Nabilonein

C.I.N.V.

Nabilonein

C.I.N.V.

August 2007August 2007

2

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)

3

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

4

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

5

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

6

A Sequential Overview of Omnineuromodulation

7

Neurotransmitter (NT) released from vesicles within the presynaptic neuron activates the postsynaptic neuron

8

Activation of the postsynaptic neuron leads to the biosynthesis and nonvesicular release of an endocannabinoid, likely via a calcium mediated process

9

The endocannabinoid diffuses back to and binds to the presynaptic CB1 receptor

10

The CB1 receptor activates a G protein which can lead to a number of presynaptic downstream events (e.g., effects on ion currents) that result in the inhibition of neurotransmitter release

11

CB agents, acting as Omnineuromodulators, circumvent this multi-step process by directly activating CB1 receptors to stimulate the endogenous CB system, enhancing its function

12

Summary of Actions of the Cannabinoids

Neurotransmitter (NT) from presynaptic neuron activates the postsynaptic neuron.

1

23

4

5

Endogenous and ExogenousCannabinoids Reduce Neuronal

Signaling

PostsynapticNeuron

NeurotransmitterReceptor

Endogenous CannabinoidRetrograde Signaling

CB1 Receptor

PresynapticNeuron

Inhibition ofNeurotransmitter

Release

Cannabinoid Therapy(nabilone)

Activated postsynaptic neuron releases endocannabinoids.

Endogenous CB1 ligand diffuses back to and binds to the presynaptic CB1 receptor.

CB1 receptor activates a G-protein, leading to inhibition of NT release.

Nabilone is thought to activate CB1 receptors directly, mimicking the effects of endocannabinoids.

1

2

3

4

5

*see notes for references

13

Anti-emetic, Anti-nausea Effects of Cannabinoids

14

Causes of nausea and vomiting/emesis: Viral illness Cancer Chemotherapy Radiotherapy

15

• 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

Dorsal Vagal Complex (DVC)

- NTS

16

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

Cortex Limbic System

Cortex Limbic System

Brainstem Emetic Circuitry

Brainstem Emetic Circuitry

17

• 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 Dorsal Vagal

Complex - NTS

Dorsal Vagal Complex

- NTS

Brainstem Emetic

Circuitry

Brainstem Emetic

Circuitry

Cortex Limbic System

Cortex Limbic System

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Summary

• CB agonists act as Omnineuromodulators—a 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

19

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

20

• Nabilone delivers:1

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, in:1

Reduction of vomiting episodes

Reduction of nausea severity

Improvement in appetite

Investigators’ global impression of efficacy3

*see notes for references

Nabilone Pivotal StudiesNabilone Pivotal Studies

22

Placebo-Controlled, Fixed-Dose Trials

Primary Endpoint: Patient-Rated Efficacy Criteria

Both Cycles Combined

Frequency of Vomits Severity of Nausea Food Intake

Average Day 1 Average Day 1 Average Day 1

Nabilone Investigator 01 8.55 8.55 2.29 2.27 0.55 0.55 Investigator 02 4.16 5.58 1.19 1.45 0.84 0.75 Investigator 03 10.27 15.20 1.73 2.00 1.20 1.20 Investigator 04 2.33 2.33 1.75 1.75 1.00 1.00 Investigator 05 2.97 2.97 1.03 1.03 1.28 1.28 Investigator 06 4.53 4.53 1.25 1.25 1.33 1.33

Composite 4.51 5.09 1.31 1.39 1.10 1.09 Placebo

Investigator 01 13.73 13.73 2.89 2.91 0.38 0.36 Investigator 02 13.05 15.03 2.08 2.39 0.63 0.61 Investigator 03 34.60 36.80 2.67 2.80 0.40 3.40 Investigator 04 14.83 14.83 2.75 2.75 0.63 0.63 Investigator 05 7.47 7.47 2.25 2.25 0.50 0.50 Investigator 06 6.87 6.86 2.06 2.06 0.92 0.92

Composite 10.81 11.43 2.25 2.34 0.64 0.64

Number of vomitsNausea severity: 0=none, 1=mild, 2=moderate, 3=severeFood intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual

Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

23

Active-Controlled, Fixed-Dose Trials

Primary Endpoint: Patient-Rated Efficacy Criteria

Number of vomitsNausea severity: 0=none, 1=mild, 2=moderate, 3=severeFood intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual

Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

24

Primary Endpoint: Investigator-Rated Efficacy and Safety

Active-Controlled, Fixed-Dose Trials

Efficacy: 1=very good, 2=good, 3=fair, 4=poor, 5=very poorSafety: Based on the frequency of adverse events

Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

25

Active-Controlled, Flexible-Dose Trial

Primary Endpoint: Patient-Rated Efficacy Criteria

Number of vomitsNausea severity: 0=none, 1=mild, 2=moderate, 3=severeFood intake: 0=none, 1=less than usual, 2=usual amount or average, 3=more than usual

Data on File: Protocols 9, 20 and 28. Valeant Pharmaceuticals International.

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Patients Prefer Nabilone

Preferred Nabilone

Preferred Placebo

No Preference

Placebo-Controlled, Fixed-Dose Trials

Preferred Nabilone

Preferred ProchlorperazineNo Preference

Active-Controlled, Fixed-Dose Trials

77%

12%

12%

73%

20%

7%

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Summary: Nabilone and Reduction of Vomiting Frequency

ChemotherapyInducedNausea- and Vomiting

28Data on File: Protocol #9, #20, and #28. Valeant Pharmaceuticals North America.

Nabilone Reduces the Frequency of Vomiting

10.8

9.6

**5.4*

4.5

0

2

4

6

8

10

12

Vomiting Frequency

Av

era

ge

Nu

mb

er

of

Vo

mit

s

N=75

**P < 0.007

N=129

*P < 0.01

Reduction in Frequency of Vomiting

Nabilone NabilonePlacebo Prochlorperazine

29Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S.

10.30

5.09

3.603.24 2.97

1.12P=.003

1.25P=.001

1.08P<.001

2.05P<.001

7.05P<.001

0

2

4

6

8

10

12

Day 1 Day 2 Day 3 Day 4 Day 5

Nu

mb

er o

f Vo

mits

Nabilone Prochlorperazine

Nabilone Significantly Reduces Vomiting Frequency

30

8%

20%

32%

68%

15%

75%P<.00172%

P<.01

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

CR PR No Response Preference

% o

f P

ati

en

ts

Nabilone Prochlorperazine

CR=complete response; PR=partial response

Herman TS, et al. N Engl J Med. 1979;300:1295-1297.

Nabilone: Superior to Prochlorperazine in Patients with Severe CINV

31

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 physician’s armamentarium against the nausea and vomiting associated with chemotherapy in

patients who have failed to respond adequately to conventional antiemetic therapy

Summary: Nabilone and Reduction of Vomiting Frequency

32

Nabilone: In reduction of Nausea

ChemotherapyInducedNausea-

33

30 randomized, comparative studies of cannabinoids with placebo or other antiemetics

(oral Nabilone [nabilone]= 16 studies; oral dronabinol=11 studies; intramuscular levonatrodol=1 study)

Active control= prochlorperazine, metoclopramide, chlorpromazine, haloperidol, domperidone, and alizapride

Tramèr MR, et al. BMJ. 2001;323:1-8.

70%

59%57%

43%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Versus Placebo Versus Active

Co

mp

lete

co

ntr

ol o

f nau

sea

(% o

f pat

ien

ts)

Cannabinoid Control (placebo or active)

Control of Nausea Cannabinoids: A Systematic Review

34

Comparative Efficacy of Nabilone vs. Prochlorperazine

Data on File: Protocol #9, #20, and #28. Valeant Pharmaceuticals North America.

*Based on patients’ report (daily average): 0=none; 1=mild; 2=moderate; 3=severe

2.3

1.8**

1.3*

1.3

0

1

2

3

4

5

6

7

8

Na

us

ea

se

ve

rity

(m

ea

n s

co

re)

Nabilone Placebo

N=129

*P < 0.001

N=75

**P < 0.007

35

2.21

1.781.53 1.48

1.380.93

P=.0030.93

P<.0010.86

P<.001

1.18P<.001

1.96P=.049

0

0.5

1

1.5

2

2.5

3

Day 1 Day 2 Day 3 Day 4 Day 5

Nau

sea

seve

rity

(mea

n s

core

)

Nabilone Prochlorperazine

Score: 0=none; 1=mild; 2=moderate; 3=severe

Einhorn LH, et al. J Clin Pharmacol. 1981;21:64S-69S.

Nabilone Significantly Reduces Nausea Severity

36

Severity of Nausea Significantly Reduced with Nabilone

11.1

0.60.3

P<.005

0.4P<.01

0.1P<.05

0

0.5

1

1.5

2

2.5

3

Day 1 Day 2 Day 3

Severity of Nausea

Sy

mp

tom

sc

ore

(m

ea

n)

Nabilone Prochlorperazine

Ahmedzai S, et al. Br J Cancer. 1983;48:657-663.

37

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)

38

Several reductions in acute pain exacerbations and nighttime pain

Relief within 1 week of beginning Nabilone (n=1)

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”

Other benefits:Impact of Nabilone on Pain

45%

5%

15%

25%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

Pain Relief Temporary Partial Complete

% o

f P

ati

en

ts

A Retrospective Chart Review

Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.

39Berlach DM, et al. Am Acad Pain Med. 2006;7:25-29.

Other Benefits of Nabilone

Improvement in quality or duration

of sleep

Decreased nausea or vomiting

3 patients continued to take Nabilone for benefits other than

pain relief

•50% of patients •25% of patients•Sleep improvements (n=1)

•Decreased nausea & increased appetite (n=1)

•Decreased nausea and vomiting and increased sleep (n=1)

40

Benefits of Cannabinoids in Cancer Patients: A Retrospective Case Study

Cancer Patients referred for Palliative CareESAS available at baseline and follow-up

N=139

No Cannabinoid Rx

n=57

Cannabinoid RxTherapy Continued

n=65

Cannabinoid RxTherapy Stopped

n=17

Methodology

*Data on file

41

Edmonton Symptom Assessment System (ESAS)

42

Reasons for Cannabinoid Discontinuation

• 12/17 (71%) due to side effectsDrowsiness

Dizziness

Delirium

• 5/17 (29%) advised by other MDs

• Discontinuation Rate:Overall = 20.7%

Adjusted = 14.6%

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NabiloneTM (nabilone) Package Insert. Valeant Pharmaceuticals North America; 2006. Marinol® (dronabinol) Package Insert. Solvay Pharmaceuticals, Inc.

Differentiating Between the Cannabinoids: Pharmacokinetics

Nabilone Marinol

Oral Dosing1-2 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 metabolites2 active metabolites and more than 20 other metabolites

ClearanceMajor excretory pathway is the

biliary systemBiliary excretion is major route of elimination

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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

Nahas GG, Surim KM, Harvet DJ, Agurell S, eds. Marihuana and Medicine. Totowa, NJ: Human Press; 1999: 74-116. .

• 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

*Main metabolizing isoenzyme

Nab

ilon

eCannabinoid Metabolism

45

Safety Overview of Cannabinoids

Nabilone™ MARINOL® (dronabinol)

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

DrowsinessVertigoDry mouthEuphoriaAtaxiaHeadacheConcentration difficulties

AstheniaPalpitationsTachycardiaVasodilatation/facial flushAbdominal painNauseaVomitingAmnesia

Nabilone (NabiloneTM) Package Insert; San Diego, Valeant Pharmaceuticals North America; 2006; Dronabinol (Marinol® ) Package Insert. Marietta, Ga: Solvay Pharmaceuticals, Inc.; 2003.

Cannabinoids should not be taken with alcohol, sedatives, hypnotics, or other psychoticomimetic substances

AtaxiaConfusionDepersonalizationDizzinessEuphoriaParanoid reactionSomnolenceThinking abnormal

46

Summary

Treatment Challenges

Unique MOA of Cannabinoids

Clinical Trial Results

• CINV—a 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

END SLIDEEND SLIDE

QUESTIONS?QUESTIONS?

48

49

Adverse Events can be reported to the drug safety

department at Valeant Pharmaceuticals at UKsafety@valeant.com