ࡱ> 5@ tbjbj22 6XXl\'\'\'\'\'|9@(Z))))U+U+U+9999999$:R<?9U+3+"U+U+U+?9))T9666U+))96U+96$666)4( @\'16E7j9096=s6F=666=7(U+U+6U+U+U+U+U+?9?96 The Other Side of Drug Discovery, Part 1  INCLUDEPICTURE "http://www.bio.com/images/shim.gif" \* MERGEFORMATINET  INCLUDEPICTURE "http://www.bio.com/images/shim.gif" \* MERGEFORMATINET  By  HYPERLINK "mailto:jasonb@scripps.edu" Jason Socrates Bardi The shop seemed to be full of all manner of curious thingsbut the oddest part of it all was, that whenever she looked hard at any shelf, to make out exactly what it had on it, that particular shelf was always quite empty: though the others round it were crowded as full as they could hold. "Things flow about so here!" she said at last in a plaintive tone, after she had spent a minute or so in vainly pursuing a large bright thing, that looked sometimes like a doll and sometimes like a work-box, and was always in the shelf next above the one she was looking at. Lewis Carroll, Through the Looking Glass, 1863 "What do you suppose is the most successful drug in the last 5,000 years?" Tamas Bartfai asks me. This question almost seems like one of those obvious ones that you should be able to guess, even if you've never thought about it before. I haven't. After a moment's demur, I offer, weakly, "aspirin." (Antibiotics, I figure, would be too obvious). "Aspirin?!" says Bartfai. "Aspirin wouldn't even be approved by the FDA [U.S. Food and Drug Administration] today [because intestinal side effects would complicate its clinical trials]. No, it's morphine."  INCLUDEPICTURE "http://www.bio.com/pics/2001.gif" \* MERGEFORMATINET   INCLUDEPICTURE "http://www.bio.com/pics/2005.gif" \* MERGEFORMATINET  This comparison between the categories and numbers of drug targets in the years 2001 and 2005 shows the influence of genomics on drug discovery-the addition of new drug targets. Opium, the poppy extract that contains morphine, has been used for 5000 years, he tells me. It was a huge breakthrough for treating the indications of diarrhea and pain. Significantly, morphine was isolated from opium by F.W.A. Serturner in the early 1800s and used by doctors for nearly two centuries before its endogenous ligand and receptors (only cloned in the last 10 years) were known. "If you can discover a [disease modulating] effect of a compound, even without knowing how it works," says Bartfai, "if the compound does something that no other drug does, then people will buy it." This is Bartfai's first lesson in drug discoverythat drugs were not always discovered the way we discover them today. Today, when scientists set about designing drugs, they often have structurally known, cloned receptors and enzymes to target that play crucial roles in the diseases. They have access to genomic information, and many times the protein structure as well as sophisticated animal models for many of these diseases. They have chemical libraries of tens of thousands of potential lead compounds to test, and work in a society that recognizes and embraces the need for new and better drugs to fight any number of ailments. And yet, despite all these advances, the diversity of chemical entities that make up the modern drug lexicon has yet to explode, though Bartfai believes there will be an explosion in the next 15 years, if society permits it. After all, he says, drug costs are only 15% of the total health care costs. A Primer on Drug Discovery While there are around 10,300 FDA-approved drugs in the United States today, most of these are made up of some combination of only 433 distinct molecules. Acetaminophen, for instance, is an ingredient in hundreds of separate drugs. Half of the 433 were approved before 1938, and at least 50 are "me too" drugs, a slightly modified form of compound already on the market. Finally, there are only eight major, chemical "scaffolds" upon which all the 433 molecules are based. "All this says," says Bartfai, "is that it is darned hard to make a new molecule that is going to be a drug these days." Over the next three weeks, Bartfai is giving a series of lectures on drug discovery sponsored by the Skaggs Institute for Chemical Biology at The Scripps Research Institute (TSRI) in order to communicate his decades of experience as a consultant and executive in the Pharma industry to San Diego's scientific community. The steps that lead to success in bringing a drug to the market are not always the most obvious ones to a scientist, says Bartfai, who came to TSRI in 1999 to join the Department of Neuropharmacology and was soon after appointed director of the Harold L. Dorris Neurological Research Center. Prior to 1999, Bartfai served as senior vice president in charge of central nervous system research at Hoffman-La Roche, a department most famous for the drug Valium, and for its Parkinson's disease drugs. He was brought there to develop a major human genetics effort to aid discovery of new treatments for schizophrenia and Alzheimer's disease. Before that, he was involved in the development of Zimelidine, the first selective serotonin reuptake inhibitor (SSRI) and two anti-psychotic agents used in the treatment of schizophrenia as a consultant for Astra (now AstraZeneca). He has been a long-term consultant for several major Pharma companies. From these experiences, Bartfai has an almost unique cache of information. He knows the reasons behind decisions made by the FDA and companies in the pharmaceutical industry. He knows how a small start-up biotech company should interact with the major pharmaceutical firms. And, most importantly, he knows how to get a drug approved by the FDAa point which he says he thinks backwards from. In any scientific project aimed at producing a therapeutic agent, after all, if you do not know how you will do the clinical trials and how you will get it FDA approved, it is not going to be a drug, no matter how great the discovery. The lectures are not necessarily designed to present new information, but rather to present a few themes that will help organize a person's understanding of the drug design processadding historical and economic perspectives. The historical perspective is in part the lesson of morphinethat successful drug discovery was not always done the high throughput way it is done now. The economic perspective is more complicated, but nevertheless essential when dealing with the pharmaceutical end of the drug-discovery business. "Nobody teaches this," he says.  "The stakes for the pharmaceutical companies are enormous," says Bartfai. "Twenty-six billion dollars was spent on developing drugs last year, and nine new chemical entity (NCE) drugs were approved." (The FDA defines an NCE as a drug with no previously approved active chemical moiety). This stakes are reflected in the typical price-to-earnings (P/E) ratios for companies involved in drug design. The P/E is the ratio of the market value of a single share of stock divided by the total earnings for that share. So a P/E of 10 means that every $10 of stock returns a dollar of profit. According to Charles Schwab Company, the historic average P/E ratio for all the fortune 500 companies is around 16 and, of course, varies with the economy. Blue chips stocks, the shares of those industries like car manufacturers or utilities companies tend to have smaller P/E ratiosunder 10. The low number reflects the fact that these industries are time-tested and established as long-term, secure earners. The P/E of growth industries, like those in the health sector, tend to be larger. The market average for major pharmaceutical companies is around 20. Biotech companies tend to be even higher. The 2001 P/E average for the largest biotechnology companies listed on the New York Stock exchange was nearly 40, according to Forbes magazine. Small publicly traded biotech companies can be higher still. The high P/E ratio of pharmaceutical companies and biotechs means that the earnings per share is low with respect to the cost of the stock, but, more importantly, that investors have high expectations for the companies to show significant growth and yield large profits in the future. Another characteristic of the pharmaceutical industry is a lack of customer brand loyalty. There are no "Upjohn people" or "Roche people" the way there are "Pepsi" or "Coke people." Unlike other industries, where products may be selected on the basis of manufacturer, pharmaceutical companies rely wholly on the effects of the drugs they produce and market. "If you succeed, nobody asks [whether you] you have made this kind of drug before," says Bartfai. "If you make a truly original drug that has a health benefit, people will eventually buy it." The drug doesn't even have to be the first one on the market to fight a particular indication. The thing that counts is that it is significantly better than any other drug out there. As an example, Bartfai points to Astra, which entered the billion-dollar-a-year heartburn market with the drug Losec (also called prilosec), which blocks a proton ATPase responsible for pumping acid into the stomach. Astra was at the time a tiny company entering a huge pond. But Losec was more effective than its competitors, Zantac and Tagamet, both well known labels, and is one of the reasons why Astra (now merged to form AstraZeneca) has emerged as the largest pharmaceutical company in the world. "Nobody even knew how to spell [Astra]," says Bartfai, who was a consultant for the company at the time "But we made a significantly better drug, [which] so far has had $36 billion in sales." The health benefit doesn't even have to be as tangible as reducing acid reflux and stopping somebody's heart burn. "You can sell something which does not cure a disease if you have a good enough argument that it can prevent a disease," says Bartfai. "High cholesterol is not a disease, but six billion dollars is spent each year on cholesterol-lowering drugs."   INCLUDEPICTURE "http://www.scripps.edu/newsandviews/images/nv_top1.gif" \* MERGEFORMATINET Please note that this story has been republished with the permission of the Scripps Research Institute, who retain full copyright protection. The Other Side of Drug Discovery, Part 2  INCLUDEPICTURE "http://www.bio.com/images/shim.gif" \* MERGEFORMATINET  INCLUDEPICTURE "http://www.bio.com/images/shim.gif" \* MERGEFORMATINET  By  HYPERLINK "mailto:jasonb@scripps.edu" Jason Socrates Bardi In " HYPERLINK "http://www.bio.com/newsfeatures/newsfeatures_features.jhtml?action=view&contentItem=49623739&Page=1" The Other Side of Drug Discovery, Part 1", TSRI investigator Tamas Bartfai says, "If you make a truly original drug that has a health benefit, people will eventually buy it." However, drug design is not all wine and roses.  INCLUDEPICTURE "http://www.bio.com/pics/bartfai2.jpg" \* MERGEFORMATINET  When companies are selecting drug candidates, they want to make sure that the candidates make good economic sense, according to TSRI investigator Tamas Bartfai. Drug development is the single most regulated human activity. The mandate of the FDA is to protect the public against dangerous drugs, and they do this in a variety of ways, including monitoring approved drugs on the market for unexpected health consequences, reviewing drug applications, and mandating full disclosure in drug labels and advertisements. Nevertheless, regulation limits the number of drugs that companies can bring on the market, and forces the pharmaceutical companies to make tough choices. Often these choices involve research and development, which sometimes directly affects investigators at universities and institutions like TSRI who partner and collaborate with scientists in industry. Bringing a drug from the test tube to the prescription bottle costs in excess of $500 million on the average. The amount of this spent on initial research and development may be miniscule by comparison with the clinical trials and the marketing expensesperhaps only 1.5-5.0 percent of the total. "The marketing costs, for instance," says Bartfai, "are usually 15 to 20 times the cost of researching the drug." For the most part, basic research is blind to this sort of decision making because an equal amount of science goes into making a small drugs and big drugs. "With equal ingenuity, you can make a drug that will sell for $100 million or one that will sell for $100 billion by the end of its lifetime," says Bartfai. But when companies are selecting drug candidates for the proverbial $500 million check, they make sure that the candidates make good economic sense. A new anti-epileptic, for instance, poses formidable economic challenges because of difficulty testing it. "If you cannot figure out how a drug can be tested, you cannot make the drug," says Bartfai. Consider that there are three types of epilepsy patients: those who are not yet diagnosed and therefore not taking medication; those who are diagnosed and currently taking approved medications; and those who are diagnosed but who are resistant to current medicines. The best population in which to test a new drug would be newly diagnosed patients, but one would have an uphill battle overcoming doctors' bias towards existing drugs. Why would a doctor put a patient on an experimental drug when there are others that seem to work just fine? One would need an extraordinary amount of data suggesting that the new compound is significantly better. And anyone who is currently taking an anti-epilepsy drug and doing just fine would not stop to take a new, experimental drug and risk having a seizure. Nor would a doctor recommend an experimental drug to a patient who is responding well to an approved one. That leaves only the group of people who are resistant to all existing anti-epileptic drugs, who would not be the best test population "Is a new anti-epilepsy drug a great discovery?" asks Bartfai. "Yes. But does it have great commercial value? No." "If you want to make a drug that acts on the brain," he adds, "if, then the marketing and clinical development departments will suggest you make a drug for Alzheimer's disease." Commercial Accessibility People will only switch to a new drug if the new drug is substantially betterfor instance if it is 10 times more powerful, if it can be taken orally rather than injected, or taken once a day as opposed to once every four hours. In the same vein, there are many drugs that fail because of their side effects, despite the fact that they actually work very well. For instance fat absorption blockers should be a raging success story in the United States, where according to Center for Disease Control and Prevention (CDC) estimates, nearly a third of the adult population is obese. These drugs should allow people to literally have their cake and eat it, but they are one of the failures in the annals of drug design, because they prevent the absorption of fat with the undesirable side effect of causing diarrhea. However, says Bartfai, if a new drug were to be invented that had the same effect without these side effects, it would be a huge success. In addition to toxicity, bioavailability, synthesis, and efficacy, a potential drug's commercial accessibility makes a big difference to pharmaceutical companies. Doctors will choose whatever drugs they know to treat the symptoms they see, and if there is not a compelling reason to switch to a new drug, they won't. "The rule of thumb is that any physician can remember three drugs for any set of symptoms," says Bartfai. "If there are 17 drugs in your category, and you are not in the top three, then forget it." That makes marketing the decisive factor for success of the Pharma companies. Novel compounds that elicit an existing effect may not be worth the effort of developing into a licensed and approved drug. "Once you make a human heart beta-receptor and a slightly better one and a slightly better one, there's not much left," says Bartfai. "People buy an effectthey don't buy a new mechanism. No physician or patient is convinced by a new mechanism." All of this adds up to a drug development landscape that is pock-marked with pitfalls and chasms that can derail a potential drug's success even after it has emerged as a highly successful candidate. Communicating how to navigate this landscape is one of Bartfai's goals for the lectures.  The Other Side of Drug Discovery, Part 2  INCLUDEPICTURE "http://www.bio.com/images/shim.gif" \* MERGEFORMATINET  INCLUDEPICTURE "http://www.bio.com/images/shim.gif" \* MERGEFORMATINET  To address this gap in knowledge between the academic and corporate worlds ,"[Bartfai] offered to give these lectures as a primer," says Skaggs Institute Director Julius Rebek. "Since I came here, I have [had] about five colleagues each week asking me something about drug development," Bartfai says. "People have asked me questions like, 'Why did they stop the development of this drug that we have worked on?'" He has been asked to look at their business plans or to clear up confusion over a decision by a large company with which they collaborate, for instance, or to help make sense of a new request. The Sociological Imperative Another perspective Bartfai hopes to address during the upcoming lectures is how the pharmaceutical industry is highly sensitive to the social context in which it exists. Drug development follows trends and these trends are informed by the public's actual and perceived wants and needs. In America today, that does not simply mean demands from patients and from doctors tending to their patients' needs, but also pressure from patients' interest groups and health maintenance organizations and other large demographic forces. We are an aging society. The CDC estimates that by the year 2030, there will be 70 million elderly Americansmore than twice the current number. And the United Nations recently estimated that population of people in the world over the age of 60 will reach two billion within 50 years. This aging of America and the rest of the world means an increased demand for better compounds to combat those diseases and indications specific to the elderly, and the pharmaceutical companies are a weathervane of this demand. For instance Alzheimer's disease, which is believed to afflict four million Americans, is now a major area of research. Our aging society has recognized and understood the need to confront the problem of Alzheimer's disease, and today, according to Bartfai, there is no self-respecting pharmaceutical company that does not have 5-15 Alzheimer's programs. Yet this has not always been the case. "If somebody stood up in 1970 and said, 'I want to make an Alzheimer's drug,' he would not only have not got any support within a drug company, but he would also not have gotten a grant from the NIH [National Institutes of Health]," says Bartfai. Similarly, other targets of pharmaceutical research are aimed at an aging America. Osteoporosis drugs are needed to combat the deterioration of bones in the elderly, one of the leading causes of loss of quality of life in later years. Some 44 million Americansmost of whom are womenhave already developed osteoporosis or the early signs of bone density loss that lead to it. As our population ages, this number will only increase, and osteoporosis blockers are a major target for pharmaceutical companies. Many companies are also taking aim at other age-related ailments like arthritis, Parkinson's disease, and urinary incontinence. Besides being an aging society, we are a society that is increasingly aware of mental illness and increasingly more willing to medicate it. Antidepressants already make up one of the largest markets in the United States, amounting for around $15 billion annually. However, there is still a great need for a fast acting antidepressant. Normal antidepressants take two or three weeks to take effect, and as many as a third of patients do not respond to the drugs. This is problematic because the core symptom of serious depression is suicidal tendencies. In 1997, for instance, 30,535 Americans committed suicide, making it the eighth leading cause of death in the United States that year. One of Bartfai's own longstanding goals is to develop a quick-acting compound for the treatment of depression. "We just don't know how to make such a tablet yet," he says. Some of the other drug targets today are high-profile diseases, like AIDS and various types of cancer. From a global perspective, there is a need for vaccines for tuberculosis and malaria, both major health problems worldwide. "People would like to have vaccines [against TB and malaria] without a shadow of a doubt," says Bartfai, "Even the rich countries have come to realize that helping to eradicated these diseases would be a formidable form of aid, not only to third world, but also to countries such as Russia with 26 million tuberculosis cases." Other drug targets are not so obvious to those outside the field, such as drugs to control asthma and other respiratory infections and constrictions, preventative migraine medicine, or a decent (safe, less side-effect prone, but efficacious) acne drugthe market for which, Bartfai insists, should not be underestimated. "If someone came up with [a decent acne drug], it would sell for billions," says Bartfai.   INCLUDEPICTURE "http://www.scripps.edu/newsandviews/images/nv_top1.gif" \* MERGEFORMATINET  Please note that this story has been republished with the permission of the Scripps Research Institute, who retain full copyright protection.  Archive Issue 12-17 Tuesday, April 23, 2002 AROUND TOWN April 25, May 2, May 9: "Skaggs Lectures in Drug Discovery" are presented by the Scripps Research Institute (TSRI) and The Skaggs Institute for Chemical Biology. All lectures by TSRI professor Tamas Bartfai, 5-6:30 p.m. at the Valerie Timken Amphitheater of Green Hospital. Info: 858-784-2255 or  HYPERLINK "mailto:lundgren@scripps.edu" lundgren@scripps.edu. --April 25: "Development of Drug Discovery Paradigms in Big Pharma Over the Last 100 Years" --May 2: "Target-Based Drug Discovery" --May 9: "Selection of Clinical Candidates: Multiple Pressures" Tamas Bartfai Named to Head Harold L. Dorris Neurological Research Center at The Scripps Research Institute La Jolla, CA. November 19, 1999 Noted neuroscientist Tamas Bartfai, Ph.D., has been named director of the newly established Harold L. Dorris Neurological Research Center at The Scripps Research Institute (TSRI). In addition, he will hold the Harold L. Dorris Chair in Neuroscience. The center was formed with a $10 million commitment from Helen L. Dorris of San Diego. Bartfai is former head of central nervous system research at Hoffman-La Roche, in Basel, Switzerland. Most of his professional career was spent in academia at Stockholm University, most recently as Chairman, Department of Neurochemistry and Neurotoxicity. Born in Budapest, Hungary, he received his undergraduate education there at Eotvos Lorand University and a Ph.D. in biochemistry at Stockholm University. He has served as a visiting scientist at Hadassah- Hebrew University Medical School, Jerusalem; Yale University Medical School; and the Neuropsychiatric Institute at University of California, Los Angeles. Bartfai holds adjunct appointments at The Rockefeller University and Stanford University. According to William H. Beers, Ph.D., TSRI Senior Vice President and Chief Operating Officer, "We look forward to the leadership that Dr. Bartfai will bring to this newly created research center at TSRI. He is internationally recognized for his accomplishments in the neurosciences and his broad range of interests across a number of disciplines within the field." Bartfai's work has been directed toward several scientific topics during his 27-year career in the field of physiological chemistry. Most notably, he has made contributions in the fields of the molecular/ biochemical basis of cognition, and the molecular/biochemical basis of fever. His work has implications for such diseases as depression, Alzheimer's disease, schizophrenia and sleep disorders. Involved in the development of psychopharmaceutical agents for the last 20 years, he developed Zimelidine, the first selective serotonin reuptake inhibitor (SSRI) and two anti-psychotic agents used in the treatment of schizophrenia. Recently, he has elucidated the molecular mechanism of a new kind of antidepressant, substance P antagonist, which modifies a previously untapped neurochemical system. This finding may lead to the development of new and more effective drug targets against depression, as well as anxiety disorders and schizophrenia. His work on the design, synthesis and biochemical and pharmacological application of the first galanin antagonists was essential for the elucidation of the biological effects of galanin in depression, cognition and pain, and led to the three galanin receptors becoming the target of more than 20 projects in the pharmaceutical industry. The author of some 260 scientific publications, Bartfai is the recipient of numerous prestigious research awards, including the Eotvos Prize in Chemistry, the Svedberg Prize and the Eriksson Prize. In addition, he has been named a Senior Fullbright Fellow as well as a Fellow of The Neuroscience Institute. The new center will bring a dedicated effort to providing education and conducting research into neurological disorders, including schizophrenia and Alzheimer's disease, as well as advancing knowledge of the process of aging of the brain. Newly recruited scientists will join in an interdisciplinary focus on the brain, expanding ongoing research currently conducted in TSRI's Departments of Neurobiology, Neuropharmacology, Chemistry and Molecular Biology. Photo available upon request.  For more information contact: Robin Goldsmith 10550 North Torrey Pines Road La Jolla, California 92037 Tel: 619.784.8134 Fax: 619.784.8118  HYPERLINK "mailto:rgoldsmi@scripps.edu" rgoldsmi@scripps.edu Copyright 1998 HYPERLINK "http://www.scripps.edu/"  TSRI. All rights reserved. Reproduction in whole or in part in any form or medium with out express written permission of TSRI is prohibited. Noted Neuroscientist To Direct Neurological Research Center at TSRI  HYPERLINK "http://www.scrippsfoundation.org/newsletter2088/newsletter_list.htm?section=New%20in%20Science&show=yes" More New in Science Noted neuroscientist Tamas Bartfai, PhD, has been named director of the newly established Harold L. Dorris Neurological Research Center at The Scripps Research Institute. The center was formed with a $10 million commitment from Helen L. Dorris, founder of the Harold L. Dorris Neurosciences Foundation. Dr. Bartfai will also hold the Harold L. Dorris Chair in Neuroscience. He is former head of central nervous system research at Hoffman-La Roche in Basel, Switzerland, and was chairman of the Department of Neurochemistry and Neurotoxicity at Stockholm University. He has served as a visiting scientist at Hadassah-Hebrew University Medical School, Jerusalem; Yale University Medical School; and the Neuropsychiatric Institute at University of California, Los Angeles. Dr. Bartfai holds adjunct appointments at The Rockefeller University and Stanford University. Dr. Bartfai's work has been directed toward several scientific topics during his 27-year career in the field of physiological chemistry. Most notably, he has made contributions in the fields of the molecular/biochemical basis of cognition and the molecular/biochemical basis of fever. His work has implications for such diseases as depression, Alzheimer's disease, schizophrenia and sleep disorders. For more information about the Dorris Neurological Research Center, contact  HYPERLINK "mailto:anderson@scripps.edu" Jo Ann Anderson. 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