New Frontiers and Combination Pharmacotherapy for Obesity Management

Donna H. Ryan, MDPennington Biomedical Research Center

Baton Rouge, LAdonna.ryan@pbrc.edu

OUTLINE

• Pharmacotherapy: What is available?• What is anticipated?

– “Druggable targets” and new agents– Combination approaches (combinations of drugs

already on market for other indications)

What is available now?PHENTERMINE

DIETHYLPROPION

FDA approved 1959 Stimulant / promotes loss of appetite Once daily with or without food Some abuse potential

SIBUTRAMINE

FDA approved 1997 Induces feeling of satiety

– satisfied with less food– greater control of intake

Once daily with or without food

ORLISTAT FDA approved 1999

Blocks absorption of ~30% dietary fat

– GI side effects

3 times daily with meals vitamin supplement

Comparison of available drugs

Mechanism CentralNoradrenergic

Central SNRI

PeripheralPancreatic lipase

inhibitor

Approval Short term useClass II-IV

Long term useClass IV

Long term useNot scheduled

Cost $ $$$ $$$$

Efficacy – drug only/ drug + LS

5%/? 5%/15% 5%/8%

Pros Patient satisfaction &

cost

Demonstrated efficacy

Safety cost

Cons Prescribing time limit

? BP elevation

BP elevation

reimbursement

Tolerability

reimbursement

PHENTERMINE DIETHYLPROPION SIBUTRAMINE ORLISTAT

OUTLINE

• Pharmacotherapy: What is available?• What is anticipated?

– “Druggable targets” and new agents– Combination approaches (combinations of drugs

already on market for other indications)

Brain

Central signalsStimulate

NPYAGRPgalanin

Orexin-Adynorphin

Inhibita-MSH

CRH/UCNGLP-ICART

NE5-HT

External factors

EmotionsFood characteristicsLifestyle behaviorsEnvironmental cues

Peripheral signals Peripheral organs

Food intake

Glucose

CCK, GLP-1, Apo A-IVVagal afferents

Insulin

Leptin

Cortisol

–

–

+

Gastrointestinal tract

Adipose tissue

Adrenal glands

Ghrelin+

Regulation of Food Intake

Energyout

The first new obesity drug developed based on new biology of obesity

Patients Before Treatment

After 3 Months of Treatment

A Family AffairHormone Leads to Dramatic Weight Loss for Three Cousins

Aug. 7 – How can three family members slim down to half their body weight without even trying? With the help of an appetite control hormone called leptin, new research suggests.

Only 10 months later, the cousins have lost nearly half their body weight.

After Ten Months of Treatment

Heymsfield, S. B. et al. JAMA 1999;282:1568-1575.

Pattern of Weight Change From Baseline to Week 24 in Obese Subjects Who Received Recombinant Methionyl Human Leptin (rL)

Leptin in Obesity Clinical Trials

“Druggable Targets” – Record to Date

• Serotonin, Norepinephrine, Dopamine– amphetamines, fenfluramine, dexfenfluramine, bupropion, phentermine,

diethylpropion, sibutramine, ecopipam • Cannabinoid receptor

– rimonabant, taranabant, at least 3 others• NPY

– Merck MK 0557 and Shionogi S2367• Uncertain neural mechanisms

– topiramate, CNTF• Leptin• Amylin

– pramlintide• GLP-1 ,GIP, PYY, oxyntomodulin

– exenatide, liraglutide, DPP IV inhibitors (sitagliptin), PYY 3-36, oxyntomodulin

“Druggable Targets” – Record to Date

• Serotonin, Norepinephrine, Dopamine– amphetamines, fenfluramine, dexfenfluramine, bupropion, phentermine,

diethylpropion, sibutramine, ecopipam • Cannabinoid receptor

– rimonabant, taranabant, at least 3 others• NPY

– Merck MK 0557 and Shionogi S2367• Uncertain neural mechanisms

– topiramate, CNTF• Leptin• Amylin

– pramlintide• GLP-1 ,GIP, PYY, oxyntomodulin

– exenatide, liraglutide, DPP IV inhibitors (sitagliptin), PYY 3-36, oxyntomodulin

On market with

weight loss indication

“Druggable Targets” – Where are we going?

• Serotonin, Norepinephrine, Dopamine– Lorcaserin, phase III– Tesofensine, phase II

• Cannabinoid receptor– ?

• NPY– ?

• Uncertain neural mechanisms– Topiramate + phentermine =Qnexa, phase III– Zonisamide + bupropion = Empatic, phase II

• Leptin• Amylin

– pramlintide• GLP-1, GIP, PYY and oxyntomodulin

– ?• POMC pathway

– Naltrexone + bupropion (Contrave) phase III

Pramlintide +leptin, phase II

3 Drugs will go before FDA Panels in 2010

• lorcaserin• bupropion + naltrexone (Contrave)• topiramate + phentermine (Qnexa)

• safety• safety• safety

3 most important factors in successful review

Zero tolerance for neuropsychiatric adverse profile: RIO-North America: Adverse Events

Leading to Drug Discontinuation in Year 1

Placebo(n = 607)

(%)

Rimonabant 5 mg(n = 1214)

(%)

Rimonabant 20 mg

(n = 1219)(%)

Psychiatric disorder 2.3 3.6 6.2

Depressed mood 1.3 2.1 2.2

Anxiety 0.3 0.6 1.0

Irritability 0 0.2 0.5

Insomnia 0.2 <0.1 0.5

Nervous system 1.0 1.2 2.2

Headache 0.3 0.3 0.5

Dizziness 0.2 0 0.7

Gastrointestinal tract 0.7 0.7 1.6

Nausea 0.2 0.2 0.9Adapted with permission from Pi-Sunyer FX, et al. JAMA. 2006;295:761-775.

FDA Guidelines for Obesity Products

Efficacy Benchmark Categorical response: > 35% of patients on drug lose at least 5% of their body weight and

that the proportion is double placebo- OR -

Mean weight loss: >5% difference between active product and placebo group

Additional Endpoints: Study markers of CV and metabolic risk

Experience in Diabetes Study measures of glycemic control

Trial Size & Duration >3,000 subjects randomized to active doses of the product and >1,500 subjects randomized

to placebo for 1 year of treatment

Lorcaserin – selective approach to the serotonin receptor

• 5-HT2C receptor is a validated target

– Located in the hypothalamus

– Regulates satiety

– May affect metabolic rate

• NME* that selectively targets the 5-HT2C receptor

– ~100-fold selectivity over 5-HT2B receptor

– ~15-fold selectivity over 5-HT2A receptor

• Fenfluramine is a non-specific serotonin receptor agonist

– Potential to activate all 14 known serotonin receptors

* New molecular entity

Lorcaserin: 1 Year Results

18

% Categoricalor

% Mean Weight Loss

BLOOMN=3182

BLOSSOMN=4008

10 mg BID

Placebo 10 mg BID

10 mg QD

Placebo

5% Per Protocol 66.4 32.1 63.2 53.1 34.9

5% ITT-LOCF 47.5 20.3 47.2 40.2 25.0

10% Per Protocol 36.2 13.6 35.1 26.3 16.1

10% ITT-LOCF 22.6 7.7 22.6 17.4 9.7

Mean Per Protocol (%) 8.2 3.4 7.9 6.5 3.9

Mean ITT-LOCF (%) 5.8 2.2 5.9 4.8 2.8

Data courtesy Arena

19

Adverse Event Year OneLorcaserin Placebo

Headache

18.0% 11.0%

Upper respiratory tract infection

14.8% 11.9%

Nasopharyngitis

13.4% 12.0%

Dizziness

8.2% 3.8%

Nausea

7.5% 5.4%

Most Frequent BLOOM Adverse Events

Headache was the only AE that exceeded placebo by ≥5%Based on clinical trial data to date, headaches associated with lorcaserin are mild or moderate and transient.

Lorcaserin Adverse Event Profile (BLOOM)LOOM Tolerability: Adverse Events

“Depression occurred infrequently, and at similar rates in active and placebo groups.

Anxiety also infrequent in all groups”

Data courtesy Arena

Lorcaserin Weight Loss Over Time(BLOSSOM)

20

17.0 lbs, 7.9% at wk 52

14.3 lbs, 6.5% at wk 52

8.7 lbs, 3.9% at wk 52

Data courtesy Arena

BLOSSOM: Secondary Endpoints

21

Risk Factor Improved ITT p-valuePer Protocol

p-value

HDL cholesterol Yes 0.0001 0.0004

Triglycerides Yes 0.0172 0.0011

LDL cholesterol Yes 0.0676 0.0727

Systolic BP Yes 0.0689 0.0003

Diastolic BP Yes 0.0804 0.0006

Top-line Results

• Data on glycemic parameters is pending but were positive in BLOOM• Inflammatory markers were not measured but were significantly reduced

in BLOOM

Data courtesy Arena

Combined Echocardiographic Data Set FDA Valvulopathy : grade I Aortic Regurgitation, grade II Mitral

Regurgitation

Valvulopathy Rates

BLOOM BLOSSOM

10 mg BID

Placebo 10 mg BID

10 mg QD

Placebo

Week 52 2.7% 2.3% 2.0% 1.4% 2.0%

Week 104 2.6% 2.7%

22

Pulmonary Artery Systolic Pressure did not increase in any group

Data courtesy Arena

Orexigen strategy: POMC Pathway Targets• POMC pathways are common

pathways of signals of energy balance – Represent a “node of influence;” can

alter how the brain perceives body weight

– Resistance to leptin in obesity– Agonist of the melanocortin system

• STEP 1: accelerate POMC neuron firing by the by-pass of leptin resistance

– reduces appetite– increases energy expenditure

• STEP 2: inhibit compensatory mechanisms thought to mitigate drug benefits over time

– Beta endorphin– AgRP

POMC*

Source: Orexigen

Contrave = Bupropion +

naltrexone

Empatic = Bupropion +

zonisimide

% ofPatientsLosing>5% ofBody

Weight

Bupropion + Naltrexone in Large Phase III Trials

NB-301 Results5% Categorical Analysis (ITT-LOCF)

NB-303 Results^ 5% Categorical Analysis (ITT-LOCF)

% ofPatientsLosing>5% ofBody

Weight

Placebo Contrave16 Contrave32

n= 456

n=825 n=511

n=471

n=471

n=511

n=471

n=471

n= 456

n=702

Note: All differences between drug and placebo highly statistically significant at p<0.001^ Results of re-randomized NB48 group not shown; no statistical difference from re-randomized NB32 group‡ Primary Endpoint* Weighted LOCF Data courtesy

Orexigen

Bupropion + Naltrexone 1 Year Weight Loss Trajectory

NB-301 Observed Case Weight Loss

NB-303 Observed Case Weight Loss *

% Weight Loss vs.

Baseline

Week 0 Week 14

Week 28

Week 42

Week 56

Week 0 Week 14

Week 28

Week 42

Week 56

Placebo Contrave32

8.2%8.2%

1.9% 1.4%

* Contrave32 weighted analysis

% Weight Loss vs.

Baseline

Data courtesy Orexigen

Bupropion + Naltrexone Most Common Treatment-Emergent Adverse Events

NB-301 & NB-303 NB-304 (Diabetes)

Placebo Contrave 16 Contrave32 Contrave32

Overall Treatment-Emergent Adverse Events

68-85% 80% 83-86% 90%

Nausea 5% – 7% 27% 29% – 30% 42%‡

Constipation 6% – 7% 16% 16% – 19% 18%

Headache 9% 16% 14 % – 18% 14%

Vomiting 2 % – 4% 6% 9% – 10% 18%

Upper respiratory infection 10% – 11% 9% 9% – 10% 8%

Insomnia 5% – 7% 6% 8% – 10% 11%

Dizziness 3% – 5% 8% 7% – 9% 12%

Dry mouth 2% – 3% 7% 8% – 9% 6%

Nasopharyngitis 5% - 14% 6% 5% – 8% 8%

Diarrhea 4% - 10% 5% 5% – 6% 16%

Note: Represents adverse event experience in trials NB-301, NB-303, NB-304. ‡ Nausea rate for patients not taking Metformin = 27% Data courtesy

Orexigen

Treatment Discontinuations due to Adverse Events

NB-301 & NB-303 NB-304 (Diabetes)

Placebo Contrave16 Contrave32 Contrave32

Overall Discontinuation Rate 41% - 50% 51% 46 – 49% 48%

Discontinuation Rate Due to AEs 10% – 15% 22% 20% – 24% 29%

Nausea + 5% 6% 10%

Headache + 2% 1% – 3% 2%

Dizziness + 2% + +

Vomiting + + + 3%

Depression 0% – 2% + + +

Insomnia + + + +

Anxiety + + + +

Diabetes mellitus (worsened) + + + +

Note: Represents adverse event experience in trials NB-301, NB-303, NB-304. (> 1% in any arm)+ Incidence < 1%

Data courtesy Orexigen

28

Qnexa: Combination Topiramate + Phentermine

• Once a day oral controlled release formulation of low dose phentermine and topiramate

0 400 mg200100 30050 150 250 350

Topiramate

0 30 mg

155 10 253.75 7.5

Phentermine

Maximum Approved Doses

20

23 46 92

Low Mid Full

Slide courtesy Vivus

Baseline characteristicsCONQUER n=2487 EQUIP n=1267

Age 51 43

Female 70% 83%

Baseline BMI 36.6 42.1

Weight (lbs) 227 256

Waist Circumference (in) 44.5 48

History of Hypertension 69% 25%

Blood Pressure (mmHg) 128/81 122/77

History of Dyslipidemia 57% 19%

Total Cholesterol (mg/dL) 205 194

History of Psychiatric Disorders 30% 26%

History of Diabetes 16%

Data courtesy Vivus

Topiramate + Phentermine

Results at 56 weeks

EQUIP CONQUER

Low dose Full dose placebo Mid dose

Full dose placebo

Retention 57% 59% 47% 57% 64% 69%

Wt loss LOCF 5.1% 11% 1.6% 8.4% 10.4% 1.8%

Wt loss observed 7.0% 14.7% 2.5% 10.5% 13.2% 2.4%

>5% weight loss 45% 67% 17% 62% 70% 21%

Data courtesy Vivus

Topiramate + Phentermine

31

 Patients Placebo

QnexaLow

QnexaFull

Randomized 514 241 512

ITT Population1

(% of randomized)498

97%234

97%498

97%

Completers2

(% of randomized)241

47%138

57%*301

59%*

1 ITT Population = randomized patients with at least one dose of therapy and one post randomization assessment

2 Completers = randomized patients completing 56-week study on drug therapy

Completion Rates with Topiramate + Phentermine

32

Treatment-Emergent Adverse Events >5%: TOPIRAMATE + PHENTERMINE (EQUIP & CONQUER)

  EQUIP (N=1,264) CONQUER (N=2,485)

% of Patients(N=3,749)

Placebo QnexaLow

QnexaFull Placebo Qnexa

MidQnexa

Full

Dry Mouth 3.7 6.7 17.0 2.4 13.5 20.8

Tingling 1.9 4.2 18.8 2.0 13.7 20.5

Constipation 6.8 7.9 14.1 5.9 15.1 17.4

Upper Respiratory Infection 10.9 15.8 12.3 12.9 12.2 13.4

Altered Taste 1.0 1.3 8.4 1.1 7.4 10.4

Insomnia 4.9 5.0 7.8 4.7 5.8 10.3

Headache 10.1 10.4 11.9 9.1 7.0 10.2

Dizziness 4.1 2.9 5.7 3.1 7.2 10.0

Common Cold 7.2 12.5 9.0 8.7 10.6 9.9

Sinus Infection 5.5 7.5 7.2 6.7 6.8 8.6

Back Pain 5.1 5.4 5.5 4.9 5.6 7.2

Nausea 4.7 5.8 7.2 4.2 3.6 6.8

Blurred Vision 3.1 6.3 4.5 3.6 4.0 6.0

Bronchitis 4.3 6.7 5.5 4.3 4.4 5.2

Diarrhea 4.5 5.0 4.7 4.8 6.4 5.8

Urinary Tract Infection 3.5 3.3 4.7 3.7 5.2 5.4

Cough 3.5 3.3 5.1 3.0 3.8 4.8

Influenza 4.7 7.5 5.1 4.3 4.6 3.5

Neuroendocrine Control of Energy Balance: Targeting Gut Signals

GI tract

Adipose tissue

Pancreatic islets

Hypothalamus

Hindbrain

CCK

Adiponectin

Insulin

Amylin

Leptin

OXM

Ghrelin

GLP-1

PYY3-36

GIP PP

ResistinVisfatin

Vagal afferents

Adapted from Badman M.K. and Flier J.S. Science 2005; 307:1909-1914.

Weight loss effect of combined amylin and leptin agonism in DIO rats and overweight/obese humans

Roth J D et al. PNAS 2008;105:7257-7262

©2008 by National Academy of Sciences

Conclusion

• Imagine a world… – where there are nine classes of drugs for managing overweight and

obesity,– where there are minimally invasive devices and surgery for obesity, – where there are sophisticated risk engines to determine health risk

from obesity and comorbidities and directs treatment approach, – and where there is reimbursement for medical and surgical

management of obesity.

Thank you

www.pbrc.edudonna.ryan@pbrc.edu