Amylin Pharmaceuticals, Arena Pharmaceuticals and Orexigen Therapeutics are among about 20 companies that are developing drugs to treat obesity.About half of those products are in late-stage clinical trials, which must show efficacy and safety before the Food and Drug Administration will approve them for market.
Representatives of the companies spoke recently at the BIO International conference in San Diego about their products and the complicated science behind them, as well as the body chemistry that makes controlling appetite so difficult for so many.
An effective weight-loss pill could be a billion-dollar market, given the more than 80 million obese people in the United States.
Each year, Americans spend more than $30 billion on weight-loss products, including devices sold on late-night television, diet programs and gym memberships. Only about $200 million is spent on prescription drugs, executives said.
And those drugs don't appear to be the therapy of choice because of side effects, they said. The most frequently prescribed medication for obesity is phentermine, which was approved several decades ago but never tested for long-term use, they said.
"I'm delighted that we are having this panel discussion, because if you look at a number of therapeutic areas, obesity stands out as one of the highest unmet medical needs, specifically with its link to hypertension, diabetes and a number of other diseases," said Christian Weyer, executive director of clinical research at Amylin.
The executives from the three publicly traded companies pointed out that excitement has built around the experimental drugs because so many previous attempts at obesity therapies have failed.
Arena has an experimental drug, lorcaserin, in Phase 3 trials. The pill targets the parts of the brain, serotonin 2c receptors, that regulate the desire for food intake, said Christen Anderson, vice president of clinical research.
"If you look at what causes obesity, it's primarily the central nervous system's regulation of what you eat and peripheral factors of what calories you are burning off," Anderson said.
Eating less can trigger the body's very sophisticated mechanism to slow down its metabolic rate, she said. It's a trait that has existed over time to protect people from starvation, she said. That is one reason why weight-loss drugs have a plateau effect.
"By targeting the center of control, hopefully we can get around the compensatory mechanism," she said.
Lorcaserin would be a first-in-class chemical entity if approved, Chief Executive Jack Lief said.
"Other compounds, while I think they've had some weight loss associated with them, are just generic combinations of compounds already available and already used by physicians in combination for treating weight management, so it's really nothing new," Lief said.
He was referring to Orexigen's two compounds, Contrave and Empatic. Contrave is in Phase 3 clinical trials, and Empatic is in mid-stage clinical trials.
Contrave is a combination of generic drugs: an antidepressant and an anti-addictive. Orexigen chose these two drugs based on its understanding of circuitries in the brain that regulate appetite and energy balance.
"The field is increasingly appreciating that obesity is a disorder of the central nervous system," said Chief Executive Gary Tollefson.
The company's drugs bypass the resistance to the hormone leptin, which senses when there is less intake of food and slows the metabolism, he said.
The second part of the therapy recognizes the behavioral aspects of obesity: eating more than one might need and consuming food when not hungry, he said. Basically addictive behavior.
"If you look at the literature, the field recognized that the genetic pool in society hasn't changed in 40 years," Tollefson said. "What has changed is our behavior and the surplus of food around us."
Empatic, the company's second drug candidate, is a combination of zonisamide, which is an anti-convulsant, and bupropion, an antidepressant.
The combination of the two aims to provide more weight loss for people who are just starting their weight-loss efforts and those looking to keep weight off over a longer period.
Amylin's drug focuses on neuronal and hormonal regulation of body weight, Weyer said. The major advance that drew Weyer into this field of research was the discovery of leptin, a hormone made in the gut in response to eating.
Leptin is key to the company's drug, which combines metreleptin and pramlintide and is designed to be injected into the abdomen.
Pramlintide is a synthetic analog of amylin, a neurohormone secreted by the pancreas that plays a role in the regulation of appetite, food intake and glucose concentrations after meals. It is the active ingredient in Symlin, a diabetes drug that Amylin has on the market.
Someone on a diet initially loses weight, but it is hard to keep it off, Weyer said. Studies show that leptin is fundamentally important, because when someone diets the leptin levels fall and trigger a host of adaptations in the body.
If leptin is replaced, the body can reduce its fight against the weight-loss efforts, he said.