessed unparalleledadvances in our under-
standing of basic biological processes thatcontribute to a host of human disorders.The highly celebrated elucidation of thesequence of the human genome and othertechnological gains have allowed identifi-cation of a broad range of regulatory proteins and complex signaling systemsthat play critical roles in a variety of normal physiological processes as well aspathological conditions in virtually allmajor organ systems.
Today we have an understanding ofthe mechanisms underlying complex humandisorders such as Alzheimer’s disease, dia-betes, multiple cancers, schizophrenia, andmany others. These key new insights mayprovide paths to fundamental advances incare or even cures for patients sufferingfrom these disorders.
Translation of this new knowledgeinto practical gains in health care hasmoved more slowly, despite the recentdoubling of the National Institutes ofHealth budget, and a 16-fold increase inresearch-and-development spending bypharmaceutical companies between 1980and 2002. Many of the drugs currentlyavailable were developed before the 1950s,prior to the recent expansion in our under-standing of the basic biology underlyinghuman disorders.
Recent years have seen a steadydecline in the number of new drugsapproved for clinical use, and many of therecent approvals represent subtle changes
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A sea change in knowledge, technology …and collaboration
By P. Jeffrey Conn, Ph.D.
Professor and DirectorProgram in Translational NeuropharmacologyVanderbilt Department of Pharmacology
Director, Program in Drug DiscoveryVanderbilt Institute of Chemical Biology
Drug discovery in the 21st Century
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to existing medications, providing incre-mental rather than fundamental advancesin therapeutic strategies. The decrease inintroduction of fundamentally new drugsinto clinical practice during a time ofincreased knowledge and increased researchspending stems in part from a fundamen-tal shift in the basic paradigms used fordrug discovery.
In the early drug discovery era, noveltherapeutic agents were derived fromknown compounds, often plant extracts,which had medicinal properties. The majorgoal was to isolate the therapeutic compo-nent of the plant and refine it by makingrelatively modest chemical modifications.
Investment was often made with nounderstanding of the basic mechanism of the drug’s action, although there wasexisting knowledge that the compoundhad properties that allowed it to reach the target organ and have clinical efficacy.Also, there was some level of understandingof the potential toxicity based on clinicalexperience with the plants from which thecompound was derived. Because of this,the risk that a drug discovery programwould fail was relatively low.
Today the properties of knownmedicinal plants have been largely realized. We rarely have the luxury ofembarking on a drug discovery programwith this level of confidence in our ulti-mate success. Instead, we begin withknowledge of a biological system andidentification of a potential drug targetfound among the many potential targetsknown from our new understanding ofthe human genome.
Instead of knowing that a drug inter-acting with this target will have clinicalefficacy, we make a hypothesis based on ourstill limited and imperfect understandingof complex biological systems.
Typically, there are no existing drugsthat interact with that target, forcing asearch for a novel compound that has thedesired effect and then engineering theproperties required for a useful drug. Thisprocess is expensive and inherently highrisk – we may reach the end of a project
that cost hundreds of millions of dollarsonly to find that our original hypothesiswas incorrect and the drug has no clinicalefficacy or has unforeseen toxicity.
Translation of the extraordinaryprogress of recent years into fundamentaladvances in human health and patient careis a major challenge facing today’s biomedicalresearch community. The complexity ofthis task requires the combined efforts ofoutstanding scientists, engineers and clini-cians with strong expertise in a broadrange of disciplines.
Traditionally, the NIH and academicinstitutions have supported basic biomedicalresearch, while industry has supportedcommercial development of medicines andmedical products. While scientists in aca-demic and other basic science settings havemade significant progress in furthering ourunderstanding in biology, chemistry andrelated disciplines, they often fail to makethe critical link that allows this informationto be useful in an industry setting.
Likewise, fiscal pressures that governresearch efforts in industry make it increas-ingly difficult for companies to invest significant resources in exploratory projectsand basic research that capitalize on trans-lating the most exciting discoveries of basicscience into marketable products.
The most innovative and high-impactadvances in therapeutics will likely comefrom aggressive efforts to provide a bridgethat allows translation of advances in basicscience to novel therapeutic agents. Whilethis translation is clearly the mission ofpharmaceutical and biotech companies, itis critical that scientists at NIH-fundedinstitutions focus increasing attention ontheir role in contributing to the therapeuticdiscovery process.
In addition to the advances in basicbiology, we have realized tremendousadvances in combinatorial chemistry,development of large libraries of smallmolecules, and other approaches to high-throughput synthetic chemistry. Theselibraries are now widely available to theresearch community, and new high-throughput screening technologies have
been developed that allow more wide-spread mining of the libraries.
The combination of high-throughputscreening and synthetic chemistry providesan unprecedented opportunity for NIH-funded investigators to engage in discoveryand development of small molecule probesof biological pathways.
These probes could provide the toolsneeded to directly test whether drug-likemolecules can be developed that interactwith a novel target of interest and have theeffects that were predicted in studies usingmolecular and genetic approaches. Suchadvances could provide a major step in thediscovery of novel therapeutic agents byidentifying the most viable approaches forfurther investment in an industry setting.
In addition, academic investigatorsare increasingly engaged in tackling othercritical issues inherent in modern drugdiscovery paradigms, such as, how do wepredict at an earlier stage whether a drugwill have clinical efficacy or toxicity?Rather than gaining answers to thesequestions at the end of a billion-dollarprogram, basic and clinical scientists cancontribute to the design and execution ofearly proof-of-concept clinical studies thatpredict ultimate efficacy, and which maylead to the development of biomarkersthat predict later toxicity.
Multiple changes in science, businessand society are forcing a fundamental shift in traditional approaches to drug discovery. Realizing the exciting promiseof recent advances in the face of fiscal constraints presents a challenging butexciting opportunity.
Individuals across the spectrum ofbiomedical research and discovery share acommon optimism that we are at thebeginning of the most exciting era yet inchanging the face of human disease. It iscritical, however, that different players inthis arena find new models to leverage ourcollective resources and talents.
This issue of Lens highlights oneapproach for bridging the gap to newtherapeutics. LENS
Translation of the extraordinary progress of recentyears into fundamental advances in human healthand patient care is a major challenge facingtoday’s biomedical research community.
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[THE PUSH TO IMPROVE THE PIPELINE]Last year only 23 truly new drugs, called “new molecular
entities,” were approved in the United States.That’s less than half of the number approved in
1996, even though annual research-and-developmentspending by the pharmaceutical industry more thandoubled – to nearly $40 billion – during the sameeight-year period.
With the sequencing of the human genome hascome a plethora of new technologies to mine it. Yet thisnew wealth of biological understanding, coupled with the growingdemand for drugs that can treat and prevent chronic disease, hasraised the bar for proving safety and efficacy to unprecedentedheights. Consequently the search for new drugs has become morecomplicated – and much more expensive.
Depending on the calculations, the journey of a single pillthrough the convoluted development pipeline can take 15 yearsand cost more than $1 billion. That’s before any money is spenton marketing.
Much has been written lately about the perceived excesses ofdrug marketing and inadequate efforts to ensure drug safety. Thisissue of Lens begins with a look at the top of the pipeline, andhow academic medical centers are partnering with industry andthe federal government to replenish the shelves of society’s medi-cine cabinet.
“Drug companies realize the need to cover a broader range ofbiology. They just can’t do it all and never have,” says Lawrence J.Marnett, Ph.D., director of the Vanderbilt Institute of ChemicalBiology (VICB). “… And so partnerships with universities, withacademic health centers, especially, make a lot of sense.”
The three-year-old institute exemplifies the growth of “trans-lational” research programs at universities around the country.
Aided and encouraged by the federal government, these efforts aredesigned to develop the tools and the knowledge base needed
to meet today’s drug-development challenges.“Our goal … is to take those very early stage discov-
eries around drug targets and lead compounds, and goanother step toward handing that information off tobiotechnology and pharmaceutical companies and other
organizations that can hopefully translate our discoveriesinto new drugs for patients,” says Jeffrey R. Balser, M.D.,
Ph.D., associate vice chancellor for Research at VanderbiltUniversity Medical Center.
Toward that end, the VICB recently opened a high-throughputscreening facility to help search for small molecules (a class oforganic chemicals) with drug-like activity. Vanderbilt also hassigned a “master research agreement” with biotechnology giantAmgen to conduct an array of collaborative research projects.
The intent of these efforts is to encourage Vanderbiltresearchers to pursue the therapeutic potential of their discoveries.
Discovering a potential drug target is not enough, explainsP. Jeffrey Conn, Ph.D., who directs VICB’s drug discovery efforts.If academic scientists took the next steps – identifying a compoundthat acted on the target, and conducting the laboratory and animaltests necessary to validate its therapeutic potential – “you can thenjustify a company really locking into a full-scale drug discoveryprogram,” he contends.
“It’s going to be difficult to bridge that gap,” cautions JasonMorrow, M.D., director of the Division of Clinical Pharmacologyat Vanderbilt, because the cultures of academic science and indus-try are so different. “Drug companies want the proprietary rightsto a particular agent,” he says. “A partnership tends to be a morerisky business.”
BYBILL
SNYDER
Pictured left:Tomorrow’s medicinechest? Three-dimen-sional model of a het-erotrimeric G protein,pursued as a possibletarget for drug therapy.
Photo illustration byDean Dixon
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Jennifer Washburn, author ofUniversity, Inc., is more than skeptical. Inthe February issue of The American Prospectmagazine, she wrote: “Instead of honoringtheir traditional commitment to teaching,disinterested research, and the broad dis-semination of knowledge, universities areaggressively striving to become researcharms of private industry.”
Gordon R. Bernard, M.D., assistantvice chancellor for Research and MelindaOwen Bass Professor of Medicine atVanderbilt, disputes that contention.
While collaborations with industrycan result in conflicts of interest, manyuniversities, including Vanderbilt, haveimplemented procedural and contractualsafeguards to identify and manage suchconflicts. These safeguards protect the academic mission while permitting oppor-tunities to transfer new information andtechnologies for the benefit of society,Bernard says.
Marnett agrees. “We are not going tobe drug companies … But we can advancethe field,” he says. “We can identify new
therapeutic concepts, new drug-designconcepts. That’s what we should be doing.”
TTuurrnn uupp tthhee lliigghhttWhere will the new drugs come
from?One area to watch: G protein-coupled
receptors (GPCRs).GPCRs are embedded in the mem-
branes of nearly every cell and are the mostcommon conduit for signaling pathwaysfound in nature.
Two-thirds of all drugs target thesereceptors. The beta-blocker drug propra-nolol lowers blood pressure by preventingadrenaline from binding to its GPCR.Drugs that are given to relieve symptomsof Parkinson’s disease act through a GPCRthat binds dopamine.
Parkinson’s disease illustrates thecomplexity of the signaling pathways thatutilize GPCRs. Characterized by tremors,difficulty walking and muscle weakness,the disease is caused by the progressive lossof dopamine-producing nerve cells and theresulting lack of dopamine, a neurotrans-
mitter involved in the coordination ofmuscle movement.
Current dopamine replacement therapysquelches the tremors and improves coordi-nation, but prolonged use of the drugs cancause significant side effects, includinginvoluntary muscle movements and halluci-nations, and the medications become lesseffective as the disease progresses.
Because loss of dopamine disrupts acomplex web of signaling pathways in thebrain, it may be possible to restore thisbalance by “tweaking” pathways involvingother neurotransmitters.
While at Merck Research Laboratories,where he was head of neuroscience, Connand his colleagues found that activating aparticular GPCR that binds the neuro-transmitter glutamate – mGluR4 – relievedsymptoms of Parkinson’s disease in animals.However, they could not find a compoundthat binds only to mGluR4, and does notactivate other glutamate receptors else-where in the brain.
Allosteric modulation might solvethe problem.
This tongue twister refers to the abilityof some compounds to bind to a secondarysite on a receptor in a way that “modulates”its activation by a primary “ligand” suchas a neurotransmitter or hormone. Primaryligands fit into the receptor’s main bindingsite like a key fitting a lock, and “turn it on.”
The modulator, on the other hand,acts like the dimmer switch in an electri-cal circuit, adjusting the intensity of thereceptor’s activation. The anti-anxiety drugsValium, Xanax, Librium and Ativan, forexample, “potentiate” or turn up theactivity of the benzodiazepine receptorwhen it binds to its primary ligand, theneurotransmitter gamma-aminobutyricacid (GABA).
Conn wondered whether he could findan allosteric potentiator that was specific
“There are real benefits … to thescientists doing the research.Even if only 10 percent of thesecompounds were picked up byindustry, the scientific programswould benefit from having potentnew tools to probe the biology incells and even in animals moredeeply, leading to new discoveries.”
Heidi Hamm, Ph.D., Earl W.Sutherland Jr. Professor and Chairof the Department ofPharmacology at Vanderbilt
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for mGluR4. However, “my departmentcould only handle a maximum of threeprograms at any given time,” he says.“And to take a kind of half-baked idea …and decide we’re going to really pull thetrigger on a drug discovery program wassuch a high risk.”
Then, in 2003, he saw an opportunityto pursue his idea at Vanderbilt.
A generation ago, Conn might havespent his entire career searching for a compound that could modulate mGluR4activity. Now, thanks to the recent installation of a high-throughput screen-ing facility at Vanderbilt, he and his colleagues can test tens of thousands ofsmall molecules for drug-like activity in a single day.
Ultra low volume liquid handlerssquirt nanoliter amounts of the compoundsinto 384-well “microplates” containingtheir target. Reactions are detected via flu-orescence or luminescence as the plates aremaneuvered by articulated robots throughthe screening system.
Compounds that bind to the allostericsite on mGluR4 will be tested in animalmodels of Parkinson’s disease to see if theyactually relieve muscle rigidity and restorecoordination.
Conn admits that there is consider-able skepticism among his colleagues inindustry about “whether we can really pullit off … it’s very high risk.” That hasn’tdiscouraged universities across the countryfrom developing similar capabilities forscreening compounds.
“This is where we fill the gap,” heexplains. “I think we are at a turning pointin the whole drug discovery industry ...We are at a point where different playersin the whole therapeutic discovery arenacan start to bring a lot more to bear tothis process …
“I see it as a really challenging time.But mostly I see it as a very exciting time.”
Pie in the skyAnother potential source of new drugs:
compounds that interact with G-proteins.G-proteins are intracellular molecular
switches, involved in nearly every physio-logical – and presumably, pathological –process. They translate and transmit signalsfrom the receptor to the “responsemachinery” deep inside the cell.
Here’s how they work:When a neurotransmitter or hormone
binds to its G protein-coupled receptor onthe surface of a cell, the receptor, in turn,activates G proteins that bind to it insidethe cell. The proteins actually split intotwo active parts – alpha subunits and
A major reason is the high attritionrate of promising compounds that nevermake it through the drug-development“pipeline” and its daunting successionof assays, studies and clinical trials.
The discovery of a potential drugtarget – a receptor involved in depres-sion, for example – is just the firststep. A pharmaceutical company mayhave to wade through several hundredthousand compounds just to find a fewthat act on the receptor.
The yield is tiny: only a few hundredwill show sufficient activity to proceedwith pre-clinical testing in cell cul-tures and animals. Of these, only ahandful will meet the criteria forhuman testing:
They must be absorbed by the bodyand reach their target tissue at ahigh-enough concentration to do thejob. Then they must be effectivelyeliminated from the body so they don’treach toxic levels.
Five years of work may be requiredto get through this pre-clinical stage.Then it’s on to human testing, whichis conducted in three “phases.”
In phase I, the compounds are testedfor safety in up to 100 healthy volun-teers. Phase II involves further safetyand efficacy testing in 100 to 500patient volunteers who have the condi-tion the compounds are meant to treat.
In phase III, the potential drugs aregiven to thousands of patient volun-teers to confirm effectiveness andappropriate dosage, and to detectadverse reactions.
Clinical development, from phase Ithrough phase III, can take eight to10 years to complete, and may cost$200 million to $350 million – foreach of the candidates that enter clin-ical testing.
Yet, on average, only one of everyfive compounds tested in humans willsatisfy the increasingly stringentrequirements to become a new drug.
Why do drugs cost somuch to develop … and buy?ILLUSTRATION BY DOMINIC DOYLE
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Blood clotting is essential for woundhealing, but too much thrombin in thewrong place can trigger a heart attack.Blood-thinning drugs like Coumadin canprevent platelets from forming clots, but –unless the dose is carefully monitored –they can cause uncontrollable bleeding.
It has been difficult to block thrombin,which actually is an enzyme that activatesits receptor by chopping it in half. SoHamm and her colleagues are trying totackle the problem from inside the cell, by blocking receptor action instead ofreceptor binding.
So far, they’ve been able to make “verypotent” small molecules that prevent thethrombin receptor from binding to or acti-vating its G protein. “In cells – we haven’tgotten to animals yet – they do exactlywhat we want them to do,” she says.“They’re inhibitors of platelet aggregation.”
Drug companies are still skeptical,but now at least Hamm’s idea doesn’t seemso pie in the sky.
The role of governmentThe onerously high cost of making
new drugs has not escaped the attention offederal health officials.
Last year in a report entitled“Innovation or Stagnation: Challenge andOpportunity on the Critical Path to NewMedical Products,” the U.S. Food andDrug Administration called for increasedpublic-private collaboration to boost drugdevelopment through the application ofnew technologies.
“We must modernize the critical devel-opment path that leads from scientific discovery to the patient,” the report urged.
Developing new tools to aid drug discovery also is the goal of the MolecularLibraries Screening Center Network, estab-lished last year by the National Institutes ofHealth as part of its Roadmap initiative to
help translate new scientific knowledgeinto “tangible benefits for people.”
The aim is to harvest the fruits of thegenomic revolution, make them availableto scientists in universities and industryalike, and encourage them to work togetheras never before, explains Christopher P.Austin, M.D., senior advisor for transla-tional research at the National HumanGenome Research Institute.
“What we hope to do … is the high-capital investment … take the assay, dothe robotic screening on a big library, dosome initial chemistry, and give (scientists)back a small molecule compound whichallows them to query the function of thatgene or pathway – to test a hypothesis,”Austin says.
The federal efforts have their share ofskeptics, including Steven M. Paul, M.D.,president of Lilly Research Laboratories. “Iam worried that obtaining the kind ofmolecular probes required for even in vivotesting may prove to be too time-consumingand expensive,” Paul says, “and may divertprecious NIH funds away from basic orclinical biomedical research.”
The federal initiatives in no way aremeant to diminish government’s role insupporting fundamental discovery, Austinresponds. Tools developed by the publicsector, however, can help establish thetherapeutic potential of new compounds,and encourage industry to push themthrough the pipeline.
“As long as … we’re all aware ofwhat we can do and can’t do, I think we’llbe fine,” he says. LENS
beta/gamma subunits – both of which canstimulate independent signaling pathways.
Drugs that target GPCRs are ratherblunt instruments; they can trigger far-ranging side effects. Is it possible to developdrugs that can be delivered – with “nano-surgical” precision – to the G protein of aspecific receptor inside a particular type ofcell? Could that achieve the therapeuticmanipulation of a unique signaling pathwaywithout affecting physiology anywhere else?
That prospect has tantalized HeidiHamm, Ph.D., for more than two decades.But until recently the idea was, as Hammputs it, “total pie in the sky.”
In 1993, Hamm helped solve thestructure of the alpha subunit with thelate Paul B. Sigler, M.D., Ph.D., and hiscolleagues at Yale.
More recently, she and colleagues atthe University of Illinois at Chicago andthe University of Wisconsin-Madisonshowed how the beta-gamma subunit ofan inhibitory G protein controls the releaseof neurotransmitters and hormones. It prevents vesicles containing these chemicalmessengers from fusing to the cell mem-brane and spilling their contents outsidethe cell.
The discovery, reported this spring inthe journal Nature Neuroscience, could leadto new ways to treat conditions as diverseas pain and diabetes.
Hamm admits that G protein “therapy”is unlikely to attract major drug companyinvestment – at least not yet. So five yearsago, about the time she was moving fromNorthwestern University to Vanderbilt,she and her colleagues formed their owndrug discovery company in Evanston,called cue BIOtech.
They chose to study a receptorembedded in the membrane of clot-form-ing platelets that binds the coagulationfactor thrombin.
Pictured left: Three-dimensional crystal structure of a G protein coupled receptor (GPCR)embedded in a cell membrane, with its loosely attached heterotrimeric G protein, con-sisting of alpha, beta and gamma subunits, inside the cell. When a ligand, such as aneurotransmitter or hormone, binds to its GPCR, the receptor changes shape in a waythat catalyzes the release of guanosine diphosphate (GDP) from the alpha subunit. GDP,an organic molecule involved in intracellular energy exchange, is replaced by the higher-energy guanine triphosphate (GTP). That, in turn, causes the alpha subunit to breakapart from the beta and gamma subunits. The subunits then interact with other intracel-lular proteins to transmit signals down two independent pathways. Within a few seconds,GTP is converted back to GDP, the subunits recombine, and the signals are "turned off."
Illustration by William Oldham
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While most researchersplumb the depths of the cell to find drug targets for modern-day ailments, Billy Hudson,Ph.D, advances into the greatexpanse beyond the cells’ mar-gins to uncover drug targetshidden in this extracellularnetherworld.
All cells exist in a sea ofamorphous protein called theextracellular matrix. Composedprimarily of insoluble collagensand proteoglycans, the matrixis more than just filler. It shapestissues and supports and influences a multitude of cellu-lar processes.
“Matrix components arespecifically involved in the etiology and pathogenesis ofdisease, making the matrix avaluable drug target,” saysHudson, director of theVanderbilt Center for MatrixBiology.
Changes within the matrixunderlie several of the compli-cations of diabetes, particularlythose involving the kidney.When glucose concentrationsremain high for long periods,matrix proteins can be alteredby glucose reacting with theamino groups of the proteins.
This process, called glycation,results in large, cross-linkedmolecules that inhibit normalcell function. In the kidney, glycation can limit the organ’s
filtering function and lead tokidney failure.
After several years of study-ing matrix changes involved indiseases of the kidney, Hudsonwas challenged to “do some-thing” to stop the process by aformer postdoctoral fellow atthe University of Kansas, J.Wesley Fox, Ph.D.
“We were making strides in understanding the process,when Wes Fox says, ‘Whydon’t you develop a drug toprevent that?’” Hudson recalls.“I said, ‘That sounds good, butI don’t really have the moneyto do that.’” Fox replied thathe would find the money ifHudson worked on the drug.
With a unique combination of scientific expertise and asharp business sense, Foxfound investors to supportHudson’s new line of inquiry. In 1994, Fox, Hudson and col-leagues at the KarolinskaInstitute in Sweden foundedBioStratum, a biotech companydedicated to pursuing thematrix as a drug target.
Efforts to pharmacologicallyarrest glycation-related pathol-ogy had shown some progress,but the most promising drugcandidate, aminoguanidine, had proven too toxic in clinicalstudies. Drawing on his studiesof the extracellular matrix,where diabetes-induced
glycation is very active, Hudsonfound an effective compoundthat inhibited multiple path-ways of glycation-relatedpathology, but was entirely natural in the body.
Hudson answered Fox’s challenge with the compoundpyridoxamine (brand namePyridorin), a vitamin B6 deriva-tive. Both in vitro studies andanimal models showed thatpyridoxamine prevented theglycation-related pathologythat contributes to diabetickidney disease.
Phase II clinical trials, com-pleted last year, showed thatPyridorin was safe and effec-tively slowed the progression tokidney failure. Phase III trialsare set to begin this year.
From this unconventionalthinking, a new approach todrug development was born,bringing together academicresearchers and the biotechindustry to chase down the nextgeneration of pharmaceutics.
In contrast with pharmaceu-tical companies taking overdrug development, this approachallows universities to continueto participate in the drug dis-covery and development processand to reap some of the finan-cial benefits: the university andresearcher can maintain thepatent on a therapy andlicense its use.
Fox has gone on to becomepresident and CEO of anotherbiotechnology company,NephroGenex, Inc., which wasco-founded by Hudson. InHudson’s case, the foray intobiotech has had a beneficialimpact on his more basicresearch interests as well.
“I now have two additionalgrants based on that drug(Pyridorin) to explore basicmechanisms – not to develop adrug – and others have beenawarded NIH grants to explorethe actions of Pyridorin,”Hudson says. “So there is apositive feedback into basicscience that can come fromthis approach.”
Thinking outside the cell BY MELISSA MARINO
Billy Hudson, Ph.D., (left) dis-cusses a research projectwith graduate studentRoberto Vanacore.
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Taking the blinders offTHE SEARCH FOR BETTER DRUGS
By Bill Snyder
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The human genome may encode a million distinct pro-tein targets, yet only about 500 of them have been “hit” bysmall-molecule drugs. Scientists are only beginning tounderstand how drugs aimed at a single target may affectdiverse physiological pathways and systems.
“If you pull one lever, it’s going to have an effect onanother lever, which is connected to two other levers,”Austin says. “Before you know it, you’ve pulled the tail ofthe elephant and activated the elephant’s brain, whichmakes the elephant pick up its foot—which you didn’tknow exists—and stomp on you ...
“You can see the leg coming up in the air, but you say,‘Is that really a leg coming up in the air? I didn’t know thatwas there.’ You don’t know until it lands on you,” he says.
That’s what happened with the selective COX-2inhibitors Vioxx and Bextra, Austin says.
The drugs were developed to relieve arthritis pain andinflammation without the gastrointestinal side effects oftraditional anti-inflammatory drugs, which block bothcyclooxygenase (COX) enzymes. Only after millions of peoplehad taken the drugs for years did it become apparent thatthey increased the risk of heart attack and stroke.
“What we still really lack in the whole drug discovery/drug development pipeline is good enough predictive toxi-cology,” says Daniel C. Liebler, Ph.D., director of theProteomics Laboratory at Vanderbilt.
“We can certainly give a very toxic drug to a rat or amouse or a dog, and observe classic signs of toxicity (such as)changes in liver and kidney function tests,” Liebler says. “Butwhat we lack are good biomarkers for more subtle dysfunctionsthat will ultimately manifest themselves after the person’staken a drug for six months … like with Vioxx.”
Proteomics, the study of the proteins, is one avenuetoward that goal.
In the last few years, through such technologies asmass spectrometry, scientists have identified proteinmarkers that seem to correlate with the emergence or progression of certain diseases, and with the response ofdisease to treatment.
The recent withdrawal of theblockbuster painkillers Vioxxand Bextra from the marketunderscores an urgent need toupgrade the tools and science ofdrug discovery, say academicand government scientists. *“We are truly a blind man andthe elephant,” says ChristopherP. Austin, M.D., of theNational Human GenomeResearch Institute.
Illustration by Antonello Silverini
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Watching drugs workImaging technologies offer another
avenue for predicting the effectiveness ofdrug therapy.
Researchers in the VanderbiltUniversity Institute of Imaging Science areexploring dynamic contrast imaging, anMRI method that can create a three-dimensional image of angiogenesis, new
blood vessel formation. When standardized,this method may provide a way to deter-mine the effectiveness of anti-angiogenicagents, says institute director John C.Gore, Ph.D.
Vanderbilt recently purchased a 7-Tesla magnet, 140,000 times the strengthof the Earth’s magnetic field, which willallow institute researchers to conductmagnetic resonance spectroscopy.
Using this technique, researchers canmeasure very precisely the levels of neuro-transmitters in the brain. “We think that’san important area,” Gore says, “not only for
In a mouse model of breast cancer, forexample, Vanderbilt researchers recentlyshowed that the level of several proteinsplummeted within 12 hours after admin-istration of Tarceva, a cancer drug thatblocks the receptor for epidermal growthfactor. This suggests that the proteins maybe “biomarkers” for tumor growth.
“You could see these changes … way
before any surgical or MRI (magnetic reso-nance images) will show tumor shrinkage,”says Richard M. Caprioli, Ph.D., directorof the Mass Spectrometry Research Center,who participated in the research.
More study is needed to determinewhether a drop in the concentration ofthese proteins can be reliably correlatedwith tumor shrinkage in response toTarceva. With the help of proteomics inthe future, however, “we might be able topredict if a drug is going to be effective in a patient – even after the first dose,”Caprioli says.
certain brain disorders such as addiction,but also for looking at the effects of drugs.”
Positron emission tomography orPET is another imaging technology that is being harnessed for drug discovery. Bytacking a radioisotope of fluoride or carbononto a drug, for example, researchers canuse PET to detect the radiation emittedby the labeled drug, and create an imageof where it goes in the body.
Fluorescence imaging techniques,such as two-photon excitation microscopy,potentially provide a way to look into theliving cell and watch what happens whena drug hits its target. This not only mayaid drug discovery; it may salvage a prom-ising class of cancer drugs called MMPinhibitors that were largely abandoned bydrug companies after several clinical trialsfailed to show any survival benefit inpatients with advanced disease.
MMP stands for matrix metallopro-teinases, enzymes that are thought tocontribute to the growth and spread of
cancer, by helping to increase the tumor’sblood supply and means of escape toother parts of the body.
Vanderbilt cancer researchers havedeveloped a “proteolytic beacon” that candetect and measure MMP activity. Thebeacon is a fluorescent probe that releasesa flash of fluorescence when split by the enzyme.
When an MMP inhibitor is given toblock the enzyme, the beacon doesn’t flashas brightly. In this way, the researchershope to determine the dose of drug neces-sary to inhibit these enzymes, as well as
“What we found was a genetic polymorphism which is much morecommon in African-Americans than inCaucasians … This was a completelyunexpected finding … When you pro-pose these genetic studies, peoplewill say, ‘Well, you’re going on a fish-ing expedition.’ And I say, ‘Yeah, butthis time we caught a whale.’”
David W. Haas, M.D., principal investigator, AIDS Clinical Trials Unit at Vanderbilt
In the future, with the help of proteomics, “we might be able topredict if a drug is going to be effective in a patient – even afterthe first dose.”
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which patients are most likely to respondto therapy.
“We’re talking about cellular-basedscreening, high-content screening,” saysDavid W. Piston, Ph.D., professor ofMolecular Physiology and Biophysics whois participating in the research. “If you’redoing front-line screening in the cell,you’re two steps closer to the patient.”
Eventually, data from these studieswill be integrated with data from genomicand proteomic studies to build “3-D models” that more accurately predict drugactivity. “You’re going to find a lot fewerthings that take you down the wrongpath,” Piston predicts.
Sidelining the side effectsOne of the biggest barriers to the
successful launch of a drug is the adversedrug effect or unexpected side effect thatmay not become apparent until late inclinical testing or after marketing.
While the adverse effect may occur inonly a tiny minority of patients, it may beserious enough that the drug company hasno choice but to flush the entire effort –perhaps 12 years of work and up to a bil-lion dollar investment – down the drain.
Advances in genetic research maycome to the rescue.
In the late 1970s and early 1980s,Vanderbilt scientists led by Grant R.Wilkinson, Ph.D., D.Sc., for example,identified some of the first polymorphisms,or genetic variations, in a group of liverenzymes called cytochrome P450s thatmetabolize or break down drugs in thebody. Drugs are more likely to reach toxiclevels in people whose enzymes do a poorjob breaking them down.
More recently, Wilkinson and his col-leagues, including Richard B. Kim, M.D.,and David W. Haas, M.D., discovered thata polymorphism in a drug-metabolizingenzyme gene impairs the ability to metabo-lize the AIDS drug efavirenz. This polymorphism is about six times morecommon in African-Americans than inCaucasians, which may explain whyefavirenz blood levels are generally higherin African-Americans.
Individuals with this genetic varianttend to accumulate higher levels of thedrug in their blood, and as a result theymay experience mental confusion, strangedreams and other central nervous systemdisturbances, says Haas, principal investiga-tor of the Vanderbilt AIDS Clinical TrialsUnit. The side effects can be so disturbingthat patients stop taking their medication.
Pharmacogenetics – the study of how genetic differences affect drug
Jackie Corbin, Ph.D., didn’t set out to develop a drug. He just wanted to do good sci-ence and understand how the body works.
He couldn’t have known at the outset of his career that his work would lay the founda-tion for the blockbuster drugs for erectile dysfunction: Viagra and related compounds.
It’s hard to pinpoint the first step down the road that led to Viagra, but Corbin, pro-fessor of Molecular Physiology and Biophysics at Vanderbilt, has forged ahead on thispath since the 1960s.
“We never had any thoughts about developing any pills when we started our research,”said Corbin. “When my research first started, we were trying to figure out how cyclicnucleotides (cyclic AMP and cyclic GMP) worked in the body. That was a very basicphysiological question.”
Cyclic GMP and cyclic AMP are second messengers, molecules that carry signalsfrom the cell surface to proteins within the cell. Earl Sutherland, M.D., the late Nobellaureate and Vanderbilt professor, discovered cyclic AMP in the 1950s while studyingthe cellular action of hormones. Cyclic GMP was discovered later.
Sutherland’s work also suggested the existence of enzymes called phosphodiesterases,or PDEs, which degrade cyclic nucleotides.
In the early 1970s, scientists knew that cyclic AMP and cyclic GMP bind to and acti-vate intracellular protein kinases, enzymes that regulate the activity of other cellularproteins. It was believed that these were the only cyclic nucleotide-binding proteinspresent in mammals.
In 1976, Corbin and his postdoctoral student Tom Lincoln, Ph.D., identified a novelprotein that bound to cyclic GMP. Corbin, Lincoln and their colleague Sharron Francis,Ph.D., currently professor of Molecular Physiology and Biophysics, eventually purifiedand characterized the newly recognized protein, determining that it was a phosphodi-esterase that degrades cyclic GMP. It was later named PDE5.
Around the same time, other groups showed that increased intracellular cyclic GMPlevels promote the relaxation of smooth muscle, while PDEs that degrade cyclic GMPcounter this action. These findings suggested that blocking the enzymes could relaxthe musculature of blood vessels, and consequently lower blood pressure.
At that point, drug companies took interest. “In the mid-’80s, drug companies would come to us and ask us for our enzyme and
for our consultation to work to develop inhibitors to block (it),” Corbin said. Pfizer Pharmaceutical developed and began testing one compound, but an interesting
side effect shifted the company’s attention – away from blood pressure.“Sharron and I were at a meeting in the early ’90s, and had dinner with some of the
Pfizer people. We knew they’d been working on these inhibitors, so we asked if theyhad any good ones. They said ‘…we’ve got one where its effect on blood pressure isnot that great, but some male patients have noticed it causes penile erection.’”
Pfizer began clinical trials of their compound, sildenafil (Viagra), on men with erectiledysfunction. The drug proved highly effective and had few side effects. Viagra hit themarket in 1998 and soon became one of the best-selling drugs in history.
Today, Viagra and related PDE5 inhibitors tadalafil (Cialis) and vardenafil (Levitra) aresome of the most financially successful drugs on the market. The drugs are now beingstudied in other conditions including pulmonary hypertension, Raynaud’s Syndrome (acirculatory disorder), recovery from stroke, cystic fibrosis, and as possible preventivesfor erectile dysfunction and heart disease.
“So we kind of accidentally entered the Viagra field by working on cyclic AMP andcyclic GMP, which just happened to be crucial mediators (of erectile dysfunction),”says Corbin, whose lab continues to investigate PDE5. “But we think that Viagrawouldn’t have been possible if we had not laid the groundwork and discovered theenzyme and the mechanism.
“Our work involved some logic, some prediction, some direction, but a lot ofserendipity. I like to think that’s the way basic science ought to be.”
– MELISSA MARINO
Viagra and the value of serendipity
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DNA on deposit Vanderbilt recently joined forces with
the U.S. Food and Drug Administration, thepharmaceutical giant GlaxoSmithKlineand First Genetic Trust, a Chicago-basedcompany that has pioneered DNA bank-ing, to advance genetic-based medicinesand diagnostics.
The goal: to expand the collection ofDNA samples from patients who suffer arare adverse drug event called long QTsyndrome. The syndrome can lead topotentially fatal arrhythmias, abnormalheart rhythms.
When physicians anywhere in thecountry report drug-induced long QT syn-drome to the FDA, the agency will refer
them and their patients to Vanderbilt forparticipation in the study.
“We’ve been interested in this rareadverse drug effect for many years, withthe idea that it is genetically determined,”says Dan M. Roden, M.D., director of theJohn A. Oates Institute for ExperimentalTherapeutics at Vanderbilt and a principalinvestigator in the collaboration.
“The key first step in searching forgenetic variants that may increase suscep-tibility is finding enough patients whohave suffered this unusual event,” Rodensays. If genetic variants are found, it maybe possible to develop diagnostic tests thatcan be used to identify, in advance, peopleat high risk for this side effect if they takecertain drugs.
Genetic testing is not an easy sell,however. “There are drugs for which there
response – may lead to more “rational” drugdevelopment and prescribing. “It may bepossible in the not-too-distant future toscreen a person’s genome for polymor-phisms that have clinical implications andthen choose an appropriate regimen or anappropriate drug dose based on knowingtheir genetic background,” Haas says.
Haas says the polymorphism thataffects the metabolism of the AIDS drugcould not have been discovered withoutthe help of a national DNA “repository”established by the Adult AIDS ClinicalTrials Group, a federally funded group of34 centers in the United States, includingVanderbilt, which evaluates new AIDStreatments.
In 2000, Haas and his colleaguesbegan developing a process for obtaininginformed consent to collect an extrablood sample for DNA studies frompatients participating in AIDS clinicaltrials. Since then, the repository, whichis housed at Vanderbilt, has collectednearly 8,000 samples from differentindividuals.
So far, about 10 genetic studies havebeen undertaken using the DNA samples.Information from these studies is beingused to help develop a vaccine against theAIDS-causing human immunodeficiencyvirus (HIV), and to develop treatmentsthat can rebuild or “reconstitute” theimmune systems of patients that havebeen damaged by HIV infection.
“It’s really just a glorious explosion ofdiscovery,” Haas says.
are potentially very effective genetic teststhat can predict, with a high degree ofprobability, side effects,” Haas says. “Butthe companies that make those drugs arenot pushing for genetic testing becausethey think … they will lose market share.
“Suppose there are three drugs forproviders to choose from, and one of themshows that a genetic test will help youprescribe it better,” he explains. “Most cli-nicians right now would rather just writethe prescription for the other drugs andavoid genetic testing.
“Genetics is not going to be used toguide prescribing just because it makessense. It will only happen if accomplished,forward-thinking investigators, in partner-
ship with the community, really push thisforward and make it a reality.”
William E. Evans, Pharm.D., directorand chief executive officer of St. JudeChildren’s Research Hospital in Memphis,agrees. Evans and his colleagues pioneeredthe use of genetic testing to improvetreatment of childhood cancers.
“The burden is on us at academicmedical centers to begin to not only provide … evidence that these geneticpolymorphisms are influencing significantlythe drug response,” Evans said during arecent lecture at Vanderbilt, “but to beginto incorporate that into treatment plansand protocols and to show … that it actu-ally makes a difference.” LENS
“What the human genome isteaching us is that there istremendous variability among individuals at the genetic level …and that it ought to be possible tounderstand how that variability …in a whole set of genes might perturb responses in an individualor in a group of people to drugs.”
Dan M. Roden, M.D., directorof the John A. Oates Institute for Experimental Therapeutics at Vanderbilt
“Genetics is not going to … guide prescribing just because itmakes sense. It will only happen if … investigators (and) the com-munity really push this forward.”
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An informal search of medicalnews Web sites on any givenday will typically return dozensof reports on the discovery of a new cancer-related gene, yetonly five new agents have beenapproved for the treatment ofcancer since 2000.
With so many new molecularand genetic targets being iden-tified, why is the pace of cancerdrug development so slow?
Leading researchers believecurrent design and analysis ofclinical trials may contribute.
In a 2003 review in NatureReviews Cancer, Vanderbilt cancer researchers MaceRothenberg, M.D., DavidCarbone, M.D., Ph.D., andDavid Johnson, M.D., identifiedfactors that may be prematurelysending some potentially usefulcancer drugs to an early grave.
From a large volume of pre-clinical studies, compoundsthat inhibited angiogenesis, theformation of new blood vessels,appeared to be the “dawn of anew era” in cancer therapy,describes Rothenberg, profes-sor of Medicine and IngramProfessor of Cancer Research.
Laboratory studies suggestedthat angiogenesis inhibitorsalone could be used to curecancer. Because blood vesselformation was one of the deci-sive factors in tumor growth,researchers thought thatinhibiting this process wouldkill tumors by robbing them oftheir blood supply. Also, angio-genesis inhibitors were thoughtto be much less toxic thanstandard chemotherapeutics.
When the first angiogenesisinhibitor trials began, an ensuinghysteria – in the form of enroll-ment “lotteries” and patientstraveling cross-country to par-ticipate – followed. The frenziedexpectation surrounding thesedrugs soon diminished as theevidence began coming in from
the clinical trials. When usedalone, the first generation ofangiogenesis inhibitors werenot clinically effective.
These “failures” forced sci-entists to rethink their strategy.The tide shifted to testingangiogenesis inhibitors as anadjunct to conventional cytotox-ic therapies and to developingbetter angiogenesis inhibitors.This strategy proved muchmore effective, leading to theapproval of the first angiogene-sis inhibitor, Avastin, last year.
“Animal/preclinical modelshave been very useful in helpingus explore the biology of cancer,but we have very few usefulmodels that have been developedthat recapitulate the complexityof human cancers in the clinicalsetting,” Rothenberg explains.
“I think the mistake hasbeen in assuming that theseresults will accurately predictclinical effect. They do not.”
In the 1990s, researchersoptimistically predicted that targeted therapies – drugsdesigned to act only on a singlecellular component – would bemore effective and would even-tually replace conventionalcytotoxic therapies. Since tar-geted therapies would onlyaffect cells that harbored thespecific target, the drugs alsowould be safer and cause lessdamage to normal tissues.
This hypothesis was basedlargely on trials of Herceptin,the first growth factor targetedmonoclonal antibody approvedto treat breast cancer. It pre-vents epidermal growth factor(EGF) from binding to a recep-tor known as Her2.
“At a very crucial time in itsdevelopment, it was recognizedthat only those tumors that hadsignificantly high levels ofexpression of the receptorHer2 would likely respond,”Rothenberg says. Because of
this, the clinical trials were lim-ited to patients whose tumorsoverexpressed Her2, and quicklyshowed that it was a beneficialagent to incorporate into therapy.
However, when the samestrategy was tried with anotherreceptor that binds EGF, Her1,“Lo and behold, this didn’tcarry over,” he says.
Her1-targeted drugs such asIressa, Tarceva and Erbituxshowed a similar activity in allpatients, whether their tumorsexpressed low, intermediate orhigh levels of the receptor.Even patients whose tumorsdon’t express Her1 benefitedfrom Erbitux.
Then, last year, scientists discovered that patients weremore likely to respond to Iressaor Tarceva if they had a muta-tion in the Her1 receptor.
“So that taught us an impor-tant lesson,” Rothenberg says.“Even though we talk about tar-geted therapies, different targetsmay have different rules ofengagement. We can’t make asweeping assumption that whatis true in one is true in all.”
Underlying the unpredictabilityis a significant amount ofcrosstalk between numerouscell-signaling pathways.
“Shutting down one pathwaydoesn’t necessarily lead todeath of the cancer,” he says.“Other regulatory pathwaysmay be abnormally functioningin these cells. Therefore, ourapproach currently is to targetcomplementary pathways, sothat we can more completelyshut down those growth factorsignaling pathways that aredriving the cancer cell.”
Rothenberg and colleaguesalso are using pharmacoge-nomic profiling to define thebiology that drives the clinicalactivity of drugs, both the anti-tumor activity and toxicity.
“To relate this informationabout drug response to genomicor proteomic profile of the tumorwill give us hopefully more use-ful and predictive informationabout what drugs might beuseful in what doses and inwhat setting,” he says.
“We are at an unprecedentedtime of opportunity in the field of drug development,”Rothenberg concludes. “Thegap that has existed for manyyears – between what weunderstand about the scienceof cancer and the way we treatcancer – is narrowing.”
Why targeted cancer therapies have not hit the ‘bull’s-eye’BY MELISSA MARINO
Mace Rothenberg, M.D.
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A[closer]
lookSeeing beauty
in the complexity
of wildflowers and clinical
pharmacology
BY LEIGH MACMILLAN
Looking through a camera lens wasnothing new for John A. Oates, M.D., butthis time the view was different. As hetrained his new macro lens on a SpringBeauty, an ordinary pink and white wild-flower that graces woody hillsides anduncultivated front lawns, he was struck by the extraordinary beauty of the magni-fied flower.
The experience 15-odd years agosparked him to enroll in a photographycourse and to add wildflower hunts to hisglobal travels.
“It is certainly true that I’ve had afascination with the intimate detail ofwildflowers – details that elude the viewfrom a distance,” he says during a recentconversation in his office at VanderbiltUniversity Medical Center. He’s silent fora long moment before launching into aquote from Henry David Thoreau’s Walden,slowly at first, then with growing confidence.
“The scenery of Walden is on a humblescale, and, though very beautiful, does notapproach to grandeur, nor can it muchconcern one who has not long frequentedit or lived by its shore …”
Leaning back in his chair, he’s carefulto note that Thoreau’s comment didn’tinspire him, but that it fits.
“What he’s saying is that the beautyisn’t something you spot while driving by –like the Rocky Mountains – it’s onlyapparent to the people who frequent theshores … to those who become intimatelyacquainted with it,” Oates says.
Oates frequents the shores – of wild-flowers, of biological signaling pathways,of the discipline of clinical pharmacology.He looks closely and sees deeply.
His dossier is thick with achievements:discoveries that shaped the field of researchrelated to biologically active moleculescalled prostaglandins; activities that builtthe foundations for the discipline of clini-cal pharmacology and made its principlescentral to drug development.
“I think he’s one of the greats ofPharmacology and of American medicine,”says Garret A. FitzGerald, M.D., chair ofPharmacology at the University ofPennsylvania School of Medicine.
At 73, Oates, the Thomas F. Frist Sr.Professor of Medicine at Vanderbilt, couldeasily choose to relax his intense gaze. Butthere are too many biological complexitiesyet to understand, too many wildflowersyet to behold.
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Oates and his team recently receiveda three-year award to study the link betweenthe cyclooxygenase (COX) enzymes – whichproduce prostaglandins and other products– and Alzheimer’s disease. The group hasongoing studies to understand how aceta-minophen and aspirin interact with theCOX enzymes to block activity, and whythose drugs are more effective in some celltypes. He is in conversation with divisioncolleagues about using acetaminophen tocombat diseases as varied as rhabdomyaly-sis and malaria.
He continues to be active in theDivision of Clinical Pharmacology hefounded more than 40 years ago, and iswatching with interest the establishmentof the John A. Oates Institute forExperimental Therapeutics at Vanderbilt.
A broad grin creeps across his face whenhe is asked how long he’ll keep all this up.“As long as I’ve got ideas,” he chuckles.
[Sowing the seeds]The ideas started coming early. As
a young medical student at the BowmanGray School of Medicine of Wake ForestCollege, Oates had the option of writing a paper or doing a research project for thephysiology course.
“A group of my friends and I decidedto test whether or not peritoneal dialysiswould be beneficial for kidney failure,” herecalls. “At the time, that idea hadn’t beenintroduced clinically.”
The group had only limited access tolaboratory equipment, but the physiologydepartment had an excess of electrocardio-gram machines. The bright medical studentsreasoned that they could use the EKG tolook for effects of elevated potassium – oneway that kidney failure leads to a fataloutcome.
Their experiments in dogs showed that peritoneal dialysis prevented elevatedpotassium following renal failure. The tasteof research whetted Oates’ appetite, andhe went looking for more.
What prompts a medical student toseek opportunities to study potassium andthe heart?
“I guess I was always curious,” Oatessays, recalling his eastern North Carolinachildhood spent exploring, camping, sailingand reading adventure novels.
Colleagues agree.“I think he’s much more curious than
most,” says Robert A. Branch, M.D.,director of Clinical Pharmacology at theUniversity of Pittsburgh, who workedclosely with Oates for 20 years. “He’s logi-cal; he’s well-informed; but primarily Ithink his driving force is curiosity.”
Pictured here, from top: John Oates,M.D., in his Vanderbilt laboratory inthe 1960s; during a family whitewaterrafting trip on the Nantahala River inNorth Carolina in 1991 (Oates isfront right); and with his researchnurse, Sheilah Winn, R.N., who hasworked with him since 1989. At bot-tom, the Oates family on vacation inthe mid-1990s. From left, Meredith,Oates’ wife of 49 years, John Oates,daughter-in-law Jennifer, youngest sonJim, daughter Larkin, granddaughterCaroline, daughter-in-law Jane, andoldest son David. Of their grandchil-dren, who now number six, MeredithOates says they think their grandfa-ther is “the best playmate.”
Photos courtesy of the Oates family
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doses of up to 1 gram per kilogram withoutlowering blood pressure or having anyadverse effect,” he recalls, a mischievoustwinkle in his eye. “They said it can’t possibly be pharmacologically active.”
Aldomet was one of the major treat-ments for severe hypertension for about 15 years, Oates says. It was replaced by anewer generation of antihypertensive agents,but is still used for certain indications,including high blood pressure in pregnancy.
Oates’ experience in the Sjoerdsma-Udenfriend unit set his career trajectory,he says.
“I think one of the most importantthings you can do as a young person entering science is to work with the rightmentor – somebody who’s successful andhaving fun with it. Science is like mostthings in life: you win some and you losesome. In order to sustain through the upsand downs, you have to have tasted successin science and had the thrill of a discovery,or two, or three ...
“At the NIH there were a lot ofyoung scientists my age who were reallyhaving a ball doing research, and it wasbecause of the senior leaders who were creative, energetic, had good ideas, andwere committed to clinical research. I wasfortunate for having landed in a group likethat,” Oates says.
It was in this dynamic and uniquelyproductive environment – where discoveriesand approaches from the laboratory wereapplied to clinical research – that Oates’vision for clinical pharmacology germinated.His ideas sprouted and took form in theDivision of Clinical Pharmacology atVanderbilt, the division Oates founded in1963 and directed for 25 years.
[Growing a discipline]Oates was not alone in embracing the
notion of a discipline that would bridge
“He has an inquisitive mind – a very,very inquisitive mind,” says L. JacksonRoberts II, M.D., professor of Pharmacologyand Medicine at Vanderbilt.
When in 1955 Oates approached one ofthe cardiologists at Wake Forest about study-ing the effects of potassium in the heart, hewas directed to the chair of the Biochemistrydepartment, Camillo Artom, M.D., Ph.D.
“I was a naïve student who thought Icould do anything,” Oates says.
Artom listened politely, told Oateshis ideas were interesting, and thenadvised him instead to work on the mainresearch area in the Artom laboratory:phospholipids – the fatty molecules thatconstitute the cell’s membrane and are thestarting materials for the production ofmany signaling molecules.
The seeds were sown. Both cardiovascu-lar biology and lipid biology would becomerecurring themes in Oates’ research career.
His time in the Artom laboratory waslikely responsible for his success in obtain-ing an internship position at CornellMedical Center, Oates says. “I wasn’t thetop student in my class ... and that was agreat institution.”
At Cornell, Oates was introduced to theidea of joining another great institution,the National Institutes of Health. The“Doctor Draft” implemented at the startof the Korean War was still in place, andOates was prepared to enter the Air Forcewhen he learned that a fellow resident wasgoing to the NIH instead of into the Army.
He applied and was offered a clinicalassociate position at the NIH.
“I think I was fortunate that I was in ahouse staff program where there were brightpeople who were interested in research andone of them put me onto this opportunityat the NIH,” Oates says.
The move to Bethesda proved to be akey one.
[The thrill of discovery]One night in 1959, Oates headed
back into the lab at the National HeartInstitute – now the National Heart, Lung,and Blood Institute – with the sense thathe and his team were onto something big.The graph he charted from the day’s datadidn’t let him down. He called one of hiscolleagues at home at 11 p.m. to relate thenews: the drug they were studyingappeared to lower blood pressure.
It was the first time Oates remembersfeeling the thrill of discovery, and he washooked.
“It’s incredibly exciting, to be workingon something for a long time, and then allof a sudden – bang! – it’s there, somethingnew that nobody has ever seen before,” hesays. “In this case, it’s fair to say that weall had hoped the drug might have aneffect on blood pressure in humans, butthere was no precedent for it in prior animal studies.”
The drug was methyldopa. At thetime of Oates’ discovery, there were noeffective drugs for treating patients withsevere hypertension – the subset of hyper-tensive patients who are most susceptibleto stroke, heart attack and kidney failure.Methyldopa, developed and marketed asAldomet by Merck, became the first.
The NIH group, headed by AlbertSjoerdsma, M.D., Ph.D., and SidneyUdenfriend, Ph.D., had not set out to discover methyldopa’s usefulness as anantihypertensive drug. The drug fromMerck was simply an experimental tool,part of ongoing efforts to understand thebiochemistry – synthesis and metabolism –of aromatic amines like norepinephrineand serotonin, as a way to gain informa-tion about hypertension and its treatment.
“The pharmacologists at Merck hadcompleted toxicology studies and com-mented to us that they had given rabbits
Pictured here: John Oates, M.D., (center) featured on the cover of theMay 3, 1971, issue of Modern Medicinewith (from left) research fellows RussMcAllister, M.D., Barton Grooms, M.D.,and Cliff Cleveland, M.D.
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Pictured here: Two examples of Oates’extensive collection of wildflower photos:Indian Paintbrush (left) and Michigan Lilies.The lilies were found on the MiddleTennessee farm of Vanderbilt colleagueMildred Stahlman, M.D., but have now dis-appeared, Oates says.
interactions; it’s really a style of thinkingthat he’s contributed to the drug discoveryand development process,” Branch adds.
[Putting together the pieces]Clinical pharmacology, perhaps more
than other biomedical research disciplines,has an obvious link to the pharmaceuticalindustry, Oates says.
“To put it simply, you like for yourwork to be where the action is. And molecules going into human beings forpharmacologic purposes are what we’reinterested in. Our cooperation with industryhas repeatedly been valuable in bringingus investigational tools for discovery.”
Methyldopa was one such “tool” thatallowed Oates and colleagues to illumi-nate aspects of blood pressure regulation.The team’s research on guanethidine,another blood pressure medication, identified drug interactions as an interestingand important area in clinical pharmacology,Oates says.
Studies of a drug candidate that nevermade it to market also had a major impacton concepts in drug metabolism.
The drug candidate, code named SU-13197, was being investigated as a potentialantiarrhythmic drug when the globalchemical company Ciba enlisted Oates’assistance in studying its metabolism andhuman pharmacology.
“It was just the beginning of the era ofrealizing that it’s important to investigatemetabolic fate early in the process of drugdevelopment,” Oates recalls.
Oates and his colleagues followed the availability of radiolabeled SU-13197, discovering that only a fraction of the unme-tabolized drug appeared in the systemiccirculation following oral administrationcompared to intravenous administration. Itwas the first solid evidence of what came tobe known as “first pass metabolism” – the
laboratory research and clinical investigation.He and a handful of other young scientists,some of them his peers from the NIH,began to call themselves clinical pharma-cologists and form units around the countryin the early 1960s.
“Clinical pharmacology became whatthose five or so investigators took it tobe,” says David Robertson, M.D., directorof Vanderbilt’s General Clinical ResearchCenter. “They all knew each other, and theymet and called themselves the ‘non-societyof clinical pharmacology.’
“They were each great scientists intheir own fields, and they insisted on care-fully controlled studies. I think if John hadan ideology with which he approachedresearch, it was that measuring thingscarefully and thinking properly about studydesign was the way to make discoveries.”
At Vanderbilt, Oates found a conflu-ence of the right ingredients for a successfulprogram, including a pharmacology chairman, Allan D. Bass, M.D., who was committed to the idea, and a thrivingclinical research center, one of the firstNIH-funded centers in the country.
“Allan Bass had a vision that thescope of pharmacology ought to includeclinical investigation and human pharma-cology,” Oates recalls, “and that wasunique at the time.”
So with Bass’ enthusiastic support andan early award from the Burroughs WellcomeFund, Oates set about building a world-class clinical pharmacology program – adivision of the Department of Medicine withstrong connections to the basic scientistsin the Department of Pharmacology. Hisefforts met with stunning success.
“I think John’s extraordinary talentshave been in having a vision for the field ofclinical pharmacology and in recruiting andretaining people who have very comple-mentary skills and creating an environment
in which they flourish,” says FitzGerald, whoserved as the second director of ClinicalPharmacology at Vanderbilt.
“Those talents have been why, underJohn’s leadership, this model of what we calltranslational research now really flourishedat Vanderbilt in a way that I don’t think itdid anywhere else, and that’s really his greatgift to that institution and to the country.”
Branch, who was a faculty member in Vanderbilt’s Clinical Pharmacologydivision for 16 years, borrowed fromOates’ model when he set up the divisionat Pittsburgh.
“The most important thing was theatmosphere of getting enterprising peopleto be enterprising,” Branch says. “He didn’ttell people what to do. He had foresightin putting together infrastructures, likethe mass spectrometry resource. He under-stood the mechanics of networking andcooperative multidisciplinary research waybefore it became popular and a buzzwordat the NIH.
“In the first generation of clinicalpharmacology centers, as the leaders retired,the centers fell apart. John’s is the onlyone, that when he moved on to becomechairman of Medicine, continued to grow.And it’s the most substantial clinical phar-macology unit anywhere.”
From the vantage of this influentialdivision, Oates shaped clinical pharmacol-ogy’s impact. He has served as a scientificadviser over the years to various pharma-ceutical and biotechnology companies,including Merck.
“He understood what was required towork out how well drugs worked, and whythey worked, and who they worked in,” saysDavid Shand, M.D., Ph.D., a retired phar-maceutical company executive who was onthe Vanderbilt faculty in the 1970s.
“He has been instrumental in our wayof thinking about groups of drugs and drug
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“He has been, first and foremost, agreat physician,” agrees Robertson. “Henever let his people stop being clinicians.”
Robertson is one of the more than300 fellows who have trained in theDivision of Clinical Pharmacology atVanderbilt. About a third of them havegone on to leadership positions in eitheracademia or industry related to drug dis-covery and development.
“If I had to pick the most influentialperson in clinical pharmacology in theUnited States over the past three decades,it’s John,” says Morrow, who also was afellow in Clinical Pharmacology atVanderbilt.
This legacy of success will be extendedin the John A. Oates Institute forExperimental Therapeutics, launched last fall.
“This new institute recognizesVanderbilt’s commitment to growing thekind of science that John made famoushere – understanding how drugs work inthe body, why not everyone responds todrugs the same way, and how we can usethat information to make better use of thedrugs we have and to develop new drugs,”says Dan M. Roden, M.D., director of theOates Institute and former director ofClinical Pharmacology.
As the new institute blooms andbegins to flourish, Oates will be watching.
Closely. LENS
clearance of an orally delivered drug bythe liver and intestinal tract on the drug’s“first pass” through these drug-metaboliz-ing organs.
The team also found evidence thatdrugs with a high first pass metabolism,like SU-13197, had a high degree of inter-individual variation, a concept that continuesto shape drug discovery and developmentnow in the genomic era.
Grant R. Wilkinson, Ph.D., whojoined the faculty in 1971, and Shandwent on to develop what Oates calls “ele-gant clearance concepts” that describe drugdisposition. But that would not have hap-pened were it not for a “very proactive”interaction with industry.
“It’s just one example of how ourinvolvement with industry gave us thetools to make discoveries,” Oates explains.“Once we had those tools, the opportunitiesfor creativity opened.”
Creativity has characterized Oates’distinguished scientific career. Among hismany discoveries, those in the field ofprostaglandin biology are most noted. Whenhe became interested in these widespreadsignaling molecules, he traveled on sab-batical to learn firsthand from a leader inthe field – the Karolinska Institute’s BengtSamuelsson, M.D., Ph.D., who went on towin the Nobel Prize for his work.
Oates has been “a trailblazer” in thedevelopment of new methodologies thatcontributed to the teasing apart of thecomponents of prostaglandin physiology,Branch says.
Prostaglandins are members of a largefamily of molecules called eicosanoids thatare derived from fatty acids, predominantlyarachidonic acid, and which have varied andprofound physiological and pathophysio-logical effects. The eicosanoid field startedwith the discovery of two compounds, andnow boasts over 2,000 family members,Roberts says.
“His group would develop a newmethod that would allow that area to bedeveloped, and then they would developanother new method and so on. It waspainstaking work, and they put a lot ofpieces of the jigsaw puzzle into theprostaglandin-eicosanoid story,” Branch says.
The Oates team defined the role ofprostaglandins in renin release by the kidney,demonstrating the importance ofprostaglandins as a pathway parallel to the adrenergic nervous system in controllingrenin release and regulating blood pressure.
The group also discovered that theprostaglandin PGD2 is the principalprostaglandin mediator in human mastcells. That finding is being explored in
drug development for allergic rhinitis andasthma, Oates says.
As for his current research projects,he says they’re at a “speculative stage,”adding, with a sly chuckle, that “these areexciting times.”
[A lasting legacy]Oates’ contributions have been hon-
ored many times over. He is a member ofthe prestigious Institute of Medicine ofthe National Academies of Science, theadviser to the nation on matters of bio-medical science, medicine and health. Heis a Fellow of the American Associationfor the Advancement of Science.
He singles out two awards as mostmeaningful to him: one from early in his career, the American Society forPharmacology and ExperimentalTherapeutics Award for “Outstanding BasicPharmacologic Investigations in Man;” and one from just last year, an Award ofExcellence in Clinical Research from theGeneral Clinical Research Centers Programof the NIH. These awards applaud thehypothesis-driven clinical research that hasdistinguished his career.
Central to such research is the patient,and Oates has never lost sight of his call-ing as a physician.
“He’s in clinic every Monday; hispatients love him,” says Jason D. Morrow,M.D., current director of ClinicalPharmacology.
“If I had to pick the most influential person in clinical pharmacology in the United States over the past three
decades, it’s John.”[ ]D
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Nancy J. Brown, M.D.,wasn’t certain whether or not she was seeing apattern among her patients.
It was 1992, and the young clinical pharmacologist at Vanderbilt UniversityMedical Center noticed that some of her patients seemed to have an allergic-typereaction to ACE-inhibitors, medications used to treat hypertension and reduce therisk of heart disease and kidney failure.
Not commonly, but often enough to notice, some of them were coming in withsymptoms of angioedema – swelling of the lips, face, tongue and throat. Even moredisconcerting, it struck her that an inordinate number of patients with side effectswere African-American.
Brown decided to pursue her hunch. First, she called various drug companies, butfew had readily available data on adverse reactions. Next she spoke with Marie R.Griffin, M.D., MPH, a Vanderbilt pharmacoepidemiologist, who contacted colleaguesat the U.S. Food and Drug Administration to see if there had been any similar reports.
As it turned out, a company had just submitted an application to the FDA for anew ACE-inhibitor drug, and had reported seeing higher rates of angioedema thananticipated. That company had included more African-Americans in its trials thanprevious studies had done.
Like sleuths, Griffin and Brown then examined the Tennessee Medicaid database,comparing rates of angioedema among both black and white patients on ACE-inhibitors with patients on calcium channel blockers, a different class of medicationfor reducing blood pressure.
“When we controlled for (type of medication) we found that blacks (on ACE-inhibitors) were four-and-a-half times more likely to have angioedema than whites,”says Brown, now a professor of Medicine and Pharmacology. “The other thing wenoticed was that there were a number of people who’d had episodes of angioedemawho’d been left on their ACE-inhibitor.”
In other words, even when patients presented with angioedema, many physicianshadn’t made the connection that the medication was the underlying cause.
Part of the reason was because angioedema, even among blacks, is a rare event.But also, while some people took only a pill or two and quickly experienced dramaticswelling of their tongue or lips, other patients had been taking the medicine formonths or even years before the side effect kicked in. Still others never experiencedbad reactions.
Brown, who has earned national recognition for her research on blood pressureregulation, now has a grant to try to weed out the biologic mechanisms for angioedemainduced by ACE-inhibitors. One of her concerns, she says, is, “How do you studysomething that is still a pretty rare side effect?”
First, DO NO HARMPHYSICIANS AND DRUG SAFETY
By Lisa A. DuBois At first,
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Nancy J. Brown, M.D.: Always vigilantfor the rare adverse side effect
Photo by Anne Rayner
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At first glance, it would seem that ifa drug has gone through the rigors of dis-covery and development, through clinicaltrials and FDA approval, any adverse sideeffects should have already been observedand noted. After all, isn’t it the responsi-bility of the FDA to ensure that only safedrugs are put on the market?
The answer is yes – if only it werethat easy.
Deadly elixirOf late, scientists and regulators have
been anxiously grappling with the problemsposed by post-marketing surveillance ofapproved pharmaceuticals. What may seemlike a miracle cure in controlled clinicaltrials, several thousand people strong, maybecome a totally different animal once it isreleased to the open market and prescribedby tens of thousands of physicians to mil-lions of patients.
Ignoring strict warning labels, manypatients take medicine off-label, meaningthey take it for illnesses for which it hasn’tbeen approved. They also take combinationsof drugs that counteract each other’s bene-ficial effects, under-dose to save money ortake more than the recommended dose totry to get quicker relief.
Even more confounding is the fact thattwo patients with the exact same diseasecan follow the exact same treatment plan– and the drug works beautifully for one,but doesn’t help the other patient at all.
All of these challenges have served tousher in a new era of pharmacoepidemiol-ogy – the study of pharmaceuticals amongpopulations of patients. According toWayne A. Ray, Ph.D., director of theDivision of Pharmacoepidemiology atVanderbilt, the field first emerged in theaftermath of two therapeutic disasters.
In 1937, a Tennessee drug companybegan selling Elixir Sulfanilamide, a sulfadrug used to treat streptococcal infections.More than 100 people, many of them children, died after taking the medication,which was dissolved in diethylene glycol,a toxic chemical normally used asantifreeze. In response, Congress passedthe Pure Food, Drugs and Cosmetics Actof 1938, requiring products to be rudi-mentarily tested for safety before theyreached consumers.
The second disaster involved the drugthalidomide, marketed in the 1950s andearly ’60s as a sleeping pill and a cure formorning sickness in pregnant women.Thalidomide caused profound birthdefects in more than 10,000 children in46 countries before it was pulled from theworldwide market.
Although a pharmacologist at theFDA, Frances Oldham Kelsey, M.D.,Ph.D., prevented thalidomide from beingmarketed in the United States, the sideeffects were so catastrophic that in 1962the United States began requiring thatdrugs undergo well-controlled studiesdemonstrating efficacy before they can besold to consumers.
The problem in our present day andage, says Ray, is that the rather cumbersomeguidelines for ensuring safety and efficacy ofdrugs slowed down the process of gettingdrugs to market, and in the 1980s con-sumers and pharmaceutical companies alikebegan pushing for quicker approval.
The upshot, he says, is that “… to getdrugs to market in a reasonable amount oftime, we put them through phase I, II andIII trials, but we still don’t know muchabout them. We know enough about adrug so that people can begin using it,but not enough about its long-termeffects. So we have to keep studying it.”
Unfortunately, that is where theexisting system falls short. “Following adrug once it’s on the market is a free-for-all,” he says.
Reporting the signalThe system the FDA uses for conduct-
ing post-marketing surveillance of drugs,MedWatch, relies on doctors, nurses andpharmacists to report safety concerns, basedon suspected serious adverse reactions theyhave observed. There are two instances inwhich this type of reporting system workswell – if a problem arises that is extreme orunusual, or if a problem appears within alarge proportion of consumers.
In the first instance, a drug may pro-duce such an unusual, distinctive form oftoxicity that physicians immediately takenotice, such as the idiosyncratic birth defectsamong pregnant users of thalidomide.
Another example is the drug-inducedarrhythmias discovered in consumers ofthe antihistamine Seldane.
“Seldane was given to millions ofpatients before the potential for severe drugreactions causing life-threatening arrhyth-mias was recognized,” says Dan M. Roden,M.D., who directs the John A. OatesInstitute for Experimental Therapeutics atVanderbilt. “Most of the adverse effectsonly occurred in patients who were usingSeldane in combination with other drugs.”
Although the arrhythmias caused bySeldane toxicity were so rare that they werehard to detect, their uniquely abnormalpatterns enabled physicians to eventuallytrack similar peculiar rhythms amongpatients and trace them back to use of the
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They said it couldn’t be done. Despite decades of research, scientists
had been unable to find a treatment forsevere sepsis, a life-threatening complicationof bacterial infection, usually of the blood-stream, that kills at least 250,000 adults inthe United States each year. During the previ-ous 25 years, more than 30 compounds hadbeen tested to treat severe sepsis. All ofthem had failed.
“Researchers were getting discouraged.They were saying that this disease is toosevere and too complex,” says Gordon R.Bernard, M.D., an internationally knownsepsis researcher and assistant vice chan-cellor for Research at Vanderbilt UniversityMedical Center.
Frustrated, some scientists argued that theU.S. Food and Drug Administration had setimpossibly high standards for treating near-death patients in the intensive care unit. TheFDA deemed an ICU drug efficacious only ifthe patient was still alive after 28 days.Despite the criticism, the agency stuck toits “28-day, all-cause mortality endpoint”required for approval.
Then in 1994, Bernard received a phonecall from investigators at Eli Lilly & Co. inIndianapolis. They had patented a recombi-nant human activated protein C (APC) as apotential heart drug, but had decided not topursue if for that use.
APC has anti-coagulant and anti-inflamma-tory properties. It can become depleted during an infection and as a result, clotscan form indiscriminately throughout thebody, cutting off the blood supply to vitalorgans. In this way, the initial infection canset off a chain of reactions, leading tomulti-organ system failure and death.
Searching for another use for their com-pound, Lilly scientists noticed that in previousstudies in baboons, APC had shown someefficacy in severe sepsis. They asked Bernard,chief of the Division of Allergy, Pulmonary andCritical Care Medicine at Vanderbilt, to designa small study of about 100 to 150 people tosee if their protein could produce effects inhumans with severe sepsis that might warrantfurther investigation.
After treating 131 patients, Bernard report-ed back to Lilly in 1996 that their compound,later named Xigris, may have saved the livesof some critically ill patients. Also, it clearlyreplenished the body’s supply of protein Cthat had been sapped by infection andimproved the coagulopathy, or coagulationdisorders, caused by sepsis.
Lilly opted to continue development.Bernard was appointed principal investigatorof an international phase III trial, known asPROWESS, which tested Xigris against aplacebo in 1,690 patients worldwide whowere in imminent danger of dying fromsevere sepsis.
Beginning in 1998, Bernard’s team ofinvestigators fielded calls from critical carephysicians in 160 centers around the globeto determine, in split-second decisions, if apatient could be included in the trial. Toqualify, all of the patients had to be dying ofsepsis and not from a primary diseasesuch as cancer or heart disease.
Within two years, it became apparent thatXigris was having a significant impact onsurvival: among the sickest patients themortality rate for those who took the drugwas 13 percent lower than the rate amongthose on placebo. An independent board ofadvisors stopped the PROWESS trial in2000, because it was no longer ethical togive the placebo.
“It was a huge day,” says William Macias,M.D., Ph.D., medical director of the XigrisProduct Team at Lilly. “First there was abrief moment of disbelief. We knew it was along shot for the overall trial to be success-ful, but to stop early was even bigger. Thiswas a once-in-a-lifetime experience.”
The PROWESS team had met what hadbeen considered an unattainable bench-mark – for every eight patients treated withXigris, one life was saved. “There are veryfew drugs for which such a sweeping state-ment can be made,” says Bernard.
“The company realized the risk of creat-ing and testing biological products,” Maciassays. “You have to invest very heavilybefore you ever know if you have a drugthat will be worth the investment.”
Vanderbilt’s involvement was crucial, addsMark Williams, M.D., medical advisor to theXigris Product Development Team. “One ofthe main reasons that PROWESS was suc-cessful was because Vanderbilt served asthe coordinating center,” he says, “a triagecenter under very difficult circumstances.”
Williams estimates that 7,500 lives havebeen saved since 2001, when the FDAapproved Xigris. With increasing use, asmany as 40,000 lives could be saved eachyear, he says. Because it can cause bleed-ing, however, not all severe sepsis patientsare candidates for the drug.
“The mortality rate (from severe sepsis) isstill too high,” says Bernard. “But to makeinroads into something this horrific is wonder-ful. It says we need to keep plugging away atscientific intervention and drug development.”
Which is exactly what is happening.Williams is currently running a large clinicaltrial in 110 sites around the world, testingthe efficacy of Xigris in critically ill children.He also is examining the drug’s effective-ness in certain cancer patients, with thecautious expectation that treating severesepsis in this patient cohort may lead to adrop in the overall cancer mortality rate.
The success of Xigris, says Williams,demonstrates how a partnership betweenuniversity scientists, industry and the FDAcan bring a life-saving product to fruition.“Each party has different expertise andstrengths,” he says, “and when they worktogether for the common good, we all seethe benefit.” LENS
Once in alifetimeFinding a way to short-circuit sepsis
BY LISA A. DUBOIS
Gordon R. Bernard, M.D.
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drug. Seldane was withdrawn from themarket in 1997.
A much more difficult problem toidentify, says Roden, is drug toxicity thatleads to an increase in a common event,such as heart attack or stroke among theelderly. The situation becomes even morecomplex if patients have been taking amedication for weeks, months or yearsbefore they suddenly have adverse reactions.Physicians may have no reason to suspectthe drug.
“Suppose a drug increases colon cancerby 20 percent. Unless they do a prospectiveclinical trial, we will never know, especiallyif the risk is only present in some patients,”Roden says. “My personal bias is that thesekinds of unrecognized drug actions are allaround us.”
A key to determining both the bene-fits and detriments of a particular drug isfinding the first “signal”– the indication ofsome unanticipated side effect – andreporting that signal to the FDA.
Many epidemiologists and pharma-cologists in the field claim that this modeof communication is inherently flawed. “It’shit or miss,” admits Vanderbilt’s Griffin,professor of Preventive Medicine.
Currently, MedWatch has littleauthority to affect change even if officialsreceive information warranting furtherinvestigation of adverse events. They candemand that a company conduct post-marketing surveillance on drugs, but theyhave no power to force a company to do so.
In effect, the FDA has only two options:demand a change of label, or withdraw thedrug from the market.
“The agency (FDA) has only a nuclearbomb (withdrawal) that they can bring tobear…or a powder puff, the powder puffbeing a change of label, which nobody readsand is totally ineffective,” says Raymond L.Woosley, M.D., Ph.D., a former Vanderbiltclinical pharmacologist whose work onSeldane led to the discovery of a safer anti-histamine now marketed as Allegra.
Beyond that, even if a drug is foundto cause a dangerous side effect in rarecases, there is no standardized mechanism
for determining what happens next orwhat should be deemed “acceptable risk.”
“Should we deprive 1,000 people ofACE-inhibitors to prevent one episode ofangioedema?” asks Griffin. “That’s a diffi-cult question.”
Search for safetyIn the past, drugs were usually given
in limited courses of days or weeks toaddress an acute medical problem. Manyof today’s medicines are administered toenhance quality of life and to prevent disease from occurring, and can be takenfor years on end.
“When you’re giving drugs to gener-ally healthy people, the standards have tobe higher,” Griffin continues. “If a drug isnot saving your life, it better not bekilling you.”
Seeking to advance the “optimal use”of drugs, medical devices and biologicalproducts, the federal government in 1999launched the Centers for Education andResearch on Therapeutics (CERTs) initiative.
Seven centers, including one atVanderbilt, conduct a wide range of researchon drug use and safety. Their reach is lim-ited, however.
“When you try to take research intopractice, there’s a lot that’s lost in transla-tion,” explains Ray, who heads up theVanderbilt CERT. “We address drug safety,but also the problem of clinicians usinginterventions appropriately. For example,it doesn’t help if beta blockers preventdeaths if nobody prescribes them.”
Meanwhile, aggressive marketing,including direct-to-consumer advertising,has created a demand for new drugs, evenamong patients for whom the compoundsmay not be effective and may even be dangerous.
The ticket to better post-marketingsurveillance might have to come from acomplete redesign of the FDA’s framework.
Currently, all the years it takes a drugto go through clinical trials and approvalcounts against its 20-year patent life.When the patent expires, competitivegeneric compounds can join the pool.
Vanderbilt clinical pharmacologistAlastair J.J. Wood, M.B., Ch.B., proposesthat the FDA reward pharmaceutical companies that conduct post-marketingstudies of their products by lengtheningtheir period of exclusivity – postponingthe right of generic knockoffs to competeagainst them.
Wood, Woosley and others also havecalled for the establishment of an inde-pendent agency to monitor drugs oncethey hit the market.
This February, in response to ballyhooby physicians, legislators and consumerwatch groups, the Department of Healthand Human Services announced that theFDA will indeed create a new independentDrug Safety Oversight Board.
Its purpose, according to a pressrelease, will be to promote a culture ofopenness and to provide emerging infor-mation to patients and doctors about therisks and benefits of medications. Theboard will be composed of FDA employeesand various government employees, inconsultation with medical experts andpatient and consumer groups.
While this is a step in the rightdirection, Ray says, “the board itself, fromwhat we know, does not appear sufficientlyindependent nor does it appear to have the authority and resources necessary to dothe job.”
“Society takes a calculated risk everytime we release a new drug onto the market,”he continues. “There needs to be someone,some independent authority, in place tomake hard decisions.” LENS
“The agency (FDA) has only a nuclear bomb (withdrawal)that they can bring to bear…or a powder puff, the powderpuff being a change of label, which nobody reads and istotally ineffective.”
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COX-2 inhibitorsA STATUS REPORT
By Bill Snyder
In February, an advisory panel to the U.S. Food and DrugAdministration considered whether the cardiovascular riskassociated with long-term use of a class of blockbuster arthri-tis drugs known as COX-2 inhibitors outweighed their benefits.
One of the drugs, Vioxx, had previously been pulled fromthe market after patients who took the drug in a long-termstudy were found to have an increased risk of heart attackand stroke.
After three days of testimony from scientists, drug com-pany executives and members of the public, a narrow majorityof panelists recommended keeping two other COX-2 blockers,Bextra and Celebrex, on the market – as long as the druglabels included stringent “black box” warnings.
In April, however, the FDA called for the withdrawal ofBextra after concluding that the drug’s overall risk-benefit profile was “unfavorable.” Celebrex was allowed to stay onthe market, but with a black box warning that the agency alsorequired for prescription non-steroidal anti-inflammatory drugs(NSAIDs).
Alastair J.J. Wood, M.B., Ch.B., professor ofPharmacology and Medicine at Vanderbilt who chaired theadvisory panel, warned that the FDA’s actions did not solvethe problem of how to improve drug safety.
“The increased risk of a common problem like a heartattack will not be picked up from our current reporting system,”he told the Los Angeles Times.
Pictured here: At top,accompanied by her attor-ney Browne Greene andson Travis, Joan BriertonJohnson of Topanga,Calif., reads testimony onbehalf of her 7-year-olddaughter Sabrina (in hat),who was blinded by anallergic reaction to anover-the-counter children'spain medicine. In herstatement, Sabrina askedthat warning labels berequired for the products.Panel chairman AlastairJ.J. Wood, M.B., Ch.B., ofVanderbilt (middle photo)listens intently. Opposite,Merck & Co. executiveshear testimony abouttheir company’s product,Vioxx. Other audiencemembers (bottom photos)reflect the tense atmos-phere.
Photos by Sam Kittner
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There is concern that fewer noveldrugs appear to be coming to mar-ket. What’s causing this, and whatcan be done to solve the problem?
Paul – (For) virtually every disease that weare working on right now, the science isincredibly rich. The number of novel,potentially disease-modifying drug targetsthat have been discovered as a result of the revolutionary advances in biomedicalresearch over the past two decades is trulyremarkable.
(But) if you look at the costs to dis-cover and develop a new drug, from theinception of a discovery project to its launchinto the marketplace, we now believe thatthe number as of 2005 is well over $1 bil-lion. It’s been rising almost exponentiallyover the last 20 years ...
The cost of discovering and developinga new medicine, of course, includes all ofthe compounds that never make it throughthe various phases of discovery and devel-opment – indeed the attrition rate for drugdiscovery and development has actuallyincreased somewhat over the past few yearsdespite the incredible science we have atour disposal.
We’ve got on the one hand this enor-mous scientific and medical opportunitythat we must take advantage of, and on theother hand this enormous challenge of cost.
One of my major concerns is that withall of the political and economic issues thatthe industry is now facing, we could literally“throw the baby out with the bath water.”We might literally need to re-invent a newindustry. My worst fear is that the pharma-ceutical industry may go the way of the steelindustry or the automobile industry or, Godforbid, the airline industry.
This would be most unfortunate.
Wood – Whatever that number is, I don’tthink that’s sustainable into the future, atleast to develop the kind of high-riskdrugs that we need ...
Just to pick Alzheimer’s, we don’t haveterrific data on the fundamental biologyright now, so developing drugs to preventAlzheimer’s rather than to treat patients’symptoms is in some ways a leap in the dark,at least in terms of an investment. If we’regoing to make these leaps and we should –God, I hope we do – then we need to devel-op some means of reducing the risk to thepeople who make that investment ...
I think we need to fundamentallychange the drug approval process ...
Paul – I disagree with Dr. Wood on thisone. I believe that Alzheimer’s disease is agreat example of how understanding thefundamental biology of a disease will likely,in my opinion, lead to effective treatments.Over the past decade or so, there have beenseveral genes identified which have beenshown to unequivocally cause the diseasein certain families or in one case to dra-matically increase one’s risk for developingthe disease.
By understanding how these genesinfluence disease pathogenesis, several novelapproaches to treatment have emerged. Wenow have three or four different types of“anti-amyloid” drugs that are in early clini-cal development – that I believe for the firsttime gives us a reasonably good chance ofmodifying the disease process itself …
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In a recent interview with Lens editor Bill Snyder, Steven M. Paul, M.D., presidentof Lilly Research Laboratories, and Alastair J.J. Wood, M.B., Ch.B., professor ofMedicine and Pharmacology at Vanderbilt University Medical Center, traded opinionsabout the challenges facing the nation’s pharmaceutical industry.
Wood, a member of the editorial board of the New England Journal of Medicine (andof this magazine), is a former candidate for FDA commissioner. Paul is former scientific director and chief of the clinical neuroscience branch at the NationalInstitute of Mental Health. Their points of agreement – and disagreement – maysurprise you.
S T E V E N M . PA U L , M . D .
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not being as transparent and objective as weshould be in presenting and publishing ourdata. Do we always publish all of the relevantdata on a given drug? Do we highlight nega-tive as well as positive results?
Just this past year at Lilly we reiterateda code of conduct called the Principles ofMedical Research, which fundamentally sayswe will publish all data that patients anddoctors need to know about our drug, period,including any negative results, and of courseall safety data we gather on our medicines.
To help communicate our clinical data,we’ve established a comprehensive clinicaltrial registry, which is on our Web site,www.lillytrials.com, so that all data on allmarketed products, phase I through phaseIV, are going to be on a public accessibledatabase …
How can the government and univer-sities help solve the problem?
Wood – I don’t think that public moneyshould be committed to the development ofdrugs. There is a total failure of any evi-dence that government resources have beensuccessful in developing drugs, at least inmy view.
I have some concerns that … NIH …(is) somehow going to get into drugdevelopment … (and that) is going to distract us from the fundamental reform of the licensing system in this country toincentivize the development of the drugsthat we need.
Paul – If you go back and look at the top50 marketed drugs, … almost every one ofthe top 50 had its origins in some researchthat somewhere in time was funded in thepublic sector, like the NIH.
However, virtually none of those drugs,with just a few exceptions, would have everbeen discovered and made available topatients without enormous investments andrisk on the part of the private sector. Notjust in the discovery and validation of thetargets that these drugs work on, but all ofthe screening, chemistry, pharmacology,toxicology/metabolism, safety testing, etc.,let alone downstream development activityand manufacturing capabilities … workthat’s required to bring a drug to market,and that most people don’t really knowabout or appreciate …
It’s the entire body of that researchthat allows us to do what we do, and with-out that enormous investment by the NIHand other federal agencies, we wouldn’thave what I have called the incredible sub-strate for drug discovery and developmentthat we currently have …
Unfortunately, most of us believe thatthe best way to treat Alzheimer’s disease isto prevent it from occurring in the firstplace (but) the current drug developmentprocess – including the current limits onintellectual property protection – providessuch incredible disincentives for discover-ing “preventative” agents that very fewcompanies would even approach this at thepresent time.
Wood – We’re talking about Alzheimer’s,but you could talk in the same way aboutother diseases of aging like osteoarthritis,for example, which is going to be a hugeproblem for my generation. We need to beprepared to develop drugs that lower amy-loid deposition (in the brain) or that slowthe deterioration of the loss of your carti-lage in your hip joints, without the confi-dence, other than a hope, that that willaffect the ultimate endpoint.
I don’t think at this stage … that weknow with any degree of certainty thatlowering amyloid deposition pharmaco-logically in the brains of humans will necessarily prevent Alzheimer’s ... but Ithink that we need to be prepared toapprove drugs based on imaging tech-niques or whatever … that show a reductionin some surrogates ...
I think we should give limited (patent)exclusivity on the basis of that, and give anextended exclusivity when people demon-strate a hard endpoint … We need to developregulatory approaches that … encourage thetaking of risk. And of course that’s going tohave to make some fundamental changes inattitude at the FDA itself.
Paul – I absolutely agree. The (intellectualproperty) challenges right now are formi-dable. The effective patent life for a newdrug today is probably averaging only 10years or so in the U.S. If it takes 15 yearsto both discover and develop a drug, fiveor even 10 years may be too little time torecoup the investments required.
We must be assured that once a drugreaches the market we have a sufficientperiod of time of patent exclusivity torecoup our investments. Right now withthe current patent laws there are also hugeincentives for generic companies … to comein and challenge patents in a way that islike winning the lottery ...
By the way, I believe that genericdrugs are one important way to reduceprescription drug prices in this country.Prescription drug costs in the U.S. couldbe reduced by 10 to 15 percent overnightif physicians would prescribe generic drugswhen they should. But there will be no
more generic drugs if there are not patentprotected drugs in the first place.
Wood – I actually think we should also offerextensions of exclusivity on the basis of cer-tain agreed performance goals. For example,if you were developing (the first) statintoday … and you demonstrate that it lowerscholesterol, that’s a demonstrable indicationfor which you would get exclusivity.
But if you come back a few years fromnow and demonstrate … that you’ve alsoreduced cardiovascular mortality or morbidityin a significant way, I think that’s not anunreasonable reason to get an extendedexclusivity … I’m trying to incentivize theperformance of the right studies.
Wouldn’t that also encourage phar-maceutical companies to do morepost-marketing surveillance?
Wood – It could be done in the same way …I think there’s a need for a liability protectionfor companies where they’re either conduct-ing a mandated phase IV (post-marketingsurveillance) study, which most of the timethey don’t conduct, of course. But if they’reconducting a safety study, they should getliability protection for that …
There are going to be companies whichmight even disappear as household namesbecause of just astronomic liability … Thenumbers are being thrown around of morethan $100 billion in terms of the liabilityrisk to Merck (over Vioxx), for example.That’s a lot of money.
Paul – Let’s not forget that somebody’s got to pay for such product liability litigation – justified or not. Because of the tremendousincentives trial lawyers have in litigating suchcases, I think the legal system is in need oftort reform. This is not to say that peopledon’t have right to recover damages whenthey’ve been injured, but in this country rightnow, I believe this system is out of whack.
Wood – I think it’s unbelievable that an indus-try that produces things that cure people ofdiseases that ail them has managed to shootthemselves so frequently in the foot and getthemselves into a position where they’re nowin public opinion polls regarded as somewheredown beside tobacco companies …
Paul – This situation hasn’t escaped most of us, and it’s a problem that we’re trying toquickly correct … For example, I believeindustry designs and executes clinical trials asgood as anyone in the world … Having saidthat, we as an industry have been accused –with some justification, in my opinion – of
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We must preserve this synergisticpublic-private partnership … but we mustfind ways to improve it further movingforward. I think that NIH resources arebest spent in funding all of the fundamentalas well as clinical translational researchthat will allow us to more definitivelyaddress the therapeutic and diagnosticapproaches we will take in the future.
I really doubt that precious NIHfunds are better diverted to discovering ordeveloping drugs, perhaps with some fewexceptions … certain orphan diseases ordrugs to combat bioterrorism, and perhapssome infectious diseases as well.
Wood – We have a system that incentivizesthe development of symptomatic therapiesand/or incentivizes the development oftherapies for very short treatments: antibi-otics … painkillers, and other symptomatictherapies. We’ve moved now into a situa-tion in which we’re developing drugs toprevent diseases. We’re developing drugsto be taken for a lifetime.
And politicians, academics and drugcompanies have done a very poor job ofarticulating that for the public … One ofthe reasons prescription drugs are a muchmore major part of our health care dollartoday is that we don’t just take 10 days ofan antibiotic …
We need to explain to people that theideal model of health care would put sur-geons and anesthesiologists out of work,and we would treat diseases by pills. Youknow, (the doctor) on Star Trek didn’t domuch surgery. He waved things at peopleand people swallowed things and so on …We’re going to have to redesign the modelof the ’50s, if you will …
And the reason that’s important is thatwhereas in a model where you’re treatingsymptoms or disease in an individual, youcan much more easily understand and artic-ulate the risk/benefit ratio for that patient,when you’re preventing a disease, you neverever know the patient benefited from thedrug, ever. But you always know the patientwho developed an adverse event.
Paul – I think it starts with society under-standing … what benefit/risk actuallymeans. It’s become clearer to me, given myexperience in the industry, but I’m not sureit’s clear to the average citizen.
All drugs have benefits and risks thatmanifest differently among patients. It iscritical that patients and doctors fullyunderstand these risks – and carefullymonitor for side effects or the usually rarerserious adverse events that can occur withvirtually all drugs. LENS
During the past 20 years,Raymond L. Woosley, M.D.,Ph.D., has contributed to currentunderstanding of antiarrhythmicdrugs, helped discover the anti-histamine Allegra and promotedpost-marketing drug surveillance.
Now the former Vanderbilt andGeorgetown researcher has anew position and challenge: serv-ing as president of The CriticalPath Institute in Tucson, Ariz. Thenon-profit institute, a joint effortof the University of Arizona, theU.S. Food and Drug Administrationand SRI International, aims tohelp develop a new “toolkit” thatcan safely speed up drug devel-opment.
“Science has generated a lot ofnew information … but the processof drug development hasn’tadvanced,” explains Woosley,who until January was vice presi-dent of the University of ArizonaHealth Sciences Center.“Companies have tried to takethe path that’s been trod beforeand they’re afraid to innovatebecause they’re afraid the FDAmight not accept the change.”
Yet in last year’s “CriticalPath” report, the FDA called forexactly that: “powerful new scien-tific and technical methods suchas animal- or computer-basedpredictive models, biomarkers forsafety and effectiveness, and newclinical evaluation techniques …
to improve predictability and efficiency along the path fromlaboratory concept to commer-cial product.”
The types of adverse reactionsthat force drugs off the marketoccur in less than one in 10,000patients, Woosley wrote in theWinter 2005 issue of Issues inScience and Technology. To haveany hope of detecting these relatively rare events before marketing, phase III trials wouldhave to be increased by morethan tenfold, to include morethan 30,000 patients. Thatwould “only further delay devel-opment and increase the price of drugs,” he wrote.
Instead, Woosley recommendsa “staged” approval process,which would allow rapid approvalfor a carefully defined patientpopulation, and then gradualexpansion to other patientgroups as long-term safety andefficacy is established. “Thisapproach is similar to the way inwhich several AIDS drugs, suchas the protease inhibitors, weredeveloped and translated intoclinical practice in two to fouryears,” he wrote.
There are other issues. TheFDA needs more money to moni-tor drugs already on the market.Industry must invest more indrug safety. And, says Woosley,university scientists should playa greater role as industry watch-dogs and helpful partners.
“We need to be there to keeptheir feet to the fire, but also toshare our expertise and makesure that the drugs are devel-oped in the very best way,” he says.
– BILL SNYDER
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Today’s scientists are hurtling into the future, discovering new targets for drugs,new compounds with drug-like activity and new tools with which to test them.
Will their efforts lead to improved drug safety and lower costs? Perhaps … but alot will depend on us – as patients and physicians.
There is growing concern, for example, that Americans are overmedicated. As aresult, we may suffer inordinately from adverse drug reactions.
“And that’s why safe drugs have to be taken off the market, not because they’reunsafe but because their use is unsafe,” says Raymond L. Woosley, M.D., Ph.D., anationally known clinical pharmacologist and president of the Critical Path Institute inTucson, Ariz.
Some observers point their fingers at direct-to-consumer advertising, but banningthe practice alone won’t solve the problem. After all, physicians prescribe drugs, and –Woosley believes – many prescribe inappropriately.
“Every school has a six-hour or one-semester course in pharmacology that talks aboutthe actions of drugs, but how to use those safely and how to address drug interactionsand how to use drugs in the proper way is not taught in 90 percent of the medicalschools in this country,” he says. “Medical education has to take a major responsibilityfor the failures of pharmaceuticals.”
Patient education is equally important,says Peter J. Neumann, Sc.D., associateprofessor of Policy and Decision Sciencesat the Harvard School of Public Health.
“We hear a lot about the cost ofdrugs. But it’s the wrong question, really.It should be about the value,” saysNeumann, whose cost-benefit evaluationshave included drug treatments for asthma,lung cancer and other diseases.
“When you go out and buy a car, youget information about the value of the carand the attributes that you care about –the safety, the way it looks, the zero-to-60power of the engine and so forth.
“When you buy a drug, you mightget information about different attributesof value –how convenient is it to take,what are the side effects, what are the ben-efits, and so forth, and what’s the price.”
Consumer Reports provides that kind ofinformation through its CRBestBuyDrugs.org Web site, which compares pre-scription drugs on price, effectiveness andsafety, Neumann notes.
But while better education of physi-cians and patients may help improve drugsafety, “at the end of the day, we’re probablygoing to be paying more for our healthcare,” he cautions.
“That’s probably not a bad thing …research shows in a very general sensewe’re getting more health – we’re livinglonger, we’re alleviating symptoms, wehave less disability, and we’re paying morefor that ...
“I’d much rather live today withtoday’s medicine,” Neumann says, “evenwith today’s prices, than 30 years ago with1970s medicine and 1970s prices.”
The key is getting the rules right.“You can swing the pendulum too fareither direction,” he says. Too much regu-lation stifles innovation. “On the otherhand, if you had no scrutiny or too little,then you’d have too many bad outcomes.
“So what’s the right mix? I don’tknow, but I think that’s the right question.” LENS
Advice for consumers: “Kick thetires” before taking new medication
Photo illustration by Don Button
By Bill Snyder
The patient’sresponsibility
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Jeffrey R. Balser, M.D., Ph.D.Anesthesiology, PharmacologyAssociate Vice Chancellor for Research
Gordon R. Bernard, M.D.MedicineAssistant Vice Chancellor for Research
Randy D. Blakely, Ph.D.PharmacologyDirector, Center for Molecular Neuroscience
Peter Buerhaus, Ph.D., R.N.Senior Associate Dean for Research, School of Nursing
Richard Caprioli, Ph.D.Biochemistry, Chemistry, PharmacologyDirector, Mass Spectrometry Research Center
Ellen Wright Clayton, M.D., J.D.Pediatrics, LawDirector, Center for Genetics and Health Policy
Raymond N. DuBois, M.D., Ph.D.Medicine, Cancer Biology, Cell & Developmental BiologyDirector, Vanderbilt-Ingram Cancer Center
John H. Exton, M.D., Ph.D.Molecular Physiology and Biophysics,PharmacologyHoward Hughes Medical Institute investigator
Steven G. Gabbe, M.D.Obstetrics and GynecologyDean, School of Medicine
William N. Hance, B.A., J.D.Director, Office of News and Public Affairs
George C. Hill, Ph.D.Microbiology & ImmunologyAssociate Dean for Diversityin Medical Education
Michael C. Kessen, B.A.Director, Corporate & Foundation RelationsMedical Center Development
Joel G. Lee, B.A.Associate Vice Chancellor, Medical Center Communications
Lee E. Limbird, Ph.D.Pharmacology
Mark A. Magnuson, M.D.Molecular Physiology & Biophysics,MedicineDirector, Center for Stem Cell Biology
Lawrence J. Marnett, Ph.D.Biochemistry, Cancer ResearchDirector, Vanderbilt Institute of ChemicalBiology
John A. Oates, M.D.Medicine, Pharmacology
Alastair J.J. Wood, M.B., Ch.B.Pharmacology, MedicineAssociate Dean for External Affairs
Bridging the gapI've just finished reading the fall
2004 issue of Lens. I suspect that most of us whose lives
were spent in the practice of clinical medi-cine, even academic physicians, have cometo realize the huge and widening gapbetween the basics that we learned inschool and the science underlying themodern practice of medicine.
The papers in general medical jour-nals such as the Journal of the AmericanMedical Association and the New EnglandJournal of Medicine now routinely containjargon and numerous acronyms for allsorts of molecules such as EGF, IL-6, TNF,CD-4, etc., that at least a general appreci-ation of developments in molecular biology,genomics and immunology are needed forthe reader to understand them.
This issue on inflammation was, asthey say, "right on." You have tied enoughhistory and biography to the articles tomake them interesting reading, and youhave kept the concepts broad and simpleso that those of us outside of the researchareas can grasp them.
So much for praise of the content.The style, the photography, the art work –altogether – make Lens an extraordinaryperiodical. I have not seen its equal. Thework of you and your co-workers signifi-cantly enhances the image of VanderbiltUniversity Medical Center.
OSCAR C. BEASLEY, M.D.
Iowa City, Iowa
Vanderbilt University School of Medicine,
Class of '52
Over-the-top imprintI am an alumnus of Vanderbilt having
earned a Ph.D. in Molecular Physiologyand Biophysics. I am currently teachingbiology at a high school in Michigan.
I thoroughly enjoy the Lens magazineand share it with the other science teachers.We often show pictures to our students fromthe magazines because the illustrations areoften better and easier to follow than thosein our texts.
I think it is simply terrific and it keepsme up-to-date with Vanderbilt research andcurrent events in science and medicine, notto mention it has the over-the-top imprintof one of my favorite Vanderbilt mentors,Dr. Lee Limbird.
TIM KNITTLE, PH.D.
Brighton, Michigan
Vanderbilt University Graduate School
Class of ‘95
Lens is going globalLater this summer, we plan to launch
the first Lens Web site, an online version ofthe magazine with links to the Web pagesof scientists at Vanderbilt UniversityMedical Center and around the country.
The Web site will archive back issuesand include a survey for you to registeryour opinion about how well we’re doing.
For more information, or to be notifiedwhen the Web site is launched, contact theeditor, Bill Snyder, at (615) 322-4747 orvia e-mail: [email protected].
Letters to the editor may be mailed to:Bill SnyderVanderbilt University Medical CenterCCC-3312 Medical Center NorthNashville, TN 37232-2390Or faxed to (615) 343-3890
Lens Editorial Board
LensL E T T E R S T O T H E E D I T O R
T h r o u g h o u r
p . 2 2 T h e H e a t T h a t H u r t sp . 1 8 I m p r o b a b l e B e g i n n i n g sp . 4 C o l l a t e r a l D a m a g e p . 1 2 A N e w V i e w o f C a n c e r04A U T U M N
Powerful techniques shed new light
Out of the shadowA PUBLICATION OF VANDERBILT UNIVERSITY MEDICAL CENTER
A N e w W a y o f L o o k i n g
a t S c i e n c e
Lens
New hopefor bodies
on fireProgress in the
fight againstinflammation
Lens Vanderbilt University Medical Center CCC-3312 Medical Center Nor thNashville, TN 37232
Functional magnetic resonance imaging (fMRI) datashows brain activity during a mathematical processingtask. The image is overlaid on a surface rendering ofthe cortex to illustrate its spatial orientation.
Illustration by Christopher J. CannistraciCourtesy of the Vanderbilt University Institute ofImaging Science
I N T H E N E X T I S S U E :Waves, rays and firefliesAdvances in imaging technologies are generatingstartling new pictures of the body – down toindividual molecules.
Revealing the brain’s secretsNew “pictures” may help scientists solve themysteries of addiction, autism and Alzheimer’sdisease.
Putting a beam on cancerFluorescent probes are being studied for theirpotential to pinpoint – and destroy – previouslyhidden cancers.
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