kpha’s 134th annual meeting - wild apricot · hypothyoidism, metabolic syndrome (insulin...

KPhA’s 134th Annual Meeting

and Trade Show

The Future of the Medical Management of Obesity

September 4, 2014

Shadrach Smith, MD Director of Weight, Health and Wellness

Kansas City Internal Medicine

KPhA’s 134th Annual Meeting and

Trade Show “The Future is Now: Envision, Educate, Empower”

KU Memorial Union

Lawrence, Kansas

Disclosures

• Speaker’s Bureau Eli Lilly-Boehringer Ingelham Vivus inc

• No financial interest in KPhA

• No honoraria from KPhA for this presentation

3

Learning Objectives

4

• Review the health risks associated with obesity • Discuss the biological factors that result in food

seeking behavior and energy deposition • Define goals for “successful” pharmacotherapy in

treatment • Review currently approved anti-obesity meds. • Identify weight “friendly” and “unfriendly”

medications used to treat co-morbid conditions • Discuss the results of studies of two new anti-obesity

medications which may be approved soon.

5

Pre-Test

A. 5% or greater weight loss B. Decrease in BMI to less than 30 kg/m2

C. 10% or greater weight loss D. Decrease in BMI to less than 25 kg/m2.

1. What is considered a successful response to pharmacotherapoy for obesity?

6

Pre-Test

A. Orlistat 120 mg TID B. Qsymia 15-92 QD C. Phentermine 37.5 mg QD D. Locasarin 10 mg BID

2. Based on double blind, placebo controlled studies, which of the following medications is likely to produce the greatest weight loss at the end of a year?

7

Pre-Test

3. Which medication is most associated with an increased risk for the serotonin syndrome?


8

Pre-Test

4. Which medication has been associated with cleft palate birth defects?


Two Sides of the Modern Civilization: The Good

We live the comfortable life

– We have 24-7 access to great tasting food

– We get where we want to go very quickly

– We have 24-7 access to entertainment

– Modern medicine has us living longer than ever

But…

Two Sides of the Modern Civilization: The Bad

… Too much food, too little physical activity, and too little sleep makes us unhealthy

Health problems more common in Civilized societies – Cardiovascular Heart disease

– High blood pressure

– Obesity

– Type 2 diabetes

– Arthritis

– Cancer (e.g., breast, uterine, cervical, colon)

70% of health problems are from an unhealthy lifestyle

Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome

Nonalcoholic fatty liver

disease cirrhosis

Coronary heart disease

Diabetes

Dyslipidemia

Hypertension

Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome

Osteoarthritis

Skin

Gall bladder disease

Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate

Phlebitis venous stasis

Gout

Medical Complications of Obesity Idiopathic intracranial hypertension

Stroke

Cataracts

Severe pancreatitis

BMI-Associated Disease Risk Classification BMI (kg/m2) Risk

Underweight <18.5 Increased

Normal 18.5-24.9 Normal

Overweight 25.0-29.9 Increased

Obese I 30.0-34.9 High

II 35.0-39.9 Very High

III >40 Extremely high

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults—The Evidence Report. Obes Res 1998;6(suppl 2).

Additional risks: • Large waist circumference (men>40 in; women >35 in) • 5 kg or more weight gain since age 18-20 y • Poor aerobic fitness • Specific races and ethnic groups

Apples, Pears, and Carrots

• Large waist circumference: Men>40 in (102 cm) Women >35 in (88 cm)

Learning Objectives

14

• Review the health risks associated with obesity

• Discuss the biological factors that result in food seeking behavior and energy deposition

• Define goals for “successful” pharmacotherapy in treatment

• Review currently approved anti-obesity meds. • Identify weight “friendly” and “unfriendly”



Causes of Obesity

Genetics/

Biology

Behavior/

Motivation

Environment/

Culture

Regulation of Food Intake Brain

NPY

AGRP

galanin

Orexin-A

dynorphin

Stimulate α-MSH

CRH/UCN

GLP-I

CART

NE

5-HT

Inhibit

Central Signals

Glucose

CCK, GLP-1, Amylin Vagal afferents

Insulin

Ghrelin Leptin Cortisol

Peripheral signals Peripheral organs

+

+

Gastrointestinal tract

Adipose tissue

Food Intake

Adrenal glands

External factors Emotions

Food characteristics

Lifestyle behaviors

Environmental cues

How to become Obese? More calories in than calories burned

Metabolic abnormalities Hypothyoidism, Metabolic Syndrome (insulin resistance), PCOS, Medications (insulin, anti-depessants, etc), Cushing Disease

Sedentary Lifestyle

Emotional Overeating, Binge Eating Disorder

Sleep deprivation

Neurological: Pseudotumor Cerebri Genetic Disorders: MCR-4 def , Prader-Willi

Leptin- Newer Piece of the Puzzle

• 1950- Discovery of genetically obese mice with very high insulin levels, but were not diabetic.

• Surgical obesity- Caused by removing portions of the lower brain that controls metabolism and connects to the emotional brain.

• Obese mice had very slow metabolic rates

• Dec 1994- Leptin discovered

• Leptin may be responsible for the long term control of weight

Leptin Deficiency

Clinical Effects of Leptin

Before After

Ghrelin

• Ghrelin is a gastric peptide that functions as short term satiety signal

• Therefore it is an appetite-stimulating hormone

• Levels of Ghrelin rise when the stomach is empty inducing hunger and then fall quickly when the stomach is full

• So ghrelin participates in “meal-to-meal” control of food intake.

• Elevated in Prader-Willi Syndrome

Learning Objectives

23


seeking behavior and energy deposition

• Define goals for “successful” pharmacotherapy in treatment

• Review currently approved anti-obesity meds. • Identify weight “friendly” and “unfriendly”



0

10

20

30

40

Modest Weight Loss Prevents Diabetes in Overweight and Obese Persons with Impaired Glucose Tolerance

Diabetes Prevention Program Research Group. N Eng J Med 2002;346:393. Copyright © 2002. Massachusetts Medical Society. All rights reserved.

Cu

mu

lati

ve In

cid

ence

of

Dia

bet

es (

%)

0

Year

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Placebo

Lifestyle

58% (48-66%)

Obesity Treatment Pyramid

Surgery

Pharmacotherapy

Lifestyle Modification

Diet Physical Activity

BMI

Currently Available Options

• Accept weight where it is

• Diet/Exercise: 3-10% weight loss

• Drugs: 5-12% weight loss

• Medically Supervised/Combination

of Diet + Drug: 10-15% weight loss

• Surgery: 15-30% weight loss

Low

High

Effectiveness

Currently Available Options

• Accept weight where it is

• Diet/Exercise: 3-10% weight loss

• Drugs: 5-12% weight loss

• Medically Supervised/Combination

of Diet + Drug: 10-15% weight loss

• Surgery: 15-30% weight loss

Low

High

Risks/Time/Money

Guide for Selecting Obesity Treatment

The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084

Treatment 25-26.9 27-29.9 30-34.9 35-39.9 >40

Diet,

Exercise,

Behavior Tx + + + + +

Pharmaco-

therapy

With co-

morbidities + + +

Surgery With co-

morbidities +

BMI Category (kg/m2)

Chronic Disease Treatment

• Long-term therapy is required for successful treatment and management.

• Drugs do not cure chronic diseases • Drugs do not work when they are not taken • Type 2 diabetes and hypertension respond well to

diet and exercise - but the primary treatments are drugs “due” to poor adherence

• Obesity responds well to diet and exercise- but primary treatment is diet and exercise “despite” poor adherence.

Learning Objectives

30



treatment

• Review current anti-obesity medications. • Identify weight “friendly” and “unfriendly”



History

• Many anti-obesity drugs in the past proved to have significant toxicity

Amphetamines Digitalis

“Rainbow pills”

Weintraub Fhen-phen

1940-60

1992

Dexfenfluramine

Withdrawal 14 million

1997

30% BMI<30 14% BMI <27 BRFSS

Dinitrophenol Thyroxine

1933

Rimonabant approval in

Europe

2006-08

Orlistat

1998

Sibutramine 1997-2010

Qnexa Locaserin

Not approved

Contrave Dec 2010 approval Feb 2011 rejected

2010

Alli

History of Obesity Medication Problems

Phases of Obesity Treatment

Phase I (Weight Loss)

3-6 months

Phase II (Weight-Loss Maintenance)

Indefinitely

Wei

ght

www.drsharma.ca

Obesity: Unmet Medical Need in Metabolic Disease Space

Weight loss (%)

10 15

50-

100-

0-

Pills

80-

5

Current goal

25 20 0 30

Surgery Future Pharmacotherapy

FDA 2007 draft guidance

Primary efficacy criteria (one of the following)

• 5% greater (statistically significant) weight loss than placebo at 1 year.

• At least 35% patients achieving 5% weight loss on drug and approximately double the proportion in the placebo-treated group.

Sample size

• 3000 randomized to active dose of drug and no fewer than 1500 on placebo for 1 year.

FDA Guidance for industry developing products for weight management, draft guidance, revision 1, Feb 2007

Drugs Approved by FDA for Treating Obesity- Aug 2014

Generic Name

Trade

Names

DEA

Schedule

Approved

Use

Year

Approved

Locasarin Belviq® IV Long-term 2012

Phentermine/

Topiramate XR Qsymia® IV Long-term 2012

Orlistat Xenical® None Long-term 1999

Diethylpropion Tenuate® IV Short-term 1973

Phentermine Adipex, ®

lonamin® IV Short-term 1973

Phendimetrazine Bontril®,

Prelu-2® III Short-term 1961

-32

-28

-24

-20

-16

-12

-8

-4

0

Effect of Continuous and Intermittent Phentermine Therapy on Body Weight

0

Time (weeks)

8 24 28

Munro JF et al. Brit Med J 1:352, 1968

Wei

ght

Loss

(lb

s)

36 4 12 16 20 32

Alternate Phentermine and Dummy QOM

Continuous Phentermine

Continuous Dummy

Orlistat

• Causes roughly 30% of dietary fat to not be absorbed via inhibition of GI lipases in gut lumen

• 120mg tid + a daily multivitamin

• Weight loss of up to 9% in one year

• Difficult to counsel patients regarding potential side effects of: • Flatulence with discharge

• Fecal incontinence

• Steatorrhea

• Oily spotting

• Increased frequency of defecation

-12

-9

-6

-3

0

Effect of Long-term Orlistat Therapy on Body Weight

0

Weeks

52

Torgenson et al. Diabetes Care 2004;27:155

Ch

ange

in W

eigh

t (k

g)

104 156 208

P<0.001 vs placebo

-4.1 kg

-6.9 kg

Placebo

Orlistat

Categorical Weight Loss With Orlistat

Weight loss during the 4-week lead-in was 5.58 lbs for the 5%–<10% group, 7.08 lbs for the 10%–<15% group, and 9.46 lbs for the 15% group. Completers population. Pooled Data (Ref. 038-024). Please see complete Product Information.

Weight Loss Category 5%–<10%

27%

10%–<15%

23%

15%

19%

-50

-45

-40

-35

-30

-25

-20

-15

-10

-5

0

-16

- 45

-26

Percent of Patients (N = 1071)

Newer Weight loss Medications (approved 2012)

• Phentermine-topiramate XR combination (Qsymia®) – Approved for long term weight maintenance

– 10 % or more weight loss in most patients

– Significant side effects

– Has REMs program • Can potentially harm the fetus in a pregnant woman

• Lorcaserin (Belviq®) – Approved for long term weight maintenance

– Serotonin receptor agonist

– Low number of side effects

Lorcaserin (Belviq)

Lorcaserin: selective 5-HT2C receptor agonist designed to promote weight loss

5-HT2C receptor activation of proopiomelanocortin (POMC) neurons results in α-MSH activation of melanocortin-4 receptors

Serotonin receptor as a pharmacologic target for weight loss was validated by fenfluramine

Fenfluramine in combination with phentermine (Fen-Phen) was highly efficacious for weight loss

Safety concerns led to withdrawal: Fenfluramine activation of 5-HT2B receptor was linked to cardiac valvular disease

Heisler LK, et al. Science. 2002;297:609-611.

Behavioral Modification and Lorcaserin for Obesity and Overweight Management (BLOOM)

Lorcaserin (Lorc) vs placebo (PBO): P < .0001 at all timepoints Lorc/Lorc vs Lorc/PBO: P < .0001 at all year 2 timepoints

8 16 24 32 40 48

-10

-8

-6

-4

-2

064 72 80 88 96 104

Lorc/LorcPBO/PBO Lorc/PBO

ITT/LOCF

ITT/LOCF

Per

Protocol

Study WeekW

eig

ht

ch

an

ge (

kg

)

N = 344 N = 140 N = 308

Smith SR, et al. ADA 2009. Late-Breaking Abstract 96.

Lorcaserin – main results

• Two phase III trials – BLOOM (2 yrs) and BLOSSOM (1yr)

• Weight change at 1 yr

• -5.8% (lorcaserin 10 mg bid) vs -2.5% (placebo)

• 5% weight loss – 47%

• FDA defined valvulopathy

• RR 1.07 (0.74, 1.55)

FDA briefing document, Advisory committee meeting for lorcaserin, 16 Sep 2010

Lorcaserin Did Not Increase the Rate of FDA Valvulopathy

N = number of evaluable echo pairs; n = number (%) with FDA valvulopathy

Treatment N n (%) P

Week 52

Lorcaserin 10 mg BID 1278 34 (2.66%) .70a

Placebo 1194 28 (2.35%)

Week 104

Lorcaserin/lorcaserin 500 13 (2.6%) .99a

Lorcaserin/placebo 258 5 (1.9%)

Placebo/placebo 627 17 (2.7%)

aVs placebo with Fisher’s exact test


Lorcaserin: Adverse Events Reported by 5% or More in Any Group in Year 1

46

N (%) Lorcaserin

(N = 1593)

Placebo

(N = 1584)

Headache 287 (18.0) 175 (11.0)

Dizziness 130 (8.2) 60 (3.8)

Nausea 119 (7.5) 85 (5.4)

Constipation 106 (6.7) 64 (4.0)

Fatigue 95 (6.0) 48 (3.0)

Dry mouth 83 (5.2) 37 (2.3)


Lorcasarin (Belviq®)

• Weight loss: 5-10%

• Side effects: headache, dizziness and nausea

• Cost: $150 to 220/month

• Unclear if physicians will prescribe off label with phentermine (no data on safety or efficacy)

Phentermine + Topiramate XR

• Phentermine available since 1959 for short-term treatment of obesity.

• Topiramate has been well studied for obesity. – Consistently demonstrated dose-dependent weight loss efficacy in

numerous trials ranging from 6 months to more than a year in obese and overweight patients with and without type 2 diabetes and hypertension.

– Reduction of BP and improvement of glycaemic control.

– Neuropsychiatric adverse events have hindered its further development for treatment of obesity.

Bray GA et al., Obes Res 2003;11:722-33. Wilding J et al., Int J Obes 2004;28:1399-1410. Toplak H et al., Int J Obes 2007;31:138-46. Rosenstock J et al., Diabetes Care 2007;30:1480-6. Tonstad S et al., Am J Cardiol 2005;96:243-51. Stenlof K et al., Diabetes Obes Metab 2007;9:360-8.

-10

-8

-6

-4

-2

0

0 2 4 6 8 10 12 14 16 18 20 22 24

Placebo (n=48)

64 mg/d TPM (n=57)

96 mg/d TPM (n=49)

192 mg/d TPM (n=50)

384 mg/d TPM (n=44)

Topiramate in Obesity: Percentage of Body Weight Change From Baseline to Week 24

P < .05 from week 4

TPM = topiramate Bray G, et al. Obes Res. 2003;11:722-733.

Weeks

We

igh

t C

han

ge (

%)

400 mg

Qsymia™ for Obesity

• Once-daily, oral, controlled-release formulation of low-dose phentermine and topiramate extended release.

• Specifically designed to affect normal eating patterns over 24 hours -- simultaneously addressing appetite, satiety, and cravings

0 200 100 300 50 150 250 350

Topiramate

0 30 mg (free base)

15 5 10 25 3.75 7.5

Phentermine

Maximum Approved Doses

20

23 46 92

Low Mid Full Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933 Accessed April 27, 2010.

http://ir.vivus.com/releasedetail.cfm?ReleaseID=407933

Low (23T, 3.75P) -7.0%, 18 lb

Placebo -2.5%, 6 lb

Full (92T, 15P) -14.7%, 37 lb

Me

an %

We

igh

t Lo

ss

Weeks

Patients Placebo Low Full

Completers (% of randomized) 241 (47%) 138 (57%)*

301 (59%)*

*Statistically greater number of patients completing study on combination drug vs placebo, P < .0001

EQUIP: Weight Loss Over Time (Completer Population)

Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

Data from patients who completed 56 weeks on treatment


Mid (46T, 7.5P) -10.5%, 24 lb

CONQUER: Weight Loss Over Time (Completer Population)

Placebo -2.4%, 6 lb

Me

an %

We

igh

t Lo

ss

Weeks

Patients Placebo Mid Full

Completers (% of randomized) 564 (57%) 344 (69%)*

634 (64%)*

Full (92T, 15P) -13.2%, 30 lb

*Statistically greater number of patients completing study on combination drug vs placebo, P < .0001

Press release. Sept 9, 2009. Available at: http://ir.vivus.com/releasedetail.cfm?ReleaseID=420114 Accessed April 27, 2010.

Data from patients who completed 56 weeks on treatment


EQUIP & CONQUER: Discontinuation Rate Due to AEs in All Doses Studied

Placebo Low Mid Full

Number of patients 1508 241 498 1507

Discontinuation due to AEs 9% 12% 12% 18%

Blurred vision 0.5% 2.1% 0.8% 0.7%

Headache 0.7% 1.7% 0.2% 0.9%

Insomnia 0.4% 0.0% 0.4% 1.7%

Depression 0.2% 0.0% 0.8% 1.4%

Tingling 0.0% 0.4% 1.0% 1.2%

Irritability 0.1% 0.8% 0.8% 1.2%

Anxiety 0.3% 0.0% 0.2% 1.1%

Dizziness 0.2% 0.4% 1.2% 0.8%

Includes adverse events (AEs) by dose for EQUIP & CONQUER, which lead to discontinuation in > 1% of patients

Phentermine/Topiramate XR

• Risk of birth defects: women need – pregnancy test on starting and monthly while using.

• Reduces blood pressure, glucose, insulin, triglycerides and raises HDL

• Unclear if physicians will prescribe off label using generic phentermine and topiramate.

• Most effective medication available 10-15% weight loss.

Phentermine/Topiramate XR

• Combination gives greater effectiveness with fewer side effects

• Cost: $150-$200/month

• Side effects: dry mouth, numbness, tingling, insomnia, dizziness, anxiety, irritability and disturbance in attention

Learning Objectives

56






Selected Medications That Can Cause Weight Gain

• Psychotropic medications

– Tricyclics

– MOA inhibitors

– Specific SSRIs

– Atypical antipsychotics

i.e. Zyprexa

– Lithium

– Anticonvulsants

i.e. Lyrica

• -adrenergic receptor blockers

Diabetes medications

– Insulin

– Sulfonylureas

– Thiazolidinediones

Highly active antiretroviral

therapy

Tamoxifen

Steroid hormones

– Glucocorticoids

– Progestational steroids

58

Produce Weight Loss Are Weight Neutral Produce Weight Gain

Bupropion Haloperidol Tricyclic

antidepressants*

Desvenlafaxine Aripiprazole Monoamine oxidase

inhibitors

Venlafaxine Paroxetine

Topiramate Escitalopram

Zonisamide Lithium

Lamotrigine Olanzapine

Ziprasidone Clozapine

Risperidone

Carbamazepine

Valproate

Divalproex

Mirtazapine

Table 3.

Categorization of Neurobehavioral Drugs

by Their Effects on Body Weight

•↵* Nortriptyline, amitriptyline, doxepin.

http://circ.ahajournals.org/content/125/13/1695/T3.expansion.html


59

Produce Weight Loss Are Weight Neutral Produce Weight Gain

Metformin Dipeptidyl peptidase-4

inhibitors (DPP-4) Insulin

Pramlintide Acarbose Sulfonylureas*

Exenatide Miglitol Glitinides

Liraglutide Bromocriptine Thiazolidinediones†

SGLT-2

Categorization of Antidiabetic Drugs by Their Effects on Body Weight

•↵* Glipizide, glimepiride, glibenclamide, chlorpropamide.

•↵† Pioglitazone, rosiglitazone.





0 10 20 30 40 50 60 70 80 90

Me

an

We

igh

t (k

g)

Exenatide Continued to Reduce Weight

Open-Label Extension – Combined

Time (wk)

Baseline Weight

98 kg 100 kg 100 kg Placebo BID

5 µg Exenatide BID 10 µg Exenatide BID

-5

-4

-3

-2

-1

0

1

82-wk completers; N = 393; Mean ± SE; Weight was a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc.

Open-Label Extension Placebo-Controlled

Week number

1 3 5 7 9 13 21 29 37 45 53 17

Placebo

Fluoxetine

N = 16

N = 14

N = 23

N = 22

Wei

ght

Loss

(kg

) Fluoxetine 60 mg and Weight Loss*

Darga et al, AJCN, 1991.

-16

-14

-12

-10

-8

-6

-4

-2

0

Pharmacotherapy- Weight Friendly

• Obese + diabetes metformin~ -5 lbs, GLP-1 agonist - exenatide~-12 lbs, liraglutide, albiglutide pramlinatide (Symlin®) ~–5 lbs, SGLT-2 : i.e. canagliflozin (Inkovana®) ~–6-10 lbs DDP-IV inhibitors, bromocryptine-QR

• Obese + depression Bupropion ~ -10 lbs, duloxetine, vilazodone (Viibryd®) desvenlafaxine (Prestiq®), vortioxetine (Brintellix™)

• Obese + PMS fluoxetine or sertraline

• Obesity + Seizure disorders Topiramate and Zonisamide

• Obesity + Migraine Headaches Topiramate

Pharmacotherapy Common Side Effects • Xenical and Alli (orlistat)- Oily stools and gas

• Appetite Suppressants – stimulants buproprion, phentermine, diethylpropion- increase blood pressure, insomnia, dry mouth palpitations, nausea, anxiety and constipation.

• Appetite Suppressant – serotonergic Locaserin- fatigue, depression, nausea

• Metformin- nausea, gas and loose stools

• GLP-1 /Amylin Agonist – Exenatide, liraqlutide and pramlinatide - Nausea and requires injections

• Topiramate- Fatigue, change in taste, tingling, word searching.

• SSRI’s- Fatigue, apathy, sexual dysfunction, weight gain?

Learning Objectives

64




medications used to treat co-morbid conditions • Discuss the results of studies of new anti-obesity


DRUGS FOR OBESITY: THE FUTURE

Medications that may be approved in 2014 (medications are available for other indications)

• Bupropion-naltrexone – Combination depression medication

with opiate blocker

– 5% to 10% weight loss

– Will have safety data in high risk cardiovascular patients

• Liraglutide 3.0 mg/day– (Victoza®) – approved for Diabetes

– Injectible GLP-1 receptor agonist

– 5% to 10% weight loss

– Will be particularly useful in patients with pre-diabetes and diabetes

New Drugs

• Contrave® –(Naltrexone & Bupropion),

• Opioid receptor antagonist plus a selective inhibitor of neuronal re-uptake of noradrenaline and dopamine

• September 2014 – FDA will review

• ‘Light’ study interim analysis submitted Dec 13

• April 2011- 7.5% weight loss vs 2.5% placebo over 1 year period

Bupropion + naltrexone

• Bupropion, primarily norepinephrine-dopamine reuptake inhibitor, is marketed for treatment of depression and as a smoking cessation aid.

• Bupropion showed modest weight loss efficacy in three obesity trials.1

• Naltrexone, an opioid receptor antagonist, is marketed to treat alcoholism and opioid addiction.

• Animal studies suggest pharmacodynamic synergy.2

1Gadde KM et al., Exp Rev Neurother 2007;7:17-24. 2Greenway FL et al., Obesity 2009;17:30-39

Naltrexone and Bupropion Rationally Designed Around MOA to Initiate and Sustain Weight Loss

Obesity: complex, multiple pathways to defend body weight

Preclinical/clinical evidence for drug synergy Naltrexone/bupropion synergistic

increase in POMC activity Synergistic decrease in food intake

and body weight β-endorphin

Bupropion

α-MSH

Naltrexone

Weight loss

MC4R = melanocortin-4 receptor; MOA = mechanism of action; MSH = melanocyte-stimulating hormone; POMC = proopiomelanocortin Greenway FL, et al. Obesity. 2009;17:30-39.

COR-I, II: Body Weight, Percentage of Change From Baseline

0 8 16 24 32 40 48 56-10

-8

-6

-4

-2

0

56

-1.3%

-5.0%*

-6.1%*

-1.9%

-6.8%*

-8.2%*

Week

Change fro

m b

ase

line (

%)

0 8 16 24 32 40 48 56-10

-8

-6

-4

-2

0

56

-1.2%

-6.4%*

-1.4%

-8.1%*

Week

Change fro

m b

ase

line (

%)

COR-II COR-I ITT-LOCF Observed# ITT-LOCF Observed

NB16 (N=471)

Completers: Placebo (N = 290): -1.8% , NB16 (N = 284): -6.7%* NB32 (N = 296): -8.1%*

Completers: Placebo (N = 267): -1.4% NB32 (N = 434): -8.2%*

NB = naltrexone/bupropion. #COR-II: NB observed data are NB32/NB48 pooled (N = 825); no differences were observed for patients rerandomized to NB32 vs NB48. LS mean ± SE; *P < .001 vs placebo at all timepoints. COR-II: week 56 ITT-LOCF data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1346886&highlight Accessed April 29, 2010.

Placebo (N=456) NB32 (N=702) NB32 (N=471) Placebo (N=511)

http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-newsArticle&ID=1346886&highlight



COR-I, II: Categoric Weight Loss at Week 56, ITT-LOCF

Data are for the ITT-LOCF population. *P < .001 vs placebo . COR-II: week 56 data from patients rerandomized to NB32 are double weighted to account for the prespecified exclusion of patients rerandomized to NB48. ITT-LOCF: patients with a baseline and ≥ 1 postbaseline weight measurement while on study drug. Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.

COR-II ITT-LOCF

COR-I ITT-LOCF

Placebo (N=456) NB32 (N=702) Placebo (N=511) NB32 (N=471)

0

20

40

60

80

16.4%

48.0%

24.6%

*

*

7.4%

11.9%*

2.0%

5% 10% 15%

Perc

enta

ge o

f su

bje

cts

0

20

40

60

80

17.1%

50.5%

28.3%

*

*

5.7%

13.5%*

2.4%

5% 10% 15%

56.3%*

Perc

enta

ge o

f su

bje

cts

patients

patients

http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight

COR-I, II: Most Common Treatment-Emergent Adverse Events (TEAE)

COR-I COR-II

Placebo N=569

NB16 N=569

NB32 N=573

Placebo N=492

NB32/48 N=992

Nausea 5.3% 27.2%* 29.8%* 6.9% 29.2%*

Headache 9.3% 16.0%* 13.8%* 8.7% 17.5%*

Constipation 5.6% 15.8%* 15.7%* 7.1% 19.1%*

Dizziness 2.6% 7.7%* 9.4%* 3.7% 6.9%*

Vomiting 2.5% 6.3%* 9.8%* 2.0% 8.5%*

Dry mouth 1.9% 7.4%* 7.5%* 2.6% 9.1%*

Patients discontinuing due to a TEAE 9.8% 21.4%* 19.5%* 13.8% 24.3%*

Nausea 0.4% 4.6%* 6.3%* 0.2% 6.0%*

Dizziness 0.5% 2.3%* 1.2% 0.2% 1.0%

Headache 0.7% 1.6% 0.9% 0.8% 2.6%*

Vomiting 0.2% 0.7% 0.9% 0% 0.8%

Insomnia 0.2% 0.7% 0.7% 1.0% 0.8% TEAEs > 5% in any NB group and 2x the incidence in the respective placebo group. Top 5 TEAEs leading to discontinuation in NB groups. Data are for the safety analysis set: patients taking ≥ 1 tablet of study drug and with ≥ 1 investigator contact/assessment at any time after the start of study treatment. *P < .05 vs placebo Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.


0

5

10

15

100

MildModerateSevere

4 8 12 16 20 24 28 32 36 40 44 48 52 56

Week

Inci

dence

of nause

a (

%)

0

5

10

15

100

MildModerateSevere

4 8 12 16 20 24 28 32 36 40 44 48 52 56

Week

Inci

dence

of nause

a (

%)

COR-I, II: Incidence of Nausea by Week and Intensity

Nausea events are shown during week of onset only. If a patient had multiple-event onsets during the same week, only the most severe event is shown. Safety analysis set: patients taking ≥ 1 tablet of study drug and with ≥ 1 investigator contact/assessment at any time after the start of study treatment. Placebo data are combined for COR-I and COR-II. All NB data are combined for COR-I and COR-II (NB16, NB32, NB48). Press release. October 27, 2009. Available at: http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1346886&highlight Accessed April 29, 2010.

NB N = 2134

Placebo N = 1061 titration period

titration period


Gastric Bypass Lap Band

Effectiveness

Risk

Low High

Sleeve Gastrectomy

Weight loss in the SOS

JAMA. 2012;307(1):56-65

Program Summary

78

• Obesity is serious medical problem that is a driver of the increase in health care cost

• Even modest weight loss (5%–10%) can reduce cardiometabolic risk factors

• Newer strategies for weight loss should include a) Limiting weight gaining pharmacotherapy b) Consideration of pharmacotherapy targeted to change the energy-balance equation c) Long term treatment because obesity is a chronic disease

Questions?

Post-Test

80

A. 5% or greater weight loss B. Decrease in BMI to less than 30 kg/m2

C. 10% or greater weight loss D. Decrease in BMI to less than 25 kg/m2.

1. What is considered a successful response to pharmacotherapoy for obesity?

Post-Test

81


2. Based on double-blind, placebo controlled studies, which of the following medications is likely to produce the greatest weight loss at the end of a year?

Post-Test

82

3. Which medication is most associated with an increased risk for the serotonin syndrome?

A. Orlistat 120 mg TID B. Qsymia 15-92 QD C. Phentermine 37.5 mg QD

D. Locasarin 10 mg BID

Post-Test

83

4. Which medication has been associated with cleft palate birth defects?


References • Clinical Assessment and Management of Adult Obesity,

Circulation. 2012;126:2870-2877,

• Bray GA, Ryan D. Medical Therapy for the Patient With Obesity. Circulation. 2012;125:1695-1703

• Ness-Abramof R, Appovian CM. Drug-induced weight gain. Drugs Today.2005; 41: 547–555.

• Hendricks EJ, Rothman RB, Greenway FL . How physician obesity specialists use drugs to treat obesity. Obesity (Silver Spring). 2009; 17: 1730–1735.

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kpha’s 134th annual meeting - wild apricot · hypothyoidism, metabolic syndrome (insulin...

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