Advances in Pharmacotherapy with a Focus on Combination Therapy Louis J. Aronne, MD, FACP Clinical Professor of Medicine Weill Cornell Medical College Adjunct Associate Professor of Clinical Medicine Columbia University College of Physicians and Surgeons Director, Comprehensive Weight Control Program NewYork-Presbyterian Hospital/Weill Cornell Medical Center New York, New York

Food Intake Gut and Liver Pancreas Autonomic Nervous System Energy Expenditure Adipose Tissue © 2007 LJ Aronne MD. Adapted from Campfield LA et al. Science. 1998;280: ; Porte D et al. Diabetologia. 1998;41: Adrenal Cortex Energy Balance and Adipose Stores Meal Size Adrenal Steroids Leptin Amylin Insulin External Factors Food Availability, Palatability Adiponectin GhrelinGLP-1CCKVagus Afferent Signals Efferent NPY AGRP galanin Orexin-A Dynorphin Endocannab Stimulate α-MSH CRH/UCN GLP-I CART NE 5-HT Inhibit Central Signals Why Is It So Hard to Lose Weight? A Simplified Model of Weight-Regulating Mechanisms

3 FDA-Approved Medications for Weight Loss MedicationSource of Data Characteristics of Study Patients Weight Loss Assessed (Weeks) Mean Weight Change Treated Patients vs Placebo (95% CI) Sibutramine Existing meta-analysis of 29 RCTs Mean age: years; 53%-100% women; average BMI, NA kg (-5.29 to kg) Phentermine Existing meta-analysis of 9 RCTs Average age: NA; 78% women; average BMI, NA kg (-6.0 to -0.6 kg) Diethylpropion Existing meta-analysis of 13 RCTs Average age: NA; 80% women; average BMI, NA kg (-11.5 to -1.6 kg) Orlistat Authors’ meta-analysis of 22 RCTs Average age: 48 years; 73% women; average BMI, 36.7 kg/m kg (-3.31 to kg) NA=not available; RCT=randomized controlled trial. Li Z et al. Ann Intern Med. 2005;142:

4 January, 2010 Sibutramine Safety – Preliminary Data from the SCOUT trial SCOUT=Sibutramine Cardiovascular OUTcomes Trial Food and Drug Administration. Available at http//: Safety. Accessed January 21, Study group Placebo (% patients) Sibutramine (% patients) HR (95% CI)P DM only Patients (n) CV events (6.5%) (6.5%) (0.737 – 1.383) CVD only Patients (n) CV events (8.3%) (10.1%) (0.915 – 1.774) CVD + DM Patients (n) CV events (11.9%) (13.9%) (1.024 – 1.354) New Contraindication: New Contraindication: History of CVD (CAD, Stroke or TIA, Heart arrhythmias, Congestive heart failure, Uncontrolled HTN)

5 There are 9 categories of antihypertensives Reduction of body weight is a far more complex mechanism; therefore, many categories should be anticipated © 2007 Louis J. Aronne, MD. Potential Targets for New Obesity Treatments Serotonin (5-HT2C receptor) Leptin receptor PYY 3-36 MC3 receptor MC4 receptor  -MSH CART receptor CCK-A receptor GLP-1 receptor Adiponectin CNTF Oxyntomodulin Human GH fragment CPT-1 TR  Amylin receptor NPY Y1 and Y5 receptors Ghrelin receptor MCH receptor DPP-4 Agouti-related protein 11  HSD1 SCD1 Fatty acid synthase GIP SOCS-3 PTP-1B

6 A Major Component of our Current Strategy: Use Weight-Neutral Medications or Those That Induce Weight Loss Within Indication Change in body weight (kg) Weeks ± 0.3 kg † * † † † † * -1.6 ± 0.4 kg -2.8 ± 0.5 kg Placebo *P≤.05 vs placebo; † P≤.001 vs placebo. Defronzo RA et al. Diabetes Care. 2005;28:  g Exenatide 10  g Exenatide *

Pramlintide: Weight loss at 16 weeks *P<0.0001, † P<.001 Placebo (n=48) Pramlintide (n=97) Aronne L et al. JCEM 2007 Aug;92(8): Epub 2007 May Time (wk) Absolute Change in Weight (kg) * † * * * * Dose Esc MaintenanceNo Drug Follow-up 3.5 kg 0

8 Weight Loss in Randomized 14-Week Trial of Liraglutide Vilsboll T et al. Diabetes. 2006;55(suppl 1):A465. Placebo Liraglutide 0.65 mg1.20 mg1.90 mg Weight loss (kg)

9 *P=.002; † P<.001. Mean ± SEM. LOCF=last observation carried forward. Smith SR et al. Presented at: NAASO 2006 Annual Meeting; October 20-24, 2006; Boston, MA. Abstract. Lorcaserin Causes Dose-Dependent Weight Loss Placebo Lorcaserin 10 mg qd Lorcaserin 15 mg qd Lorcaserin 10 mg bid Study drug stopped Study day Weight change from baseline (kg) LOCF * † * † † † † † † † † † † † † † † † † †

10 Science, Feb 7, 2003, Vol 299 Illustration by Katharine Sutliff Combination Interventions  Food intake  energy expenditure  food intake  energy expenditure Zonisamide Sibutramine PYY analog Pramlintide Leptin Bupropion

Synergy of sibutramine and low-dose leptin in treatment of diet-induced obesity in rats Boozer, Leibel, Love, Cha and Aronne. Metabolism Aug;50(8): Vehicle Leptin Sibutramine + Leptin

12 Advantages of Combination Therapy Greater weight loss Fewer side effects given the amount of weight loss – If you try to go beyond the plateau by increasing dose, side effects increase

13 Novel Combination Obesity Treatments in Clinical Trials Mode of ActionDrug NameCompany Phentermine+TopiramateQnexaVivus Bupropion + naltrexoneContrave Orexigen Bupropion+ zonisamideEmpatic( Excalia)Orexigen Pramlintide + LeptinAmylin

Slide 14 Contrave and Empatic: Designed to Offset Compensatory Weight Loss Mechanisms MC-4 AgRP POMC Monoamines (DA, 5-HT) Bupropion:  DA leading to POMC activation:  -MSH release Naltrexone:  -endorphin-mediated POMC autoregulation leading to:  -MSH release Zonisamide:  5-HT and DA and  AgRP leading to:  -MSH release a-MSH Weight loss Empatic™ (zonisamide SR / bupropion SR) Contrave™ (naltrexone SR / bupropion SR) B-endorphin

Slide 15 Contrave Phase IIb Mean Weight Loss over 48 Weeks Naltrexone + Bupropion Completer Population Bupropion SR 400mg + Naltrexone IR 48mg Bupropion SR 400mg + Placebo Bupropion SR 400mg + Naltrexone IR 32mg Bupropion SR 400mg + Naltrexone IR 16mg BL Mean Change (%) B-Placebo + N-Placebo Naltrexone IR 48mg + Placebo

Slide 16 Empatic Phase IIb Mean Weight Loss over 24 Weeks Zonisamide + Bupropion Completer Population Placebo Z120/B280 Z120/B360 Z240/B280 Z240/B360 Z360/B280 Z360/B360

17 Screening Study Visits: Visit No. Treatment week 2 weeks 1 Screen Qnexa Top 92 / Phen 15 - Full Strength Phentermine 7.5 IR mg Topiramate CR 92 mg Placebo Topiramate CR 46 mg Phentermine 15 IR mg Qnexa Top 46/ Phen Mid-dose Titration (4 weeks) Treatment (24 weeks) QNEXA: Phentermine and Topamax EQUATE Trial Design Adults  70 years of age with BMI between 30 and 45

18 QNEXA: Phentermine and Topamax Double-blind, randomized, parallel-design, 7- arm placebo-controlled study 756 subjects randomized at 32 investigational sites Primary efficacy endpoints of – % weight loss – % of subjects achieving at least 5% weight loss Safety assessments include – Adverse events – Depression assessments (PHQ-9) – Suicidality assessment (C-SSRS)

19 QNEXA: % Weight Loss- ”Mid-dose” *†*† * p<0.001 vs. placebo † p<0.001 vs. single-agent PHEN and TPM ITT-LOCF

20 QNEXA: Most Frequent Adverse Events Total (n = 753) Treatment Group Placebo (n = 109) Qnexa 7.5/46 (n = 106) Qnexa 15/92 (n = 108) Headache91 (12.1%)14 (12.8%)16 (15.1%)17 (15.7%) Paraesthesia90 (12.0%)3 (2.8%)17 (16.0%)25 (23.1%) Upper respiratory infection85 (11.3%)12 (11.0%)14 (13.2%)14 (13.0%) Dry mouth69 (9.2%)0 (0.0%)14 (13.2%)20 (18.5%) Nasopharyngitis60 (8.0%)11 (10.1%)3 (2.8%)11 (10.2%) Constipation59 (7.8%)9 (8.3%)7 (6.6%)17 (15.7%)

21 QNEXA: Psychiatric AEs Total (n = 753) Treatment Group Placebo (n = 109) Qnexa 7.5/46 (n = 106) Qnexa 15/92 (n = 108) Insomnia58 (7.7%)6 (5.5%)13 (12.3%)11 (10.2%) Depression20 (2.7%)3 (2.8%)1 (0.9%)4 (3.7%) Depressed mood2 (0.3%)1 (0.9%)0 (0.0%)1 (0.9%) History of depression16%15%17%11% SSRI Use12%9%12%10% Depressed mood typically reported as “sadness.”

22 QNEXA: Cognitive AEs Total (n = 753) Treatment Group Placebo (n = 109) Qnexa 7.5/46 (n = 106) Qnexa 15/92 (n = 108) Disturbance in attention20 (2.7%)1 (0.9%)7 (6.6%)4 (3.7%) Cognitive disorder5 (0.7%)0 (0.0%) 2 (1.9%) Memory impairment3 (0.4%)1 (0.9%)0 (0.0%) Disturbance in attention typically described by subjects as “difficulty concentrating.” Cognitive disorder typically described as “delayed cognitive thinking” or “decreased cognitive function.” Majority of events were transient, and resolved spontaneously or with drug withdrawal.

23 Pramlintide + Phentermine or Sibutramine Produced Significant Weight Loss Aronne LJ Obesity (2010) doi: /oby

24 Frequent Adverse Events ( ≥10% in Any Group) PlaceboPramlintide Pramlintide + Sibutramine Pramlintide + Phentermine ITT (n) Nausea Heart rate increased Dry mouth Constipation Insomnia/sleep disorders Blood pressure increased Headache Upper respiratory infection Urinary tract infection Values are % of subjects for the ITT population 3 serious adverse events occurred –2 with placebo, 1 with pramlintide + phentermine –None of these was judged to be related to the study medication

Amylin Lead-in A, L or A+L Treatment Vehicle Leptin 250 µg/kg/d Amylin 100 µg/kg/d Amylin + Leptin 250 µg/kg/d Leptin Alone Doesn’t Work, but Amylin + Leptin Produces Additive Weight Loss Diet-induced obese (DIO) rats Week % change in body weight (vehicle corrected)

26 –Design: Randomized, double-blind, controlled, multicenter –Study population: Overweight or obese subjects (BMI kg/m 2 ) –Treatment: 4-week lead-in requiring 2-8% weight loss followed by 20 weeks randomized treatment  2:2:1 pramlintide: pramlintide/metreleptin: metreleptin –Primary efficacy endpoint: Weight loss in pramlintide vs pramlintide/metreleptin Pramlintide, an Amylin Analog, + Metreleptin: Phase 2 Clinical Proof-of-Concept Study Placebo-P + Metreleptin 5 mg BID Pramlintide 360 µg BID + Placebo-M Pramlintide 360 µg BID + Metreleptin 5 mg BID 360 µg BIDPramlintide 180 µg BIDPramlintide 40% kcal deficit 20% kcal deficit Lead-in Randomized Treatment Day 1 Screen Data on file, Amylin Pharmaceuticals, Inc. N=27 N=56

27 Pramlintide/Metreleptin Reduced Weight More Than Either Treatment : Evidence that Responsiveness to Leptin is Restored Metreleptin 5 mg BID Pramlintide 360 µg BID + Metreleptin 5 mg BID Evaluable N = 93; Least square mean ± SE; *P<0.05, **P<0.01, ***P<0.001 vs monotherapies. LOCF, last observation carried forward. Adapted from Roth JD, et al. Proc Natl Acad Sci USA. 2008;105:7257–7262.

Better understanding of the target systems and counter-regulatory systems Treatments that are targeted to specific central and peripheral targets will be developed Rational combined therapies and medical- surgical will be developed The Future of Obesity Treatment