Advances in Pharmacotherapywith a Focus on Combination

Therapy

Louis J. Aronne, MD, FACPClinical Professor of MedicineWeill Cornell Medical College

Adjunct Associate Professor of Clinical MedicineColumbia University College of Physicians and Surgeons

Director, Comprehensive Weight Control ProgramNewYork-Presbyterian Hospital/Weill Cornell Medical Center

New York, New York

Food Intake

Gut and Liver

Pancreas

AutonomicNervousSystem

Energy Expenditure

Adipose Tissue

© 2007 LJ Aronne MD. Adapted from Campfield LA et al. Science. 1998;280:1383-1387; Porte D et al. Diabetologia. 1998;41:863-881.

Adrenal Cortex

Energy Balance

and Adipose Stores

Meal Size

Adrenal Steroids

Leptin

AmylinInsulin

External FactorsFood Availability,

Palatability

Adiponectin

GhrelinGLP-1CCKVagus

Afferent Signals

Efferent

NPYAGRPgalanin

Orexin-ADynorphinEndocannab

Stimulateα-MSHCRH/UCNGLP-I

CARTNE5-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

DataCharacteristics 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: 34-54 years; 53%-100% women;

average BMI, NA52

-4.45 kg (-5.29 to -3.62 kg)

Phentermine

Existing meta-

analysis of 9 RCTs

Average age: NA; 78% women;

average BMI, NA2-24 -3.6 kg (-6.0 to -0.6 kg)

Diethylpropion

Existing meta-

analysis of 13 RCTs

Average age: NA; 80% women;

average BMI, NA6-52 -3.0 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/m2

52-2.75 kg (-3.31 to -

2.20 kg)

NA=not available; RCT=randomized controlled trial. Li Z et al. Ann Intern Med. 2005;142:532-546.

4

January, 2010Sibutramine Safety –

Preliminary Data from the SCOUT trial

SCOUT=Sibutramine Cardiovascular OUTcomes TrialFood and Drug Administration. Available at http//:www.fda.gov/Drugs/Drug Safety. Accessed January 21, 2010.

Study group

Placebo (% patients)

Sibutramine(% patients)

HR (95% CI) P

DM only

Patients (n)

CV events

1178

77 (6.5%)

1207

79 (6.5%)

1.010

(0.737 – 1.383)

0.951

CVD only

Patients (n)

CV events

793

66 (8.3%)

759

77 (10.1%)

1.274

(0.915 – 1.774)

0.151

CVD + DM

Patients (n)

CV events

2901

346 (11.9%)

2906

403 (13.9%)

1.182

(1.024 – 1.354)

0.023

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• PYY3-36

• 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• 11HSD1• 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

Ch

an

ge in

bod

y w

eig

ht

(kg

)

Weeks

0 5 10 15 20 25 30

-0.3 ± 0.3 kg

†

*

†

†

† †

*

-1.6 ± 0.4 kg

-2.8 ± 0.5 kgPlacebo

*P≤.05 vs placebo; †P≤.001 vs placebo.Defronzo RA et al. Diabetes Care. 2005;28:1092-1100.

-4.0

-3.5

-3.0

-2.5

-2.0

-1.5

-1.0

-0.5

0

0.5

5 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):2977-83. Epub 2007 May 15.

-5

-4

-3

-2

-1

0

1

Time (wk)2 4 8 12 16 24

Absolute Change in Weight (kg)

*

†

*

**

*

DoseEsc Maintenance No 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 mg 1.20 mg 1.90 mg-3.5

-3

-2.5

-2

-1.5

-1

-0.5

01

Weig

ht

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

Lorcaserin10 mg qd

Lorcaserin15 mg qd

Lorcaserin10 mg bid

Study drug stopped

Study day

Weig

ht

ch

an

ge f

rom

baselin

e (

kg

)

15 30 45 60 75 90

-4

-3

-2

-1

0

1LOCF

*†

*

†

†

††

†

†

† † † † †

†

††

†

†

†

10Science, Feb 7, 2003, Vol 299

Illustration by Katharine Sutliff

Combination Interventions

­Food intake¯­energy expenditure

¯ food intake ­energy expenditure

Zonisamide Sibutramine

PYY analogPramlintide

Leptin

Bupropion

Synergy of sibutramine and low-dose leptin in treatment of diet-induced obesity in rats

Boozer, Leibel, Love, Cha and Aronne. Metabolism. 2001 Aug;50(8):889-93

Vehicle

Leptin

Sibutramine

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 Action Drug Name Company

Phentermine+Topiramate Qnexa Vivus

Bupropion + naltrexone Contrave Orexigen

Bupropion+ zonisamide Empatic( Excalia) Orexigen

Pramlintide + Leptin Amylin

Slide 14

Contrave and Empatic: Designed to Offset Compensatory Weight Loss Mechanisms

MC-4

AgRPPOMC

Monoamines

(DA, 5-HT)

Bupropion: DA leading to POMC activation:a-MSH release

Naltrexone:b-endorphin-mediated POMC autoregulation leading to:a-MSH release

Zonisamide:­ 5-HT and DA and ¯ AgRP leading to:a-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 WeeksNaltrexone + Bupropion Completer Population

Bupropion SR 400mg +Naltrexone IR 48mg

Bupropion SR 400mg +Placebo

0

-1

-2

-3

-4

-5

-6

-7

-8

-9

-10

-11

-12

-13

Bupropion SR 400mg +Naltrexone IR 32mg

Bupropion SR 400mg +Naltrexone IR 16mg

BL 4 8 12 16 20 24 28 32 36 40 44 48

Me

an

Ch

an

ge

(%

)

B-Placebo + N-PlaceboNaltrexone IR 48mg + Placebo

Slide 16

Empatic Phase IIb Mean Weight Loss over 24 WeeksZonisamide + Bupropion Completer Population

-11%

-10%

-9%

-8%

-7%

-6%

-5%

-4%

-3%

-2%

-1%

0%

4 8 12 16 20 24

Study Week

Mea

n W

eig

ht L

oss

Placebo

Z120/B280

Z120/B360Z240/B280Z240/B360

Z360/B280

Z360/B360

1717

Screening

Study Visits:

Visit No. Treatment week

2 weeks

1Screen

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 7.5 - Mid-dose

20

3

2

4

4

Titration(4

weeks)

5

8

612

716

820

924

1028

Treatment (24 weeks)

QNEXA: Phentermine and Topamax EQUATE Trial Design

Adults 70 years of age with BMI between 30 and 45

1818

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)

1919

QNEXA: % Weight Loss-”Mid-dose”

1.71

5.45 5.13

8.46

0

2

4

6

8

10

Pe

rce

nt

Mid Dose

Placebo

PHEN

TPM

Qnexa

*†

* p<0.001 vs. placebo† p<0.001 vs. single-agent PHEN and TPM

ITT-LOCF

2020

QNEXA: Most Frequent Adverse Events

Total(n = 753)

Treatment Group

Placebo(n = 109)

Qnexa 7.5/46(n = 106)

Qnexa 15/92(n = 108)

Headache 91 (12.1%) 14 (12.8%) 16 (15.1%) 17 (15.7%)

Paraesthesia 90 (12.0%) 3 (2.8%) 17 (16.0%) 25 (23.1%)

Upper respiratory infection 85 (11.3%) 12 (11.0%) 14 (13.2%) 14 (13.0%)

Dry mouth 69 (9.2%) 0 (0.0%) 14 (13.2%) 20 (18.5%)

Nasopharyngitis 60 (8.0%) 11 (10.1%) 3 (2.8%) 11 (10.2%)

Constipation 59 (7.8%) 9 (8.3%) 7 (6.6%) 17 (15.7%)

2121

QNEXA: Psychiatric AEs

Total(n = 753)

Treatment Group

Placebo(n = 109)

Qnexa 7.5/46(n = 106)

Qnexa 15/92(n = 108)

Insomnia 58 (7.7%) 6 (5.5%) 13 (12.3%) 11 (10.2%)

Depression 20 (2.7%) 3 (2.8%) 1 (0.9%) 4 (3.7%)

Depressed mood 2 (0.3%) 1 (0.9%) 0 (0.0%) 1 (0.9%)

History of depression 16% 15% 17% 11%

SSRI Use 12% 9% 12% 10%

Depressed mood typically reported as “sadness.”

2222

QNEXA: Cognitive AEs

Total(n = 753)

Treatment Group

Placebo(n = 109)

Qnexa 7.5/46(n = 106)

Qnexa 15/92(n = 108)

Disturbance in attention 20 (2.7%) 1 (0.9%) 7 (6.6%) 4 (3.7%)

Cognitive disorder 5 (0.7%) 0 (0.0%) 0 (0.0%) 2 (1.9%)

Memory impairment 3 (0.4%) 1 (0.9%) 0 (0.0%) 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:10.1038/oby.2009.478

24

Frequent Adverse Events ( ≥10% in Any Group)

Placebo Pramlintide Pramlintide + Sibutramine

Pramlintide + Phentermine

ITT (n) 63 61 59 61

Nausea 0 30 34 23

Heart rate increased 3 5 14 30

Dry mouth 0 3 14 16

Constipation 2 3 15 3

Insomnia/sleep disorders 2 0 14 18

Blood pressure increased 6 2 14 8

Headache 5 16 9 13

Upper respiratory infection 11 12 12 10

Urinary tract infection 5 5 10 5

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

AmylinLead-in

A, L or A+LTreatment

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

0 1 2 3 4 5 6

-20

-15

-10

-5

0

Week

% c

han

ge

in b

od

y w

eig

ht

(veh

icle

co

rrec

ted

)

26

– Design: Randomized, double-blind, controlled, multicenter– Study population: Overweight or obese subjects (BMI 27-35 kg/m2)– 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 BID36

0 µ

g B

IDP

ram

lin

tid

e

18

0 µ

g B

IDP

ram

lin

tid

e

40% kcal deficit 20% kcal deficit

Lead-in Randomized Treatment

Day 1Screen -4 161 4 8 12 20-2

Data on file, Amylin Pharmaceuticals, Inc.

N=27

N=56

N=56

27

Pramlintide/Metreleptin Reduced Weight More Than Either

Treatment : Evidence that Responsiveness to Leptin is Restored

-4 0 4 8 12 16 20-15

-10

-5

0

PramlintidePretreatment

Monotherapy orCombination Treatment

***

*

**

***

ITT-LOCFEvaluable

**

20

***

Time (wk)

Bo

dy

We

igh

t (

%)

Metreleptin 5 mg BIDPramlintide 360 µg BIDPramlintide 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