Arena Pharma (ARNA) Presents New Phase 3 Data for Lorcaserin on Cardiac Valvular Regurgitation
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On October 3, 2011, Arena Pharmaceuticals (Nasdaq: ARNA) presented new data analyses from its lorcaserin Phase 3 clinical trial program at Obesity 2011, the 29th Annual Scientific Meeting of The Obesity Society.
The presentation was titled: Effects of Lorcaserin, a Selective Serotonin 2C Agonist, on Cardiac Valvular Regurgitation in Obese and Overweight Patients During Exposures up to Two Years Presenting Authors: Neil J. Weissman, M.D.,
President of MedStar Health Research Institute and Professor of Medicine, Georgetown University; and Christen M. Anderson, M.D., Ph.D., Arena’s Vice President, Lorcaserin Development
Arena previously announced the incidences of FDA-defined valvulopathy (which is mild or greater aortic regurgitation and/or moderate or greater mitral regurgitation) among patients taking lorcaserin 10 mg dosed twice daily, or BID, and patients taking placebo in the lorcaserin Phase 3 clinical trial program. As presented below, a number of additional analyses were performed to assess the effect of lorcaserin on cardiac valvular regurgitation.
In each trial of the lorcaserin Phase 3 clinical program — BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management), BLOSSOM (Behavioral modification and LOrcaserin Second Study for Obesity Management) and BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus) — echocardiograms were performed at baseline and every six months to measure heart valve regurgitation. The trial designs entailed combining data from all three trials to provide a sufficient number of patients to rule out a 50% or greater increase in risk of FDA-defined valvulopathy at Week 52 in patients taking lorcaserin as compared to patients taking placebo, with ³ 80% statistical power.
The proportions of patients who developed FDA-defined valvulopathy at Week 52 in the three trials were as follows: lorcaserin 10 mg BID (2.37%; N=2,696) and placebo (2.04%; N=2,553). All identified valvulopathy was limited to incidental echocardiographic findings; no patient with FDA-defined valvulopathy had clinical signs or symptoms.
The primary pre-specified statistical analysis was a test of the difference in proportions between placebo and lorcaserin using Modified Intent-to-Treat, Last Observation Carried Forward (MITT-LOCF) analysis, relative to a non-inferiority margin of 1.25% (50% of the assumed placebo proportion of 2.5%). According to this primary analysis of risk difference, lorcaserin 10 mg BID was non-inferior to placebo.
Point estimates for relative risk of FDA-defined valvulopathy associated with lorcaserin treatment were 1.03 (completers, 95% confidence interval: 0.68, 1.57) and 1.16 (MITT-LOCF, 95% confidence interval: 0.81, 1.67) at Week 52. Using additional statistical analyses that included all available echocardiograms over up to two years of exposure to lorcaserin, the risk or hazard ratios ranged from 1.08 to 1.09, with the upper bound of the 95% confidence intervals less than 1.5.
Association Between Valvulopathy and Change in BMI and Body Weight
An analysis of echocardiographic data from the Framingham Offspring Study (Singh et al., Am J Cardiol 1999; 83: 897-902) showed that the apparent prevalence of mitral regurgitation was inversely related to Body Mass Index, or BMI—that is, obese individuals tended to have a lower prevalence of significant mitral regurgitation than non-obese individuals. To determine whether changes in BMI or body weight in the lorcaserin trials were associated with changes in apparent incidence of valvulopathy, the pooled placebo echocardiographic data alone and the pooled placebo and lorcaserin echocardiographic data were separately analyzed. Changes in BMI and body weight were negatively associated with FDA-defined valvulopathy regardless of treatment group, and the statistical modeling projected that:
Lorcaserin Reduced Weight and Improved Glycemic Control Across Patient Subgroups in Patients with Type 2 Diabetes
Presenting Author: Brian L. Raether, Arena’s Senior Clinical Project Manager, Clinical Operations
BLOOM-DM evaluated 604 obese (BMI ³30) and overweight (BMI ³27) patients with type 2 diabetes over a one-year treatment period. The data were analyzed to determine whether baseline characteristics affected the response to lorcaserin.
Overall using MITT-LOCF analysis, 37.5% of lorcaserin 10 mg BID patients lost at least 5% of their body weight, compared to 16.1% for placebo; lorcaserin 10 mg BID patients achieved a 0.9% reduction in HbA1c, compared to a 0.4% reduction for placebo, and a 27.4 mg/dL reduction in fasting plasma glucose, compared to an 11.9 mg/dL reduction for placebo. The data show that patients who took lorcaserin 10 mg BID achieved greater reductions in body weight, HbA1c and fasting plasma glucose than the placebo group in all subgroups evaluated, as defined by gender, age, ethnicity and baseline HbA1c and BMI.
The lorcaserin plasma concentrations (ng/mL) at Week 12 were similar across subgroups. The adverse event profiles were also similar across subgroups; the most frequent lorcaserin-associated adverse events (defined as events occurring in at least 5% of lorcaserin patients and at least 1.5 times the placebo incidence) included headache, urinary tract infection, cough, viral gastroenteritis, fatigue, hypertension and procedural pain.
The presentation was titled: Effects of Lorcaserin, a Selective Serotonin 2C Agonist, on Cardiac Valvular Regurgitation in Obese and Overweight Patients During Exposures up to Two Years Presenting Authors: Neil J. Weissman, M.D.,
President of MedStar Health Research Institute and Professor of Medicine, Georgetown University; and Christen M. Anderson, M.D., Ph.D., Arena’s Vice President, Lorcaserin Development
Arena previously announced the incidences of FDA-defined valvulopathy (which is mild or greater aortic regurgitation and/or moderate or greater mitral regurgitation) among patients taking lorcaserin 10 mg dosed twice daily, or BID, and patients taking placebo in the lorcaserin Phase 3 clinical trial program. As presented below, a number of additional analyses were performed to assess the effect of lorcaserin on cardiac valvular regurgitation.
In each trial of the lorcaserin Phase 3 clinical program — BLOOM (Behavioral modification and Lorcaserin for Overweight and Obesity Management), BLOSSOM (Behavioral modification and LOrcaserin Second Study for Obesity Management) and BLOOM-DM (Behavioral modification and Lorcaserin for Overweight and Obesity Management in Diabetes Mellitus) — echocardiograms were performed at baseline and every six months to measure heart valve regurgitation. The trial designs entailed combining data from all three trials to provide a sufficient number of patients to rule out a 50% or greater increase in risk of FDA-defined valvulopathy at Week 52 in patients taking lorcaserin as compared to patients taking placebo, with ³ 80% statistical power.
The proportions of patients who developed FDA-defined valvulopathy at Week 52 in the three trials were as follows: lorcaserin 10 mg BID (2.37%; N=2,696) and placebo (2.04%; N=2,553). All identified valvulopathy was limited to incidental echocardiographic findings; no patient with FDA-defined valvulopathy had clinical signs or symptoms.
The primary pre-specified statistical analysis was a test of the difference in proportions between placebo and lorcaserin using Modified Intent-to-Treat, Last Observation Carried Forward (MITT-LOCF) analysis, relative to a non-inferiority margin of 1.25% (50% of the assumed placebo proportion of 2.5%). According to this primary analysis of risk difference, lorcaserin 10 mg BID was non-inferior to placebo.
Point estimates for relative risk of FDA-defined valvulopathy associated with lorcaserin treatment were 1.03 (completers, 95% confidence interval: 0.68, 1.57) and 1.16 (MITT-LOCF, 95% confidence interval: 0.81, 1.67) at Week 52. Using additional statistical analyses that included all available echocardiograms over up to two years of exposure to lorcaserin, the risk or hazard ratios ranged from 1.08 to 1.09, with the upper bound of the 95% confidence intervals less than 1.5.
Association Between Valvulopathy and Change in BMI and Body Weight
An analysis of echocardiographic data from the Framingham Offspring Study (Singh et al., Am J Cardiol 1999; 83: 897-902) showed that the apparent prevalence of mitral regurgitation was inversely related to Body Mass Index, or BMI—that is, obese individuals tended to have a lower prevalence of significant mitral regurgitation than non-obese individuals. To determine whether changes in BMI or body weight in the lorcaserin trials were associated with changes in apparent incidence of valvulopathy, the pooled placebo echocardiographic data alone and the pooled placebo and lorcaserin echocardiographic data were separately analyzed. Changes in BMI and body weight were negatively associated with FDA-defined valvulopathy regardless of treatment group, and the statistical modeling projected that:
- Each 2 kg/m2 decrease in BMI will increase apparent incidence of FDA-defined valvulopathy by 1.16 times
- Each 5% decrease in body weight will increase apparent incidence of FDA-defined valvulopathy by 1.15 times
Lorcaserin Reduced Weight and Improved Glycemic Control Across Patient Subgroups in Patients with Type 2 Diabetes
Presenting Author: Brian L. Raether, Arena’s Senior Clinical Project Manager, Clinical Operations
BLOOM-DM evaluated 604 obese (BMI ³30) and overweight (BMI ³27) patients with type 2 diabetes over a one-year treatment period. The data were analyzed to determine whether baseline characteristics affected the response to lorcaserin.
Overall using MITT-LOCF analysis, 37.5% of lorcaserin 10 mg BID patients lost at least 5% of their body weight, compared to 16.1% for placebo; lorcaserin 10 mg BID patients achieved a 0.9% reduction in HbA1c, compared to a 0.4% reduction for placebo, and a 27.4 mg/dL reduction in fasting plasma glucose, compared to an 11.9 mg/dL reduction for placebo. The data show that patients who took lorcaserin 10 mg BID achieved greater reductions in body weight, HbA1c and fasting plasma glucose than the placebo group in all subgroups evaluated, as defined by gender, age, ethnicity and baseline HbA1c and BMI.
The lorcaserin plasma concentrations (ng/mL) at Week 12 were similar across subgroups. The adverse event profiles were also similar across subgroups; the most frequent lorcaserin-associated adverse events (defined as events occurring in at least 5% of lorcaserin patients and at least 1.5 times the placebo incidence) included headache, urinary tract infection, cough, viral gastroenteritis, fatigue, hypertension and procedural pain.
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