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Investigational Drug Produces Significant Weight Loss for Obese

Posted: Friday, July 07, 2006

Investigators reported that — Lorcaserin, an investigational drug for the treatment of obesity, produced weight losses between four and 7.9 pounds (1.8 to 3.6 kg) in a 12-week phase IIb dose-ranging study.

"Lorcaserin demonstrated excellent weight loss in this study, coupled with excellent tolerability and a positive impact on associated physical measures and most lipid measures in obese patients," said Steven Smith, M.D., of the Pennington Biomedical Research Center in Baton Rouge, La.

The compound selectively stimulates the 5-HT2C serotonin receptor in the hypothalamus to provide central regulation of satiety and to influence metabolic rate.

In contrast Redux/Phen-Fen (phentermine and fenfluramine) an earlier anti-obesity drug combination pulled from the market because of cardiovascular complications, was non-selective, and targeted both central and peripheral 5-HT2B receptors. That lack of selectivity likely accounted for the adverse events of valvulopathies and primary pulmonary hypertension seen in some patients who took Phen-Fen, said Dominic P. Behan, Ph.D., chief scientific officer for Lorcaserin's maker, Arena Pharmaceuticals in San Diego.

In the phase IIb randomized double-blinded study conducted at about 40 sites in the United States, the investigators enrolled 469 obese women (87%) and men (13%). The participants had body mass indices from 29 to 46 kg/m2. The average baseline weight was 100 kg (220 pounds), and the mean BMI was 36.4 kg/m2.

Because of the checkered history of 5-HT2 serotonin receptor agents, the investigators screened patients with echocardiography at baseline and at the study's end. Patients were not disqualified from the study if they were on therapy for hypertension or dylipidemias.

The patients were randomized to placebo or lorcaserin at 10 mg, 15 mg, or 20 mg (10 mg twice daily).
The primary efficacy endpoint of the 12-week trial was a reduction in weight in patients who completed the study.

The investigators found that the drug was associated with significant, dose-dependent weight loss, with average losses in an as-treated analysis of 1.8 kg (4.0 pounds) for the 10-mg dose, 2.6 kg (5.7 pounds) for the 15-mg dose, and 3.6 kg (7.9 pounds) for the 20-mg dose. Patients in the placebo group had a weight loss of 0.3 kg (0.66 pounds). The differences for each group versus placebo were statistically significant (P<0.001),

Significantly more of the patients in the as-treated groups who were taking the drug had weight losses of greater than 5% of body weight at outset. In all, 31.2% of patients in the 20-mg group lost more than 5% of their body weight, compared with 19.5% of those in the 15-mg group, 12.8% of those in the 10-mg group and 2.3% in the placebo group (P<0.001-0.015).
There were also dose-dependent and significant improvements in BMI for all three doses, waist circumference for the two higher doses, cholesterol for the 15-mg and 20-mg doses, and fasting plasma glucose for the 20-mg dose.

There were positive but nonsignificant trends for improvement in LDL and triglycerides. Blood pressure remained unchanged.
There was, however, a non-dose dependent significant decrease of 3.3%-3.5% in HDL levels, resulting in a small but not significant change in LDL/HDL ratios. The small decline in HDL is not likely to be harmful and may be offset by improvements in other parameters, Dr. Behan said in an interview.

The primary adverse events were headache, nausea, dizziness, vomiting, dry mouth, nasopharyngitis, fatigue, and urinary tract infections.

The company plans to begin phase III studies later this year, pending discussions with the FDA, he said.

Source: Diabetes In Control: Smith S et al. "APD356, an Orally-Active Selective 5-HT2C Agonist, Reduces Body Weight in Obese Adult Men and Women." Presented June 12, 2006 at the ADA Scientific Sessions