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Targeting Drugs For Each Unique Genetic Profile BY ROBERT LANGRETH And MICHAEL WALDHOLZ
Staff Reporters of THE WALL STREET JOURNAL THE PHARMACEUTICAL industry makes bil- The consortium will launch a two-year, $45 million pro-
lions of dollars a year selling one-size-fits-all medi- gram to identify several hundred thousand chemical sign- cines. But now the race is on to come up with posts that will help gene hunters explore the vast regions of tailor-made drugs that will treat people based on their indi- As first reported last month in The Wall Street Journal, Drug companies hope to create a map of genetic landmarks the companies and their gene-hunting partners in university that will become a potent new tool for uncovering the minute labs will use this information to assemble a catalog of the inborn differences that make some individuals particularly sus- biological diversities that explain many of the physical dif- ceptible to certain diseases. With that knowledge, the drug ferences among humans. The companies believe this infor- makers hope to develop safer, more potent drugs that can more mation will help them create drugs specifically designed to precisely target the variety of biological quirks that underlie target each person’s unique genetic profile.
each major disease. Their goal: a cornucopia of personalized For example, consortium-member Bristol-Myers is sponsoring a research program at the Whitehead/MIT medicines that will produce huge profits into the next century.
Center for Genome Research, using existing gene markers “One of the more important things going on right now in to search for genes that cause or increase the risk of heart human biology is distinguishing the large genetic variability disease, diabetes and asthma. The MIT group is sifting among individuals,” says John Keller, vice president and through hundreds of genes to identify those that are altered director of the alliance and technology group at SmithKline
in people who get disease. These genes, in turn, will illu- Beecham PLC, the British-American drug company.
minate biochemical pathways that Bristol-Myers can target Already, several major drug makers, including Bristol-
Myers Squibb Co., Roche Holding Ltd. and Novartis AG,
Eric Lander, who directs the MIT genome center, calls are using the small number of genetic signposts currently the gene map “the framework for the future of medicine available to them to finetune the delivery of existing drugs in and biomedical science.” He says the drug makers’ plan to an attempt to increase their effectiveness. Roche, the Swiss publicly release their findings is especially valuable, drug giant, is using gene markers to identify breast-cancer because it means the findings won’t be exclusively con- patients who are most likely to respond to its drug Xeloda.
trolled by small biotech companies or even large drug The drug is converted to its active form by enzymes inside the makers rushing to produce their own private gene data- body. Roche believes that patients who don’t respond to the bases. One small company, Genset SA of Paris, says it has
drug may have defects or alterations in these enzymes that already used its preliminary gene map to identify three make it hard for them to process the medicine.
genes involved in prostate cancer. But so far the company The project to map human genes involves an unprece- has declined to identify the genes so that other cancer dented alliance of 10 of the world’s largest drug compa- researchers can begin working to understand the genes’ nies, including Roche, Novartis and Glaxo Wellcome PLC.
The Oncologist 1999;4:426-427
to the next by a single letter. Scientists now believe theseSNPs, short for single nucleotide polymorphisms, are the ever-so-slight genetic variations between human beings that predis-pose some people to disease and explain why some respondbetter to certain drugs. The new project will draw up a map ofat least 150,000 SNPs distributed evenly throughout the DNA, DNA, which carries the instructions
much like mile markers along a long stretch of highway.
that allow cells to make proteins, is found While many drug makers are now convinced that all major new drug advances will come from understanding the genetic basis of disease, even company scientists say there isa big gap between identifying a genetic susceptibility anddeveloping a safe and effective medicine. Indeed, companiesare just beginning to use SNP technology to explore how tocreate drugs and diagnostic tools. “It is a grand experiment inpharmaceutical R&D,” says Elliott Sigal, vice president ofapplied genomics at Bristol-Myers. He cautions that the SNPmap is “step one” in a long research process and that no oneknows how well the SNPs will work.
Companies also hope the SNPs will be the basis of sim- ple blood tests that will tell doctors who will benefit from cer-tain drugs and who risks developing serious side effects.
Right now, even the best medicines work in only 50% to 70% A SNP is a spot
of the patients who get them, and the companies hope SNP technology will raise that percentage.
Researchers at Novartis also hope to resurrect sales of its schizophrenia drug Clozaril, which is considered one of the most powerful schizophrenia drugs ever invented. Because 1.3% of patients who take it develop a serious and potentiallydeadly blood disorder, the drug is usually given only as a How Fine-Tuning By Drug Makers Will Work
treatment of last resort, and even then patients must get ■ Herceptin from Genentech Inc.
weekly blood tests. The company hopes to use SNPs to iden- Breast-cancer drug developed specifically to treat a minority ofpatients whose tumors have elevated levels of a protein, her-2.
tify which patients are likely to get the blood disorder. Those ■ Xeloda from Roche Holding Ltd.
patients would avoid the drug, but the vast majority of other Some patients may respond better to this breast-cancer drug patients would no longer need the blood test.
than others because of differences in enzymes that process it.
At Roche, investigators are hoping the new map will Clozaril from Novartis AG
Old schizophrenia drug that causes rare blood disorder in a
help predict which patients are likely to get the greatest small number of patients; researchers hope to use gene-map long-term benefit from its experimental Xenical obesity data to develop test to predict who will get the disorder.
drug. The company also hopes to find genetic markers that Orzel from Bristol-Myers Squibb Co.
Colorectal cancer drug currently under FDA review; company
will help predict which women with osteoporosis are most is performing studies to identify which patients are more likely at risk for hip fractures. Such a finding could be the basis to develop diarrhea and other side-effects from the drug.
for a diagnostic test to identify those patients that need to be The mapping project is separate from the Human Genome Project sponsored by the federal government that Ultimately, says Paul Herrling of Norvartis, the map will expects to produce a complete sequence of the entire three bil- help drug companies “move away from symptomatic treat- lion subunits, or nucleotide letters, that constitute human ment of disease to disease prevention, disease modification DNA. But the sequencing project and the new mapping plan are expected to make it possible for both groups to completetheir tasks more quickly.
[This article appeared in THE WALL STREET JOURNAL,
The map will be made up of so-called SNPs (pronounced “snips”), which are minute genetic alterations sprinkled in mil- Republished by permission of Dow Jones, Inc. via Copyright lions of locations across human DNA. Essentially, they are Clearance Center, Inc. 1999 Dow Jones and Company, Inc. All places in the genetic code where DNA differs from one person

Source: http://www.bioinformatics.auckland.ac.nz/restricted/General%20commentaries/Langreth.pdf