Quebec City, Canada, March 9, 2004 - Results of a Phase III clinical trial (RIO-Lipids or Rimonabant In Obesity) comparing rimonabant, the first drug in a new class called Selective CB1 Blockers (or SCB1Bs), to placebo found that overweight or obese patients with untreated dyslipidemia (high triglycerides, low HDL-cholesterol) lost almost 20 lbs (8.6 kg) when treated for a year with rimonabant 20mg.

Weight loss was accompanied by a decrease in waist size of 3.4 inches (9.1 cm) demonstrating a significant reduction in abdominal obesity, an independent marker for heart disease.

Dramatic improvements were also seen in lipid profile with a 23% increase in HDL-cholesterol (good cholesterol) and a 15% decrease in triglycerides. Improvements in glucose tolerance and insulin levels were also observed. In another important finding, the number of patients diagnosed at baseline with metabolic syndrome,¹ who were treated with rimonabant 20mg, was reduced by half. The drug was also found to be safe and well-tolerated.

Rimonabant works by inhibiting the CB1 receptor, one of two receptors found in a newly described physiological system called the Endocannabinoid System (EC System), believed to play a critical role in the regulation of food intake and energy expenditure.

"While the weight loss was clinically relevant, what is truly remarkable in the RIO-Lipids study is the significant effect rimonabant had on improving associated cardiovascular risk factors," said Jean-Pierre Despr's, principal investigator for RIO-Lipids and Professor in the Department of Food Sciences and Nutrition and Medicine at Laval University, and Director of Research at the Quebec Heart Institute located at the Laval Hospital Center in Quebec City, Canada.

"Rimonabant appears to have a direct effect on fat cells which may be contributing to the beneficial effects of this drug on abdominal obesity and associated risk factors. Couple this with the markedly reduced plasma insulin levels and the changed size of LDL particles, we now may have a drug that targets the most frequent cause of clustering risk factors."

RIO LIPIDS FINDINGS

A multi-center, double-blind, placebo-controlled study, RIO-Lipids enrolled 1,036 obese patients with dyslipidemia and a BMI between 27 and 40 kg/m2. Patients were randomized into three treatment groups receiving either a daily, fixed dose of 5mg or 20mg of rimonabant or placebo along with a reduced calorie diet for one year.

Patients treated for one year with rimonabant 20mg lost almost 20 lbs (8.6 kg) vs. a loss of only 5 lbs (2.4 kg) on placebo (p<0.001). Nearly three-fourths (72.9%) of these patients treated for a year with rimonabant 20mg lost more than 5% of their body weight vs. placebo (p<0.001) while nearly half (44.3%) lost in excess of 10% of their body weight vs. placebo (p<0.001). While weight loss was the primary endpoint, a waist circumference reduction of 3.4 inches (9.1 cm) in patients completing a year of treatment on rimonabant 20 mg was statistically significant (p<0.001 vs. placebo).

Researchers also designed the RIO-Lipids study to determine if rimonabant, in a group of overweight/obese patients at risk for cardiovascular disease, could improve important factors such as lipid profile, glucose metabolism and other features of the metabolic syndrome. Results show that both the 5 mg and 20 mg doses of rimonabant significantly improved two important indicators of cardiovascular risk, HDL-cholesterol and triglycerides vs. placebo. The patients treated for a year in the 20 mg group achieved an average 23% increase (p<0. 001 vs. placebo) in HDL-cholesterol and a reduction of 15% in triglycerides (p<9x10-5 vs. placebo).

No difference in LDL-cholesterol was observed between rimonabant and placebo. However, rimonabant 20mg delivered positive changes in LDL particle size, a known indicator of atherogenic risk. In patients treated with rimonabant 20mg there was a statistically significant reduction (p=0.002 vs. placebo) in the proportion of small dense atherogenic LDL, which are associated with higher cardiovascular risk, and an increase in the proportion of large, less atherogenic LDL particles (p<0.001 vs. placebo). A positive shift from smaller to larger LDL particles is predictive of reduced cardiovascular risk.

All improvements in metabolic risk factors were statistically significant vs. the control group. In fact, the number of patients diagnosed as having metabolic syndrome at baseline, 52.9%, was reduced by half to 25.8% after treatment with rimonabant 20 mg (p<0.001) compared to placebo.

C-reactive protein (CRP), an important inflammation marker, predictive of cardiovascular risk, was reduced by 27% in the rimonabant 20 mg group, compared with an 11% reduction in the placebo group (p<0.01). In a sub-sample of patients the investigators also measured a specific product of adipose tissue, adiponectin, since abdominally obese patients have markedly reduced plasma adiponectin levels. They found a 41% increase in plasma adiponectin concentration in the rimonabant 20 mg group, compared to an increase of 13.6% in the placebo group (p<0.001). Such an increase in adiponectin levels could partly explain the beneficial effects of the drug on some metabolic risk factors, such as HDL-cholesterol.

Reduced insulin sensitivity (decreased ability of the body's cell to use insulin resulting in impaired glucose control) increases the risk of diabetes and cardiovascular disease. The RIO-Lipids study investigated rimonabant's effect on improving insulin sensitivity using a standard test to measure glucose control, the Oral Glucose Tolerance Test (OGTT). The OGTT showed that even in this non-diabetic population, patients in the rimonabant 20mg group had improved glucose control (p<0.001 over two hours vs. placebo), and their bodies had to produce less insulin (-22% vs. baseline) to achieve this better control (p<0.001 over two hours vs. placebo). By improving insulin sensitivity, rimonabant reduces another cardiovascular risk factor.

There was no difference in the overall drop out rate between patients on rimonabant or placebo. The number experiencing side effects in the rimonabant groups were slightly higher than those in the placebo group. Side effects were mostly mild and transient. The most common side effects where incidence was higher with rimonabant 20mg than placebo were nausea (12.7% vs. 3.2%) and dizziness (10.4% vs. 6.7%). The drop out rate due to side effects was higher in the rimonabant 20mg group vs. placebo (15% vs. 7%). Importantly, no cardiovascular safety concerns were identified with rimonabant.

"It is apparent from these studies that rimonabant could significantly impact the way our bodies regulate energy balance by acting in the brain and on fat cells throughout the body," says Dr. Despres. "This suggests the importance of the Endocannabinoid System that we are only beginning to understand. The promise of rimonabant is that it may provide an entirely new therapeutic strategy that targets the cause (abdominal obesity) of multiple risk factors for a more integrated approach to cardiovascular disease risk management."