FDA Panel Votes Against Approval for Weight-Loss Drug Lorcaserin

ADELPHI, Md.  – A Food and Drug Administration advisory on Sept. 16 panel voted 9-5 that the potential risks of the serotoninergic drug lorcaserin outweighed its potential benefits as a long-term treatment for weight loss in overweight and obese people and, therefore, did not support approval.

At the meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed data from two phase III clinical trials of more than 7,000 obese and overweight patients, comparing 10 mg lorcaserin administered once or twice daily with placebo over 1-2 years, combined with lifestyle modifications. The manufacturer, Arena Pharmaceuticals Inc., has proposed that lorcaserin, a selective serotonin 5-HT2c agonist, be approved for weight loss and for maintenance of weight loss, in people with a body mass index of at least 30 kg/m2 or a BMI of at least 27 kg/m2 and at least one weight-related comorbid condition. Most of the patients in the phase III studies were women in their early 40s, whose mean weight was about 100 kg; about two-thirds were white, about 20% were black, and about 12% were Hispanic.

Patients treated with the 10-mg twice-daily dose – the dose proposed for approval – lost a mean of almost 6% of their body weight in both studies, compared with a mean loss of 2.2% and 2.8% in the placebo groups, which were statistically significant differences. But the mean percentage of body weight lost among treated patients was only 3%-3.7% more than that of placebo patients, and in one study that continued for a second year, patients on lorcaserin gained the weight back, the FDA pointed out.

Panelists who voted no on the risk-benefit question cited the modest weight-loss effect in a highly selected group of patients in the studies, whom they said did not represent the broader, real-world population of probable lorcaserin candidates.

The long list of exclusion criteria included a diagnosis of diabetes, recent episode of major depression or anxiety, and treatment with a serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor within the previous 1-2 years. The manufacturer is conducting a study comparing lorcaserin with placebo in 600 patients with diabetes, but the panel agreed that the study was too small to produce any useful data in this population.

Panelists were also concerned about the development of mammary tumors in rats exposed to the drug at doses close to therapeutic doses in humans and said that this issue needed to be studied further.

They were encouraged, however, that the modest weight loss in the studies was accompanied by modest improvements in weight-related comorbidities, blood pressure, lipids, and glycemic parameters.

Evidence of valvular heart disease on echocardiograms after 1 year of treatment was identified in about 2% of patients in both the treatment and placebo arms during the studies. But several panelists pointed out that, if approved, lorcaserin might be used in combination with another weight-loss drug, phentermine, which has been associated with drug-induced valvular heart disease. One of the cardiologists on the panel said that, if approved, patients on the drug should have a follow-up echocardiogram.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of potential conflicts related to the topic under discussion. Although in some cases, the FDA grants a waiver to a member with a potential conflict, this did not occur at this meeting.

ADELPHI, Md.  – A Food and Drug Administration advisory on Sept. 16 panel voted 9-5 that the potential risks of the serotoninergic drug lorcaserin outweighed its potential benefits as a long-term treatment for weight loss in overweight and obese people and, therefore, did not support approval.

At the meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed data from two phase III clinical trials of more than 7,000 obese and overweight patients, comparing 10 mg lorcaserin administered once or twice daily with placebo over 1-2 years, combined with lifestyle modifications. The manufacturer, Arena Pharmaceuticals Inc., has proposed that lorcaserin, a selective serotonin 5-HT2c agonist, be approved for weight loss and for maintenance of weight loss, in people with a body mass index of at least 30 kg/m2 or a BMI of at least 27 kg/m2 and at least one weight-related comorbid condition. Most of the patients in the phase III studies were women in their early 40s, whose mean weight was about 100 kg; about two-thirds were white, about 20% were black, and about 12% were Hispanic.

Patients treated with the 10-mg twice-daily dose – the dose proposed for approval – lost a mean of almost 6% of their body weight in both studies, compared with a mean loss of 2.2% and 2.8% in the placebo groups, which were statistically significant differences. But the mean percentage of body weight lost among treated patients was only 3%-3.7% more than that of placebo patients, and in one study that continued for a second year, patients on lorcaserin gained the weight back, the FDA pointed out.

Panelists who voted no on the risk-benefit question cited the modest weight-loss effect in a highly selected group of patients in the studies, whom they said did not represent the broader, real-world population of probable lorcaserin candidates.

The long list of exclusion criteria included a diagnosis of diabetes, recent episode of major depression or anxiety, and treatment with a serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor within the previous 1-2 years. The manufacturer is conducting a study comparing lorcaserin with placebo in 600 patients with diabetes, but the panel agreed that the study was too small to produce any useful data in this population.

Panelists were also concerned about the development of mammary tumors in rats exposed to the drug at doses close to therapeutic doses in humans and said that this issue needed to be studied further.

They were encouraged, however, that the modest weight loss in the studies was accompanied by modest improvements in weight-related comorbidities, blood pressure, lipids, and glycemic parameters.

Evidence of valvular heart disease on echocardiograms after 1 year of treatment was identified in about 2% of patients in both the treatment and placebo arms during the studies. But several panelists pointed out that, if approved, lorcaserin might be used in combination with another weight-loss drug, phentermine, which has been associated with drug-induced valvular heart disease. One of the cardiologists on the panel said that, if approved, patients on the drug should have a follow-up echocardiogram.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of potential conflicts related to the topic under discussion. Although in some cases, the FDA grants a waiver to a member with a potential conflict, this did not occur at this meeting.

ADELPHI, Md.  – A Food and Drug Administration advisory on Sept. 16 panel voted 9-5 that the potential risks of the serotoninergic drug lorcaserin outweighed its potential benefits as a long-term treatment for weight loss in overweight and obese people and, therefore, did not support approval.

At the meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed data from two phase III clinical trials of more than 7,000 obese and overweight patients, comparing 10 mg lorcaserin administered once or twice daily with placebo over 1-2 years, combined with lifestyle modifications. The manufacturer, Arena Pharmaceuticals Inc., has proposed that lorcaserin, a selective serotonin 5-HT2c agonist, be approved for weight loss and for maintenance of weight loss, in people with a body mass index of at least 30 kg/m2 or a BMI of at least 27 kg/m2 and at least one weight-related comorbid condition. Most of the patients in the phase III studies were women in their early 40s, whose mean weight was about 100 kg; about two-thirds were white, about 20% were black, and about 12% were Hispanic.

Patients treated with the 10-mg twice-daily dose – the dose proposed for approval – lost a mean of almost 6% of their body weight in both studies, compared with a mean loss of 2.2% and 2.8% in the placebo groups, which were statistically significant differences. But the mean percentage of body weight lost among treated patients was only 3%-3.7% more than that of placebo patients, and in one study that continued for a second year, patients on lorcaserin gained the weight back, the FDA pointed out.

Panelists who voted no on the risk-benefit question cited the modest weight-loss effect in a highly selected group of patients in the studies, whom they said did not represent the broader, real-world population of probable lorcaserin candidates.

The long list of exclusion criteria included a diagnosis of diabetes, recent episode of major depression or anxiety, and treatment with a serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor within the previous 1-2 years. The manufacturer is conducting a study comparing lorcaserin with placebo in 600 patients with diabetes, but the panel agreed that the study was too small to produce any useful data in this population.

Panelists were also concerned about the development of mammary tumors in rats exposed to the drug at doses close to therapeutic doses in humans and said that this issue needed to be studied further.

They were encouraged, however, that the modest weight loss in the studies was accompanied by modest improvements in weight-related comorbidities, blood pressure, lipids, and glycemic parameters.

Evidence of valvular heart disease on echocardiograms after 1 year of treatment was identified in about 2% of patients in both the treatment and placebo arms during the studies. But several panelists pointed out that, if approved, lorcaserin might be used in combination with another weight-loss drug, phentermine, which has been associated with drug-induced valvular heart disease. One of the cardiologists on the panel said that, if approved, patients on the drug should have a follow-up echocardiogram.

The FDA usually follows the recommendations of its advisory panels. Members of advisory panels have been cleared of potential conflicts related to the topic under discussion. Although in some cases, the FDA grants a waiver to a member with a potential conflict, this did not occur at this meeting.