FDA Panel Supports Combination for Weight Loss

SILVER SPRING, Md. – More than half of a Food and Drug Administration advisory panel on Dec. 7 supported approval of a weight-loss agent that combines naltrexone and bupropion, despite concerns about associated effects on blood pressure and heart rate.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13 to 7 that the potential benefits of the naltrexone-bupropion combination outweighed the potential risks when used on a long-term basis to treat overweight and obese people – with strong recommendations that a controlled clinical study evaluating the impact of increased blood pressure and pulse on the risk of major adverse cardiac events be conducted after approval.

The agency turned to the committee to discuss whether the cardiovascular risk assessment should be conducted before approval, or if it could be handled postmarket. The panel agreed by 11 to 8, with one abstention, that the trial could be conducted as a post-approval requirement.

Before the vote, Office of Drug Evaluation II Director Dr. Curtis Rosebraugh assured members that the FDA has determined that the study is needed, so they can assume that the study will indeed be conducted.

That assurance helped tip the vote for approval. Jacqueline S. Gardner, Ph.D., professor of pharmacy at the University of Washington, Seattle, said that she was influenced by “the promise of definite studies and monitoring going forward.”

The post-approval setting offers a better one for assessing cardiovascular risk, some of the panelists noted.

The proposed indication for the fixed dose, sustained-release oral formulation of bupropion and naltrexone is the treatment of obesity and weight management, including weight loss and the maintenance of weight loss, combined with lifestyle modification, in people with an initial body mass index (BMI) of at least 30 kg/m2, or those with a BMI of at least 27 kg/m2 with at least one risk factor, such as diabetes or hypertension. The recommended dose is a total of 32 mg of naltrexone plus 360 mg bupropion a day, taken in two divided doses.

The rationale for developing the combination as a weight-loss agent is that bupropion (a norepinephrine and dopamine reuptake inhibitor that has been associated with "modest" weight loss) and naltrexone (a mu-opioid receptor antagonist shown to enhance the effects of bupropion in the hypothalamus in preclinicial studies) when taken together, increase satiety and reduce food intake, according to the product’s manufacturer, Orexigen Therapeutics Inc.

In four phase III studies of more than 4,000 predominantly female, white patients, whose mean age was 45 years and who had a BMI of 30-45 kg/m2 or a BMI of 27-45 kg/m2, with one or more comorbidities, three different doses of naltrexone plus 360 mg of bupropion (2,545 patients) were compared with placebo (1,515). (Patients’ mean weight was about 100 kg.)

After 56 weeks, those on the proposed dose (32 mg of naltrexone plus 360 mg bupropion per day, taken in two divided doses) lost 5%-8% of their baseline body weight, compared with about 1%-2% of those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45% to 56% of those on the proposed dose, compared with 16%-43% of those on placebo.

In the studies, 25% of those on naltrexone-bupropion had increases in systolic blood pressure of at least 10% over baseline, compared with 19% of those on placebo; and increases in diastolic blood pressure of at least 5 mm Hg over baseline in 37% of those on the combination, compared with 29% of those on placebo. In addition, 26% of those on naltrexone-bupropion had increases in heart rate of at least 10 beats per minute over baseline, compared with 19% of those on placebo.

The main safety issue discussed was the small but significant mean increases in blood pressure and heart rate among those on treatment compared to placebo, and uncertainty over the impact of treatment on long term cardiovascular outcomes. In the studies, 25% of those on naltrexone-bupropion had increases in systolic blood pressure of at least 10% over baseline, compared with 19% of those on placebo; and increases in diastolic blood pressure of at least 5 mm Hg over baseline in 37% of those on the combination, compared with 29% of those on placebo. In addition, 26% of those on naltrexone-bupropion had increases in heart rate of at least 10 beats per minute over baseline, compared with 19% of those on placebo.

Those who agreed that the potential benefits outweighed the potential risks said that the drug combination had met one of the two criteria set by the FDA for being an effective weight loss agent, and cited the extensive clinical experience with the two drugs and the company’s commitment to conduct a postmarketing long-term safety and efficacy study, which would also evaluate the risk for major cardiac events.

Dr. Allison Goldfine, section head of clinical research at the Joslin Diabetes Center, Boston, said that because of the epidemic of obesity, “I have a greater threshold for accepting the potential risk,” despite the uncertainty over the magnitude of that potential risk. She added that she was concerned about the use of the product in people with underlying coronary disease, and that there should be clear warnings about the use of the drug in certain patients, such as those with depression, the elderly and with a seizure history.

Also voting positively, Dr. Gardner said she was influenced by “the preponderance of existing experience” and by “the promise of definite studies and monitoring going forward.”

Dr. Jules Hirsch, physician-in-chief emeritus, in the Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, voted no, citing “the very marginal efficacy of the drug barely meeting the [FDA] requirements and the lack of any information as to what the efficacy might be after the one year.” Based on past experience with other weight loss agents, he predicted that “efficacy will wane rather quickly” and that this would likely become another failed weight-loss drug.

Bupropion was approved for depression in 1985, for smoking cessation in 1997, and for seasonal affective disorder in 2006; a sustained-release formulation was approved in 1996. Naltrexone was approved for treating opioid addiction in 1984.

This is the first of three new weight-loss products recently reviewed by the panel to be recommended for approval. In October, sibutramine (Meridia) was taken off the U.S. market because of long-standing safety concerns over increases in pulse and blood pressure associated with treatment.

If approved, Orexigen plans to market the combination as Contrave. The FDA usually follows the recommendations of its advisory panels, outside experts who have been cleared of potential conflicts related to the product under review. In rare cases, a waiver is granted to a panel member, but not at this meeting. The FDA is expected to make a decision by Jan. 31, 2011.

The product has not been submitted for approval outside of the United States, according to Orexigen.

SILVER SPRING, Md. – More than half of a Food and Drug Administration advisory panel on Dec. 7 supported approval of a weight-loss agent that combines naltrexone and bupropion, despite concerns about associated effects on blood pressure and heart rate.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13 to 7 that the potential benefits of the naltrexone-bupropion combination outweighed the potential risks when used on a long-term basis to treat overweight and obese people – with strong recommendations that a controlled clinical study evaluating the impact of increased blood pressure and pulse on the risk of major adverse cardiac events be conducted after approval.

The agency turned to the committee to discuss whether the cardiovascular risk assessment should be conducted before approval, or if it could be handled postmarket. The panel agreed by 11 to 8, with one abstention, that the trial could be conducted as a post-approval requirement.

Before the vote, Office of Drug Evaluation II Director Dr. Curtis Rosebraugh assured members that the FDA has determined that the study is needed, so they can assume that the study will indeed be conducted.

That assurance helped tip the vote for approval. Jacqueline S. Gardner, Ph.D., professor of pharmacy at the University of Washington, Seattle, said that she was influenced by “the promise of definite studies and monitoring going forward.”

The post-approval setting offers a better one for assessing cardiovascular risk, some of the panelists noted.

The proposed indication for the fixed dose, sustained-release oral formulation of bupropion and naltrexone is the treatment of obesity and weight management, including weight loss and the maintenance of weight loss, combined with lifestyle modification, in people with an initial body mass index (BMI) of at least 30 kg/m2, or those with a BMI of at least 27 kg/m2 with at least one risk factor, such as diabetes or hypertension. The recommended dose is a total of 32 mg of naltrexone plus 360 mg bupropion a day, taken in two divided doses.

The rationale for developing the combination as a weight-loss agent is that bupropion (a norepinephrine and dopamine reuptake inhibitor that has been associated with "modest" weight loss) and naltrexone (a mu-opioid receptor antagonist shown to enhance the effects of bupropion in the hypothalamus in preclinicial studies) when taken together, increase satiety and reduce food intake, according to the product’s manufacturer, Orexigen Therapeutics Inc.

In four phase III studies of more than 4,000 predominantly female, white patients, whose mean age was 45 years and who had a BMI of 30-45 kg/m2 or a BMI of 27-45 kg/m2, with one or more comorbidities, three different doses of naltrexone plus 360 mg of bupropion (2,545 patients) were compared with placebo (1,515). (Patients’ mean weight was about 100 kg.)

After 56 weeks, those on the proposed dose (32 mg of naltrexone plus 360 mg bupropion per day, taken in two divided doses) lost 5%-8% of their baseline body weight, compared with about 1%-2% of those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45% to 56% of those on the proposed dose, compared with 16%-43% of those on placebo.

In the studies, 25% of those on naltrexone-bupropion had increases in systolic blood pressure of at least 10% over baseline, compared with 19% of those on placebo; and increases in diastolic blood pressure of at least 5 mm Hg over baseline in 37% of those on the combination, compared with 29% of those on placebo. In addition, 26% of those on naltrexone-bupropion had increases in heart rate of at least 10 beats per minute over baseline, compared with 19% of those on placebo.

The main safety issue discussed was the small but significant mean increases in blood pressure and heart rate among those on treatment compared to placebo, and uncertainty over the impact of treatment on long term cardiovascular outcomes. In the studies, 25% of those on naltrexone-bupropion had increases in systolic blood pressure of at least 10% over baseline, compared with 19% of those on placebo; and increases in diastolic blood pressure of at least 5 mm Hg over baseline in 37% of those on the combination, compared with 29% of those on placebo. In addition, 26% of those on naltrexone-bupropion had increases in heart rate of at least 10 beats per minute over baseline, compared with 19% of those on placebo.

Those who agreed that the potential benefits outweighed the potential risks said that the drug combination had met one of the two criteria set by the FDA for being an effective weight loss agent, and cited the extensive clinical experience with the two drugs and the company’s commitment to conduct a postmarketing long-term safety and efficacy study, which would also evaluate the risk for major cardiac events.

Dr. Allison Goldfine, section head of clinical research at the Joslin Diabetes Center, Boston, said that because of the epidemic of obesity, “I have a greater threshold for accepting the potential risk,” despite the uncertainty over the magnitude of that potential risk. She added that she was concerned about the use of the product in people with underlying coronary disease, and that there should be clear warnings about the use of the drug in certain patients, such as those with depression, the elderly and with a seizure history.

Also voting positively, Dr. Gardner said she was influenced by “the preponderance of existing experience” and by “the promise of definite studies and monitoring going forward.”

Dr. Jules Hirsch, physician-in-chief emeritus, in the Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, voted no, citing “the very marginal efficacy of the drug barely meeting the [FDA] requirements and the lack of any information as to what the efficacy might be after the one year.” Based on past experience with other weight loss agents, he predicted that “efficacy will wane rather quickly” and that this would likely become another failed weight-loss drug.

Bupropion was approved for depression in 1985, for smoking cessation in 1997, and for seasonal affective disorder in 2006; a sustained-release formulation was approved in 1996. Naltrexone was approved for treating opioid addiction in 1984.

This is the first of three new weight-loss products recently reviewed by the panel to be recommended for approval. In October, sibutramine (Meridia) was taken off the U.S. market because of long-standing safety concerns over increases in pulse and blood pressure associated with treatment.

If approved, Orexigen plans to market the combination as Contrave. The FDA usually follows the recommendations of its advisory panels, outside experts who have been cleared of potential conflicts related to the product under review. In rare cases, a waiver is granted to a panel member, but not at this meeting. The FDA is expected to make a decision by Jan. 31, 2011.

The product has not been submitted for approval outside of the United States, according to Orexigen.

SILVER SPRING, Md. – More than half of a Food and Drug Administration advisory panel on Dec. 7 supported approval of a weight-loss agent that combines naltrexone and bupropion, despite concerns about associated effects on blood pressure and heart rate.

The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 13 to 7 that the potential benefits of the naltrexone-bupropion combination outweighed the potential risks when used on a long-term basis to treat overweight and obese people – with strong recommendations that a controlled clinical study evaluating the impact of increased blood pressure and pulse on the risk of major adverse cardiac events be conducted after approval.

The agency turned to the committee to discuss whether the cardiovascular risk assessment should be conducted before approval, or if it could be handled postmarket. The panel agreed by 11 to 8, with one abstention, that the trial could be conducted as a post-approval requirement.

Before the vote, Office of Drug Evaluation II Director Dr. Curtis Rosebraugh assured members that the FDA has determined that the study is needed, so they can assume that the study will indeed be conducted.

That assurance helped tip the vote for approval. Jacqueline S. Gardner, Ph.D., professor of pharmacy at the University of Washington, Seattle, said that she was influenced by “the promise of definite studies and monitoring going forward.”

The post-approval setting offers a better one for assessing cardiovascular risk, some of the panelists noted.

The proposed indication for the fixed dose, sustained-release oral formulation of bupropion and naltrexone is the treatment of obesity and weight management, including weight loss and the maintenance of weight loss, combined with lifestyle modification, in people with an initial body mass index (BMI) of at least 30 kg/m2, or those with a BMI of at least 27 kg/m2 with at least one risk factor, such as diabetes or hypertension. The recommended dose is a total of 32 mg of naltrexone plus 360 mg bupropion a day, taken in two divided doses.

The rationale for developing the combination as a weight-loss agent is that bupropion (a norepinephrine and dopamine reuptake inhibitor that has been associated with "modest" weight loss) and naltrexone (a mu-opioid receptor antagonist shown to enhance the effects of bupropion in the hypothalamus in preclinicial studies) when taken together, increase satiety and reduce food intake, according to the product’s manufacturer, Orexigen Therapeutics Inc.

In four phase III studies of more than 4,000 predominantly female, white patients, whose mean age was 45 years and who had a BMI of 30-45 kg/m2 or a BMI of 27-45 kg/m2, with one or more comorbidities, three different doses of naltrexone plus 360 mg of bupropion (2,545 patients) were compared with placebo (1,515). (Patients’ mean weight was about 100 kg.)

After 56 weeks, those on the proposed dose (32 mg of naltrexone plus 360 mg bupropion per day, taken in two divided doses) lost 5%-8% of their baseline body weight, compared with about 1%-2% of those on placebo. The proportion of those who lost at least 5% of their baseline body weight ranged from 45% to 56% of those on the proposed dose, compared with 16%-43% of those on placebo.

In the studies, 25% of those on naltrexone-bupropion had increases in systolic blood pressure of at least 10% over baseline, compared with 19% of those on placebo; and increases in diastolic blood pressure of at least 5 mm Hg over baseline in 37% of those on the combination, compared with 29% of those on placebo. In addition, 26% of those on naltrexone-bupropion had increases in heart rate of at least 10 beats per minute over baseline, compared with 19% of those on placebo.

The main safety issue discussed was the small but significant mean increases in blood pressure and heart rate among those on treatment compared to placebo, and uncertainty over the impact of treatment on long term cardiovascular outcomes. In the studies, 25% of those on naltrexone-bupropion had increases in systolic blood pressure of at least 10% over baseline, compared with 19% of those on placebo; and increases in diastolic blood pressure of at least 5 mm Hg over baseline in 37% of those on the combination, compared with 29% of those on placebo. In addition, 26% of those on naltrexone-bupropion had increases in heart rate of at least 10 beats per minute over baseline, compared with 19% of those on placebo.

Those who agreed that the potential benefits outweighed the potential risks said that the drug combination had met one of the two criteria set by the FDA for being an effective weight loss agent, and cited the extensive clinical experience with the two drugs and the company’s commitment to conduct a postmarketing long-term safety and efficacy study, which would also evaluate the risk for major cardiac events.

Dr. Allison Goldfine, section head of clinical research at the Joslin Diabetes Center, Boston, said that because of the epidemic of obesity, “I have a greater threshold for accepting the potential risk,” despite the uncertainty over the magnitude of that potential risk. She added that she was concerned about the use of the product in people with underlying coronary disease, and that there should be clear warnings about the use of the drug in certain patients, such as those with depression, the elderly and with a seizure history.

Also voting positively, Dr. Gardner said she was influenced by “the preponderance of existing experience” and by “the promise of definite studies and monitoring going forward.”

Dr. Jules Hirsch, physician-in-chief emeritus, in the Laboratory of Human Behavior and Metabolism, Rockefeller University, New York, voted no, citing “the very marginal efficacy of the drug barely meeting the [FDA] requirements and the lack of any information as to what the efficacy might be after the one year.” Based on past experience with other weight loss agents, he predicted that “efficacy will wane rather quickly” and that this would likely become another failed weight-loss drug.

Bupropion was approved for depression in 1985, for smoking cessation in 1997, and for seasonal affective disorder in 2006; a sustained-release formulation was approved in 1996. Naltrexone was approved for treating opioid addiction in 1984.

This is the first of three new weight-loss products recently reviewed by the panel to be recommended for approval. In October, sibutramine (Meridia) was taken off the U.S. market because of long-standing safety concerns over increases in pulse and blood pressure associated with treatment.

If approved, Orexigen plans to market the combination as Contrave. The FDA usually follows the recommendations of its advisory panels, outside experts who have been cleared of potential conflicts related to the product under review. In rare cases, a waiver is granted to a panel member, but not at this meeting. The FDA is expected to make a decision by Jan. 31, 2011.

The product has not been submitted for approval outside of the United States, according to Orexigen.