1. New Frontiers and Combination Pharmacotherapy for Obesity Management
Donna H. Ryan, MD
Pennington Biomedical Research Center
Baton Rouge, LA

2. OUTLINE Pharmacotherapy: What is available? What is anticipated?
“Druggable targets” and new agents
Combination approaches (combinations of drugs already on market for other indications)

3. What is available now? Slide 3 PHENTERMINE DIETHYLPROPION
FDA approved
Stimulant / promotes loss of appetite
Once daily with or without food
Some abuse potential
SIBUTRAMINE
FDA approved
Induces feeling of satiety
satisfied with less food
greater control of intake
ORLISTAT
FDA approved 1999
Blocks absorption of ~30% dietary fat
GI side effects
3 times daily with meals
vitamin supplement
Slide 3

4. Comparison of available drugs
PHENTERMINE
DIETHYLPROPION
SIBUTRAMINE
ORLISTAT
Mechanism
Central
Noradrenergic
SNRI
Peripheral
Pancreatic lipase inhibitor
Approval
Short term use
Class II-IV
Long term use
Class IV
Not 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

5. OUTLINE Pharmacotherapy: What is available? What is anticipated?
“Druggable targets” and new agents
Combination approaches (combinations of drugs already on market for other indications)

6. Regulation of Food Intake
Brain
Central signals
Stimulate
NPY
AGRP
galanin
Orexin-A
dynorphin
Inhibit
a-MSH
CRH/UCN
GLP-I
CART NE
5-HT
External factors
Emotions
Food characteristics
Lifestyle behaviors
Environmental cues
Peripheral signals
Peripheral organs
Food intake
Glucose
CCK, GLP-1,
Apo A-IV
Vagal afferents
Insulin
Leptin
Cortisol – +
Gastrointestinal tract
Adipose tissue
Adrenal glands
Ghrelin
Energy
out

7. The first new obesity drug developed based on new biology of obesity Patients Before Treatment

8. After 3 Months of Treatment

9. After Ten Months of Treatment
A Family Affair
Hormone 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.

10. Leptin in Obesity Clinical Trials
Heymsfield, S. B. et al. JAMA 1999;282:
Pattern of Weight Change From Baseline to Week 24 in Obese Subjects Who Received Recombinant Methionyl Human Leptin (rL)

11. “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

12. “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

13. “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

14. 3 Drugs will go before FDA Panels in 2010
lorcaserin
bupropion + naltrexone (Contrave)
topiramate + phentermine (Qnexa)
safety
3 most important factors in successful review

15. 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
0.2
0.5
Insomnia
<0.1
Nervous system
1.2
Headache
Dizziness
0.7
Gastrointestinal tract
1.6
Nausea
0.9
The percentage of patients reporting at least 1 adverse event was similar across treatment groups. Compared with patients receiving placebo, the overall incidence of adverse events leading to study withdrawal in year 1 was slightly higher in patients receiving 5 mg of rimonabant and even greater in patients receiving 20 mg rimonabant, mainly due to psychiatric, nervous system, and gastrointestinal tract adverse events.
Adapted with permission from Pi-Sunyer FX, et al. JAMA. 2006;295:
Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devlin JM, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295:

16. 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

17. 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 17

18. Lorcaserin: 1 Year Results
% Categorical or
% Mean Weight Loss
BLOOM
N=3182
BLOSSOM
N=4008
10 mg BID
Placebo
10 mg QD
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
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 18

19. Lorcaserin Adverse Event Profile (BLOOM)LOOM Tolerability: Adverse Events
Most Frequent BLOOM Adverse Events
Adverse Event
Year One
Lorcaserin 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%
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.
“Depression occurred infrequently, and at similar rates in active and placebo groups.
Anxiety also infrequent in all groups”
Data courtesy Arena

20. Lorcaserin Weight Loss Over Time (BLOSSOM)
8.7 lbs, 3.9% at wk 52
14.3 lbs, 6.5% at wk 52
17.0 lbs, 7.9% at wk 52
Data courtesy Arena 20

21. BLOSSOM: Secondary Endpoints
Top-line Results
Risk Factor
Improved
ITT p-value
Per Protocol p-value
HDL cholesterol
Yes
0.0001
0.0004
Triglycerides
0.0172
0.0011
LDL cholesterol
0.0676
0.0727
Systolic BP
0.0689
0.0003
Diastolic BP
0.0804
0.0006
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 21

22. Pulmonary Artery Systolic Pressure did not increase in any group
Combined Echocardiographic Data Set FDA Valvulopathy : grade I Aortic Regurgitation, grade II Mitral Regurgitation
Valvulopathy Rates
BLOOM
BLOSSOM
10 mg BID
Placebo
10 mg QD
Week 52
2.7%
2.3%
2.0%
1.4%
Week 104
2.6%
Pulmonary Artery Systolic Pressure did not increase in any group
Data courtesy Arena 22

23. 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*
Contrave = Bupropion + naltrexone
Empatic = Bupropion + zonisimide
Source: Orexigen

24. Bupropion + Naltrexone in Large Phase III Trials
NB-301 Results
5% Categorical Analysis (ITT-LOCF)
NB-303 Results^
5% Categorical Analysis (ITT-LOCF)
Placebo
Contrave16
Contrave32
% of
Patients
Losing
>5% of
Body
Weight
% of
Patients
Losing
>5% of
Body
Weight
n=511
n=471
n=471
n=511
n=471
n=471
n= 456
n=825
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

25. Bupropion + Naltrexone 1 Year Weight Loss Trajectory
NB-301 Observed Case Weight Loss
NB-303 Observed Case Weight Loss *
Week 0
Week 14
Week 28
Week 42
Week 56
Week 0
Week 14
Week 28
Week 42
Week 56
1.4%
1.9%
% Weight Loss vs. Baseline
% Weight Loss vs. Baseline
8.2%
8.2%
* Contrave32 weighted analysis
Placebo
Contrave32
Data courtesy Orexigen

26. Bupropion + Naltrexone Most Common Treatment-Emergent Adverse Events
NB-301 & NB-303
NB-304 (Diabetes)
Placebo
Contrave 16
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%
14 % – 18%
14%
Vomiting
2 % – 4% 6%
9% – 10%
Upper respiratory infection
10% – 11% 8%
Insomnia
5% – 7%
8% – 10%
11%
Dizziness
3% – 5%
7% – 9%
12%
Dry mouth
2% – 3% 7%
8% – 9%
Nasopharyngitis
5% - 14%
5% – 8%
Diarrhea
4% - 10% 5%
5% – 6%
Note: Represents adverse event experience in trials NB-301, NB-303, NB-304.
‡ Nausea rate for patients not taking Metformin = 27%
Data courtesy Orexigen

27. Treatment Discontinuations due to Adverse Events
NB-301 & NB-303
NB-304 (Diabetes)
Placebo
Contrave16
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%
Dizziness
Vomiting 3%
Depression
0% – 2%
Insomnia
Anxiety
Diabetes mellitus (worsened)
Note: Represents adverse event experience in trials NB-301, NB-303, NB (> 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
Maximum Approved Doses 23 46 92
Topiramate 50
100
150
200
250
300
350
400 mg
Phentermine
3.75 5
7.5 10 15 20 25
30 mg
Low
Mid
Full
Slide courtesy Vivus

29. Baseline characteristics
Topiramate + Phentermine
Baseline characteristics
CONQUER 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

30. Topiramate + Phentermine Results at 56 weeks
EQUIP
CONQUER
Low dose
Full dose
placebo
Mid dose
Retention
57%
59%
47%
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

31. Completion Rates with Topiramate + Phentermine
Patients
Placebo
Qnexa
Low
Full
Randomized
514
241
512
ITT Population1
(% of randomized)
498
97%
234
Completers2
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

32. Treatment-Emergent Adverse Events >5%: TOPIRAMATE + PHENTERMINE (EQUIP & CONQUER)
EQUIP (N=1,264)
CONQUER (N=2,485)
% of Patients
(N=3,749)
Placebo
Qnexa
Low
Full
Mid
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
11.9
9.1
7.0
10.2
Dizziness
4.1
2.9
5.7
3.1
7.2
10.0
Common Cold
12.5
9.0
8.7
10.6
9.9
Sinus Infection
5.5
7.5
8.6
Back Pain
5.1
5.4
5.6
Nausea
3.6
Blurred Vision
6.3
4.5
4.0
6.0
Bronchitis
4.3
4.4
5.2
Diarrhea
4.8
6.4
Urinary Tract Infection
3.5
3.3
Cough
3.0
3.8
Influenza
4.6
Treatment emergent adverse events occurring in 5% or more of any treatment group across more than 3700 patients
Many clearly not drug-related
Most common – dry mouth, tingling, constipation
No new events, nothing unexpected – no surprises

33. Neuroendocrine Control of Energy Balance: Targeting Gut Signals
Vagal afferents
Hypothalamus
GI tract
Adipose tissue
Ghrelin
Hindbrain
Leptin
CCK
PYY3-36
Insulin
Amylin
GLP-1
Resistin
Visfatin
Adiponectin
OXM
GIP PP
Pancreatic islets
Adapted from Badman M.K. and Flier J.S. Science 2005; 307:

34. Weight loss effect of combined amylin and leptin agonism in DIO rats and overweight/obese humans
Translational research findings: Weight loss effect of combined amylin and leptin agonism in DIO rats and overweight/obese humans. (A) Change in body weight for DIO rats pretreated for 14 d with amylin and then maintained on amylin (open triangles) or switched to either leptin monotherapy (filled inverted triangles) or amylin+leptin combination therapy (filled squares) for an additional 28 d. (B) Change in body weight for 93 evaluable human subjects pretreated with pramlintide for 4 weeks and then treated with pramlintide (open triangles), metreleptin (filled inverted triangles), or pramlintide+metreleptin combination (filled squares). Mean ± SE (A) and LS mean ± SE (B): *, P < 0.05 vs. vehicle controls; #, P < 0.01; ##, P < 0.01; ###, P < vs. monotherapies.
Roth J D et al. PNAS 2008;105:
©2008 by National Academy of Sciences

35. 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.

36. Thank you