ADA: Investigational Drug Produces Significant Weight Loss for Obese

WASHINGTON, June 13 - 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, reported investigators here.

"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., in a presentation at the American Diabetes Association meeting here.

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 selectively 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.

In addition, the participants were not given diet or exercise advice, in order not to dilute the drug effect. Participants were required to abstain from alcohol for the duration of the study.

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),

In an intent-to-treat, last-observation-carried-forward analysis, the results were similar, with average weight losses of 1.68 kg (3.7 pounds), 2.2 kg (4.8 pounds) and 3.1 kg (6.8 pounds) for the doses of 10 mg 15 mg, and 20 mg, respectively. Patients in the placebo group in this analysis lost 0.18 kg (0.4 pounds).

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.

There were four serious adverse events. These included a kidney stone and a case of pneumonia in the placebo group, one case of clinical depression in the 10-mg group, and one new-onset seizure in the 20-mg group.

Four patients in the placebo group dropped out of the study, as did two in the 10-mg group, nine in the 15-mg group, and six in the 20-mg group.

There were no apparent drug-related effects on heart valve function or pulmonary artery pressure on ECG, the investigators reported.

Asked whether weight loss may plateau after longer treatment with lorcaserin, Dr. Behan said that it was too early to tell, but that the weight loss observed thus far was progressive.

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