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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