July 15, 2010 (Winter Park, Florida) — Treatment with the investigational obesity drug lorcaserin (Arena Pharmaceuticals, San Diego, CA) results in significantly greater weight loss than placebo in obese or overweight patients, a new study shows . After one year of treatment, patients treated with the novel weight-loss drug lost 4 kg more than those treated with placebo, with significantly more lorcaserin-treated patients losing more than 5% of their body weight compared with the placebo-treated patients.
"I see the obesity epidemic in the US as a medical issue of pretty amazing proportions when you have one-third of the US population that's obese," lead investigator Dr Steven Smith (Florida Hospital, Winter Park) told heartwire . "If you look at the risk for developing diabetes, cardiovascular disease, and all the way down to orthopedic problems, I think there is a huge unmet need out there for multiple medical conditions . . . a huge unmet need that lorcaserin has the potential to fill."
Importantly, an assessment of adverse events at one and two years did not show any difference in the rates of cardiac valvulopathy, a problem that was observed with less selective obesity agents, report investigators. "In phase 3 studies, particularly in obesity studies, the sample size goes up, which gives us a better picture not just of the efficacy, which I don't think requires many thousands of patients, but lets us really nail some of the safety issues regarding lorcaserin," added Smith.
Lorcaserin is a selective serotonin 2C receptor agonist, and previous studies have shown that drugs targeting serotonin are beneficial in weight loss. The nonselective serotonin agonist fenfluramine, which, along with phentermine, made up the antiobesity medication fen-phen, for example, was approved by the Food and Drug Administration (FDA) in the early 1970s as an adjunct for the treatment of obesity. It was pulled from the market after reports it caused valve disease and pulmonary hypertension.
The results of the study, known as the Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM) trial, are published in the July 15, 2010 issue of the New England Journal of Medicine.
Safety of the 5-HT2C Receptor
In BLOOM, 3182 obese or overweight patients--defined as a body-mass index (BMI) between 30 to 45 kg/m2 (or BMI 27 to 45 with at least one preexisting condition, including hypertension, diabetes, cardiovascular disease, impaired glucose tolerance, or sleep apnea)--were randomized to lorcaserin 10 mg twice daily or placebo for 52 weeks. All patients were instructed to exercise moderately for 30 minutes daily and to reduce caloric intake 600 kcal below their estimated daily energy requirements.
At one year, 47.5% of the lorcaserin-treated patients lost 5% or more of their body weight compared with 20.3% of the placebo-treated patients. In addition, 22.7% of the lorcaserin-treated individuals lost 10% of their body weight, while just 7.7% lost the same amount of weight in the placebo arm. On average, individuals treated with lorcaserin lost 5.8 kg compared with 2.2 kg lost in the placebo-treated patients.
After one year of treatment, patients who received lorcaserin were randomly assigned 2:1 to continue treatment for an additional year or to receive placebo. The lorcaserin patients switched to placebo regained the weight lost in the first year and ended year two with roughly the same body weight as those who received placebo for the full two-year study.
"I have thought that for not only lorcaserin, but for other pharmacotherapy approaches, that obesity is a chronic condition, like high blood pressure and hypercholesterolemia," said Smith. "We know that, [just like with other drugs], if you stop taking them, just like you saw here, people regain their body weight. I personally believe that long-term treatment with antiobesity therapies matches the disease and makes a lot of sense, just like treating hypertension."
Asked about the 5.8-kg reduction in weight, Smith told heartwire that for individuals with obesity, every pound lost counts. Medically accepted weight loss, he noted, is approximately 5% of body weight and is generally needed to improve cardiovascular risk factors. Overall, there were small but statistically significant improvements in blood pressure, triglycerides, insulin sensitivity, fibrinogen, and C-reactive protein (CRP), among other measures, compared with placebo. "All the arrows are pointing in the right direction," he said.
In BLOOM, the percentage of patients who remained in the trial at one year was 55.4% in the lorcaserin arm and 45.1% in the placebo arm. The high dropout rate, said Smith, is on par with other antiobesity studies and is likely the result of individuals being able to observe the drug effects by stepping on a scale or tightening their belt buckles, and deciding they no longer needed or wanted to take the drug. He noted that the most frequently reported side effects with lorcaserin were headache, dizziness, and nausea, which occurred early and usually went away. That more people stayed on the drug than on placebo speaks to the tolerability of lorcaserin, said Smith.
Regarding the more serious concern of cardiac valvulopathy, the BLOOM investigators report that at one year FDA-defined valvulopathy developed in 2.3% of patients in the placebo arm and 2.7% of patients in the lorcaserin group, a nonsignificant difference. At two years, the rates were similar.
The Heart Valves
Recent evidence suggests that different serotonin receptors are responsible for different effects, with the 5-HT2B receptor believed responsible for the adverse cardiac valvular effects, while the 5-HT2C receptor targeted by lorcaserin is responsible for weight loss. A smaller 12-week study with lorcaserin showed the drug reduced weight without any adverse effects on the cardiac valves or pulmonary arterial pressure. The Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) trial, previously reported by heartwire , showed lorcaserin did not increase the risk of cardiac valvulopathy or worsen valve problems, including in some patients with preexisting mild to greater aortic or mitral regurgitation.
Speaking with heartwire , Dr Frank Greenway (Pennington Biomedical Research Center, Baton Rouge, LA), an obesity expert who does research in obesity drug development but was not affiliated with the BLOOM trial, agreed that most of the concerns with antiobesity drugs stemmed from the lack of specificity with earlier agents.
"Everybody was very excited about fen-phen because it caused a 15% to 20% reduction in weight loss, so after it was taken off the market, the pharmaceutical industry tried to developed a drug specific to the 5-HT2C receptor, which is in the brain and regulates appetite," he said. "Judging from the affinity constants and so forth, it would appear there shouldn't be a problem with heart-valve pathology with lorcaserin because it's a specific 5-HT2C receptor agonist."
The lack of valve problems in a study extended to two years suggests this is no longer a problem, and "the issue has been put to rest," said Greenway.
In an editorial accompany the study , Dr Arne Astrup (University of Copenhagen, Denmark) writes that the "history of pharmacologic treatment of obesity is characterized by repetition," with drugs approved and then later yanked because of serious adverse effects detected during postmarketing surveillance.
In addition to fenfluramine, Astrup cites rimonabant, which was scrapped by Sanofi-Aventis after concerns were raised about the drug's psychiatric side effects, and sibutramine (Meridia, Abbott Laboratories), which has been removed from the European market and is contraindicated in individuals with a history of cardiovascular disease. Still, despite these setbacks, Astrup notes that "it makes good sense to develop more selective agents" that work on the 5-HT2C receptors.
However, putting lorcaserin on the market to treat obesity should be based not on the greater efficacy of the drug, which is slightly less than other compounds, but on improved safety and an improved adverse-event profile, as well as meaningful benefits on risk factors for type 2 diabetes mellitus and cardiovascular disease. "Given the history, we will need to be doubly sure about the safety of lorcaserin, used either alone or in combination with other weight-loss drugs," writes Astrup.
Arena Pharmaceuticals sponsored the BLOOM study. Smith reports consulting fees/honorarium from Arena Pharmaceuticals and has received financial support for travel expenses related to the BLOOM study. Smith spoke with heartwire on a conference call set up by Russo Partners, a public-relations firm. Present on the call were David Schull (Russo Partners, New York), Lena Evans (Russo Partners), and Cindy McGee (Arena Pharmaceuticals). Astrup reports receiving grant support from NeuroSearch and Novo Nordisk and currently sits on an external advisory board for Merck and NeuroSearch.