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Experimental Drugs Take Aim at Obesity

Experimental Drugs Take Aim at Obesity Five years after the US Food and Drug Administration (FDA) banned the popular weight-loss drug fenfluramine after reports of heart-valve problems, three prescription weight-loss drugs remain on the US market. Just two are approved for long-term use. Phentermine, the first half of the infamous "Phen-Fen" combination, is still approved for short-term use. In a nation of 60 million obese adults, the drug industry should be hungry to treat the condition. Yet, the Pharmaceutical Research and Manufacturers of America (PhRMA) lists only 11 new antiobesity drugs in clinical trials. This trend has nothing to do with a lack of effort, according to researchers. Instead, the drought of drugs stems from obesity's complex nature. Only recently have researchers mapped the basic endocrinology of hunger and satiation, and many mysteries remain. "It's been a long haul, and nothing much is around the corner," said Madelyn Fernstrom, PhD, director of the Weight Management Center at the University of Pittsburgh Medical Center. However, two new drugs with novel mechanisms are poised to break the famine. On page 1826 of this issue of JAMA, researchers report preliminary but promising phase 2 trial results for recombinant human variant ciliary neurotrophic factor (CNTF). A second drug, rimonabant, is in late-stage trials. Drawbacks of current drugs Drawbacks of current drugs The two drugs currently approved for long-term use for obesity are known as much for their adverse effects as for their weight-loss action. Orlistat, approved by the FDA in 1999 as Xenical (Hoffman La Roche), blocks fat absorption by the gut but also inhibits absorption of water and vitamins in some obese patients; cramping and diarrhea often follow. And the weight-loss figures are not astounding: one meta-analysis found that during the course of a year, orlistat helps patients lose an average of 2% to 3% of their weight beyond that lost by dieting alone (J Hypertens. 2002;20:1873-1878) . Drawbacks of current drugs The other drug, sibutramine, sold by Abbot Laboratories as Meridia, is in the same chemical class as amphetamine. As such, it works by suppressing appetite, but it may also increase blood pressure, heart rate, or both. In fact, the FDA is investigating the safety of the drug, which was pulled from Italian pharmacy shelves in March 2002. Two deaths possibly linked to the drug prompted the response. Drawbacks of current drugs However, in August 2002, Italian officials allowed sibutramine back on the market after finding that the deaths were not caused by the drug. Sibutramine received a second boost in March of this year, when Health Canada, the national agency, decided against a ban after deciding that the risks did not outweigh the benefits. Drawbacks of current drugs The FDA is still looking into adverse event reports in the United States, said a spokeswoman who declined to comment any further on the ongoing investigation. Drawbacks of current drugs Fernstrom said that the physicians she works with consider a patient's "eating style" when deciding whether to prescribe either drug. Drawbacks of current drugs Sibutramine works best for patients who are preoccupied with food and feel constantly hungry, she said. "It can help them focus on the day instead of thinking about food all the time." Orlistat works best for patients who feel that cutting fat from their diet would be punitive. "It's for people who can't stay away from pizza," said Fernstrom. On the rebound On the rebound However, both drugs can cause rebound weight gain. "If a patient loses 10 or 15 pounds with diet and Meridia, it's not uncommon to see them gain a lot of it back," said Michael Andersen, MD, an internal medicine specialist at Meritcare Medical Center, Fargo, ND. On the rebound Todd M. Sheperd, MD, assistant professor of family medicine at the Medical University of South Carolina, recently noted that sibutramine can help with "modest, short-term weight loss" but that he discourages long-term prescriptions because safety data are lacking beyond one year. After that point, the rebound effect is common (J Fam Pract. 2003;52:34-42). On the rebound Fernstrom said that some obese people have a high "hunger and fullness set point," which sibutramine temporarily lowers. But once the drug is gone, the hunger and fullness bite back. On the rebound Recent research has pinpointed a hormonal suspect in the process, ghrelin. Released by the stomach when empty, ghrelin triggers hunger signals in the hypothalamus. Blood levels of the hormone peak before each meal and decrease after. In addition to boosting appetite, ghrelin apparently slows metabolism, sabotaging long-term weight loss efforts, said Fernstrom. Small studies show that ghrelin levels are higher in obese patients who have recently lost weight compared with obese patients at a steady weight. On the rebound Subsequently, drug companies are reportedly searching for drugs that block ghrelin's effects. None have reached clinical trials. On the rebound Another new approach seeks to augment levels of ghrelin's hormonal counterpoint, a peptide known as PYY. After eating, the stomach and digestive tract release PYY, signaling, "I'm full" to the hypothalamus. In one study, volunteers injected with the hormone ate a third less food from a buffet, according to research from Stephen Bloom, PhD, Imperial College of London, and colleagues. "It's what stops you having the third helping," he said. (Nature. 2002;418:650-654). On the rebound However, Fernstrom pointed out that conscious decisions to overeat can override the PYY signal. On the rebound While drugs inhibiting ghrelin and enhancing PYY appear far off, another appetite-suppressing drug, a modified form of CNTF called Axokine, has reached late-stage trials. On the rebound The early results reported in this week's issue of JAMA led the FDA to move the drug onto its "fast track" status, reserved for promising new drugs that treat life-threatening illnesses—which obesity qualifies as, given its role in diabetes, heart attack, and stroke. On the rebound Subsequently, the company has completed the treatment segment of a phase 3 trial with 2000 patients, said Hans-Peter Gular, MD, vice president of Axokine developer Regeneron Pharmaceuticals Inc, Tarrytown, NY. Gular added that preliminary data show that patients who inject CNTF may not experience the same rebound effect seen with sibutramine. Two prospective trials are evaluating the possibility. On the rebound Although the company is optimistic and is reformulating the injectable drug as a pill—a key to widespread acceptance by patients—Gular cautioned that "there is still a lot of work to do." On the rebound Regeneron originally investigated CTNF as a neuroprotective agent. But in early trials with ALS patients, while CNTF did not slow the disease, patients lost substantial weight. On the rebound Intrigued, the company reformulated CNTF and began investigating possible modes of action. They eventually found that the drug suppresses neuropeptide Y, a signaling molecule in the hypothalamus triggered by ghrelin. In hungry people, the hypothalamus pumps up neuropeptide Y production, but in ravenous rodents given CNTF, neuropeptide Y levels stay stable. On the rebound "We don't know why it doesn't go up, but we know that this is important," said Gular. Blocking the "munchie receptor" Blocking the "munchie receptor" The mechanism of rimonabant, the other weight-loss drug in phase 3 trials, is probably well-known to many college students: it blocks the "munchie receptor." Discovered in the early 1990s, cannabinoid receptors respond to the active ingredient in marijuana and to natural cannabinoids. Blocking the "munchie receptor" Soon, researchers realized that the "munchies," common after smoking marijuana, might signal a role for the receptors in appetite. After all, they were finding that the so-called CB-1 receptor played a role in pain relief, muscle relaxation, and other basic body functions. A series of animal studies confirmed the idea. The most recent study found that mice, obese from a high-fat diet, lost weight while fed a cannabinoid blocker (Am J Physiol Regul Integr Comp Physiol. 2003;284:R345-R353). Blocking the "munchie receptor" That compound, SR141716, was originally developed by the Paris, France-based company Sanofi-Synthelabo, as an anti-marijuana agent. And indeed, it works as such: a study sponsored by the National Institute on Drug Abuse found that the compound reduced how "high" or "stoned" experienced marijuana smokers felt by around 40% (Arch Gen Psychiatry. 2001;58:322-328). Blocking the "munchie receptor" Sanofi quickly latched onto the drug's potential as an antiobesity agent. The company named the compound rimonabant and began small, 2-week human studies. Initial positive results led to the ongoing phase 3 study, which the company declined to discuss. Animal Studies Suggest Obesity Subtypes Animal Studies Suggest Obesity Subtypes New research has identified two subtypes of obesity in mice, a finding that hints at a future of tailored therapy for people (Nature. 2003;422:297-302). Animal Studies Suggest Obesity Subtypes By combining two workhorse techniques of early 21st genetics—DNA microarrays and whole-genome sequencing—Eric Schadt, PhD, of Rosetta Inpharmatics, Kirkland, Wash, and colleagues arrived at a way to study the heritability of gene expression. This new approach can ferret out chromosomal hot spots that control complex traits, such as obesity, diabetes, and asthma. Animal Studies Suggest Obesity Subtypes In this case, the researchers sifted through some 27 000 genes in three generations of mice and identified obesity hot spots on chromosomes 2 and 19 that correlated with different types of clinical obesity. When the scientists zoomed in on the chromosome 2 hot spot, they found that it controlled genes for cholesterol, triglyceride levels, and other obesity-related traits. Animal Studies Suggest Obesity Subtypes Applying the technique to humans could help unravel the genetic pathways that control subtypes of obesity, said Schadt. That, in turn, could prompt the development of drugs acting on distinct proteins in each network. In such a scenario, genetic screening could then identify patients who would benefit from each drug. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Experimental Drugs Take Aim at Obesity

JAMA , Volume 289 (14) – Apr 9, 2003

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Publisher
American Medical Association
Copyright
Copyright © 2003 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.289.14.1763
Publisher site
See Article on Publisher Site

Abstract

Five years after the US Food and Drug Administration (FDA) banned the popular weight-loss drug fenfluramine after reports of heart-valve problems, three prescription weight-loss drugs remain on the US market. Just two are approved for long-term use. Phentermine, the first half of the infamous "Phen-Fen" combination, is still approved for short-term use. In a nation of 60 million obese adults, the drug industry should be hungry to treat the condition. Yet, the Pharmaceutical Research and Manufacturers of America (PhRMA) lists only 11 new antiobesity drugs in clinical trials. This trend has nothing to do with a lack of effort, according to researchers. Instead, the drought of drugs stems from obesity's complex nature. Only recently have researchers mapped the basic endocrinology of hunger and satiation, and many mysteries remain. "It's been a long haul, and nothing much is around the corner," said Madelyn Fernstrom, PhD, director of the Weight Management Center at the University of Pittsburgh Medical Center. However, two new drugs with novel mechanisms are poised to break the famine. On page 1826 of this issue of JAMA, researchers report preliminary but promising phase 2 trial results for recombinant human variant ciliary neurotrophic factor (CNTF). A second drug, rimonabant, is in late-stage trials. Drawbacks of current drugs Drawbacks of current drugs The two drugs currently approved for long-term use for obesity are known as much for their adverse effects as for their weight-loss action. Orlistat, approved by the FDA in 1999 as Xenical (Hoffman La Roche), blocks fat absorption by the gut but also inhibits absorption of water and vitamins in some obese patients; cramping and diarrhea often follow. And the weight-loss figures are not astounding: one meta-analysis found that during the course of a year, orlistat helps patients lose an average of 2% to 3% of their weight beyond that lost by dieting alone (J Hypertens. 2002;20:1873-1878) . Drawbacks of current drugs The other drug, sibutramine, sold by Abbot Laboratories as Meridia, is in the same chemical class as amphetamine. As such, it works by suppressing appetite, but it may also increase blood pressure, heart rate, or both. In fact, the FDA is investigating the safety of the drug, which was pulled from Italian pharmacy shelves in March 2002. Two deaths possibly linked to the drug prompted the response. Drawbacks of current drugs However, in August 2002, Italian officials allowed sibutramine back on the market after finding that the deaths were not caused by the drug. Sibutramine received a second boost in March of this year, when Health Canada, the national agency, decided against a ban after deciding that the risks did not outweigh the benefits. Drawbacks of current drugs The FDA is still looking into adverse event reports in the United States, said a spokeswoman who declined to comment any further on the ongoing investigation. Drawbacks of current drugs Fernstrom said that the physicians she works with consider a patient's "eating style" when deciding whether to prescribe either drug. Drawbacks of current drugs Sibutramine works best for patients who are preoccupied with food and feel constantly hungry, she said. "It can help them focus on the day instead of thinking about food all the time." Orlistat works best for patients who feel that cutting fat from their diet would be punitive. "It's for people who can't stay away from pizza," said Fernstrom. On the rebound On the rebound However, both drugs can cause rebound weight gain. "If a patient loses 10 or 15 pounds with diet and Meridia, it's not uncommon to see them gain a lot of it back," said Michael Andersen, MD, an internal medicine specialist at Meritcare Medical Center, Fargo, ND. On the rebound Todd M. Sheperd, MD, assistant professor of family medicine at the Medical University of South Carolina, recently noted that sibutramine can help with "modest, short-term weight loss" but that he discourages long-term prescriptions because safety data are lacking beyond one year. After that point, the rebound effect is common (J Fam Pract. 2003;52:34-42). On the rebound Fernstrom said that some obese people have a high "hunger and fullness set point," which sibutramine temporarily lowers. But once the drug is gone, the hunger and fullness bite back. On the rebound Recent research has pinpointed a hormonal suspect in the process, ghrelin. Released by the stomach when empty, ghrelin triggers hunger signals in the hypothalamus. Blood levels of the hormone peak before each meal and decrease after. In addition to boosting appetite, ghrelin apparently slows metabolism, sabotaging long-term weight loss efforts, said Fernstrom. Small studies show that ghrelin levels are higher in obese patients who have recently lost weight compared with obese patients at a steady weight. On the rebound Subsequently, drug companies are reportedly searching for drugs that block ghrelin's effects. None have reached clinical trials. On the rebound Another new approach seeks to augment levels of ghrelin's hormonal counterpoint, a peptide known as PYY. After eating, the stomach and digestive tract release PYY, signaling, "I'm full" to the hypothalamus. In one study, volunteers injected with the hormone ate a third less food from a buffet, according to research from Stephen Bloom, PhD, Imperial College of London, and colleagues. "It's what stops you having the third helping," he said. (Nature. 2002;418:650-654). On the rebound However, Fernstrom pointed out that conscious decisions to overeat can override the PYY signal. On the rebound While drugs inhibiting ghrelin and enhancing PYY appear far off, another appetite-suppressing drug, a modified form of CNTF called Axokine, has reached late-stage trials. On the rebound The early results reported in this week's issue of JAMA led the FDA to move the drug onto its "fast track" status, reserved for promising new drugs that treat life-threatening illnesses—which obesity qualifies as, given its role in diabetes, heart attack, and stroke. On the rebound Subsequently, the company has completed the treatment segment of a phase 3 trial with 2000 patients, said Hans-Peter Gular, MD, vice president of Axokine developer Regeneron Pharmaceuticals Inc, Tarrytown, NY. Gular added that preliminary data show that patients who inject CNTF may not experience the same rebound effect seen with sibutramine. Two prospective trials are evaluating the possibility. On the rebound Although the company is optimistic and is reformulating the injectable drug as a pill—a key to widespread acceptance by patients—Gular cautioned that "there is still a lot of work to do." On the rebound Regeneron originally investigated CTNF as a neuroprotective agent. But in early trials with ALS patients, while CNTF did not slow the disease, patients lost substantial weight. On the rebound Intrigued, the company reformulated CNTF and began investigating possible modes of action. They eventually found that the drug suppresses neuropeptide Y, a signaling molecule in the hypothalamus triggered by ghrelin. In hungry people, the hypothalamus pumps up neuropeptide Y production, but in ravenous rodents given CNTF, neuropeptide Y levels stay stable. On the rebound "We don't know why it doesn't go up, but we know that this is important," said Gular. Blocking the "munchie receptor" Blocking the "munchie receptor" The mechanism of rimonabant, the other weight-loss drug in phase 3 trials, is probably well-known to many college students: it blocks the "munchie receptor." Discovered in the early 1990s, cannabinoid receptors respond to the active ingredient in marijuana and to natural cannabinoids. Blocking the "munchie receptor" Soon, researchers realized that the "munchies," common after smoking marijuana, might signal a role for the receptors in appetite. After all, they were finding that the so-called CB-1 receptor played a role in pain relief, muscle relaxation, and other basic body functions. A series of animal studies confirmed the idea. The most recent study found that mice, obese from a high-fat diet, lost weight while fed a cannabinoid blocker (Am J Physiol Regul Integr Comp Physiol. 2003;284:R345-R353). Blocking the "munchie receptor" That compound, SR141716, was originally developed by the Paris, France-based company Sanofi-Synthelabo, as an anti-marijuana agent. And indeed, it works as such: a study sponsored by the National Institute on Drug Abuse found that the compound reduced how "high" or "stoned" experienced marijuana smokers felt by around 40% (Arch Gen Psychiatry. 2001;58:322-328). Blocking the "munchie receptor" Sanofi quickly latched onto the drug's potential as an antiobesity agent. The company named the compound rimonabant and began small, 2-week human studies. Initial positive results led to the ongoing phase 3 study, which the company declined to discuss. Animal Studies Suggest Obesity Subtypes Animal Studies Suggest Obesity Subtypes New research has identified two subtypes of obesity in mice, a finding that hints at a future of tailored therapy for people (Nature. 2003;422:297-302). Animal Studies Suggest Obesity Subtypes By combining two workhorse techniques of early 21st genetics—DNA microarrays and whole-genome sequencing—Eric Schadt, PhD, of Rosetta Inpharmatics, Kirkland, Wash, and colleagues arrived at a way to study the heritability of gene expression. This new approach can ferret out chromosomal hot spots that control complex traits, such as obesity, diabetes, and asthma. Animal Studies Suggest Obesity Subtypes In this case, the researchers sifted through some 27 000 genes in three generations of mice and identified obesity hot spots on chromosomes 2 and 19 that correlated with different types of clinical obesity. When the scientists zoomed in on the chromosome 2 hot spot, they found that it controlled genes for cholesterol, triglyceride levels, and other obesity-related traits. Animal Studies Suggest Obesity Subtypes Applying the technique to humans could help unravel the genetic pathways that control subtypes of obesity, said Schadt. That, in turn, could prompt the development of drugs acting on distinct proteins in each network. In such a scenario, genetic screening could then identify patients who would benefit from each drug.

Journal

JAMAAmerican Medical Association

Published: Apr 9, 2003

Keywords: obesity

There are no references for this article.