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RIO-North America Study Shows Rimonabant Maintains Improvements in Multiple Cardiometabolic Risk Factors for Up to 2 Years

PARIS, FRANCE -- February 15, 2006 -- Sanofi-aventis announced that the results of the RIO-North America trial were published today in the Journal of the American Medical Association (JAMA).

The trial evaluated 2-year treatment with rimonabant in overweight or obese patients, many of whom were at increased risk for diabetes and heart disease through the presence of additional risk factors including increased waist circumference, elevated blood pressure or abnormal lipid levels.

The findings showed that patients treated with rimonabant 20 mg once daily experienced significant reduction of their waist circumference and body weight as well as improvements in multiple cardiometabolic risk factors, including HDL (good) cholesterol, triglycerides and an estimate of insulin sensitivity.

"The RIO-North America trial results indicate that rimonabant 20 mg once daily produced sustained clinically meaningful weight loss and improvements in associated risk factors during two years of treatment," said Xavier Pi-Sunyer, MD, Chief of the Division of Endocrinology, Saint Luke's -- Roosevelt Hospital Center, Columbia University, New York, Professor of Medicine at Columbia University College of Physicians and Surgeons; and Principal Investigator of the RIO-North America trial.

"The sustained improvements we see in several risk factors were beyond what was expected from the observed weight loss and suggests that rimonabant represents an exciting breakthrough in our quest to improve the multiple cardiometabolic risk factors contributing to increased risk for diabetes and heart disease in patients who have abdominal obesity."

At 1 year, the weight loss and reduction in waist circumference for all patients treated with rimonabant 20 mg once daily enrolled in the RIO-North America trial were significantly greater than placebo. Patients treated with rimonabant 20 mg once daily for two years achieved an average 3.6 kg (7.9lbs.) greater weight loss than those in the placebo group (P < 0.001). In contrast, those patients switched to placebo for the second year of treatment regained the majority of the weight they had lost the previous year.

Consistent with the weight loss achieved, patients treated with rimonabant 20 mg once daily experienced an average reduction in waist circumference of 2.8 cm (2.1 inches) more than those in the placebo group (P <.001).

High waist circumference is a practical indicator of intra-abdominal adiposity (excess fat in the abdomen), which is acknowledged as a risk factor for cardiovascular disease and type 2 diabetes.(1)

Rimonabant-treated patients achieved significant improvements in multiple cardiometabolic risk factors that often form a high-risk cluster in overweight or obese patients with an increased waist circumference. In patients treated with rimonabant 20 mg once daily for two years, HDL cholesterol increased by 6.3% more than those in the placebo group (P <.001) and triglycerides were reduced by 8.5% more than those in the placebo group (P <.001).

Although patients with diabetes were not included in the study, patients in the ITT population on rimonabant 20 mg once daily had significantly improved HOMA estimated insulin sensitivity at both one and two years compared to those on rimonabant 5 mg once daily and those on placebo (P <.01). A statistical analysis suggested that the effect of rimonabant on HDL-cholesterol, triglycerides, fasting insulin and insulin sensitivity were approximately twice what could be expected from the weight-loss achieved.

Consistent with the findings of other RIO trials, the percentage of patients who received treatment with rimonabant 20 mg once daily for two years and who achieved a greater than 5% reduction in overall body weight was 40% compared with 19% in those patients receiving placebo (P <.001).

The percentage of patients achieving a greater than 10% reduction in body weight was also greater with rimonabant 20 mg compared to placebo (17% vs. 8%; P <.001). The percentage of patients achieving a 5% or greater weight loss at one year was 48.6% for patients receiving 20 mg of rimonabant (P <.001) and 20% for patients receiving placebo.

The percentage of patients achieving a 10% or greater weight loss at 1 year was 25.2% for patients receiving 20 mg of rimonabant (P <.001) and 8.5% for patients receiving placebo. The 5 mg dose did not show statistical significance for all comparative criteria versus placebo.

Importantly, the RIO-North America trial results suggest that patients taking rimonabant 20 mg once daily maintained their weight loss during the second year of treatment and continued to experience favorable improvements across multiple cardiometabolic risk factors.

"These findings highlight that sustained weight loss and associated improvements in multiple cardiometabolic risk factors require long-term treatment," said Louis Aronne, MD, Director of the Comprehensive Weight Control Program at New York-Presbyterian Hospital/Weill Cornell Medical Center, Associate Professor of Medicine at Weill Medical College of Cornell University, President of the North American Association for the Study of Obesity (NAASO), and investigator in the RIO-North America trial. "As with any chronic disorder, such as diabetes, high cholesterol or hypertension, treatment is often effective when patients remain on therapy long-term."

Safety and tolerability were consistent with other reported RIO studies. In the first year, rimonabant 20 mg once daily was generally well-tolerated and adverse events were mostly mild to moderate. The most common side effects for the placebo and rimonabant 20 mg arms included upper respiratory tract infection (15.2% vs. 18.5%), nasopharyngitis (14.0% vs. 17.0%), nausea (5.8% vs. 11.2%), influenza (7.7% vs. 8.8%), anxiety (2.1% vs. 6.1%), and depressed mood (3.1% vs. 5.2%).

Overall, discontinuation rates due to adverse events in the first year of the trial were 7.2% in placebo treated patients vs. 12.8% for rimonabant 20 mg patients. The most common adverse events leading to discontinuation for the placebo and rimonabant 20 mg patients respectively were depressed mood disorder (1.3% vs. 2.2%), anxiety (0.3% vs. 1.0%) and nausea (0.2% vs. 0.9%).

In the second year, overall rates of adverse events, discontinuations and adverse event-related discontinuations were lower than in the first year, with no significant differences between rimonabant 20 mg and placebo.

The RIO-North America trial publication concluded that, rimonabant, the first CB1 blocker, produced sustained clinically meaningful weight loss and favorable changes in cardiometabolic risk factors including HDL-C, triglycerides, and HOMA estimated insulin sensitivity.

About the RIO-North America Trial
RIO-North America was a two-year, phase 3 multinational, multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose study of 3,045 patients treated with rimonabant 20 mg, rimonabant 5 mg or placebo. Study centers were located in Canada and the United States.

Study participants were male and female 18 years of age or older with a Body Mass Index (BMI) greater than 30 kg/m2 or 27 kg/m2. The study did not include diabetic patients, but many of the patients had elevated blood pressure and/or abnormal lipid levels, and of these a proportion were receiving treatment for their risk factors. After a screening period of 1 week, all patients entered a 4-week single-blind placebo run-in period after which patients were randomly allocated to one of the three treatment groups: placebo or rimonabant 5 mg or 20 mg for 52 weeks of double-blind treatment using a randomized ratio of 1:2:2.

After the first year of treatment, patients who received rimonabant 5 mg or 20 mg were re-randomized to either the same dose of rimonabant or placebo using a randomized ratio of 1:1 for an additional 1 year treatment period (the placebo group remained on placebo during the second year). During the 2-year trial period patients were asked to reduce their diet by 600 kcal/day and increase their level of physical activity.

RIO-North America is one of four phase III trials -- RIO-Diabetes, RIO-Lipids, RIO-Europe and RIO-North America -- examining the effects of rimonabant on cardiometabolic risk factors in 6,600 overweight or obese patients with or without comorbidities for up to two years.

In these studies, rimonabant has demonstrated a wide array of cardiometabolic improvements in blood sugar levels (HbA1C), blood lipid levels (HDL-cholesterol and triglycerides), blood pressure, weight and waist circumference as well as improvements in such emerging cardiometabolic risk factors as adiponectin and C-reactive protein (CRP) which are markers of inflammation associated with cardiovascular risk.(2),(3)

The improvements seen in HbA1c, HDL-cholesterol, triglycerides, adiponectin and CRP were beyond what could be explained by weight loss alone, suggesting a possible direct effect of rimonabant on cardiometabolic risk factors.

The results of the RIO-North America trial were first released at the American Heart Association congress in New Orleans in November 2004.

About Rimonabant
Rimonabant is the first selective CB1 receptor blocker currently under review by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMEA). Rimonabant, discovered by researchers at sanofi-aventis, works by selectively blocking CB1 receptors found centrally in the brain, as well as in peripheral tissues, including fat cells, the liver and muscle. Rimonabant works to regulate the activity of the endocannabinoid system (EC system).

The EC system is a newly discovered physiological system believed to play an important role in regulating body weight, controlling energy balance, as well as glucose and lipid (or fat) metabolism. The EC system is potentially overactivated in overweight and obese patients.

About Cardiometabolic Risk
Cardiometabolic risk (CMR) consists of modifiable risk factors that may predispose people to type 2 diabetes and heart disease. Many of these factors present clinically in specific clusters. CMR factors include: intra-abdominal adiposity (abdominal fat), low HDL levels, elevated triglycerides, insulin resistance and elevated blood glucose (high blood sugar), elevated blood pressure (hypertension), smoking, and elevated LDL levels (bad cholesterol). CMR factors also comprise emerging risk markers such as adiponectin, a protein associated with reduced risk of diabetes and heart disease, and CRP, a marker of inflammation associated with cardiovascular risk.

REFERENCES:
(1) Sharma A. M. Adipose tissue: a mediator of cardiovascular risk. Int J Obes Relat Metab Disord. 2002; 26 Suppl 4: S5-S7
(2) Van Gaal L.F., Rissanen A.M, Sheen A.J., Ziegler O., Rossner S., for the RIO-Europe study group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005; 365:1389-97.
(3) Despres J-P., Golay A., Sjostrom L., for the RIO-Europe study group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. New Engl J Med 2005; 353:2121-34.


SOURCE: sanofi-aventis

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