nonclinical overview: cns toxicity with rimonabant endocrinologic & metabolic drugs advisory...

Nonclinical Overview:Nonclinical Overview:CNS Toxicity with RimonabantCNS Toxicity with RimonabantNonclinical Overview:Nonclinical Overview:CNS Toxicity with RimonabantCNS Toxicity with Rimonabant

Endocrinologic & Metabolic Drugs Endocrinologic & Metabolic Drugs Advisory CommitteeAdvisory Committee

June 13, 2007June 13, 2007

Karen Davis-Bruno, Ph.D.Karen Davis-Bruno, Ph.D.Division of Metabolism & Endocrinology ProductsDivision of Metabolism & Endocrinology Products

Endocrinologic & Metabolic Drugs Endocrinologic & Metabolic Drugs Advisory CommitteeAdvisory Committee

June 13, 2007June 13, 2007

Karen Davis-Bruno, Ph.D.Karen Davis-Bruno, Ph.D.Division of Metabolism & Endocrinology ProductsDivision of Metabolism & Endocrinology Products

Center for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

2Endocrinologic & Metabolic Drugs Advisory Committee Endocrinologic & Metabolic Drugs Advisory Committee June 13, 2007June 13, 2007

Presentation OverviewPresentation OverviewPresentation OverviewPresentation Overview

• Role of the endogenous endocannabinoid system (ECS)

• Rimonabant pharmacology focused on its MOA

• Nonclinical toxicology focused on CNS

• Clinical relevance of CNS toxicity

• Role of the endogenous endocannabinoid system (ECS)

• Rimonabant pharmacology focused on its MOA

• Nonclinical toxicology focused on CNS

• Clinical relevance of CNS toxicity


ECS Modulatory RoleECS Modulatory RoleECS Modulatory RoleECS Modulatory Role

• Complex cellular signaling system

• Endogenous– CNS, PNS

• Neuroprotection– Functions

• Motor• Behavior• Cognitive• Memory

• Complex cellular signaling system

• Endogenous– CNS, PNS

• Neuroprotection– Functions

• Motor• Behavior• Cognitive• Memory

From: www.endocannabinoid.net


Endocannabinoid SystemEndocannabinoid SystemEndocannabinoid SystemEndocannabinoid System


On-Demand Activation of ECS:On-Demand Activation of ECS:Retrograde NeurotransmissionRetrograde NeurotransmissionOn-Demand Activation of ECS:On-Demand Activation of ECS:Retrograde NeurotransmissionRetrograde Neurotransmission

From: www.endocannabinoid.net


ECS Modulatory Role is ComplexECS Modulatory Role is ComplexECS Modulatory Role is ComplexECS Modulatory Role is Complex

• Tissue Level Effects: – Motor, behavior, cognition, memory, sensory

• Cellular Level Effects:– Neurotransmission

• Retrograde neurotransmission• Modulation of neurotransmitter activity

– e.g. GABA, DA, 5HT, glutamate, vanilloid, NMDA, Ach, NE, orexin-1

– Ion channel function (Ca, K channels)– Multimeric interaction of CB1R with other CNS receptors

• CB, DA, opioid, adenosine• Molecular Level:

– Pleiotropic effects on signal transduction• Inhibition of AC & PKA• Stimulation of MAPK• Effects on gene expression• Multiple G-proteins coupled to CB receptor

• Tissue Level Effects: – Motor, behavior, cognition, memory, sensory

• Cellular Level Effects:– Neurotransmission

• Retrograde neurotransmission• Modulation of neurotransmitter activity

– e.g. GABA, DA, 5HT, glutamate, vanilloid, NMDA, Ach, NE, orexin-1

– Ion channel function (Ca, K channels)– Multimeric interaction of CB1R with other CNS receptors

• CB, DA, opioid, adenosine• Molecular Level:

– Pleiotropic effects on signal transduction• Inhibition of AC & PKA• Stimulation of MAPK• Effects on gene expression• Multiple G-proteins coupled to CB receptor


Rimonabant Inverse Agonist Rimonabant Inverse Agonist PropertiesProperties

Rimonabant Inverse Agonist Rimonabant Inverse Agonist PropertiesProperties

• Binds at agonist receptor binding site

• Results in opposite effect- negative intrinsic activity

• Effective in receptors with intrinsic activity (e.g. CB1)

• Effect depends on:

– Ligand

– Tissue

– Dose

U-shaped dose-response curves seen for EC

• Binds at agonist receptor binding site

• Results in opposite effect- negative intrinsic activity

• Effective in receptors with intrinsic activity (e.g. CB1)

• Effect depends on:

– Ligand

– Tissue

– Dose

U-shaped dose-response curves seen for EC


Rimonabant Pharmacology Rimonabant Pharmacology Rimonabant Pharmacology Rimonabant Pharmacology

1. Rimonabant competes with endogenous endocannabinoids for CB1 receptor binding

2. Inverse agonism resulting from negative modulation of CB1 receptor constitutive activity

• Allosteric effects• Active/on to inactive/off state

3. CB1 receptor independent mechanisms• For example: antagonism of endogenous

adenosine at A1 receptors

1. Rimonabant competes with endogenous endocannabinoids for CB1 receptor binding

2. Inverse agonism resulting from negative modulation of CB1 receptor constitutive activity

• Allosteric effects• Active/on to inactive/off state

3. CB1 receptor independent mechanisms• For example: antagonism of endogenous

adenosine at A1 receptors


Rimonabant

?

Animal Adverse Effects:SeizuresTremors

Impaired movementSleep disturbance

HyperesthesiaAnxiety

Hyperexcitability

Desired Effects:

Appetite

Food Intake

Body Weight

Other Beneficial Effects: TG, HDL-C, HbA1c

?

CB1

CB1

(─)

(─)

Rimonabant Pharmacology


ECS Effects ECS Effects ± Rimonabant± RimonabantECS Effects ECS Effects ± Rimonabant± Rimonabant Endocannabinoid System EffectsModulation

ofConstitutive Effect

Rimonabant Effect

Motor↓ activityanti-convulsant

seizures, tremors,Impaired and ↓ movement

Sensory ↓ pain

Hyperesthesia,↓ body temperature,hyper-excitability,↑ startle response

Behavioranti-anxietysomnolenceorexigenic

Anxiety,sleep disturbances,anti-orexigenic


CB1 receptors:CB1 receptors:Conservation Across SpeciesConservation Across Species

CB1 receptors:CB1 receptors:Conservation Across SpeciesConservation Across Species

• Similarity of √ CNS regional distribution√ Receptor homology√ Ligand affinity

Animal models have clinical relevance

• Similarity of √ CNS regional distribution√ Receptor homology√ Ligand affinity

Animal models have clinical relevance


Key Points Key Points CB1 Receptor PharmacologyCB1 Receptor Pharmacology

Key Points Key Points CB1 Receptor PharmacologyCB1 Receptor Pharmacology

• The ECS has pleiotropic neuromodulatory functions

• ECS is involved in the regulation of CNS activity through CB1 receptors

• CB1 receptor sequence & distribution are highly conserved across species

• Rimonabant is a CB1 receptor antagonist with complex pharmacology and similar affinity across species

• The ECS has pleiotropic neuromodulatory functions

• ECS is involved in the regulation of CNS activity through CB1 receptors

• CB1 receptor sequence & distribution are highly conserved across species

• Rimonabant is a CB1 receptor antagonist with complex pharmacology and similar affinity across species


Nonclinical Toxicology of Rimonabant Nonclinical Toxicology of Rimonabant Nonclinical Toxicology of Rimonabant Nonclinical Toxicology of Rimonabant − Pharmacology− General toxicology in mice, rats, dogs, and

monkeys− Chronic tox rat (6 mo) & monkey (12 mo)

− Two-year rat & mouse carcinogenicity studies− Genotoxicity studies− Reproductive toxicity studies in rats and rabbits

CNS major target organ of concern

− Pharmacology− General toxicology in mice, rats, dogs, and

monkeys− Chronic tox rat (6 mo) & monkey (12 mo)

− Two-year rat & mouse carcinogenicity studies− Genotoxicity studies− Reproductive toxicity studies in rats and rabbits

CNS major target organ of concern


Lowest Effective Dose for CNS Toxicities atLowest Effective Dose for CNS Toxicities at Clinical Exposure (20 mg/day)Clinical Exposure (20 mg/day)

Lowest Effective Dose for CNS Toxicities atLowest Effective Dose for CNS Toxicities at Clinical Exposure (20 mg/day)Clinical Exposure (20 mg/day)

CNS Toxicities Mouse Rat Monkey Dog Rabbit

Mortality 2X 1X >3X >5X <1X

Convulsion 3X 1X 2X

Tremor 1X 4X

Motor effects 1X 1X 3X 5X

Aggressiveness 1X 5X

Anxiety 1X 2X 5X


Seizure: No Safety MarginsSeizure: No Safety MarginsSeizure: No Safety MarginsSeizure: No Safety Margins

CNS Toxicity

Effect of RimonabantMultiple of Human

Exposure

SpeciesNOAEL (mg/kg)

Safety Margin*

Based on AUC

Safety Margin*

Based on Cmax

Convulsion

Mouse 20 1X 2X

Rat 2.5 <1X <1X

Monkey 4 <1X <1X

Dog 15 3X 3X

TremorRat 2.5 <1X <1X

Dog 5 1X 2X

Safety Margin = Exposure in animals at NOAEL / Exposure in humans at 20 mg/day


Time-Dependent Progressive Convulsive Time-Dependent Progressive Convulsive Activity in Multiple SpeciesActivity in Multiple Species

Time-Dependent Progressive Convulsive Time-Dependent Progressive Convulsive Activity in Multiple SpeciesActivity in Multiple Species

Minimum Dose Associated with Convulsions

Species Tested

Acute ToxicityStudies(mg/kg)

Sub-acute Toxicity Studies

(mg/kg/day)

Chronic Toxicity Studies

(mg/kg/day)

Mouse 2000 120 60

Rat 60 6

Monkey 15 12


Dose-Dependent SeizuresDose-Dependent SeizuresLifetime Rat BioassayLifetime Rat Bioassay

Dose-Dependent SeizuresDose-Dependent SeizuresLifetime Rat BioassayLifetime Rat Bioassay

0

5

10

15

20

25

Control LD MD HD

An

imal

s w

ith

Co

nvu

lsio

n (

%)

Male Female


Rimonabant potentiates PTZ-induced Rimonabant potentiates PTZ-induced convulsions & mortality in mice after S.D.convulsions & mortality in mice after S.D.

Rimonabant potentiates PTZ-induced Rimonabant potentiates PTZ-induced convulsions & mortality in mice after S.D.convulsions & mortality in mice after S.D.

NDA21-888 Sanofi


Key Points: Rimonabant CNS Toxicity Key Points: Rimonabant CNS Toxicity Key Points: Rimonabant CNS Toxicity Key Points: Rimonabant CNS Toxicity

• Rimonabant blockade of CB1 receptors appears to influence the anti-convulsant tone of ECS

• Rimonabant induced dose-dependent seizures in association with CB1 receptor antagonism in multiple species

• Seizures were dependent on the dose and duration of rimonabant treatment

• Seizures occurred at animal exposures equivalent to systemic exposure in humans at the proposed clinical dose (20 mg/day)

• Rimonabant blockade of CB1 receptors appears to influence the anti-convulsant tone of ECS

• Rimonabant induced dose-dependent seizures in association with CB1 receptor antagonism in multiple species

• Seizures were dependent on the dose and duration of rimonabant treatment

• Seizures occurred at animal exposures equivalent to systemic exposure in humans at the proposed clinical dose (20 mg/day)


Experience with other CB1 Experience with other CB1 antagonistsantagonists

Experience with other CB1 Experience with other CB1 antagonistsantagonists

• Several applications for CB1 receptor antagonists under review

• CNS toxicity is observed but at ≥ 10X therapeutic exposure– Convulsions– Tremor– Motor dysfunction– Suggests rimonabant differs from others in the

class by its narrow therapeutic index

• Several applications for CB1 receptor antagonists under review

• CNS toxicity is observed but at ≥ 10X therapeutic exposure– Convulsions– Tremor– Motor dysfunction– Suggests rimonabant differs from others in the

class by its narrow therapeutic index


Clinical Relevance of CNS ToxicityClinical Relevance of CNS ToxicityClinical Relevance of CNS ToxicityClinical Relevance of CNS Toxicity

Clinically Relevant

Rimonabant Effects

Multiples of Human Therapeutic Exposure*

Mouse Rat Monkey Dog Rabbit

Desired pharmacologic activity

Weight loss <1 <1 <1 1 <1

CNS toxicities

Mortality 2 1 >3 >5 <1

Convulsion 3 1 2

Tremor 1 4

Motor effects 1 1 3 5

Anxiety 1 2 5*Animal exposure at NOAEL / Clinical exposure at 20 mg/day

↓ Weight & CNS Toxicity at Similar Drug Exposures


SummarySummarySummarySummary

• CNS toxicity occurs in multiple species at therapeutic exposure levels based on a 20 mg clinical dose

• Dose-dependent CNS toxicities occur as a result of antagonism of the CB1 receptor and disturbance of the ECS homeostatic regulation

• The plausible MOA associated with weight loss appears associated with CNS toxicity

• Other drugs in the class show similar toxicities but occur at much higher animal exposures

• There are limited, if any, differences between exposures generating the desired pharmacologic effect and those associated with significant animal toxicity (seizures, mortality) supporting the clinical relevance of the CNS toxicity

• CNS toxicity occurs in multiple species at therapeutic exposure levels based on a 20 mg clinical dose

• Dose-dependent CNS toxicities occur as a result of antagonism of the CB1 receptor and disturbance of the ECS homeostatic regulation

• The plausible MOA associated with weight loss appears associated with CNS toxicity

• Other drugs in the class show similar toxicities but occur at much higher animal exposures

• There are limited, if any, differences between exposures generating the desired pharmacologic effect and those associated with significant animal toxicity (seizures, mortality) supporting the clinical relevance of the CNS toxicity


ConclusionsConclusionsConclusionsConclusions• Rimonabant is a 1st in class, CB1 receptor antagonist for the

management of obesity

• Sufficient information to demo complex pharmacologic profile

• Blockade of ECS-mediated orexigenic stimulus may be desirable for obesity but a similar blockade of other CNS functions under regulation by ECS would not be desirable

• Studies in relevant animal species show CNS toxicities at clinically relevant therapeutic exposures

• European Regulators (EMEA) 2006: “….nonclinical studies could provide no reassurance regarding margins to the clinical exposure. Consequently, the safe use of rimonabant has to rely more on the clinical safety data and post-approval pharmacovigilance programme.”

• CNS adverse events consistent with the MOA are reported in the clinic and post-marketing

• Rimonabant is a 1st in class, CB1 receptor antagonist for the management of obesity

• Sufficient information to demo complex pharmacologic profile

• Blockade of ECS-mediated orexigenic stimulus may be desirable for obesity but a similar blockade of other CNS functions under regulation by ECS would not be desirable

• Studies in relevant animal species show CNS toxicities at clinically relevant therapeutic exposures

• European Regulators (EMEA) 2006: “….nonclinical studies could provide no reassurance regarding margins to the clinical exposure. Consequently, the safe use of rimonabant has to rely more on the clinical safety data and post-approval pharmacovigilance programme.”

• CNS adverse events consistent with the MOA are reported in the clinic and post-marketing

nonclinical overview: cns toxicity with rimonabant endocrinologic & metabolic drugs advisory...

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