IT STARTED with a spliff. Back in the 1960s, psychologists studying the effects of cannabis on short-term memory noticed that the subjects couldn’t keep their hands off the free marshmallows. What the researchers were seeing was confirmation of a well-known side effect of smoking cannabis – intense hunger pangs known as the munchies.
Fast-forward 40 years, and scientists are talking about the munchies again, albeit in a rather different way. Early next year, if everything goes to plan, French pharmaceutical company Sanofi-Aventis will start selling a drug designed to induce the “anti-munchies”. Rimonabant taps into the same brain circuits as cannabis, but instead of turning them on, it turns them off. If what has been made public from the clinical trials is anything to go by, rimonabant has almost miraculous powers, helping people to control their appetites, shrink their waistlines and banish many of the metabolic problems associated with being too fat.
And that’s not all. Rimonabant has also been successfully tested as an aid to quitting smoking and might even be useful in treating alcoholism and other addictions. In a world in which obesity, smoking and drug abuse are three of the biggest causes of premature death, that’s a pretty impressive profile. No wonder many industry analysts are backing it to become the first blockbuster drug of the 21st century.
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But while many consider rimonabant a major breakthrough, some are yet to be convinced. They agree that the available results look promising, but point out that there has been only one peer-reviewed article from the clinical trials. And although the drug’s reported side effects are minor, no existing drug works in the same way, so nothing is known about the potential long-term effects of taking it.
The appetite-stimulating effects of cannabis have been known for centuries, but it wasn’t until the 1980s that we began to understand what triggers them. In 1988, researchers at St Louis University School of Medicine in Missouri discovered that the active ingredient of cannabis exerts its effects by binding to specific receptors in the brain. These cannabinoid receptors, known as CB1s, turned out to be part of an extensive network throughout the brain and body whose main role is to damp down the activity of other signalling systems. Over the past few years researchers have discovered that this “endocannabinoid” system is involved in all kinds of functions, including memory, nausea, pain, reproduction and immunity. Crucially, it also plays a part in appetite and fat storage.
The details are unclear, but animal studies suggest that cannabis-like molecules produced in the body bind to CB1 receptors on neurons in the hypothalamus, the brain’s main control centre for food intake. In doing so, the molecules inhibit other signals that tell us not to eat, and so make us feel hungry. When we then eat, the endocannabinoid system sends signals to the reward centre of the brain, where pleasure molecules such as dopamine and serotonin are released. This makes us associate food with pleasure. Endocannabinoids also orchestrate these pleasure signals in response to cigarettes, alcohol and recreational drugs.
Rimonabant blocks CB1 receptors, which appears to reduce the motivation to eat. “That’s the difference with rimonabant,” says Tim Kirkham, a psychologist at the University of Liverpool, UK, who studies the neurochemical pathways that govern appetite. “It appears to target the area in the brain that tells you that you are hungry in the first place.”
The first signs that blocking CB1 receptors could promote weight loss came from animal studies in the 1990s. George Kunos, then at Virginia Commonwealth University in Richmond, and his colleagues showed that mice that were genetically engineered to lack the CB1 receptor ate less, were thinner than normal and did not overindulge and become obese even when offered a fat-laden diet that normal mice found irresistible. Meanwhile, scientists at what was then known as Sanofi-Synthelabo were starting to experiment with rimonabant. When they gave the drug to obese mice, the animals ate much less, lost 20 per cent of their body weight and had lower levels of blood lipids and glucose.
On the back of this and other data, Sanofi-Synthelabo recruited 6600 overweight or obese people into four clinical trials to test rimonabant’s effect on humans. At the same time, the company enlisted another 6500 volunteers in smoking cessation trials. All four obesity trials are now complete. Sanofi has only published one set of results, from the halfway point of a two-year European study involving 1507 volunteers (The Lancet, vol 365, p 1389), but if the results are replicated in all the trials, the drug looks like a winner.
All the volunteers in the European study were put on a calorie-restricted diet and an exercise programme, plus a daily dose of either a placebo or a low or high dose (5 or 20 milligrams) of rimonabant. After a year of this regime, all three groups had lost weight (see Diagram). Those on the placebo had shed an average of 1.8 kilograms and seen their waists shrink by 2.4 centimetres. But those taking rimonabant were doing significantly better. The high-dose group had lost an average of 6.6 kilograms and reduced their waist size by 6.5 centimetres. What is more, more than two-thirds of this group had lost 5 per cent or more of their body weight – the minimum requirement for a weight-loss treatment to be considered effective.
And that’s not all. Those on the high dose also saw significant improvements in their cholesterol and triglyceride levels and insulin sensitivity. And there was a big drop in the proportion that had the “metabolic syndrome” – a cluster of symptoms associated with obesity, including lipid imbalance, high blood pressure and insulin resistance, which can lead to cardiovascular disease and diabetes. The number with the syndrome fell from about 42 per cent to 20 per cent in the high-dose group, compared with a fall from 40 to 31 per cent in the placebo group.
Perhaps this metabolic benefit should come as no surprise, given that weight loss itself would be expected to have knock-on effects on measures such as cholesterol level. But the researchers who analysed the results, led by Luc Van Gaal of Antwerp University Hospital in Belgium, found that the improvements were better than could be expected from the observed weight loss alone. That suggests rimonabant does not just reduce appetite, but also has direct metabolic effects, says Louis Aronne, director of the Comprehensive Weight Loss Center at the Weill Medical College of Cornell University in New York and one of the investigators in the North American rimonabant trials. “This is the first effective treatment for the metabolic syndrome with weight loss as a side effect,” he says.
Sanofi cannot fully explain how rimonabant works on metabolism, but there is some evidence that the drug acts outside the brain to directly ramp up fat metabolism. Rimonabant appears to bind to CB1 receptors on fat cells and causes the up-regulation of adiponectin, a hormone that is involved in fat metabolism. Lean people are known to have much higher levels of adiponectin in their blood than obese people, though no one knows why. Whatever the reason, it is possible that rimonabant may raise adiponectin levels in obese people, helping them burn more fat.
“Sanofi would like to believe that it’s a miracle drug, but I’m not totally convinced of that”
Animal studies are also shedding light on how rimonabant intervenes in metabolism. Kunos, now at the US National Institute on Alcohol Abuse and Alcoholism in Bethesda, Maryland, and his team gave rimonabant to obese rats. After three weeks the rats’ appetite and food intake returned to normal, but the weight stayed off. “Somehow rimonabant helps them burn off the excess intake they have – it revs up the fat burning mechanism,” says Kunos, who has evidence suggesting that the liver, as well as fat cells, is a target of the drug. “It looks like the major effect of rimonabant is not on food intake, but on how the body handles the excess calories.”
As for the smoking cessation trials, Sanofi-Aventis is keeping tight-lipped. So far, the company has only released the results of a 10-week trial involving 787 people, but these look promising. Smokers who took 20 milligrams of rimonabant daily nearly doubled their chances of quitting: 28 per cent stayed abstinent compared with 16 per cent on the placebo. Those who quit didn’t on average gain any weight and one-third actually lost weight. Since weight gain is a common side-effect of giving up, this feature could give rimonabant an edge in the smoking cessation market.
Sanofi-Aventis submitted its results to the US Food and Drug Administration and the European Medicines Agency earlier this year, and is now awaiting a decision. If it gets the go-ahead, rimonabant will go on sale as Acomplia. Industry analysts expect it to fly off the shelves. For example, investment bank JP Morgan predicts that sales will reach €5 billion a year by 2010, which would make rimonabant one of the highest-grossing drugs of all time.
Curiously, however, Sanofi-Aventis does not intend to market rimonabant for weight-loss or smoking cessation, preferring to cast it as a heart medication on the back of the cardiovascular benefits of curbing metabolic syndrome and giving up cigarettes. Nor is Sanofi interested in trying to get the drug approved for alcohol abuse or other drug addictions, despite successful tests in alcoholic rats. This could make good business sense, since US health insurance companies rarely pay for anti-obesity drugs but will cover the cost of cardiovascular medication. And the regulatory agencies tend to be extra critical of weight-loss medications.
But even if it is marketed only as a medication for heart disease, the drug could be huge. “Rimonabant is meant to treat the epidemic of heart disease that’s associated with smoking and obesity,” says Douglas Greene, vice-president of regulatory affairs at Sanofi-Aventis. “We have something that will be as important, we hope, in preventing heart disease as statins.”
Jason Halford at the University of Liverpool, UK, who studies how rimonabant affects appetite and food intake in humans, agrees. “This is good news for heart disease,” he says. “Cardiologists are looking for drugs to manage smoking and obesity, two things they can’t do with existing heart disease drugs.”
Unexpected effects
But while there is a lot of optimism for rimonabant, many say the health benefits remain unclear. “This is a bizarre situation as a scientist because you’re assessing a PowerPoint presentation of the clinical trials given at a venture-capital fund meeting,” says Les Iversen, professor of pharmacology at the University of Oxford, referring to the fact that Sanofi-Aventis has chosen to announce most of its findings at business conferences rather than in peer-reviewed journals. “Sanofi would like to believe that it’s a miracle drug. But I’m not totally convinced of that.”
Perhaps a greater concern is that taking rimonabant may be a lifelong commitment. People in the obesity trials tended to reach a plateau after about 34 weeks, and if they stopped taking the drug, they regained all the lost weight. Sanofi-Aventis thinks that people will be able to continue taking the drug indefinitely, but some obesity experts are wary.
“What is this doing to the brain, and elsewhere in the body?” asks Steve Bloom of Imperial College London. He points out that the appetite circuits in the brain use neurotransmitters and receptors that control other body processes, so targeting these things in the long term might risk serious side effects.
The side effects in the European obesity trial were “mild and transient”, but even so about 40 per cent of those taking rimonabant dropped out during the first year. Some complained of nausea, diarrhoea, vomiting, dizziness and headaches, as well as mood disorders including anxiety and depression.
The dropout rate in the placebo group, however, was even higher. Many left the trial suffering nothing worse than disappointment: they did not lose as much weight as they had hoped. “This is not for cosmetic weight loss, to look good in a bikini or to make fat people thin,” says Greene. “This is for people who need to lose weight for medical reasons.”
Another concern is that quelling appetite through the endocannabinoid system might suppress other desires. “Life could become bland,” says Kirkham, noting that rats tend to lose their motivation to work for a reward when they are on rimonabant. Although this was not reported during the trials, it could be a problem when the drug is more widely distributed, especially in people predisposed to depression or anxiety, says Kirkham.
Another problem might be blood pressure, which was not significantly lowered in the trial participants even though this normally occurs alongside weight loss. Recent findings by Kunos may explain why. He and his team gave rimonabant to rats with high blood pressure and found that the drug increased their blood pressure to such dangerously high levels that some of the animals died.
“If you block the CB1 receptors, you aggravate hypertension,” says Kunos. But he points out that he gave the rats a dose of rimonabant equivalent to 10 times that given to the people. “Still, when people lose 15 pounds by diet alone, you expect a significant drop in blood pressure. This suggests that there could be an effect on the cardiovascular system, and that rimonabant may be preventing a further decrease in pressure.”
Although no one dropped out of the trials because of elevated blood pressure, the effect in long-term users is unknown. “Millions could be taking rimonabant, so it’s something to look at because some side effects only show up in the larger population,” says Kunos. “I would be careful about giving rimonabant to someone with significantly high blood pressure, and I would be very cautious with the dosage.”
Even with these concerns, rimonabant looks destined to join Prozac and Viagra on that select list of “celebrity pharmaceuticals”. Even Sanofi’s determination to keep the focus on heart disease is unlikely to stop it being seen as a lifestyle drug. A pill that helps you lose weight and quit smoking? Now there’s a blockbuster waiting to happen.
