Review of CV Effects of Obesity Drugs in Development and their Potential Mechanisms

Boaz Mendzelevski, MDVice President Cardiology, CoreLab Partners Inc.

5th DIA CV Safety Conference, 3-4 November 2011,Barcelona, Spain

The Economist. Cover illustration. Dec 13, ‘03

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Defining Overweight and Obesity• Overweight and obesity are both labels for ranges of weight

that are greater than what is generally considered healthy for agiven height. The terms also identify ranges of weight that havebeen shown to increase the likelihood of certain diseases and other health problems.

Definitions for Adults• For adults, overweight and obesity ranges are determined by

using weight and height to calculate a number called the "body mass index" (BMI). BMI is used because, for most people, it correlates with their amount of body fat.– An adult who has a BMI between 25 and 29.9 is considered

overweight. – An adult who has a BMI of 30 or higher is considered obese.

Percent of Obese (BMI > 30) U.S. Adults

Past and projected prevalence of overweight (BMI ≥25 kg/m2)

The Lancet 2011; 378:815-825 (DOI:10.1016/S0140-6736(11)60814-3)

Biologic Mechanisms Protecting Adipose Tissue Mass

NEJM 2008;358:1941-50

Clinical manifestations of obesity

Type 2 diabetes and glycemic disorders

↑FFAs

Dyslipidemia

• Low HDL

• Small, dense LDL

• Hypertriglyceridemia

Hypertension

Endothelial dysfunction/inflammation (hsCRP)

Impaired thrombolysis↑PAI-1

Atherosclerosis

Insulinresistance

Glucotoxicity

Lipotoxicity

↓Adiponectin

↑Leptin

Courtesy of Selwyn AP, Weissman PN. 2006.

Intra-abdominal adiposity promotes insulin resistance and increased CV risk

Hepatic FFA flux(portal hypothesis)

Secretion ofmetabolically active

substances (adipokines)

suppression oflipolysis by insulin

FFA

Insulin resistanceDyslipidaemia

PAI-1

Adiponectin

IL-6

TNFα

Intra-abdominaladiposity

Net result: Insulin resistanceInflammationPro-atherogenic

Heilbronn et al 2004; Coppack 2001; Skurk & Hauner 2004

The Metabolic Syndrome

The Metabolic Syndrome

Criteria for a diagnosis of Metabolic Syndrome

Why Treat Obesity?

• Contributes to approximately 300,000 deaths a year, making it 2nd only to smoking as a cause of death

• Contributes or causes to many other health problems including:– Type 2 Diabetes Mellitus– Coronary Artery Disease– Degenerative Joint Disease– Certain Types of Cancer– Nonalcoholic Steatohepatitis

Weight loss improves CV risk factors

-25-20-15-10

-505

10152025

Weight SBP DBP HDL-C FPG

Change from

baseline* (%)

Conventional treatment (n = 1660)

Gastric surgery (n = 1845)

N = 4047 with obesity

*At 2 yearsSjöström L et al. N Engl J Med. 2004;351:2683-93.

Costs of Obesity

• Costs the US health-care system more than $99 billion each year

• Consumers also spend over $33 billion annually on weight-reduction products and services

• Annual health-care costs for patients with BMIs of 20 to 24.9 were 20% lower than costs for patients with BMIsfrom 30 to 34.9 and almost 33% lower than for patients who had BMIs of 35 or more.

IMS Report 2009

Potential Strategies for Anti-Obesity Drug Action

• Reducing food intake. Either amplify effects of signals/factors that inhibit food intake or block signals/factors that augment food intake

• Blocking nutrient absorption (especially fat or carbohydrates) in the intestine.

• Increasing thermogenesis. Either increase metabolism and dissipate food energy as heat or increase energy expenditure through the enhancement of physical activity.

• Modulating fat metabolism/storage. Regulate fat synthesis/breakdown by making appropriate adjustments to food intake or energy expenditure.

• Modulating the central regulation of body weight. Either alter the internal set point or modulate the signals presented regarding fat stores.

Currently Available Agents Indicated for Treatment of Obesity

Generic/Brand Name

Usual Dose Mechanism of Action

Side Effects

Orlistat/Xenical 120 mg with each meal

Peripheral: Blocks absorption of about 30% of consumed fat

GI symptoms (oily spotting, flatus with discharge, fecal urgency, oily stools, incontinence)

Sibutramine

/Meridia(withdrawn EU/US)

5-15 mg/d Central: Inhibits synaptic reuptake of norepinephrine and serotonin

Dry mouth, constipation, headache, insomnia, increased blood pressure, tachycardia

Phentermine/ Adipex, Fastin, Ionamin and others

15-37.5 mg per day as a single or split dose

Central: Stimulates release of norepinephrine

CNS stimulation, tachycardia, palpitations, dry mouth, insomnia,

Agents sometimes used for Treatment of Obesity NOT Indicated or FDA approved

Generic/Brand Name Usual Dose Mechanism of Action

Side Effects

Ephedrine+/-caffeine "Elsinore"pill

Varies: usually 75-150 mg ephedrine and 100-150 mg caffeine

Central: Stimulates adrenergic receptors

CNS stimulation, tachycardia, palpitations, dry mouth, insomnia,

Bupropion/Wellbutrin(constituent of Contrave)

100-300 mg/d Central: Inhibits reuptake of dopamine norepinephrine and serotonin

CNS stimulation, dry mouth, headache, GI effects

Topiramate/Topamax(constituent of Qnexa)

96-192 mg/d Uncertain: Central ? CNS: paresthesia, fatigue, dizziness, memory difficulty, concentration difficulty, and depression

Anti-obesity Drug Market

Datamonitor 2010

Obesity Regulatory Guidelines

• Both FDA (2007) and EMA (2006) guidelines require phase 3 studies to be designed as randomised, double-blind, placebo-controlled trials including patients with a BMI of ≥ 27 kg/m2 accompanied by co-morbidities and with a BMI of ≥ 30 kg/m2, without co-morbidities.

• The FDA recommends efficacy to be based on 12-month data showing statistical differences in – the mean placebo subtracted weight loss ≥ 5%; – or the proportion of subjects who lose ≥ 5% of baseline body

weight in the active-product group is at least 35% and approximately double the proportion in the placebo treated group, with the difference between groups being statistically significant.

Obesity Regulatory Guidelines

• The FDA requires the safety database to include at least 3,000 subjects randomised to active doses of the product and no fewer than 1,500 subjects randomised to placebo for one year of treatment.

• The EMA recommends efficacy to be based on a significant weight loss at 12 months of 10% of the baseline weight that is also significantly different from the placebo change from baseline.

Sibutramine (Meridia)

• Appetite suppressant that works by blocking reuptake of serotonin and norepinephrine.

• Maintaining weight loss has long been the major downfall to most diet programs.

• Removed from the market in EU and US in 2010 following the SCOUT study showing increased CV risk

Sibutramine effects on CV risk factors

Source: Am J Cardiovasc Drugs @ 2010 Adis Data Information BV

Mechanisms for sibutramine acute CV effects

Source: Am J Cardiovasc Drugs @ 2010 Adis Data Information BV

Sibutramine Cardiovascular outcomes and regulatory actions

Abbott voluntary withdrawal

Source: Am J Cardiovasc Drugs @ 2010 Adis Data Information BV

Orlistat (Xenical)

• Pancreatic lipase inhibitor that blocks the absorption of up to one third of ingested fat.

• In addition to helping reduce weight, orlistat has been shown to also:– lower plasma low-density lipoprotein cholesterol

(LDL) cholesterol levels. – The decline in LDL cholesterol is greater than that

expected due to weight loss alone. – Lower HbA1C in diabetic patients

Orlistat- XENDOS

Orlistat- XENDOS

Weight Loss of Approved Medications in Obese and Overweight Patients

Medication Source of Data

Treatment Duration (Week)

Mean Weight-Change in Treated Patients

Compared With Placebo (95% CI)

Sibutramine meta-analysis of 29 RCTs 52 -4.45 kg

(-5.29 to -3.62)

Orlistat meta-analysis of 22 RCTs 52 -2.75 kg

(-3.31 to -2.20)

Phentermine* meta-analysis of 9 RCTs 2 to 24 -3.6 kg

(-6.0 to -0.6)

Li Z et al. Ann Intern Med. 2005;142:532-546.BMI=body mass index; N/A=not available; RCT=randomized controlled trial.* Approved for short-term use only.

Long-Term Weight-Loss MedicationsEffects on Cardiometabolic Risk Factors

Medication

Waist circum (cm)

LDL-C (mg/dL)

HDL-C (mg/dL)

TG (mg/dL)

A1c (%)

FPG (mg/dL)

Systolic BP

(mm Hg)

Sibutramine - 3.99 N/A + 1.5 - 15.9 N/A N/A + 1.7

Orlistat - 2.06 - 10.0 - 1.2 - 2.7 - 0.38 - 18.6 - 1.5

N/A, not availableValues are weighted mean differences (active minus placebo).LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TG, triglycerides; A1c, hemoglobin A1c; FPG, fasting plasma glucose; BP, blood pressure.Rucker D, et al. BMJ. 2007;335:1194-1199.

Average weight loss of subjects completing a minimum 1-year weight-management intervention; based on review of

80 studies (N=26,455; 18,199 completers [69%]).

Exercise aloneDiet + exercise Diet aloneMeal replacementsV. Low energy dietOrlistatSibutramineAdvice alone

Advice alone

Diet alone

Orlistat

6-mo 12-mo 24-mo 36-mo 48-mo

Wei

ght L

oss

(kg)

Sibutramine

V. Low energy diet

Diet + exercise

Franz MJ , et al. J Am Diet Assoc. 2007;107:1755-67.

Long-term Persistence with Orlistat and Sibutramine in Canada

Padwal R, et al. Int J Obes 2007;31(April)

18%-O26%-S

6%-O8%-S

2%-Orlistat2%-Sibutramine

Perc

ent R

emai

ning

on

Ther

apy

Time (days)

Cannabinoids

• Cannabinoids are a group of terpenophenoliccompounds present in Cannabis sativa

• Cannabinoids are structurally related to tetrahydro-cannabinol (THC) or that bind to cannabinoid receptors

• Cannabinoids are exogenous and endogenous ligandsfor these receptors

• Autoprotection by the endocannabinoid system

• Cannabinoid receptors

• CB1 and CB2 receptors

Endocannabinoid system (ECS): Overview

Endocannabinoid ligands

• Produced on demand• Act locally• Inactivated rapidly• Bind to transmembrane G-protein receptors,

principally inhibiting neurotransmitter release

Cannabinoid receptor type 1 (CB1)Cannabinoid receptor type 2

(CB2)Cannabinoid receptor type 1

(CB1)

Most widespread CB receptor (brain, spinal cord; peripheral nervous

system, organs, tissues)

Immune cells

J Am Coll Cardiol. 2006;47:1919-26.Ann Med. 2005;37:270-5.

Implications of CB1 receptor activation

Peripheral tissue

↑Appetite ↑Motivation to eat/smoke

↑LipogenesisAltered glucose metabolism

Adipose tissueLiver GI tract

Skeletal muscle

Hypothalamus Limbic system

Central nervous system

CB1 receptors are present in the brain, adipose tissue, the GI tract and possibly also in skeletal muscle and liver

J Am Coll Cardiol. 2006;47:1919-26.Ann Med. 2005;37:270-5.

Sites of CB1 Receptor and Effects of CB1 Blockade

Site of Action Mechanism(s) Clinical Implications

Hypothalamus/ Nucleus accumbens Food intake

Body weightAbdominal obesity

Adipose tissue Adiponectinipogenesis

DyslipidemiaInsulin resistance

Muscle Glucose uptake Insulin resistance

LiverLipogenesisFatty acidsynthesis

DyslipidemiaInsulin resistance

Endocr Rev. 2006;27:73-100 Lancet. 2005;365:1389-1397. Int J Obes. 2005;29:183-187

J Clin Invest. 2005;115:1298-1305

Rimonabant (CB1 Blocker): A Multi-Impact Drug Mode Of Action

RimonabantRimonabant

CB1

Adipocyte

BrainCB1

Adiponectin

FA oxidation

↓ Body weight

↓ food intake

Central effects

Metabolic peripheral effects

FFA clearance

↓ HyperinsulinemiaInsulin sensitivity restored↓ TG↑ HDL-C

Changes in Weight & Waist Circumference

Weight (kg)Weight (kg) Waist (cm)Waist (cm)

Weeks

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Wei

ght c

hang

e (k

g)

Completers

-3.6

-4.8

-8.6

Weeks

-10

-8

-6

-4

-2

0

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Completers

-4.5 - 5.3

-8.5

Wai

st c

ircum

fere

nce

chan

ge (c

m)

Placebo Rimonabant 5mg Rimonabant 20mg

Lancet 2005;365:1389–97

Rimonabant - The Epilogue

• Due to safety concerns, primarily psychiatric in nature (suicidalily), Rimonabant has not received approval in the United States or Canada, either as an anti-obesity treatment nor as a smoking-cessation drug.

• Rimonabant was approved as an anti-obesity drug in the European Union, subject to some restrictions. However, in October 2008, the European Medicines Agency (EMA) recommended that Acomplia no longer be available in EU.

• One month later, Sanofi-Aventis decided it would no longer develop rimonabant for any further indication.

Topiramate

• Topiramate is an antiepileptic drug approved by the FDA as an anti-seizure medication in 1996.

• When reports surfaced that patients enrolled in initial trials of the drug and also in clinical practice were experiencing unexpected weight loss, the effects of the drug on weight began to be studied.

• Mechanism for weight loss is still poorly understood

Topiramate

• After 32 weeks, the changes in body weight were: – Placebo -11.2%, – 96-mg -16.3% (P </= .001)– 192-mg -17.3% (P </= .001)

• Visceral abdominal fat (VAF) measured by MRI after 32 wks: – Placebo -27.1%, – 96-mg -36.7% (P </= .001)– 192-mg -34.7% (P </= .001)

Exenatide

• Exenatide (Byetta) is a long-acting analogue of the hormone GLP-1, which the intestines secrete in response to the presence of food.

• Among other effects, GLP-1 delays gastric emptying and promotes a feeling of satiety.

• Some obese people are deficient in GLP-1.• Byetta is currently available as a treatment for type 2

diabetes. • Some, but not all, patients find that they lose substantial

weight when taking Byetta. • Drawbacks of Byetta include that it must be injected

subcutaneously twice daily, and that it causes severe nausea in some patients.

• Byetta is recommended only for patients with Type 2 Diabetes.

Lorcaserin - Mechanism of action

• Lorcaserin is a selective 5-HT2C receptor agonist• 5-HT2C receptors are located almost exclusively in the

brain (choroid plexus, cortex, hippocampus, cerebellum, amygdala, thalamus, and hypothalamus).

• Activation of 5-HT2C receptors in the hypothalamus is supposed to activate proopiomelanocortin (POMC) production and consequently promote weight loss through satiety.

• While it is generally thought that 5-HT2C receptors help to regulate appetite as well as mood, and endocrine secretion, the exact mechanism of appetite regulation is not yet known.

Lorcaserin – Safety Profile

• Lorcaserin produced side effects in clinical trials at rates not significantly different than placebo and mostly with mild and transient severity.

• The most common side effect was headache, experienced by about 18% of drug arm participants compared to 11% of placebo participants.

• Other reported side effects were: upper respiratory tract infection (14.8% vs. 11.9%; L:P), nasopharyngitis (13.4% vs. 12.0%), sinusitis (7.2% vs. 8.2%) and nausea (7.5% vs. 5.4%).

• Adverse events of depression, anxiety and suicidal ideation were infrequent and were reported at a similar rate in each treatment group.

• On 15 September 2010 it was reported that lorcaserinwas associated with the development of cancer in laboratory rats.

Lorcaserin – Safety Profile

• The manufacturer, Arena Pharmaceuticals, in agreement with FDA, agreed to perform ECHO sub-study to rule out an increase in the rate of valvulopathy, because a number of other drugs in this class have been withdrawn for these cardiovascular side-effects.

• Multiple echocardiograms were performed during the phase III studies, primarily at the BLOOM trial, and did not show any significant increase in valvulopathy at 3, 6, and 12-month intervals, compared with baseline

• Rates of new FDA-defined valvulopathy in BLOOM were as follows: lorcaserin 10 mg bid (2.7%) and placebo (2.3%) at Week 52 and lorcaserin 10 mg bid (2.6%) and placebo (2.7%) at Week 104.

• For BLOSSOM, rates of new FDA-defined valvulopathyat Week 52 were: lorcaserin 10 mg bid (2.0%), 10 mg once daily (1.4%) and placebo (2.0%).

Lorcaserin – State of affairs

• However, late last year the FDA rejected an application for lorcaserin, on the grounds that its benefits were outweighed by safety concerns.

• Part of the decision was related to carcinogenicity studies in animals, however, a key issue involved CV safety data from the randomized trials.

• For lorcaserin to be considered safe, the trials had to exclude the possibility that it raised the risk for cardiac valvular disease by 50% or more, ie, the upper bound of the 95% CI for RR had to be less than 1.5.

• However, lorcaserin was associated with a nonsignificant7% increase in the RR for valvular heart disease, with a 95% CI of 0.74-1.55. As a result, the trial missed its target and the drug's safety could not be confirmed.

• Key reason for this was that the lorcaserin event rate for valvular disease was only 2% (out of about 2500 patients in each group).

Contrave

• Contrave (NB) is a combination of bupropion, a relatively weak inhibitor of the neuronal uptake of norepinephrine (NE) and dopamine (DA), combined with naltrexone, a mu-opioid receptor antagonist.

• Both naltrexone, an opioid antagonist, and bupropion, an inhibitor of neuronal uptake of norepinephrine and dopamine, are already FDA approved for other indications;– naltrexone for opioid and alcohol addiction and – bupropion for depression, smoking cessation, and

seasonal affective disorder.

Contrave Mechanism of Action

• Bupropion has been shown to stimulate hypothalamic pro-opiomelanocortin (POMC) neurons that release alpha-melanocyte stimulating hormone (α-MSH) which, in turn, binds to MC4 receptors.

• The binding of α-MSH to MC4 receptors initiates a cascade of actions that results in reduced energy intake and increased energy expenditure.

• When α-MSH is released, POMCs simultaneously release β-endorphin, that mediates a negative feedback loop on POMC neurons leading to a decrease in the release of α-MSH.

• Blocking this inhibitory feedback loop with naltrexone is thought to facilitate a more potent and longer-lasting activation of POMC neurons, thereby amplifying effects on energy balance.

Contrave Mechanism of Action

• As a result, co-administration of bupropion and naltrexone produces a substantially greater effect on the POMC firing rate than either compound administered alone, suggesting that the drugs act synergistically.

Contrave Efficacy Data

• The mean weight-loss difference between contrave and placebo groups in the combined registration trials was 4.2%.

• This difference does not meet the 5% mean weight loss at one year criterion set out by the FDA in its 2007 guidance.

• However, in three of the four studies, the proportion of subjects taking contrave who lost at least 5% of their initial weight was 35% or more, double that seen in the placebo-treated group - meeting the FDA's second criterion for efficacy.

Contrave CV safety data

• Contrave was associated with statistically significant increases in both systolic and diastolic BP, compared with placebo, as well as increased heart rate.

• For other CV risk factors, compared with placebo contrave was associated with slight increases in HDL, more substantial decreases in triglycerides, minimal LDL changes, improvements in glucose and insulin parameters, and statistically significant decreases in HbA1c.

• One fatal MI, 1 nonfatal stroke, and 2 additional nonfatal MIs were seen among contrave-treated subjects.

• The FDA review concluded that: "Cardiovascular risk with naltrexone /bupropion cannot be adequately assessed due to the small number of ischemic CV events in the database and the very limited number of individuals with known CV disease at baseline in the development program."

Qnexa

• Qnexa is an investigational, once a day, proprietary, oral, controlled-release formulation of low dose phentermine and topiramate, which is believed to address both appetite and satiety - the two main mechanisms that impact eating behavior– Phentermine was approved in 1959 and is currently indicated as short

term treatment for weight reduction as an adjunct to exercise, behavior modification and caloric restriction. Phentermine is currently the most widely prescribed weight loss therapy in the U.S.

– Topiramate was first approved in 1996 as a treatment for epilepsy and more recently as a prophylactic for migraine.

• Three pivotal phase 3 trials evaluating Qnexa in over 4,500 patients as a treatment for obesity were recently completed under a Special Protocol Assessment by the U.S. FDA. Qnexa is currently under review by the FDA for the treatment of obesity and is not approved.

Qnexa: Phentermine

• Originally approved as short-term adjunct treatment in weight reduction by FDA in 1959

• Anorectic activity mediated through hypothalamic release of norepinephrine

• Published clinical studies demonstrating modest weight loss

Qnexa: Topiramate

• Approved in the US for treatment of seizure disorders (1996) and for prophylaxis of migraine headache (2004)

• Works through a combination of inhibition of food intake, increased energy expenditure and decreased energy efficiency

• Multiple mechanisms supporting positive effects on hypertension, diabetes and lipids

Qnexa Weight Reduction

Vi-0521 (Qnexa®) Advisory Committee Briefing Document

Qnexa CV Effects - Heart RateC

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asel

ine

in H

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Rat

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pm)

Vi-0521 (Qnexa®) Advisory Committee Briefing Document

Qnexa CV Effects – Blood Pressure

Vi-0521 (Qnexa®) Advisory Committee Briefing Document

Qnexa CV Effects – Blood Pressure

Blood Pressure Change From Baseline at Week 56 in Subjects With Hypertension

Vi-0521 (Qnexa®) Advisory Committee Briefing Document

Qnexa CV safety summary

• Thorough QT Study - No QTc prolongation of clinical or regulatory concern - Study validated using moxifloxacin positive control

• No increase in cardiovascular SAEs with QNEXA• Mean decline in systolic and diastolic BP observed

consistently across studies. • Small dose-related increase in heart-rate associated with

baseline values• Echocardiographic assessment performed on 50 subjects

excluded the presence of any valvular heart abnormalities.

Qnexa - state of affairs

• The FDA rejected Qnexa last October citing concerns the medicine may cause birth defects and increased HR.

• FDA asked Vivus to further characterize the CV profile by providing two-year follow-up data as well as additional information from the clinical program.

• Vivus agreed to conduct an analysis to assess fetal outcomes in offspring of women exposed to topiramate during the first trimester of pregnancy. Initial results of the study, titled "Fortress," are due for release in December.

• Vivus Inc. resubmitted Qnexa for FDA approval after updating the drug’s label to say it shouldn’t be used by women with childbearing potential.

• In addition to the label warning, the resubmission includes a risk evaluation and mitigation strategy.

The Myth of Anti-Obesity Drugs

• Poor patient compliance• Large market, short sale half-life• High Cost of developing New Drug• Long approval time (especially USA)• Safety outweighs efficacy (so far…)

Thanks You!