Eating Behavior Defect: Consequences and New treatment Modalities

Eating Behavior Defect: Consequences and New treatment Modalities

Charles SAAB MD / CEHP / MAACE Consultant EndocrinologistDir.Clin.Res.Prog. Dept of Endoc&Metab. Diseases SCUH – Beirut –LebanonPresident AACE Lebanon ChapterMGSD Executive Board MemberPast-President Lebanese Society Endoc.Diab&LipidsANNUAL LSEDL MEETING BEIRUT JUNE 30, 2017

1

OUTLINEOBESITY “A CHRONIC DISEASE”: THE EVIDENCE

THE “NORMAL” EATING BEHAVIORDEFECTS LEADING TO OBESITYNEW TREATMENT MODALITIES2

3

40%201533%2008

# 50%

2025

CDC/NCHS

Data No. 219

November 2015

USA

Obesity is recognised as a disease and global health issue

“…obesity is a primary disease, and the full force of our medical knowledge should be brought to bear on the prevention and treatment of obesity as a primary disease entity”1

“Recognizing obesity as a disease will help change the way the medical community tackles this complex issue that affects approximately one in three

Americans”

2

“Obesity

is a

chronic disease

, prevalent in

both

developed and developing countries,

and

affecting children as well as

adults”

3

“FDA

agrees with these comments that

obesity is a

disease.” “Being overweight

,

ie

being more than one's ideal weight but less

than obese

, however, is not a

disease”

3

AACE, American Association of Clinical Endocrinologists; AMA, American Medical Association; FDA, Food and Drug Administration;

WHO, World Health Organization

References: 1

. Mechanick JI et al. Endocr Pract 2012; 18:642–8; 2. AMA. 2013. Available at: www.ama-assn.org/ama/pub/news/news/2013/2013-06-18-new-ama-policies-annual-meeting.page; 3. Allison DB et al. Obesity (Silver Spring) 2008; 16:1161–77.

4

Obesity Is a Major contributor to disease and is Associated With Comorbid Diseases

5aBased on a review of >1000 epidemiologic studies to assess the effects of weight control on cancer risk, performed by a working group of the International Agency for Research on Cancer (IARC).bBased on data from the 2001 Behavioral Risk Factor Surveillance Survey (BRFSS), including US residents aged 18 years and older.cBased on a meta-analysis summarizing available prospective cohort studies (as of March 2008).BMI=body mass index; CHD=coronary heart disease.1. Lauby-Secretan B et al. N Engl J Med. 2016;375:794-798. 2. Mokdad AH et al.

JAMA

. 2003;289:76-79. 3.

Luppino

FS et al.

Arch Gen Psychiatry

. 2010:67:220-229.

4. Mathew B et al.

J Am Board Fam Med

. 2008;21:562-568.

1.1–7.1x

increased risk for certain cancers

1a

including corpus uteri, esophageal, stomach, liver, kidney, pancreatic, meningioma,

multiple myeloma, colorectal, gallbladder, ovarian, breast, and thyroid

3–7x

higher prevalence of diabetes

2b

compared with normal-weight adults

55%

increased risk for depression

3c

among individuals with BMI ≥30 kg/m

2

~2x

increased risk for CHD and stroke4 compared with normal-weight adults

Obesity Is a Chronic Condition With Serious Implications for Life Expectancy1

6aBased on a meta-analysis of 57 international prospective studies predominantly based in Europe, the United States, and Australia, including BMI information for 894,576 adults.BMI=body mass index.1. Whitlock G et al. Lancet. 2009;373:1083-1096. 2. Garvey WT et al. Endocr Pract. 2016;22(Suppl 3):1-203.

BMI

2

:

Healthy weight

Overweight

Obesity

18.5

30+

25

BMI 30–35 kg/m

2

Life expectancy reduced

2–4 years

BMI 40–50 kg/m

2

Life expectancy reduced

8–10 years

Each 5 kg/m

2

higher BMI

~40% higher mortality rate

for ischemic heart disease, stroke, and other vascular

diseases

a

Modest Weight Loss Helps to Confer Health Benefits for Patients With Obesity

Weight loss has been associated with:7HbA1c=hemoglobin A1c; HDL=high-density lipoprotein.1. Wing RR et al. Diabetes Care. 2011;34:1481-1486. 2. Courcoulas AP et al. JAMA. 2013;310:2416-2425. 3. Hassan MK et al. Int J Obes Relat Metab Disord. 2003;27:1227-1232.

4.

Sarwer

DB et al.

Eur

Eat

Disord

Rev

. 2015;23:504-508. 5. Hamman RF et al.

Diabetes Care

. 2006;29:2102-2107. 6. Held M et al.

PLoS

One

. 2014;9:e107480.

Significant improvements in

cardiometabolic

risk factors

1

HbA

1c

,

Fasting glucose,

Blood pressure,

Triglycerides, HDL cholesterol

Improvement or remission in diabetes, dyslipidemia, and hypertension2

Improvements in obesity-associated comorbidities and quality of life domains

3,4Reduced risk of diabetes5

Significant improvements in pulmonary function

6

Disrupture

of Energy-balance equation

Intake

Expenditure

Hunger

Satiety

Nutrient

absorption

Metabolic

rate

Thermogenesis

Exercise

NEAT

NEAT, non-exercise activity thermogenesis

8

WHAT LEADS TO OBESITY?

Normal Eating Behavior & Defects…

Food

Amounts

Time

Hunger(start)

Appetite

Palatability

Appetite

Satiation

Satiation

Alliesthesia

Priv

Coll

CS

2002

Satiety

THIS DEFECTS MAY LEAD

TO

FOOD “ADDICTION”

& OBESITY

9

Hunger

Hedonic

10

GENETICSEPIGENETICS

11

E.Finger : EAS 2011 GOTHENBURG-SWEEDEN

AND… EXERCISE A LOOOOOOOOOT

Complexity of Eating Behavior

14

15

Complex Obesity Causes Require New Approach…

Endocrine Society outlines mechanisms underlying obesity epidemic

June 29, 2017

A growing body of research indicates that obesity is a

disorder of the energy homeostasis system

, according to a new Endocrine Society scientific statement.

The statement appeared online in the Endocrine Society's journal,

Endocrine Reviews 2017

Dysregulation

of Energy homeostasis (balance)

as Major Obesity

mecanism

Multiple (Neuro-Endocrine) signals influence EB

1–3CCK, cholecystokinin; GLP-1, glucagon-like peptide-1; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YYReferences: 1. Berthoud HR, Levin BE. In: Handbook of Obesity. Epidemiology, Etiology and Physiopathology, 2014; 2. Woods SC, Seeley RJ. Int

J Obes Relat

Metab

Disord

2002; 26:S8–10

;

3.

Badman

MK, Flier JS.

Science

2005; 307:1909–14.

16

Adipose tissue

Leptin, adiponectin,

resistin

Gut

GLP-1, ghrelin,

OXM, PYY, CCK, lipids

Pancreas

Amylin, insulin, PP

Circulation

Hypothalamus, brainstem,

c

orticolimbic system

Meal

timing/size

Energy

expenditure

Nodose

ganglion

(

Convay

taste)

Vagus

nerve

Spinal

cord

Dorsal

root

ganglion

(sensations

Chemo

mechanics)

Hedonic inputs

(reward)

Reward-driven (hedonic) feeding has a different basis than physiological hunger1

Reference: 1.

Appelhans

BM.

Obesity (Silver Spring

)

2009; 17:640–7.

Prefrontal cortex,

mesolimbic dopamine system

Delay discounting

Feeding behaviour

Selective attention

17

Social

Food costs

Food availability

Palatable food

( override Satiety

)

Adipose tissue

Pancreas

Gut

Circulation

Leptin, adiponectin,

resistin

GLP-1, ghrelin,

OXM, PYY, CCK, lipids

Amylin, insulin, PP

Neural system

Hedonic inputs

(not

calory

related)

CCK

,

cholecystokinin; GLP-1,

glucagon-like

peptide-1; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide YY

“Evolved to protect

against

starvetion

and

promote fat storage”

Peripheral signals modulate appetite and energy expenditure through hypothalamic neurons

1

Effectors

Hypothalamus

Feeding

Gastric emptying

Metabolic rate

Hindbrain

Non conscious

Function

Vagal afferents

Nucleus tractus solitarius

Hunger

Satiety

Second-order

neurons

MC4R

Y1/Y5R

AgRP

α

-MSH

Arcuate

nucleus

Ghrelin

Hunger signals

NPY/

AgRP

POMC/CART

Leptin Insulin

Adiposity signals

PYY GLP-1

Satiety peptides

Appetite

Appetite

AgRP, agouti-related protein;

α-

MSH,

α-

melanocyte‒stimulating hormone; CART, cocaine and amphetamine regulated transcript;

GLP-1R

, glucagon-like peptide-1 receptor; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; PYY, polypeptide

YY

Reference: 1.

Badman

MK,

Flier JS.

Science

2005; 307:1909‒14.

18

ANY LONG TERM DISRUPTION OF THIS WELL REGULATED CLOCK, WILL LEAD TO AN EATING BEHAVIOR WITH A POSITIVE FEED BACK … LEADING TO O-W & OBESITY

19

References: 1.

Woods SC, Seeley RJ. Int J Obes Relat Metab Disord 2002; 26:S8–10; 2. Ludwig DS, Friedman MI. JAMA 2014; 311:2167–8; 3. Speliotes

EK

et al.

Nat

Genet

2010; 42:937–48;

4

.

Garvey

WT

et al.

Endocr

Pract

2014; 20:977–89;

5

.

Bray

GA, Ryan

DH. Ann NY Acad Sci 2014; 1311:1–13; 6. Guyenet SJ, Schwartz MW. J Clin

Endocrinol Metab 2012; 97:745–55.

Obesity is a complex and multifactorial disease

1–6

Adipose tissue

Gut

Pancreas

Genetics

Medications

Experienced palatability or pleasure

Hedonic input

20

Energy expenditure

Energy intake

Socioeconomic

Environment

High obesity

rates NOT explained by genes only 21References: 1. Davidson TL et al. J Exp Psychol Anim Learn Cogn 2014; 40:261–79; 2. Making Health Easier. Available at:

http://makinghealtheasier.org/newabnormal

;

3.

Egger G, Dixon J.

Biomed Res Int

2014

; 2014:731685

;

4

.

Milagro

FI

et al.

Mol

Aspects

Med

2013

; 34:782–812.

Dramatic changes in the

“food environment”1We are eating larger portions and thus greater meal sizes2

Other contributing factors

3

DNA

methylation

// Epigenetic modifications?

4

QUICK LSM

1950(RURAL) 2012(URBAN)68% OW/OBESE

KUWAIT 1955

KUWAIT 2010 > 75% OW

1955

201525-30% OBESE

Adding to Complexity of the Disease: Hormonal status after weight loss

25From Sumithran P, et al,1 ©2011 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.CCK=cholecystokinin; ITT=intent to treat; YY=tyrosine tyrosine.1. Sumithran P et al. N Engl J Med. 2011;365:1597-1604.Amylin, pg/mL

Postprandial Time, min

0

180

240

30

60

120

200

100

0

Week 62

Baseline

Appetite Suppressing Hormone Was Lower

Appetite Stimulating Hormone Was Higher

Ghrelin, pg/mL

0

180

240

30

60

120

200

100

0

Postprandial Time, min

Week 62

Baseline

Appetite Suppressing Hormone Was Lower

CCK, fmol/mL

Postprandial Time, min

0

180

240

30

60

120

4

2

0

1

3

Week 62

Baseline

Appetite Suppressing Hormone Was Lower

Peptide YY, pg/mL

60

20

0

0

180

240

30

60

120

Postprandial Time, min

Week 62

Baseline

Compensatory mechanisms encourage weight regain after weight

loss

1

Prevention of obesity is the key,

But in Overt obesity could we intervene??? 26Effective Treatment Options

AHA/ACC/TOS Guideline-Recommended Obesity Management Options1,a

27Patients with BMI ≥40 kg/m2Patients with BMI ≥35 kg/m2 and obesity-related comorbiditiesMotivated to lose weight

Have not responded to previous behavioral treatment (with or without pharmacotherapy)

Pharmacotherapy

Surgery

Patients with BMI ≥30 kg/m

2

Patients with BMI ≥27 kg/m

2

and

≥1 obesity-related comorbidity

(

eg

, hyperlipidemia, hypertension, T2DM)

Motivated to lose weight

Lifestyle modifications, the backbone of treatment,

include dietary modifications, exercise, and behavioral changes

Recommended as adjunct to lifestyle modifications:

a

According

to recommendations from the AHA/ACC/TOS 2013 obesity treatment guidelines, created in collaboration with the NIH-NHLBI.

ACC=American College of Cardiology; AHA=American Heart Association; BMI=body mass index; NHLBI=National Heart, Lung, and Blood Institute; NIH=National Institutes of Health;

T2DM=type 2 diabetes mellitus; TOS=The Obesity Society.

1. Jensen MD et al.

Circulation

. 2014;63:2985-3023.

MARKETED DRUGS IN 2017(ONE DRUG & COMBI)

AMPHETAMIN DERIVED/SHORT TERMUSA

Drugs for short-term treatment (8-12 weeks) Diethylpropion, (TENUATE®)Phendimetrazine, (OBEZINE®,ADIPOST®…)Benzphetamine, (DIDREX®) Phentermine, (ADIPEX®…)29

Orlistat

-induced Weight Loss*

Change in

body weight

(%)

0

–2

–4

–6

–8

–10

–12

–4

0

10

20

30

40

52

Week

Placebo (n=340)

Xenical

®

120 mg (n=343)

*

p<0.001

–6.1%

–10.2%

ITT population: BM14119C

(Sjöström L, et al. Lancet 1998, 352; 167



172)

30

LORCASERIN Lorcaserin

Selectively activate 5-HT 2C receptors on anorexigenic pro-opiomelanocortin neurons in the hypothalamus. Approved by the FDA in June 2012 as an adjunct to a reduced-calorie diet and exercise for long-term weight management in individuals with an initial BMI of> 30 kg/m2 31

32

LIRAGLUTIDE 3 MG

33LIRAGLUTIDE

COMBINATION DRUG APPROACH

34

Phentermine / Topiramate XR

Phentermine and topiramate XR Approved by the FDA in July 2012 as an adjunct to a reduced-calorie diet and exercise for long-term weight management in individuals with an initial BMI of 30 kg/m2.CNS adverse effects such as drowsiness, paresthesias, memory loss, and confusion are causes of concern. 35

PT PROFILE

Jennifer Morrow (MEDSCAPE SEPT 2012) 36

Naltrexone/Bupropion (NB) Overview & MOA

37

NB Is a Combination of Two Compounds:Naltrexone and Bupropion1

38Naltrexone HCl1,2An opioid receptor antagonistIndications: treatment of alcohol dependence and prevention of relapse to

opioid dependence

FDA approved since

1984

Bupropion HCl

1,3,4

A dopamine and norepinephrine reuptake inhibitor

Indications:

major depressive disorder

and

as an aid to

smoking cessation

FDA approved since

1985

FDA=Food and Drug Administration.

1.

Contrave

[prescribing information]. La Jolla, CA:

Orexigen

Therapeutics, Inc.; 2016. 2.

Vivitrol® [package insert]. Waltham, MA: Alkermes; 2015. 3. Wellbutrin SR [package insert].

Research Triangle Park, NC: GlaxoSmithKline; 2014. 4. Zyban [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

NB

is available in a unique formulation of extended-release tablets that contain

8 mg naltrexone

HCl

and 90 mg bupropion HCl1:

Naltrexone and Bupropion Act Synergistically to Activate the POMC Neurons in the Hypothalamic Hunger System, Resulting in Appetite Suppression1

39Figure adapted from Billes et al,1 © 2014, with permission from Elsevier.MSH=melanocyte-stimulating hormone; POMC=pro-opiomelanocortin. 1. Billes SK et al. Pharmacol Res. 2014;84:1-11.

Increased POMC activity

Reduced Hunger

Reduced Weight

Hypothalamus

Bupropion

Directly increases POMC activity

POMC

neuron

Naltrexone

Indirectly increases POMC activity by blocking

the

negative feedback loop

β-endorphin

α

-

MSH

↓ Appetite↑ Energy Expenditure

Naltrexone/Bupropion: Influence on Energy Balance and Reward140Figure adapted from Billes et al,1 © 2014, with permission from Elsevier.MC4-R=melanocortin-4 receptor; MSH=melanocyte-stimulating hormone; POMC=pro-opiomelanocortin. 1. Billes SK et al. Pharmacol Res. 2014;84:1-11.

Hypothalamus

MC4-R

α

-

MSH

Bupropion

POMC stimulus

POMC

neuron

Naltrexone

µ-opioid receptor

POMC negative feedback loop

(

β-

endorphin

)

Weight loss

MC4-R gene mutations associated with

INHERITED HUMAN OBESITY/ FEEDING/ED/

SEXUAL BEHAVIOR

Mesolimbic

Reward System

NB Phase 3 Clinical Development Program41

Efficacy and Safety of NB Was Assessed in a Comprehensive Phase 3 Clinical Development Program1

42aBMOD consisted of group sessions led by dietitians, psychologists, or exercise specialists to educate subjects on weight control techniques. Subjects were also asked to follow individualized hypocaloric diets and were encouraged to increase moderately vigorous physical activity from 180 min/week to 360 min/week.BMI=body mass index; BMOD=behavior modification; NB16=naltrexone 16 mg SR/bupropion 360 mg SR; NB32=naltrexone 32 mg SR/bupropion 360 mg SR; T2DM=type 2 diabetes mellitus.1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016. 2. Greenway FL et al. Lancet. 2010;376:595-605. 3. Apovian CM et al. Obesity. 2013;21:935-943. 4. Wadden TA et al.

Obesity

. 2011;19:110-120. 5. Hollander P et al.

Diabetes Care

. 2013;36:4022-4029.

COR-BMOD

4

N=793

COR-I

2

N=1742

COR-DM

5

N=505

COR-II

3

N=1496

Behavioral modification

Type 2 diabetes

The clinical development program consisted of four 56-week, placebo-controlled studies

(N=4536 subjects)

Study Design

56 weeks, placebo-controlled, including 3-week dose escalation

(COR-II: primary endpoint 28 weeks)

Population

BMI 30



45 kg/m

2

BMI 27



45 kg/m

2

(with comorbidities)

T2DM, BMI 27



45 kg/m

2

Diet and

Exercise

Diet and exercise counseling

Intensive

BMOD

a

Diet and exercise counseling

Dose and Randomization

NB16 and NB32

1:1:1

NB32

2:1

NB32

3:1

NB32

2:1

Phase 3 Clinical Development Program: Baseline Characteristics1

43

Mean=

46 years

Age

Men:

17%

Women:

83%

Sex

Mean=

36 kg/m

2

BMI

Mean=

110 cm

Waist Circumference

White:

77%

Black:

18%

Other:

5%

Race

Hypertension:

24%

Dyslipidemia:

54%

Type 2 diabetes:

10%

Comorbidities

BMI=body mass index.

1.

Contrave

[prescribing information]. La Jolla, CA:

Orexigen

Therapeutics, Inc.; 2016.

Subject Characteristics Across All 4 Phase 3 Trials (N=4536)

NB Was Significantly More Efficacious Than Placebo in Phase 3 Trials

1-444 NB

Placebo

LS Mean % Change in

Body Weight From Baseline

*

*

*

*

*

*

COR-BMOD

1,3

COR-I

1,2

COR-DM

1,4

Average weight loss of 25 pounds in patients completing 56 weeks

of therapy with NB

(COR-BMOD)

1,3

n=536

n=538

n=196

n=565

n=166

n=321

n=290

n=296

n=106

n=301

n=100

n=175

*

P

<0.001 vs placebo.

BMOD=behavior modification; DM=diabetes mellitus; ITT=intent-to-treat; LS=least squares; T2DM=type 2 diabetes mellitus.

1.

Contrave

[prescribing information]. La Jolla, CA:

Orexigen

Therapeutics, Inc.; 2016. 2. Greenway FL et al.

Lancet

. 2010;376:595-605. 3.

Wadden

TA et al.

Obesity

. 2011;19:110-120.

4. Hollander P et al.

Diabetes Care

. 2013;36:4022-4029.

Treatment with NB resulted in significant weight loss at 56 weeks

The Percentage of Subjects With ≥5% or ≥10% Body Weight Loss

Was Greater With NB Compared With Placebo in Phase 3 Trials

1-3

45

% of Patients

(Co-Primary Endpoint)

NB

Placebo

≥

5% Weight Loss

≥

10% Weight Loss

62

23

24

53

11

34

30

55

8

26

a

Completer

population at 56-week endpoint.

BMOD=behavior modification; DM=diabetes mellitus.

1. Greenway FL et al.

Lancet

. 2010;376:595-605. 2.

Wadden

TA et al.

Obesity

. 2011;19:110-120. 3. Hollander P et al.

Diabetes Care

. 2013;36:4022-4029.

More patients taking NB achieved ≥5% or ≥10% weight loss from baseline at 56 weeks than placebo (completer analysis)

a

Mean Percent Change in Total Body Fat Mass With NB Plus Diet and Exercise at 52 Weeks1

46A subset of COR-I patients (n=124; LOCF) were assessed for body composition using DEXA

COR-I

sub-study

Mean Change From Baseline (%)

Placebo

+ diet and exercise

(n=45)

NB

+ diet and exercise

(n=79)

*LOCF; Treatment Difference, -7.4% (-7.3

lb

),

P

<0.01.

DEXA=dual energy X-ray absorptiometry; LOCF=last observation carried forward.

1.

Contrave

[prescribing information]. La Jolla, CA:

Orexigen

Therapeutics, Inc.; 2016.

Weight loss with NB plus diet and exercise was associated with a significant decrease in mean total body fat mass

NB Treatment Resulted in Greater Reductions in Waist Circumference Compared With Placebo1

47

LS Mean Change from Baseline (inches)

*

*

*

P

<0.001 vs placebo.

a

Full

analysis set, LOCF: based on 56-week endpoint.

BMOD=behavior modification; DM=diabetes mellitus; LOCF=last observation carried forward; LS=least squares.

1.

Contrave

[prescribing information]. La Jolla, CA:

Orexigen

Therapeutics, Inc.; 2016.

Reductions in waist circumference from baseline at 56 weeks was greater in patients taking NB compared with placebo

a

Inche

=2.5 cm

NB Has Demonstrated Improvements in Glycemic Control1,2

48-0.1%

-0.6%

*

*

*

*

44.1%

of patients

achieved

HbA1c

<7

%

(44.1

vs.

placebo 26.3

%;

P<0.001)

Baseline HbA

1c

=8.0%

Republished with permission of the American Diabetes Association, from Hollander P et al,

2

© 2013; permission conveyed through Copyright Clearance Center, Inc.

*

P

<0.001 vs placebo.

a

mITT-LOCF.DM=diabetes mellitus; HbA1c=hemoglobin A1c; LS=least squares; mITT-LOCF=modified intent-to-treat/last observation carried forward; T2DM=type 2 diabetes mellitus.

1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016. 2. Hollander P et al. Diabetes Care. 2013;36:4022-4029.

Patients with T2DM had significantly improved mean HbA1c levels with NB treatment compared with placebo over 56 weeks

a

COR

-DM

Mean Changes in Several Cardiometabolic Risk Factors With NB Plus Diet and Exercise

1-349aBased on LOCF (last observation carried forward) while on study drug.bChanges in triglycerides and HDL achieved statistical significance as reported in the primary manuscripts.2,3BMOD=behavioral modification; HDL=high-density lipoprotein; LDL=low-density lipoprotein; LS=least squares.1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016. 2. Greenway FL et al. Lancet. 2010;376:595-605. 3. Wadden TA et al. Obesity. 2011;19:110-120.

No significant differences were observed between groups in LDL cholesterol

2,3

COR-BMOD

COR

-I

COR-BMOD

COR-I

HDL Cholesterol

Triglycerides

Median Change

From Baseline (%)

LS Mean Change

From Baseline (%)

NB treatment resulted in greater improvements in triglycerides and HDL cholesterol compared with placebo

a,b

NB

Placebo

COR-BMOD

COR

-I

RESULTS ON FOOD CRAVING

50

Safety Evaluated in 5 Double-Blind Placebo-Controlled Trials in 4754 Patients Up to 56 Weeks1,a

51Adverse Reaction

NB

32 mg/360 mg

n=2545

Placebo

n=1515

Nausea

32.5%

6.7%

Constipation

19.2%

7.2%

Headache

17.6%

10.4%

Vomiting

10.7%

2.9%

Dizziness

9.9%

3.4%

Insomnia

9.2%

5.9%

Dry mouth

8.1%

2.3%

Diarrhea

7.1%

5.2%

a

2545 patients received naltrexone

HCl

/bupropion

HCl

32 mg/360 mg total daily dose; some patients were treated with other combination daily doses. 1515 patients were treated with placebo.

1.

Contrave

[prescribing information]. La Jolla, CA:

Orexigen

Therapeutics, Inc.; 2016.

Adverse reactions reported with ≥5% incidence with NB and more commonly than placebo:

LIGHT STUDY / (NB)CVOT 52

PRIMARY ENDPOINT: TIME TO FIRST MACE

Nalterxone/ Bupropion Precautions1

No suicide or suicide attempts were reported in studies up to 56 weeks duration with naltrexone/ bupropion and suicidal ideation was not more commonly reported in subjects treated with naltrexone/ bupropion compared to placeboHepatotoxicity: Cases of hepatitis and clinically significant liver dysfunction observed with naltrexone exposureAngle-closure glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with

antidepressants

Use of Antidiabetic Medications:

Weight loss may cause hypoglycemia. Monitor blood glucose

1.

Contrave

[prescribing information]. La Jolla, CA:

Orexigen

Therapeutics, Inc.; 2016.

53

SUMMARY/CONCLUSIONObesity is a chronic, relapsing disease that requires long-term treatment

There are hormonal, physiologic, genetic and epigenetic adaptations our body exhibits to MAINTAIN adiposity by hindering weight loss and promoting weight gainRealistic expectations of 5-10% weight loss is achievable and has shown to produce significant improvement of multiple co-morbid medical problems.Behavior modification remains the cornerstone of treatment , helped with safe and efficient pharmacotherapies acting on both mesolimbic reward and Hypothalamic hunger systems54

THANK YOU 55

Some Pathways through Which Excess Adiposity Leads to Common Chronic Diseases.

Heymsfield SB, Wadden TA. N

Engl

J Med 2017;376:254-266

METFORMIN IN IGT?

Meta-analysis1: metformin treatment in obese persons at risk for diabetes mellitus. 31 Trials RCT n= 4500Decrease weight, (-3Kg/Y)Improve lipid profilesImproves insulin sensitivity,and reduces new-onset diabetes by 40%.1.Salpeter SR,Am J Med Feb 2008; 121(2)

57

Components of NB Individually Interact With the

Mesolimbic

Reward System Resulting in Long-term Behavior Change

1

58

Nucleus

Accumbens

Ventral

Tegmental Area

Naltrexone HCl

1,4

Bupropion HCl

1,2,3

Indicated for the treatment of

major depressive disorder

and

as an aid to

smoking cessation

Indicated for the treatment of

alcohol dependence

and for prevention of relapse to

opioid dependence

Mesolimbic Reward System

Figure adapted from

Billes

et al,

1

© 2014, with permission from Elsevier.

1.

Billes

SK et al.

Pharmacol

Res

. 2014;84:1-11. 2. Wellbutrin SR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014.

3.

Zyban

[package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2014. 4.

Vivitrol

®

[package insert]. Waltham, MA:

Alkermes

; 2015.

Components of NB Also Individually Interact With the Hypothalamic Hunger System to Affect Appetite1

59Figure adapted from Billes et al,1 © 2014, with permission from Elsevier.POMC=pro-opiomelanocortin. 1. Billes SK, et al. Pharmacol Res. 2014;84:1-11.

Hypothalamus

Naltrexone

HCl

Bupropion

HCl

Indicated for the treatment of

major depressive disorder

and

as an aid to

smoking cessation

Indicated for the treatment of

alcohol dependence

and for prevention of relapse to

opioid dependence

Mesolimbic Reward System

Stimulates

POMC cells

, which suppresses appetite

Blocks

β-endorphin negative feedback loop

on POMC neurons, which further contributes to appetite suppression

Hypothalamic Hunger System

Combination Naltrexone + Bupropion Resulted in Greater Weight Loss vs the Individual Components1

60*Data are for Completer Population.IR=immediate release; SR=sustained release.1. Greenway FL et al. J Clin Endocrin Metab. 2009;94:4898-4906.

Naltrexone 32 mg IR + Bupropion 400 mg SR (n=45)

Bupropion 400 mg SR (n=44)

Naltrexone 48 mg IR (n=33)

Placebo (n=60)

Naltrexone + Bupropion

Bupropion

Naltrexone

Placebo

-4.8%

Change in body weight

Potential Synergistic Effect

Phase 2 Study Completers at 24 Weeks*

NB Dosing and Administration1

61NB dosing should be escalated over a 4-week period

Morning

Evening

Week 1

Week 2

Week 3

Week 4 and onwards

Administration

Tablets should be taken by mouth in the morning and evening and

should not be cut, chewed or crushed

In clinical trials, NB was administered with meals. However, NB

should not be taken with a high-fat meal

because of a resulting significant increase in bupropion and naltrexone systemic exposure

The need for treatment should be evaluated after 16 weeks and reevaluated annually.

1.

Contrave

[prescribing information]. La Jolla, CA:

Orexigen

Therapeutics, Inc.; 2016.

The maximum recommended daily dose of NB is 2 tablets twice daily for a total dose of

32 mg naltrexone

HCl

and 360 mg bupropion HCl

1

Studies in twins estimate the heritability of BMI as 40–80% in children and adults1,2Genome-wide association studies have identified a large number of genetic loci associated with obesity risk3

In one meta-analysis, the most common 97 loci only accounted for 2.7% of BMI variance, while genome-wide estimates accounted for ~20%4Therefore, a large proportion of heritability remains unexplained3It has been proposed that epigenetic modifications could account for some of this ‘missing’ heritability3Epigenetics may help to explain the heritability of obesity62

BMI, Body Mass Index

References

: 1.

Stunkard

AJ

et al.

N Engl J

Med

1990; 322:1483–7;

2.

Wardle J et al.

Am

J Clin

Nutr 2008; 87:398–404;

3

.

van Dijk

SJ et

al.

Clin

Epigenetics 2015; 7:66; 4. Locke AE et al. Nature 2015; 518:197–206.

Obesity Remains Undertreated Compared With Type 2 Diabetes1

Almost half of the adults in the United States meet recommendations for anti-obesity pharmacotherapy; however, only 2% of those adults receive proper pharmacotherapy treatment a63Figure adapted from Thomas et al,1 © 2016 The Obesity Society, with permission from John Wiley and Sons.aAnti-obesity pharmacotherapy is indicated as an adjunct to diet and physical activity in adults with a BMI ≥30 kg/m2 or ≥27 kg/m

2

with hypertension, type 2 diabetes, or dyslipidemia.

1. Thomas CE et al.

Obesity

. 2016;24:1955-1961.

US Adult Population (%)

2%

of adults with

obesity

received pharmacotherapy

86%

of adults with

T2DM

received pharmacotherapy

Nonclinical Studies Suggest NB Affects Both the Hypothalamic Hunger and Mesolimbic Reward Systems1

64POMC=pro-opiomelanocortin; VTA=ventral tegmental area.1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016.

The exact neurochemical effects of combined NB leading to weight loss are not fully understood

Combined, naltrexone and bupropion reduced food intake when injected directly into the

VTA

of the mesolimbic circuit in mice, an area associated with regulation of reward pathways

1

Mesolimbic Reward System

1

Combined, naltrexone and bupropion increased the firing rate of

POMC

neurons

in vitro

, which are associated with the regulation of appetite

1

Hypothalamic Hunger System

1

PRAMLINTIDEPramlintide (Symlin

):synthetic analogue of the pancreatic hormone amylin, used T1D/T2D does not have an FDA indication for obesity managementClearly associated with variable weight loss in people with type 1 or 2 diabetes.65

Weight Loss at 1 Year with High-Intensity Lifestyle Interventions or Pharmacotherapy

Combined with Low-to-Moderate-Intensity Lifestyle Counseling.

Heymsfield

SB,

Wadden

TA. N

Engl

J Med 2017;376:254-266

>15% W # 16%Pts

The Percentage of Subjects With ≥5% or ≥10% Body Weight Loss Was Greater With NB Compared With Placebo in Phase 3 Trials1

67*P<0.01 vs placebo; **P<0.001 vs placebo.BMOD=behavior modification; DM=diabetes mellitus; ITT=intent-to-treat; LOCF=last observation carried forward; LS=least squares.1. Contrave [prescribing information]. La Jolla, CA: Orexigen Therapeutics, Inc.; 2016.

More patients taking NB achieved ≥5% or ≥10% weight loss from baseline at 56 weeks than placebo (ITT-LOCF analysis)

% of Patients

(Co-Primary Endpoint)

≥

5% Weight Loss

≥

10% Weight Loss

**

42

17

18

**

36

7

**

21

21

**

35

5

*

15

43

**

57

NB

Placebo

68