Nabilone in C.I.N.V.

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NabiloneinC.I.N.V.

• August 2007

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Introduction

• Present a scientific validation for cannabinoids
  (CBs) asserting their therapeutic effects through
  Omnineuromodulation
• CBs activate CB1 endocannabinoid receptors, which
  are omnipresent throughout the Central Nervous
  System (CNS)
• Action on these receptors modulates neuronal
  signaling
• Review evidence showing how omnineuromodulation
  underlies the therapeutic role of CBs in the
  management of Chemotherapy-Induced Nausea and
  Vomiting (CINV)

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The Ubiquitous CB1

• Endogenous CBs are a major class of
  neuromodulators, acting through receptors, CB1
  and CB2
• CB1 receptors are primarily located on CNS
  neurons
• Levels exceed those of nearly all
  neurotransmitter receptors
• Exogenous CBs exert their effects by driving this
  innate system, often mimicking and enhancing its
  natural functions

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The Ubiquitous CB1

• The omnipresent central distribution of CB1, has
  led to the term, Omnineuromodulator, to
  describe CB action
• Therapeutic effects are primarily due to agonist
  action in brain regions that mediate
  nausea/vomiting, appetite, and neuropathic pain

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Omnineuromodulation

• Nabilone acts on presynaptic CB1 receptors,
  similar to endocannabinoids
• Inhibits the release of excitatory (e.g.,
  glutamate) and inhibitory (e.g., GABA)
  neurotransmitters
• The primary effect on neuronal signaling appears
  to be inhibitory, but network effects may be
  complex and hence modulatory in nature
• Endogenous CB1 ligands act backwards from
  classical neurotransmitters by serving as
  retrograde synaptic messengers

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A Sequential Overview of Omnineuromodulation
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CB agents, acting as Omnineuromodulators,
circumvent this multi-step process by directly
activating CB1 receptors to stimulate the
endogenous CB system, enhancing its function
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Summary of Actions of the Cannabinoids
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Cannabinoid Therapy(nabilone)
Neurotransmitter (NT) from presynaptic neuron
activates the postsynaptic neuron.
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Inhibition ofNeurotransmitterRelease
Activated postsynaptic neuron releases
endocannabinoids.
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CB1 Receptor
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PresynapticNeuron
Endogenous CB1 ligand diffuses back to and binds
to the presynaptic CB1 receptor.
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1
Endogenous CannabinoidRetrograde Signaling
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2
CB1 receptor activates a G-protein, leading to
inhibition of NT release.
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NeurotransmitterReceptor
PostsynapticNeuron
Nabilone is thought to activate CB1 receptors
directly, mimicking the effects of
endocannabinoids.
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Endogenous and ExogenousCannabinoids Reduce
Neuronal Signaling
see notes for references
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Anti-emetic, Anti-nausea Effects of Cannabinoids
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Causes of nausea and vomiting/emesis Viral
illness Cancer Chemotherapy
Radiotherapy
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• The Nucleus of the Solitary Tract (NTS) in the
  DVC receives information about
• Blood-borne emetics via the brainstem (BS)
  Chemo-receptor Trigger Zone
• Abdominal irritants via vagal afferents
• NTS neurons, in turn, project to a BS central
  pattern generator, which coordinates vomiting
  behavior

Dorsal Vagal Complex (DVC) - NTS
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Higher cortical and limbic regions (governing
taste, smell, sight, pain, memory and emotion)
can suppress or stimulate nausea/vomiting through
descending connections to the BS emetic circuitry
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• Cannabinoids are thought to exert their
  antiemetic effects primarily via action on CB1
  receptors in the NTS and higher cortical and
  limbic regions
• Indirect, partial actions on 5-HT and DA
  signaling via 5-HT3 and D2 receptors are
  implicated

Cortex Limbic System
Brainstem Emetic Circuitry
Dorsal Vagal Complex - NTS
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Summary

• CB agonists act as Omnineuromodulatorsa term
  that describes their role in activating CB1
  endocannabinoid receptors, which are omnipresent
  throughout the CNS and modulate neuronal
  signaling
• Evidence shows that Omnineuromodulation underlies
  the therapeutic role of CB agents in the
  treatment of CINV, Cachexia, and Neuropathic Pain

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• Approved License for the treatment of nausea and
  vomiting associated with cancer chemotherapy in
  patients who have failed to respond adequately to
  conventional anti-emetic treatments

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• Nabilone delivers1
• Convenient BID dosing The usual adult dosage is
  1 or 2 mg BID
• Predictable pharmacokinetics Peak plasma
  concentrations occur within 2 hours following
  oral administration
• Long acting 8 to 12 hour duration of action
• Not detected by the EMIT test2
• In anti-emetic phase III studies, involving 316
  cancer patients receiving a variety of
  chemotherapeutics (including cisplatin), nabilone
  was shown to be superior in efficacy to placebo,
  as well as to prochlorperazine, in1
• Reduction of vomiting episodes
• Reduction of nausea severity
• Improvement in appetite
• Investigators global impression of efficacy3
• see notes for references

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Nabilone Pivotal Studies
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Placebo-Controlled, Fixed-Dose Trials
Number of vomits Nausea severity 0none, 1mild,
2moderate, 3severe Food intake 0none, 1less
than usual, 2usual amount or average, 3more
than usual
Data on File Protocols 9, 20 and 28. Valeant
Pharmaceuticals International.
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Active-Controlled, Fixed-Dose Trials
Primary Endpoint Patient-Rated Efficacy Criteria
Number of vomits Nausea severity 0none, 1mild,
2moderate, 3severe Food intake 0none, 1less
than usual, 2usual amount or average, 3more
than usual
Data on File Protocols 9, 20 and 28. Valeant
Pharmaceuticals International.
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Active-Controlled, Fixed-Dose Trials
Primary Endpoint Investigator-Rated Efficacy and
Safety
Efficacy 1very good, 2good, 3fair, 4poor,
5very poor Safety Based on the frequency of
adverse events
Data on File Protocols 9, 20 and 28. Valeant
Pharmaceuticals International.
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Active-Controlled, Flexible-Dose Trial
Primary Endpoint Patient-Rated Efficacy Criteria
Number of vomits Nausea severity 0none, 1mild,
2moderate, 3severe Food intake 0none, 1less
than usual, 2usual amount or average, 3more
than usual
Data on File Protocols 9, 20 and 28. Valeant
Pharmaceuticals International.
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Patients Prefer Nabilone
Active-Controlled, Fixed-Dose Trials
Placebo-Controlled, Fixed-Dose Trials
77
73
12
20
12
7
Preferred Nabilone
Preferred Nabilone
Preferred Prochlorperazine
Preferred Placebo
No Preference
No Preference
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Summary Nabilone and Reduction of Vomiting
Frequency
C
I
N
V
-
Chemotherapy
Induced
Nausea
and Vomiting
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Nabilone Reduces the Frequency of Vomiting
Reduction in Frequency of Vomiting
N75 P lt 0.007
N129 P lt 0.01
Prochlorperazine
Nabilone
Placebo
Nabilone
Data on File Protocol 9, 20, and 28. Valeant
Pharmaceuticals North America.
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Nabilone Significantly Reduces Vomiting Frequency
Einhorn LH, et al. J Clin Pharmacol.
19812164S-69S.
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Nabilone Superior to Prochlorperazine in
Patients with Severe CINV
CRcomplete response PRpartial response
Herman TS, et al. N Engl J Med.
19793001295-1297.
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Summary Nabilone and Reduction of Vomiting
Frequency

• CINV is an established indication for Nabilone
• Clinical trials have confirmed the efficacy of
  Nabilone in reducing frequency of vomiting in
  cancer patients receiving chemotherapy
• Nabilone is an important addition to the
  physicians armamentarium against the nausea and
  vomiting associated with chemotherapy in patients
  who have failed to respond adequately to
  conventional antiemetic therapy

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Nabilone In reduction of Nausea
C
I
N
V
-
Chemotherapy
Induced
Nausea
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Control of Nausea Cannabinoids A Systematic
Review
30 randomized, comparative studies of
cannabinoids with placebo or other antiemetics
(oral Nabilone nabilone 16 studies oral
dronabinol11 studies intramuscular
levonatrodol1 study)
Active control prochlorperazine, metoclopramide,
chlorpromazine, haloperidol, domperidone, and
alizapride
Tramèr MR, et al. BMJ. 20013231-8.
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Comparative Efficacy of Nabilone vs.
Prochlorperazine
N129 P lt 0.001
N75 P lt 0.007
Based on patients report (daily average)
0none 1mild 2moderate 3severe
Data on File Protocol 9, 20, and 28. Valeant
Pharmaceuticals North America.
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Nabilone Significantly Reduces Nausea Severity
Score 0none 1mild 2moderate 3severe
Einhorn LH, et al. J Clin Pharmacol.
19812164S-69S.
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Severity of Nausea Significantly Reduced with
Nabilone
Ahmedzai S, et al. Br J Cancer. 198348657-663.
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Summary Nausea

• Nausea is more difficult to control than is
  vomiting
• Control of nausea remains a significant unmet
  need in cancer patients receiving chemotherapy
• Nabilone has demonstrated efficacy in reducing
  the severity of nausea
• Patients prefer Nabilone over placebo and active
  controls (prochlorperazine, metoclopramide,
  chlorpromazine, thiethylperazine, haloperidol,
  domperidone, alzapride)

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Other benefitsImpact of Nabilone on Pain
A Retrospective Chart Review

• Several reductions in acute pain exacerbations
  and nighttime pain
• Relief within 1 week of beginning Nabilone (n1)
• Patients testimonial
• Taking Nabilone at night made pain more
  localized, and relief lasted until the following
  afternoon
• Nabilone made pain livable
• Nabilone takes the edge off

Berlach DM, et al. Am Acad Pain Med. 2006725-29.
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Other Benefits of Nabilone
3 patients continued to take Nabilone for
benefits other than pain relief
Improvement in quality or duration of sleep
Decreased nausea or vomiting

• Sleep improvements (n1)
• Decreased nausea increased appetite (n1)
• Decreased nausea and vomiting and increased sleep
  (n1)

• 25 of patients

• 50 of patients

Berlach DM, et al. Am Acad Pain Med. 2006725-29.
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Benefits of Cannabinoids in Cancer Patients A
Retrospective Case Study
Methodology
Data on file
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Edmonton Symptom Assessment System (ESAS)
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Reasons for Cannabinoid Discontinuation

• 12/17 (71) due to side effects
• Drowsiness
• Dizziness
• Delirium
• 5/17 (29) advised by other MDs
• Discontinuation Rate
• Overall 20.7
• Adjusted 14.6

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Differentiating Between the Cannabinoids
Pharmacokinetics
Nabilone Marinol
Oral Dosing 1-2 mg 1-3 hrs before chemotherapy, and 2 times per day for up to 48 hrs afterwards 5 mg/m2 1-3 hrs before chemotherapy, and every 2-4 hrs afterwards for a total of 4-6 doses per day
Source Synthetic ?9-THC analog Synthetic ?9-THC
Formulation Crystalline powder capsule Capsule formulated with sesame oil, among other ingredients (contraindicated in patients with a hypersensitivity to sesame oil)
Onset of Action 60-90 min 30-60 min
Peak plasma concentrations (Tmax) 2 hrs 2-4 hrs
Duration of Action 8-12 hrs 4-6 hrs for psychoactive effects
Metabolites 2 active metabolites 2 active metabolites and more than 20 other metabolites
Clearance Major excretory pathway is the biliary system Biliary excretion is major route of elimination
NabiloneTM (nabilone) Package Insert. Valeant
Pharmaceuticals North America 2006. Marinol
(dronabinol) Package Insert. Solvay
Pharmaceuticals, Inc.
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Cannabinoid Metabolism
CYP450 Metabolizing Enzymes CYP450 Enzyme Inhibition CYP450 Enzyme Induction
Nabilone 2C9, 3A4 (aldehyde oxygenase) None to Date None to Date
Marinol 2C9, 2C11, 3A4 (aldehyde oxygenase) 3A4 None to Date
Main metabolizing isoenzyme

• Metabolized principally through the CYP450 2C9
  isoenzyme
• No inhibitory or inducing effect on any of the
  isoenzymes
• Competes with very few medications at the
  metabolic level, including opioids
• Examples of medications metabolized by CYP3A4
  anti-fungals, methadone, many anti-depressants,
  HIV protease inhibitors

Nabilone
Nahas GG, Surim KM, Harvet DJ, Agurell S, eds.
Marihuana and Medicine. Totowa, NJ Human Press
1999 74-116. .
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Safety Overview of Cannabinoids
Cannabinoids should not be taken with alcohol,
sedatives, hypnotics, or other psychoticomimetic
substances
Nabilone MARINOL (dronabinol)
Contraindications Contraindications
In patients with a history of hypersensitivity to any cannabinoid In patients with a history of hypersensitivity to any cannabinoid or sesame oil
Most Commonly Occurring Adverse Effects Most Commonly Occurring Adverse Effects
Drowsiness Vertigo Dry mouth Euphoria Ataxia Headache Concentration difficulties Asthenia Palpitations Tachycardia Vasodilatation/facial flush Abdominal pain Nausea Vomiting Amnesia
Ataxia Confusion Depersonalization Dizziness Eupho
ria Paranoid reaction Somnolence Thinking abnormal
Nabilone (NabiloneTM) Package Insert San Diego,
Valeant Pharmaceuticals North America 2006
Dronabinol (Marinol ) Package Insert. Marietta,
Ga Solvay Pharmaceuticals, Inc. 2003.
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Summary
Treatment Challenges
Clinical Trial Results
Unique MOA of Cannabinoids

• CINVa highly prevalent side effect of cancer
  treatment
• Persistent CINV is associated with several
  adverse sequelae
• Pain is often under-diagnosed and under-treated

• Target ubiquitous CB receptors in the CNS and
  periphery
• CINV agonism of CB1 receptors inhibits
  neurotransmitters
• Pain neuromodulatory effects involving both CB1
  and CB2 receptors

• Support the use of cannabinoids to treat
  refractory CINV
• Suggest that cannabinoids may be useful
  adjunctive therapy for pain

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• QUESTIONS?

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Adverse Events can be reported to the drug safety
department at Valeant Pharmaceuticals at
UKsafety_at_valeant.com