Lorcaserin (APD356), a Selective 5-HT5

Transcription

1 (APD356), a Selective 5-HT5 2C Agonist, Safely Induces Weight Loss in a 12-week Study of Healthy Obese Patients Steven R. Smith, Warren Prosser, David Donahue, Christen Anderson, William Shanahan, and the APD356-4 Study Group

2 Properties of Potent, highly selective 5-HT5 2C receptor agonist HT 2C ~15-fold selectivity versus 5-HT5 HT 2A ~1-fold selectivity versus 5-HT5 HT 2B No preclinical evidence of effects on heart valves or pulmonary vasculature Efficacious for weight loss in obese patients in a 4-week clinical study at a dose of 15 mg QD 2

3 Study Design 12 week, double blind, randomized, placebo controlled evaluation of the efficacy and safety of lorcaserin in healthy obese patients Screening Randomization Treatment period 2-wk follow-up Stop study drug Day: ECHO X X Safety X X X X X X X X Efficacy X X X X X X X X doses: 1 mg QD, 15 mg QD, 1 mg BID No diet or exercise modifications No run-in period 3

4 Demographics at Baseline Placebo N=118 1 mg QD N= mg QD N=118 1 mg BID N=116 All Patients N=469 Age (yr) 41.6 ± ± ± ± ± 11.4 Baseline Weight (kg) 1.2 ± ± ± ± ± 15.4 Baseline BMI (kg/m 2 ) 36.4 ± ± ± ± ± 4.1 Gender (%) Male Female Ethnicity (%) African American Hispanic Caucasian Other

5 Disposition of Patients Study Retention Rate = 71% Placebo 1 mg QD 15 mg QD 1 mg BID Number of Patients Randomized Completers ITT Per Protocol Discontinuations Adverse Event Protocol Deviation Subject Decision PI Decision 5 LTFU Lack of Efficacy Other

6 Causes Dose-Dependent Dependent Weight Loss: Completer Analysis study day Placebo weight change from baseline (kg) stop study drug 1 mg QD 15 mg QD 1 mg BID p=.2; p<.1 mean ± sem 6

7 Causes Dose-Dependent Dependent Weight Loss: ITT-LOCF Analysis study day Placebo weight change from baseline (kg) mg QD 15 mg QD 1 mg BID p<.1 mean ± sem -4 7

8 Increases the Proportion of Patients with >5% Weight Loss at 12 Weeks 35 3 % of Patients Placebo 1 mg QD 15 mg QD 1 mg BID p=.15; p<.1 Completer subset analysis 8

9 Shifts the Weight Loss Distribution Dose Dependently 5 Placebo 5 1 mg QD % wt change -5-1 % wt change mg QD 5 1 mg BID % wt change -5-1 % wt change Completer subset analysis 9

10 Reduces BMI, Waist Circumference and Hip Circumference Placebo 1 mg QD 15 mg QD 1 mg BID BMI Waist circumference Hip circumference Baseline: 36.4 ± 4.1 kg/m ± 11.7 cm ± 9.7 cm Change at Day p<.5; p<.1; data are mean ± sd for BL, ± sem for change; Completer subset analysis 1

11 Decreases Cholesterol with Favorable Trends in LDL and Triglycerides Placebo 1 mg QD 15 mg QD 1 mg BID.2 Change at Day Cholesterol LDL-Cholesterol LDL:HDL Ratio Triglycerides Baseline: 5. ±.9 mmol/l 2.9 ±.8 mmol/l 2.1 ± ±.8 mmol/l p<.5; p<.1; data are mean ± sd for BL, ± sem for change; Completer subset analysis 11

12 Adverse Events (>5% of Patients in Any Group) Event (%) Placebo (n=118) 1 mg (n=117) 15 mg (n=118) 1 mg bid (n=116) Headache Nausea Dizziness URI Nasopharyngitis Dry Mouth Diarrhea Fatigue Vomiting UTI Dyspepsia All randomized patients 12

13 Echocardiograms: Baseline and Day 85 Echocardiograms performed at screening and Day 85 Interpreted by a single, blinded, academically-based reader All valves except pulmonic rated on scale of 5 for insufficiency: Absent, trace, mild, moderate, severe Pulmonic insufficiency rated as present or absent Pulmonary artery systolic pressure estimated 13

14 Has No Effect on Heart Valve Regurgitation at 12 Weeks No Changes Increased Regurgitation Decreased Regurgitation Number of Events (%) 1 Aortic Mitral Tri 2 Aortic Mitral Tri Aortic Mitral Tri Placebo mg QD mg QD mg BID Expressed as % of evaluable valves 2 Tri, tricuspid valve Analysis of completer set with evaluable echocardiograms 14

15 Has No Effect on Pulmonary Artery Pressure at 12 Weeks Pulmonary Artery Pressure (mm Hg) Baseline Day 85 Change Placebo 26.9 ± ± ± 5. 1 mg QD 26.5 ± ± ± mg QD 26.3 ± ± ± mg BID 27.6 ± ± ± 4.2 Mean ± sd Analysis of completer set with evaluable echocardiograms 15

16 Summary was well tolerated at all doses caused significant, progressive, dose- dependent weight loss at 1 mg QD, 15 mg QD and 1 mg BID decreased BMI, waist and hip circumference and total cholesterol Efficacy was observed across the entire range of obesity studied (BMI 3-4+) Non-responder rate was very low No apparent drug effects on heart valves or pulmonary artery pressures were observed 16

17 APD356-4 Study Group Jeffrey M. Adelglass, MD Dallas, TX Ronald D. Emkey, MD Wyomissing, PA Roy A. Kaplan, MD Concord, CA Michele D. Reynolds, MD Dallas, TX John M. Agaiby, MD Gurnee, IL Roy M. Fleischmann, MD Dallas, TX Mark S. Kipnes, MD San Antonio, TX Joseph Sapanaro, MD Jupiter, FL Andrew J. Ahmann, MD Portland, OR Arthur Frank, MD Washington, DC 237 Diane R. Krieger, MD Miami, FL Douglas Schumacher, MD Columbus, OH James W. Anderson, MD Lexington, KY Jeffrey G. Geohas, MD Chicago, IL Sharyl Magnuson, MD Albuquerque, NM Randall J. Severance, MD Chandler, AZ Harold Bays, MD Louisville, KY Larry I. Gilderman, DO Pembroke Pines, FL Thomas C. Marbury, MD Orlando, FL Lawrence Sherman, MD San Diego, CA Bruce Berwald, MD St. Louis, MO Gloria C. Hakkarainen, MD West Palm Beach, FL F. Timm McCarty, DO Scottsdale, AZ Stuart J. Simon, MD Austell, GA Robert S. Call, MD Richmond, VA Stephen W. Halpern, MD Santa Rosa, CA James McKenney, PharmD Richmond, VA Steven R. Smith, MD Baton Rouge, LA Antonio Caos, MD Ocoee, FL Dana Headapohl, MD Center; Missoula, MT Michael J. Noss, MD Cincinnati, OH Michael W. Warren, MD Reading, PA David G. Carfagno, DO Phoenix, AZ Curtis Scott Horn, MD San Antonio, TX Monica R. Pierson, MD Overland Park, KS James H. Zavoral, MD Minneapolis, MN Gordon T. Connor, MD Birmingham, AL Spencer B. Jones, MD Salt Lake City, UT Bryan C. Pogue, MD Boise, ID William T. Ellison, MD Greer, SC Ken Fujioka, MD San Diego, CA Krishna K. Pudi, MD Simpsonville, SC 17