NEWS Rimonabant adds appetizing choice to slim obesity market If there’s going to be a Prozac of obesity, it might helped smokers kick the habit without gaining Decision Resources, a Massachusetts-based well be rimonabant. A pill that could hit the weight, boosted insulin sensitivity and improved pharmaceutical market research firm, more than market as early as spring 2006, rimonabant is cholesterol and blood lipid levels (New Engl. J. 80% listed depression triggered by the drug as being touted as a blockbuster that could net six Med. 353, 2121–2134, 2005). “This is a medical their primary concern; insomnia ran a distant billion dollars in annual sales by 2010. But the drug for people at medical risk that have no second at 45%. checkered history of diet drugs has some experts treatment, rather than a diet pill,” says Greene. Still, physicians trying to help a burgeoning worried about the pill’s potential side effects. “Our clinical program has been focused on obese population don’t have many alternatives. To fight fat, rimonabant cleverly harnesses establishing that.” The drugs on the market—Abbott’s Meridia the endocannabinoid neurotransmitter system. Despite its promise as a metabolic magic (sibutramine, marketed as Reductil in Europe) Activating the endocannabinoid receptor CB1 bullet, rimonabant will have to overcome and Roche’s Xenical (orlistat)—offer ho-hum in the brain gives marijuana users the munchies. skepticism about its side effects. Trial subjects effectiveness and side effects ranging from high Rimonabant (trade name Acomplia) blocks regained their weight when they stopped taking blood pressure to fecal incontinence. What’s that same receptor and triggers the reverse. the pill, suggesting that they would need to take more, because insurers refuse to reimburse for In one trial in Europe, 363 participants taking it indefinitely. The most common reported side the pills, patients are quick to give up on them. the highest daily dose of the drug dropped 8.6 effects have been nausea, dizziness, diarrhea This set of circumstances bodes well for kilograms on average in a year (Lancet 365, and joint pain, which investigators described rimonabant, notes Donny Wong, an analyst with 1389–1397; 2005). The drug also acts on CB1 as “mild and transient.” Decision Resources. “It comes at a time when receptors elsewhere in the body, including fat However, in that same study, investigators there’s a lot of dissatisfaction with existing drugs,” cells, where it is thought to make obese patients also reported that ten participants taking the he says, “and it will be the only novel therapy to http://www.nature.com/naturemedicine burn fat more quickly. drug—compared to two in the placebo group— emerge on the market for at least another three, In the languishing obesity market, that’s cause dropped out of the trial because of depression. four or perhaps five years.” for celebration. In a 2005 survey of 142 doctors conducted by Meredith Wadman, Washington DC “If rimonabant lives up to its promise, this single-handedly will change the [obesity] Major obesity drugs on the US market marketplace,” Bernice Welles, vice president of development at DiObex, a San Francisco-based Drug Manufacturer Mechanism Launched 2004 Side effects Daily cost of action US sales (approx.) biotechnology company, told an obesity conference in September 2005. Blocks fat Oily spotting, Orlistat $102 Others are more cautious—with good reason, Roche absorption in 1998 abdominal pain, $3.40 (Xenical) million perhaps. Obesity drugs have a troubled past, the gut fecal urgency Nature Publishing Group Group Nature Publishing 6 from decades-old misuse of amphetamines Inhibits reuptake Headache, dry mouth, to the fen-phen debacle of the mid-1990s, Sibutramine of neurotransmit- $73 anorexia, constipation, 200 Abbott 1999 $3.10 when one component of the popular pill (Meridia) ters, producing million insomnia, high blood © feeling of fullness pressure combination was found—but only after several Gate Increases levels of Tremor, increased Phentermine years on the market—to cause irreversible heart Pharmaceuticals, catecholamines, $49 heart rate, palpitations, (Adipex-P, 1970 $1.00 valve damage. Medeva producing feeling million insomnia, high blood Ionamin) When drugs target the central nervous system Pharmaceuticals of fullness. pressure to control appetite, “how they influence peripheral function only comes out after people have Selected obesity drugs in development been on the drugs for a period of time,” notes Jeffrey Bland, president of Metagenics, a Drug Manufacturer Mechanism of action Stage of Side effects development California-based maker of nutritional products. Rimonabant Under FDA Nausea, dizziness, Because weight loss usually requires long-term Sanofi-Aventis CB1 receptor antagonist (Acomplia) review diarrhea, joint pain treatment, he says, the risks of chronic adverse ATL-962 Blocks fat absorption in Phase 3 to begin Some gastrointestinal Alizyme effects become more significant. (Cetilistat) the gut in 2006 side effects Sanofi-Aventis, the drug’s maker, points out Human growth hormone Metabolic Some gastrointestinal that it has tested the drug in clinical trials with AOD9604 fragment that promotes Phase 2b Pharmaceuticals effects at high doses 13,000 subjects, some on the drug for two years, fat-burning without seeing serious side effects. “Obviously Selectively stimulates sero- once a drug comes into the marketplace we learn APD356 Arena tonin receptor in hypothala- Phase 2b Nausea, headache much more,” says Douglas Greene, vice president mus, decreasing appetite for corporate medical and regulatory affairs at Similar to other CB1 CP-946,598 Pfizer CB1 receptor antagonist Phase 2 antagonists the Paris-based company. He says the company Synthetic form of the recently enrolled another 17,000 patients in a Nastech Nausea, headache, PYY3-36 appetite-suppressing Phase 1 Pharmaceuticals/Merck dizziness five-year trial to monitor cardiovascular effects. hormone PYY The company is betting that the new trial Solvay Pharmaceuticals, SLV-319 CB1 receptor antagonist Phase 1 Undisclosed will strengthen a case for the drug’s use beyond Bristol-Myers Squibb weight loss. In initial clinical trials, rimonabant Sources: IMS Health, Decision Resources NATURE MEDICINE VOLUME 12 | NUMBER 1 | JANUARY 2006 27.