1. The Cardiovascular Pipeline
Steven E. Nissen MD
Disclosure
Clinical Trials: AstraZeneca, Eli Lilly, Novartis, Takeda, Resverlogix, Orexigen, Vivus, and Pfizer.
Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor a tax deduction is received.

2. Steven E. Nissen, MD
Clinical Trials: AstraZeneca, Eli Lilly, Novartis, Takeda, Resverlogix, Orexigen, Vivus, and Pfizer.
Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor a tax deduction is received.

3. Some Interesting Drugs in Development
CETP Inhibitors (evacetrapib and anacetrapib)
Apo A1 Milano
Daraplapib (Lp-PLA2 inhibitor)
Vorapaxar
PCSK9 inhibitors
SGLT2 inhibitors
Buproprion/natrexone
Phentermine/topiramate

4. Obesity

5. Prevalence of Obesity (BMI >30) in 2010
NHANES Data from National Center for Health Statistics

6. 150 T2DM patients (HbA1c >7.0%, BMI 27- 43 kg/m2 age 20-60 years)
Study Design
150 T2DM patients (HbA1c >7.0%, BMI kg/m2 age years)
Intensive medical therapy (IMT) alone (n=50)
Standard Therapy
IMT + Roux-en-Y gastric bypass surgery (n=50)
IMT + Sleeve gastrectomy surgery (n=50)
Month –3 6 9 12 15 18 21 24 30 36 42 48 54 60 3
Change Regular Therapy to “Community based therapy”
Change 3 arrows Intensive Medical Therapy alone (n=50), IMT + Roux-en-Y Gastric Bypass (N=50), IMT + Sleeve Gastrectomy (n=50)
Time 0 = Randomization with arrow
Screening – Intervention Period or “study” Period
Study
Completion
Surgery
Primary
Endpoint
Sub Study
CIMT
Retinal
Randomization
Screening
Treatment Period 6

7. Average Number of Medications
Average Number of Diabetes Medications
Average Number of Medications
P<0.001
P<0.001
IMT
RYGB SG

8. Limited Options Between Lifestyle and Surgery
# | Vivus Corporate Template
2/25/2018
Limited Options Between Lifestyle and Surgery
The Treatment Gap
Adjustable Gastric Band
Lifestyle (3-5%)
Gastric
Bypass
0% 5% 10% 15% 20% 25% 30% 35%
Percent Weight Loss from Baseline at 1 Year
Copyright © 2009 VIVUS Inc. All rights reserved. |

9. Phentermine-Topiramate (Qsymia™) Dosages

10. Phentermine-Topiramate: Weight Loss Over Time
Analysis of approximately 60% of patients completing 56 weeks
Obesity (2011) doi: /oby

11. Effect of Phentermine-Topiramate on Biomarkers
Favorable effects on some cardiovascular risk factors
Placebo controlled
Placebo subtracted
14.3%
Placebo subtracted
Placebo
Phentermine-topiramate (top dose)

12. Effect of Phentermine-Topiramate on BP

13. Natrexone-Buproprion Mechanism of Action
POMC
Integrate multiple energy balance signals
Increased firing leads to weight loss
Activated by bupropion
β-endorphin
Released with α-MSH
Inhibits POMC firing
Effect blocked by naltrexone
appetite
energy expenditure
= weight loss
MC4-R
-MSH +
-endorphin negative feedback loop -
Naltrexone
Bupropion +
POMC
Hypothalamus (ARH)

14. Buproprion-Naltrexone Preclinical Efficacy Studies: 1-Hour Food Intake in Obese Mice**
Vehicle
Naltrexone
Bupropion NB
**p<0.01 vs vehicle
IP administration; Greenway, et al. Obesity. 2009

15. Buproprion-Naltrexone Weight Loss Over Time
Study 302
P<0.001

16. Effect of Buproprion-Natrexone on Biomarkers
Favorable effects on some cardiovascular risk factors
-16.6%

17. CETP Inhibitors with Human Studies
Torcetrapib
Dalcetrapib
Anacetrapib
Evacetrapib
CF3
F3C N O S O HN O
F3C N F
CF3
Cao et al. J Lipid Res 2011; 52:2169 17

18. Evacetrapib: Lipid Effects in Phase II Trial
Change in HDL-C
Change in LDL-C
Plac
30 mg
100 mg
500 mg

19. LDL-C Reduction and Major Coronary Events
Proportional Reduction in Events
Reduction in LDL-C (mmol/L)
14 Trials
90,056 patients
Lancet 2005; 366: 1267–78

20. PCSK9 and the LDL receptor

21. Effects of PCSK9 Nonsense Mutation
Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. N Engl J Med Mar 23;354(12):

22. AMG 145 Dosed Every 4 Weeks Percentage Change in LDL-C10
–10
–20
p <
–30
–40
Mean % Change from Baseline
–50
–60
–70
–80
–90
–100
Baseline
Week 2
Week 4
Week 6
Week 8
Week 10
Week 12
Study Week

23. ApoA1 Milano: Change in Atheroma Volume
-2.9 mm3
P = 0.97
-12.6 mm3
-14.1 mm3
-15.1 mm3
P = 0.007
P < 0.001
P = 0.02
Placebo
Low Dose
High Dose
Combined