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
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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
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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
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Endocannabinoid SystemEndocannabinoid SystemEndocannabinoid SystemEndocannabinoid System
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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