Thu, Apr 11, 2002 page19

• No stone left unturned in obesity drug search

  One firm is designing a drug which turns off the `switch' that makes people hungry when they smoke cannabis

  • By Ben Hirschler / REUTERS
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  A pill to stop you getting fat is an enticing prospect for couch potatoes and drug companies alike.

  With more than 300 million people around the world affected, obesity is the Western world's fastest-growing health problem and one of the hottest areas of pharmaceutical research.

  But despite the multi-billion-dollar prize, producing effective treatments for a condition that can cause diabetes and heart disease is proving a long, difficult and risky business.

  Abbott Laboratories Inc became the latest firm to hit trouble last month when its Reductil drug was withdrawn in Italy on safety grounds and the consumer group Public Citizen called for a ban in the US, where it is sold as Meridia.

  Critics link the drug to at least 33 deaths in the US and Europe. Abbott says there is no evidence to connect its product with the deaths and insists it is safe.

  The row has done nothing to reassure doctors and patients about a therapy area littered with past failures -- including the 1997 recall of two drugs linked to heart problems used in a slimming cocktail known as "fen-phen" taken by six million Americans.

  American Home Products, now renamed Wyeth, is only now recovering from the fallout, having been forced to take a record US$13.2 billion in charges for fen-phen liabilities.

  Slow sales

  Today, there are just two major obesity medicines on the market -- Meridia/Reductil, which suppresses appetite, and Roche Holding AG's Xenical, which limits fat absorption.

  In both cases, the weight-loss benefits are modest and Xenical comes with some unpleasant side effects, such as diarrhoea after a high-fat meal.

  Sales of the two drugs, as a result, have been slow. Xenical, once flagged as the main hope for Swiss drugmaker Roche, raked in 963 million Swiss francs (US$578 million) in 2001 while Abbott's drug sold US$202 million -- relatively small beer in the US$350-billion-a-year global drugs industry.

  Despite a rocky past, however, obesity remains a priority area for research in pharmaceutical laboratories in Europe, the US and Japan.

  Jonathan de Pass, who heads the London-based drugs consultancy Evaluate, counts more than 30 anti-obesity drugs in development, with many more at the early research stage.

  A number of new approaches are being adopted in the fight against flab -- but the jury is still out as to whether their benefits will outweigh the inevitable side effects.

  Much recent research effort has gone into a class of drugs known as beta-3 agonists, designed to encourage the body to burn more energy without additional physical exertion.

  Leading drug companies including Pfizer Inc, GlaxoSmithKline Plc, Merck and Co Inc and Bristol-Myers Co have all been working on beta-3 products but have yet to find the perfect molecule that does not over-stimulate the heart and cause cardiovascular problems.

  Cannabis and Cactus

  The French firm Sanofi-Synthelabo has taken a different tack by designing a drug which turns off the biological "switch" in the human brain that makes people hungry when they smoke cannabis.

  The so-called cannabinoid receptor antagonist, known by the codename SR141716, is in final Phase III studies, after demonstrating significant weight reduction in early tests.

  Other unusual drug candidates include a product, P57, derived from a rare cactus which British plant-based drug firm Phytopharm Plc has licensed to Pfizer.

  It is now in Phase II trials and, if successful, will earn a windfall profit for the Kalahari bushmen who have been using the Hoodia plant to stave off hunger for thousands of years.

  The new science of genomics -- understanding the links between genes and disease -- is also being brought to bear on obesity with the US group Millennium Pharmaceuticals Inc working with Abbott on the first such genomics-derived product.

  Millennium's drug, which started tests on humans last November, works by blocking an enzyme called carboxypeptidase that encourages the body to store fat. Inhibiting its action should prompt patients to burn fat instead.

  Scientists do not expect to find a "smoking gun" in the form of a single gene that causes obesity. But by studying how genes differ in people who are overweight, Millennium and rivals like Iceland's deCODE Genetics Inc believe they can tease out new leads for treatment, although new drugs based on this knowledge are many years away.

  Safety barrier

  A truly effective anti-obesity pill would generate billions of dollars of sales -- but proving it is safe is always going to be the number one problem for eager pharmaceutical firms.

  That means massive clinical studies, according to Paul Diggle, an industry analyst at WestLB Panmure in London, who says companies are now waking up to the fact that obesity drugs will be among the most costly and time-consuming to develop.

  Evaluate's de Pass believes the drug industry has still to convince many medics and society at large that pricey medicines -- rather than simply eating less -- are the answer to obesity.

  "It's a classic instance of the pharmaceutical industry turning something that has historically been perceived as a social problem into a disease," he said.

  "Fifty years ago, high blood pressure was little more than a curiosity before it was realized it was a real threat to health. Obesity hasn't reached the point where it is considered an equal health risk, although it probably is."
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