Obese Lose 14% of Weight on Novel Combo Drug

PHOENIX — Obese individuals lost 14% of their weight on average at the highest dose in a blinded, randomized, placebo-controlled trial of a novel weight loss drug combining slow-release formulations of the anticonvulsant zonisamide and the antidepressant bupropion.

Weight loss was reported as of 48 weeks, with nearly a third of the original participants continuing in a 24-week extension trial after a 24-week dose-optimization study of the experimental drug. At 48 weeks, each of 6 doses tested in the study had produced a median weight loss of 10% or more in study completers.

“And this is absent diet and exercise,” Dr. Gary Tollefson, president and CEO of the study's sponsor, Orexigen Therapeutics Inc. of La Jolla, Calif., said in an interview.

Orexigen is developing the combination under the brand name Empatic. If adding diet and exercise can bring average weight loss to 20%, that would be comparable to invasive procedures such as bariatric surgery, according to Dr. Tollefson, who presented 48-week data at the annual meeting of the Obesity Society.

All told, 623 obese individuals were randomized into 7 groups (6 doses and 1 placebo) at 14 sites in the initial 24-week dose-optimization study. About 70% were white, and women comprised 80% of the baseline population. They had an average age in the mid-40s, average weight of 220 lbs, and average body mass index (BMI) of 36 kg/m

By 24 weeks, average weight loss ranged from 4.5% to 8.6% with the zonisamide-bupropion combination, according to Dr. Tollefson, and was higher in those who stayed on drug (5.3%–10.3%). Meanwhile, the placebo group lost 1.2% on average.

Adverse events and adverse events leading to discontinuation were notably higher at the three highest doses tested, but the discontinuation rate at the top dose was not significantly different from placebo: 16.9% vs. 9.1%. The most common adverse events at this point were insomnia, headache, and nausea, occurring, respectively, in 16.9%, 13.5%, and 12.4% of patients at the top dose (360 mg zonisamide SR/360 mg bupropion SR, once daily).

Participants still in the study at 24 weeks had the option of continuing in a blinded extension trial. Of 87 people randomized to the highest dose, 64 completed the first 24 weeks and 56 stayed the full 48 weeks. This final group had an average weight loss of 14% at 48 weeks, with two-thirds achieving a weight loss of 10% or more.

Orexigen has already started a phase II study at this dose and at a lower dose (120 mg zonisamide SR/360 mg bupropion SR, once daily). Dr. Tollefson said the company hopes to market the drug in more than one formulation. In the group that had been randomized to the lower dose, 71 of 85 patients completed the first 24 weeks, and 45 stayed the full 48 weeks. This last group averaged 12.5% weight loss, and 55% reached the benchmark of 10% or more.

These highest- and lower-dose groups showed improvement in secondary metabolic, cardiovascular, and quality of life end points reported by Dr. Tollefson. Among the statistically significant changes in both groups were an increase in HDL (+ 7.8 mg/dL in the low group and + 7.4 mg/dL in the high group), and reductions in waist circumference (−8.5 cm and −11 cm, respectively), and in systolic blood pressure (−2.5 mmHg and −4.5 mmHg, respectively).

At the highest dose, changes in the following measures were highly significant statistically: triglycerides (−24 mg/dL), insulin (−3.7 mcU/mL), diastolic blood pressure (−2 mm Hg), and pulse rate (3 bpm). Scores on the Impact of Weight on Quality of Life-Lite scale improved significantly at both doses.

Meanwhile, fewer adverse events were reported in the highest- and lower-dose groups during weeks 25–48. The most common adverse events in this period were dry mouth, constipation, and upper respiratory infection, reported respectively in 8.9%, 10.7%, and 12.5% of the high-dose group. One patient at the lower dose discontinued after experiencing major depression and suicidal ideation.

Concern about the weight loss drug rimonabant causing depression and suicidality led a Food and Drug Administration advisory committee to recommend against U.S. approval in 2007, even though it had been approved in Europe. Merck & Co. recently stopped development of another weight-loss drug, taranabant, because of similar concerns about psychiatric adverse events. (Joseph Proietto, Ph.D., of the University of Melbourne, presented phase III data on taranabant at the meeting. He said Merck had just notified him about the decision.)

One in five obese individuals suffers from some form of depression, according to Dr. Tollefson. They could benefit from the incorporation of bupropion, a drug used for depression (Wellbutrin) and smoking cessation (Zyban), into Empatic and a second combination weight loss drug that Orexigen is developing under the brand name Contrave.

The latter combines bupropion with naltrexone (Vivitrol), a drug used for narcotic addiction and alcohol dependency. It is in phase III trials, and the company aims to submit a new drug application to the FDA for Contrave late next year. In addition to Dr. Tollefson, the investigators included the founder of Orexigen and a vice president of the company.

If adding diet and exercise can bring average weight loss to 20%, that would be comparable to bariatric surgery. DR. TOLLEFSON

PHOENIX — Obese individuals lost 14% of their weight on average at the highest dose in a blinded, randomized, placebo-controlled trial of a novel weight loss drug combining slow-release formulations of the anticonvulsant zonisamide and the antidepressant bupropion.

Weight loss was reported as of 48 weeks, with nearly a third of the original participants continuing in a 24-week extension trial after a 24-week dose-optimization study of the experimental drug. At 48 weeks, each of 6 doses tested in the study had produced a median weight loss of 10% or more in study completers.

“And this is absent diet and exercise,” Dr. Gary Tollefson, president and CEO of the study's sponsor, Orexigen Therapeutics Inc. of La Jolla, Calif., said in an interview.

Orexigen is developing the combination under the brand name Empatic. If adding diet and exercise can bring average weight loss to 20%, that would be comparable to invasive procedures such as bariatric surgery, according to Dr. Tollefson, who presented 48-week data at the annual meeting of the Obesity Society.

All told, 623 obese individuals were randomized into 7 groups (6 doses and 1 placebo) at 14 sites in the initial 24-week dose-optimization study. About 70% were white, and women comprised 80% of the baseline population. They had an average age in the mid-40s, average weight of 220 lbs, and average body mass index (BMI) of 36 kg/m

By 24 weeks, average weight loss ranged from 4.5% to 8.6% with the zonisamide-bupropion combination, according to Dr. Tollefson, and was higher in those who stayed on drug (5.3%–10.3%). Meanwhile, the placebo group lost 1.2% on average.

Adverse events and adverse events leading to discontinuation were notably higher at the three highest doses tested, but the discontinuation rate at the top dose was not significantly different from placebo: 16.9% vs. 9.1%. The most common adverse events at this point were insomnia, headache, and nausea, occurring, respectively, in 16.9%, 13.5%, and 12.4% of patients at the top dose (360 mg zonisamide SR/360 mg bupropion SR, once daily).

Participants still in the study at 24 weeks had the option of continuing in a blinded extension trial. Of 87 people randomized to the highest dose, 64 completed the first 24 weeks and 56 stayed the full 48 weeks. This final group had an average weight loss of 14% at 48 weeks, with two-thirds achieving a weight loss of 10% or more.

Orexigen has already started a phase II study at this dose and at a lower dose (120 mg zonisamide SR/360 mg bupropion SR, once daily). Dr. Tollefson said the company hopes to market the drug in more than one formulation. In the group that had been randomized to the lower dose, 71 of 85 patients completed the first 24 weeks, and 45 stayed the full 48 weeks. This last group averaged 12.5% weight loss, and 55% reached the benchmark of 10% or more.

These highest- and lower-dose groups showed improvement in secondary metabolic, cardiovascular, and quality of life end points reported by Dr. Tollefson. Among the statistically significant changes in both groups were an increase in HDL (+ 7.8 mg/dL in the low group and + 7.4 mg/dL in the high group), and reductions in waist circumference (−8.5 cm and −11 cm, respectively), and in systolic blood pressure (−2.5 mmHg and −4.5 mmHg, respectively).

At the highest dose, changes in the following measures were highly significant statistically: triglycerides (−24 mg/dL), insulin (−3.7 mcU/mL), diastolic blood pressure (−2 mm Hg), and pulse rate (3 bpm). Scores on the Impact of Weight on Quality of Life-Lite scale improved significantly at both doses.

Meanwhile, fewer adverse events were reported in the highest- and lower-dose groups during weeks 25–48. The most common adverse events in this period were dry mouth, constipation, and upper respiratory infection, reported respectively in 8.9%, 10.7%, and 12.5% of the high-dose group. One patient at the lower dose discontinued after experiencing major depression and suicidal ideation.

Concern about the weight loss drug rimonabant causing depression and suicidality led a Food and Drug Administration advisory committee to recommend against U.S. approval in 2007, even though it had been approved in Europe. Merck & Co. recently stopped development of another weight-loss drug, taranabant, because of similar concerns about psychiatric adverse events. (Joseph Proietto, Ph.D., of the University of Melbourne, presented phase III data on taranabant at the meeting. He said Merck had just notified him about the decision.)

One in five obese individuals suffers from some form of depression, according to Dr. Tollefson. They could benefit from the incorporation of bupropion, a drug used for depression (Wellbutrin) and smoking cessation (Zyban), into Empatic and a second combination weight loss drug that Orexigen is developing under the brand name Contrave.

The latter combines bupropion with naltrexone (Vivitrol), a drug used for narcotic addiction and alcohol dependency. It is in phase III trials, and the company aims to submit a new drug application to the FDA for Contrave late next year. In addition to Dr. Tollefson, the investigators included the founder of Orexigen and a vice president of the company.

If adding diet and exercise can bring average weight loss to 20%, that would be comparable to bariatric surgery. DR. TOLLEFSON

PHOENIX — Obese individuals lost 14% of their weight on average at the highest dose in a blinded, randomized, placebo-controlled trial of a novel weight loss drug combining slow-release formulations of the anticonvulsant zonisamide and the antidepressant bupropion.

Weight loss was reported as of 48 weeks, with nearly a third of the original participants continuing in a 24-week extension trial after a 24-week dose-optimization study of the experimental drug. At 48 weeks, each of 6 doses tested in the study had produced a median weight loss of 10% or more in study completers.

“And this is absent diet and exercise,” Dr. Gary Tollefson, president and CEO of the study's sponsor, Orexigen Therapeutics Inc. of La Jolla, Calif., said in an interview.

Orexigen is developing the combination under the brand name Empatic. If adding diet and exercise can bring average weight loss to 20%, that would be comparable to invasive procedures such as bariatric surgery, according to Dr. Tollefson, who presented 48-week data at the annual meeting of the Obesity Society.

All told, 623 obese individuals were randomized into 7 groups (6 doses and 1 placebo) at 14 sites in the initial 24-week dose-optimization study. About 70% were white, and women comprised 80% of the baseline population. They had an average age in the mid-40s, average weight of 220 lbs, and average body mass index (BMI) of 36 kg/m

By 24 weeks, average weight loss ranged from 4.5% to 8.6% with the zonisamide-bupropion combination, according to Dr. Tollefson, and was higher in those who stayed on drug (5.3%–10.3%). Meanwhile, the placebo group lost 1.2% on average.

Adverse events and adverse events leading to discontinuation were notably higher at the three highest doses tested, but the discontinuation rate at the top dose was not significantly different from placebo: 16.9% vs. 9.1%. The most common adverse events at this point were insomnia, headache, and nausea, occurring, respectively, in 16.9%, 13.5%, and 12.4% of patients at the top dose (360 mg zonisamide SR/360 mg bupropion SR, once daily).

Participants still in the study at 24 weeks had the option of continuing in a blinded extension trial. Of 87 people randomized to the highest dose, 64 completed the first 24 weeks and 56 stayed the full 48 weeks. This final group had an average weight loss of 14% at 48 weeks, with two-thirds achieving a weight loss of 10% or more.

Orexigen has already started a phase II study at this dose and at a lower dose (120 mg zonisamide SR/360 mg bupropion SR, once daily). Dr. Tollefson said the company hopes to market the drug in more than one formulation. In the group that had been randomized to the lower dose, 71 of 85 patients completed the first 24 weeks, and 45 stayed the full 48 weeks. This last group averaged 12.5% weight loss, and 55% reached the benchmark of 10% or more.

These highest- and lower-dose groups showed improvement in secondary metabolic, cardiovascular, and quality of life end points reported by Dr. Tollefson. Among the statistically significant changes in both groups were an increase in HDL (+ 7.8 mg/dL in the low group and + 7.4 mg/dL in the high group), and reductions in waist circumference (−8.5 cm and −11 cm, respectively), and in systolic blood pressure (−2.5 mmHg and −4.5 mmHg, respectively).

At the highest dose, changes in the following measures were highly significant statistically: triglycerides (−24 mg/dL), insulin (−3.7 mcU/mL), diastolic blood pressure (−2 mm Hg), and pulse rate (3 bpm). Scores on the Impact of Weight on Quality of Life-Lite scale improved significantly at both doses.

Meanwhile, fewer adverse events were reported in the highest- and lower-dose groups during weeks 25–48. The most common adverse events in this period were dry mouth, constipation, and upper respiratory infection, reported respectively in 8.9%, 10.7%, and 12.5% of the high-dose group. One patient at the lower dose discontinued after experiencing major depression and suicidal ideation.

Concern about the weight loss drug rimonabant causing depression and suicidality led a Food and Drug Administration advisory committee to recommend against U.S. approval in 2007, even though it had been approved in Europe. Merck & Co. recently stopped development of another weight-loss drug, taranabant, because of similar concerns about psychiatric adverse events. (Joseph Proietto, Ph.D., of the University of Melbourne, presented phase III data on taranabant at the meeting. He said Merck had just notified him about the decision.)

One in five obese individuals suffers from some form of depression, according to Dr. Tollefson. They could benefit from the incorporation of bupropion, a drug used for depression (Wellbutrin) and smoking cessation (Zyban), into Empatic and a second combination weight loss drug that Orexigen is developing under the brand name Contrave.

The latter combines bupropion with naltrexone (Vivitrol), a drug used for narcotic addiction and alcohol dependency. It is in phase III trials, and the company aims to submit a new drug application to the FDA for Contrave late next year. In addition to Dr. Tollefson, the investigators included the founder of Orexigen and a vice president of the company.

If adding diet and exercise can bring average weight loss to 20%, that would be comparable to bariatric surgery. DR. TOLLEFSON