Dr. Geoffrey W. GuyExecutive Chairman

GW Pharmaceuticals plc, UK

NIH, 21 April 2005

GW Pharmaceuticals plc

• Founded in 1998 by Dr Geoffrey Guy and Dr Brian Whittle

• All research carried out under UK Government licences. Strong support from UK Home Office (Drugs Branch).

• Total investment raised - £60 million (US $110m)

• Publicly traded on London Stock Exchange

• Located on 4 UK sites

• 110 staff– Integrated R&D infrastructure (CMC, clinical, regulatory)

• Marketing partnership with Bayer HealthCare in UK and Canada

• Lead product, Sativex® buccal spray, approved in Canada April 2005 Neuropathic Pain in Multiple Sclerosis

Sativex® emphasises the importance of pharmaceutical solution– Required to meet standards of modern medicine: quality,

safety, efficacy– Standardized for composition and dosage– Non-smoked; delivered like other pharmaceutical products– Maintains integrity of physician-patient relationship– Clinical studies ensure physicians have appropriate

prescribing information– Prescription only; patients obtain only through monitored

health care sources, i.e., pharmacy– Reimbursed by health insurance– Eliminates physician liability for recommending unapproved

drug– Legal; no patient stigma– Remove patients from the broader controversy over marijuana

Sativex: Public Health Rationale

Cannabinoid System

• CB1 and CB2 receptors

• Pain, movement, neuromodulation, smooth muscle, inflammation, cytoprotection, feeding, perception, reward, cognition

• Pre-synaptic at Dopamine, GABA, Glutamate, 5HT, NA, ACH…

• Cross-talk – endorphine, vanilloid - organs

• Effects – TNF, ILs, NO, oxygen radicals, anti-oxidant

• Endocannabinoids:– Anandamide (AEA), 2-Arachidonoylglycerol (2-AG), Noladin ether,

Virodhamine, N‑arachidonoyl‑dopamine (NADA), Arachidonoyl‑serine (ARA‑S)

Homeostatic super-modulatory systemHomeostatic super-modulatory system

Phyto-Cannabinoids

• Cannabinoids - molecules unique to the cannabis plant

• Initial focus on two principal cannabinoids:THC (Tetrahydrocannabinol) and CBD (Cannabidiol)

• THC Analgesic, Anti-spasmodic, Anti-tremor, Anti-inflammatory, Appetite stimulant, Anti-emetic

• CBD Anti-inflammatory, Anti-convulsant, Anti-psychoticAnti-oxidant, Neuroprotective, Immunomodulator

• Other Cannabinoids• CBC (Cannabichromene)• CBG (Cannabigerol)• CBN (Cannabinol)• THC-V / CBC-V (Propyl derivatives)

Cannabinoid Therapeutic Window

• Objective: To provide and maintain therapeutic blood and tissue levels of key cannabinoid components without incurring unacceptable side effects

• Challenges– Inter-subject pharmacokinetic variability– Minimise Side Effects (psychoactivity) caused by

rapid rate of rise of plasma levels– Limitations to oral route– Poor aqueous solubility

Predictable Maintenance of acceptable risk / benefit Predictable Maintenance of acceptable risk / benefit

0

20

40

60

80

100

120

0 60 120 180 240 300 360

VaporisedTetranabinex® (THC BDS)

Mea

n TH

C P

lasm

a C

once

ntra

tion

(ng/

ml)

Time (Minutes) *Mean Dose in Study GWPK0114

THC plasma levels following administration of 6.65mg* of vaporised THC

Cannabinoid Therapeutic Window - Solutions

• Cannabinoid ratios widen window– CBD counters some of the side effects– CBD delays and reduces intensity of intoxication

• Route and method of delivery (DDS)– Mucosal route far less variable than Oral (GI)– Mucosal absorption decreases first pass

• Rate of absorption controlled and matches rate of redistribution in to lipid compartment

• Formulation and dosage form– Oromucosal spray

• Self-titration– Predictability

Predictable Maintenance Within Therapeutic Window Is Achieved

Predictable Maintenance Within Therapeutic Window Is Achieved

0

2

4

6

8

10

0 60 120 180 240 300 360

Oro-mucosalSativex®

Mea

n TH

C P

lasm

a C

once

ntra

tion

(ng/

ml)

Time (Minutes)#Mean Dose in Study GWPk0215

THC Plasma levels following administration of4 sprays of Sativex® (10.8mg THC & 10mg CBD#)

0

20

40

60

80

100

120

0 60 120 180 240 300 360

VaporisedTetranabinex®(THC BDS)

Oro-mucosalSativex®

Mea

n TH

C P

lasm

a C

once

ntra

tion

(ng/

ml)

Time (Minutes) *Mean Dose in Study GWPK0114#Mean Dose in Study GWPk0215

Comparison of THC plasma levels following administration of 6.65mg* of vaporised THC or4 sprays of Sativex® (10.8mg THC & 10mg CBD#)

Cannabinoid Botanical Medicines

• Breeding and cultivation of cannabis plant varieties

– Varieties bred for content of selected cannabinoid molecules

– Strict control of growing environment• Controlled breeding of cloned plants • Computer-controlled glasshouses • Strict quality control procedures

• Standardised whole plant extracts (GMP extraction)

• Formulation into non-smoked drug delivery systems

• Full commercial pharmaceutical development programme including pre-clinical and clinical research

• Submission and approval from regulatory authorities

Data must provide robust evidence for Quality, Safety, Efficacy

Data must provide robust evidence for Quality, Safety, Efficacy

Quality

Control of Starting Materials: Chemovar Consistency

• Extracts produced from specially bred plants (“chemovars”)• Result of a 15 Year Breeding Programme• Each plant selectively bred for:

– High rate of cannabinoid production

– High yield of cannabinoid per unit area

– High level of purity of the desired cannabinoid (purity as used here defines the consistency of cannabinoid content as a ratio)

– High inflorescence to leaf ratio (the ‘harvest index’)

– Natural resistance to pests and diseases

– Sturdy growth capable of bulk plant handling

– Ease of harvesting

– Minimal production of anthers on female plants

– Plant height

– Optimal time to flowering (critical day length)

 

Propagation from ‘mother plants’

Grow plants under controlled conditions (light, water, growth medium, heat, humidity, pest control)

Harvest plants

Dry plants under controlled conditions (temperature, humidity, light exclusion)

Mill dried plant to defined particle size

QC & Release Botanical Raw Material (BRM; contains: THCA + CBDA)

Strip dried plants from stems

Apply BRM specification

Control of Starting Materials: GAP Cultivation

 

GMP ExtractionStorage of BRM under appropriate conditions

Selection of batch of stored BRM for extraction

Controlled decarboxylation of BRM

Primary Extraction of BRM under controlled conditions

Secondary Extract – Botanical Drug Substance (BDS)

QC & Release BDS (contains: THC + CBD)

Apply BDS specification

QC sampling / Release

QC / In process control

Further processing of Primary Extract under controlled conditions

Apply macro / micro appearance

GMP ManufactureStorage of BDS under appropriate conditions

Selection of batch of stored BDS for formulation

Dissolve BDS in Solvent 1

Dissolved BDS in vehicle

Filter & fill final bulk Solution – Botanical Drug Product (BDP)

QC & Release BDP (contains: THC + CBD)

Apply BDP specification

QC sampling / Release

Add Solvent 2

Mix final bulk solution

Add Flavouring

QC / In process control

Sativex® Characterisation

•Principal Cannabinoids– THC* 27 mg/ml– CBD* 25 mg/ml

•Minor Cannabinoids– CBC*, CBG*, CBN*, THC-V*, CBD-V*, THCA*, CBDA*, CBO#, CBE#,

CBC-V, CBL•Terpenes

– trans-caryophyllene#, α-caryophyllene#, caryophyllene oxide,– α-pinene, β-pinene, terpinolene, myrcene, limonene, linalool– cis-nerolidol, trans-nerolidol, phytol, squalene

•Carotenoids– β-carotene#

•Fatty Acids– Linoleic acid, Palmitoleic acid, Linolenic acid, Palmitic acid, Oleic acid,

Stearic acid, Myristic acid, Arachidic acid and Behenic acid•Sterols

– Β-sitosterol, campesterol, stigmasterol•Vitamins

– Vitamin E•Triglycerides

– Trilinolenin, Trilinolein……. *Items controlled in the BDP specification

#Items controlled in the BDS specification

THCV Pharmacology

• Modulates / modifies CNS effects of THC

• Had been considered as less potent agonist at CB1

• THCV (e.g. 10 nM) antagonized WIN55212-2- & anandamide-induced inhibition of electrically-evoked contractions of the mouse vas deferens in a competitive, surmountable manner.

• This it does as potently as the established CB1 agonist, SR141716A (Rimonabant- Sanofi)

• Two targets for THCV seem to be present in the vas deferens• The CB1 receptor • A second non-CB1 target

• Further experiments are required to investigate• the location of this putative non-CB1 target in the vas deferens• the distribution of this putative non-CB1 outside the vas deferens • the nature of this putative non-CB1 target• SAR of ligands that interact with this putative non-CB1 target

• Further experiments are also required to investigate – if & how THCV modulates activity of the endocannabinoid system– the clinical consequences of any such modulation

THCV Implications

THCV may therefore have therapeutic use as:

• Appetite suppressant• Cessation of addictive behaviour (e.g. smoking)• Treatment for disorders which are abnormalities of CB1

mediated processes:– movement and postural control, pain and sensory

perception, memory, cognition, emotion, autonomic and endocrine functions

– obesity, schizophrenia, epilepsy or cognitive disorders such as Alzheimers, bone disorders, bulimia, obesity associated with type II diabetes (non-insulin dependant diabetes)

– the treatment of drug, alcohol or nicotine abuse or dependency

PRODUCT INDICATION Pre-clin Phase I Phase II Phase III Submit ApprovalSativex Multiple Sclerosis

THC:CBD MS Pain

(1:1 ratio) MS Spasticity

MS Bladder

Peripheral Neuropathic Pain

Allodynia

Diabetic Neuropathy

Central Neuropathic Pain

MS

Brachial Plexus

Spinal Cord Injury

Cancer Pain

High CBD Rheumatoid Arthritis

ratios Inflammatory Bowel Diseases

Neurogenic Symptoms

Psychotic Disorders

CNS (Epilepsy / Neuroprotection)

High THC Post-operative Pain

Chronic Pain

THC-V Neurotherapeutics

Methadone Drug Dependency

Diamorphine Drug Dependency

Product Portfolio

Safety & Efficacy:Clinical Program

• Over 1500 subjects participated in clinical program to date

• Approx 1000 patient-years of safety data

• Substantial body of positive clinical data– 7 Phase III trials – 5 Phase II trials – 13 Phase I trials– Long term extension studies

• All patients remain on current medication throughout trials, hence improvements seen are over and above that achieved with available medication

• 2 additional Phase III trials fully recruited and due to report in H1 2005

• No evidence of diversion/abuse to date

• Results presented at scientific meetings and published in peer reviewed journals

Clinical Trials Program

Positive Findings in Phase II & III Studies

Study Key Result P-value

PHASE III STUDIES

MS Spasticity (n=189) Spasticity 0.048

MS Symptoms (n=160) SpasticitySleep

0.0010.047

MS Neuropathic Pain (n=66) PainSleep

0.0050.003

Neuropathic Pain (allodynia) (n=125) PainSleep

0.0040.001

Cancer Pain (n=177) PainConstipation

0.0140.077

Pain in MS / other conditions (n=70) Pain(escape meds) 0.004

Neuropathic Pain (Brachial Plexus) (n=48) Pain,Sleep

0.0050.017

Positive Findings in Phase II & III Studies

Study Key Result P-value

PHASE II STUDIES

MS / Spinal Cord Injury (n=34) PainSleep

<0.0001 <0.0001

MS Symptoms (n=25) SpasticitySleep

0.0420.024

MS Bladder (n=21)

IncontinenceNocturiaUrgencyFrequency

<0.05<0.05<0.05<0.05

Rheumatoid arthritis (n=58)PainSleepDisease Activity

0.0180.0270.002

• Multi centre, double-blind, randomised, placebo-controlled parallel group study of Sativex for the treatment of peripheral neuropathic pain characterised by allodynia

• N=125 (n=63 Sativex, n=62 placebo)

• Treatment duration: 5 weeks

• 6 study centres

• All patients remain on current medication throughout trial

• Primary endpoint

– Change from baseline in average daily pain score after 5 weeks of treatment, evaluated from daily pain diaries and measured on a Numerical Rating Scale (NRS, 0-10) of pain severity

• Range of secondary endpoints, including sleep disturbance, allodynia, Pain Disability Index

Phase III Trial: Peripheral Neuropathic Pain

Abstract presented by Dr. M. Serpell at the UK Pain Society Meeting, Edinburgh, Scotland: 08-11 March 2005;Abstract accepted for poster presentation by Dr M Serpell at ENS, Vienna, 18-22 June,

Also presented by Prof. T. J. Nurmikko to the American Academy of Neurology (AAN), Miami, FL, USA09-16 April 2005, and IASP, Sydney, 21-26 August 2005

Phase III Trial: Study DesignPeripheral Neuropathic Pain

Randomised Treatment Period (5 weeks)

TitrationPeriod1 week

V1Day 0

BaselineNo

Treatment

Study Entry

SATIVEX®

Placebo

Open Label Extension Study

GWEXT0102

Randomisation& Dose

Introduction

Completion / Withdrawal

4 weeks steady state

1 week 1 week 4 weeks

V2Day 7

V3Day 14

V4 FinalDay 42

Peripheral Neuropathic PainStudy Dosing

Study GWNP0101 - Dosing by Study Week

0

5

10

15

20

25

Week 1 Week 2 Week 3 Week 4 Week 5

Study Week

Sativex

Placebo

Mea

n (

+/-

SE

) N

o. o

f S

pra

ys p

er D

ay

Peripheral Neuropathic Pain:Improvement in NRS Pain Score from BL

Study GWNP0101Improvement in BS-11 Pain Scores from Baseline

0

1

2

3

Sativex Placebo

Study Week

Ad

just

ed M

ean

BS

-11

Pai

n

Sco

re

SativexPlacebo

p=0.004*

*ANCOVA, ITT

Peripheral Neuropathic Pain:NRS Pain Scores: Responder Analysis

Study GWNP0101 BS-11 Pain Score: Responder Analysis

0

5

10

15

20

25

30

>= 30% >= 50%

% Improvement from Baseline

% o

f Pat

ient

s

SativexPlacebo

ITT Population

Peripheral Neuropathic Pain:Total PDI Score - Improvement from BL

Study GWNP0101 - Pain Disability IndexImprovement in Mean Total PDI Score from Baseline

-2

0

2

4

6

8

10

Sativex Placebo

SativexPlacebo

Ad

jus

ted

Mea

n C

ha

ng

e in

To

tal P

DI S

co

re

p=0.003*

Phase III Trial: Study DesignCentral Neuropathic Pain in MS

• Double blind, randomised, parallel group placebo controlled study of Sativex in central neuropathic pain in MS

• Single UK Centre Study

• N = 66

• Treatment duration: 5 weeks

• All patients remain on current medication throughout trial

• Primary endpoint

– Change from baseline in pain score averaged over last 7 days, evaluated from daily pain diaries and measured on a Numerical Rating Scale (NRS, 0-10) of pain severity

• Range of secondary endpoints, including neuropathic pain scale, sleep disturbance

Abstract presented by Dr. D. Rog at ECTRIMS 2003, September 17–20, 2003, Milan, ItalyAbstract presented by Dr D Rog at the American Pain Society, Boston, MA, USA, 30 March – 02 April 2005

Abstract submitted by Dr D Rog to CAPM&R Conference, Ottowa, June 15-18 2005 Abstract submitted by Dr. C.A. Young to IASP, Sydney, 21-26 August 2005

Phase III Trial: Central Neuropathic Pain in MS: Dosing

Mean Number Sprays per Day

Placebo THC:CBD

Tot

al S

pray

s pe

r D

ay

0

10

20

30

Treatment Day Number

0 7 14 21 28

SATIVEX®

Central Neuropathic Pain in MSImprovement in NRS Pain Scores from BL

p-value obtained using ANCOVA, ITTScale = BS11 Scale 0-10

Study MS0107 - Change in Adjusted Mean Pain BS11 Score from Baseline

0.00

0.50

1.00

1.50

2.00

2.50

3.00

Sativex PlaceboStudy Treatment

Red

uc

tio

n B

S1

1 S

co

re

fro

m B

as

eli

ne p =0.005*

Central Neuropathic Pain in MSNeuropathic Pain Scale ScoresMean Change from Baseline

Scale = 0-1000=No Pain, 100=Worst Possible

p-value obtained using ANCOVA, using Adjusted Means, ITT

Study MS0107 - Change in Mean Pain NPS Score from Baseline

0.00

2.00

4.00

6.00

8.00

10.00

12.00

14.00

16.00

18.00

Sativex PlaceboStudy Treatment

Re

du

cti

on

NP

S S

co

re f

rom

Ba

seli

ne

p =0.039*

Neuropathic Pain in MS Study Reduction in Sleep DisturbanceWeek 4 Analysis

p=-value obtained using ANCOVA, ITT

Scale = 0-10: 0 = did not disrupt10=completely disrupts

0.00

0.50

1.00

1.50

2.00

2.50

3.00

Sativex PlaceboStudy Treatment

Re

du

cti

on

NP

S S

co

re f

rom

Ba

seli

ne

p =0.003*

Study MS0107 - Change in Mean Sleep Disturbance Score from Baseline

Phase III Trial: Cancer Pain

• Design:

– Double blind, randomised, parallel group, placebo controlled, comparative study of Sativex and THC extract in patients with cancer pain

– 14-20 days treatment period

• Investigators:

– 20+ Centres

• Countries:

– UK, Belgium & Romania

• No. of Patients:

– N = 177 (n=60 Sativex®, n=58 THC extract, n=59 placebo)

• Patient characteristics:

- Pain not wholly relieved by strong opioids (e.g. morphine)

- Patients remain on existing opioid treatment during trial

Abstract presented by Dr. J. R. Johnson at the UK Pain Society Meeting, Edinburgh, Scotland: 08-11 March 2005.Abstract submitted by Dr J. Johnson to IASP, Sydney 21-26 August 2005.

Improvement from Baseline

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

Sativex THC Extract Placebo

Study Treatment

Re

du

cti

on

in

Me

an

NR

S P

ain

S

co

re

p=0.014*

p=0.24*

*ANCOVA, compared to placebo

Phase III Trial: Cancer PainPain Scores (ITT)

Responder Analysis (ITT)

0

10

20

30

40

50

60

70

80

> 0 >= 10% >= 20% >= 30% >= 40% >= 50%

% Response Level

% o

f P

ati

en

ts A

ch

iev

ing

R

es

po

ns

e L

ev

el

Sativex

THC Extract

Placebo

1.49*

1.66*

2.44*

2.81*

p=0.024#

2.17*

1.77*

* = Odds Ratio Sativex v placebo# = Fisher's Exact Test

Phase III Trial: Cancer Pain Responder Analysis (ITT)

Safety:Adverse Event (AE) Type• The Adverse Events likely to be present on Product Label are as

follows: – Ear & Labyrinth disorders

Vertigo– Gastrointestinal disorders

Dry mouth, Nausea, Oral discomfort, oral pain, diarrhoea, mouth ulceration– General disorders and administration site conditions

Application site pain, fatigue, feeling drunk, weakness, falling, lethargy, thirst.– Metabolism and Nutrition disorders– Appetite increased– Nervous system disorders

Disturbance in attention, dizziness, somnolence.– Psychiatric disorders

Disorientation, euphoric mood, dissociation.– Respiratory, thoracic and mediastinal disorders

Pharyngitis

• These are AEs most frequently observed in the SATIVEX® group in Phase III clinical trials and not seen at an equivalent incidence among placebo treated patients (greater than 3% incidence and SATIVEX® to placebo odds ratio 2)

Safety & Efficacy:Long Term Data

Tolerance: Definition

“Tolerance is a state of adaptation in which exposure to a drug induces changes that result

in a diminution of one or more of the drug’s effects over time.”

Consensus from American Academy of Pain Medicine, the American Pain Society, and the American Society of Addiction Medicine

Tolerance: Efficacy v Safety

Tolerance:

Undesirable: Loss of efficacy / beneficial effects or requirement for increasing dose to achieve same effect

Desirable: Loss / reduction in incidence /severity of side effects

Multiple Sclerosis SymptomsLong Term Data

Study GWMS0001 EXT - All SymptomsPatients Ongoing at 1 Year

0

10

20

30

40

50

60

70

80

0 13 26 39 52 65 78

Study Week Number

Pain(n=47)

Spasm(n=54)

Spasticity(n=66)

Bladder(n=57)

Tremor(n=35)

Mea

n S

ymp

tom

VA

S S

core

(0-

100m

m)

0 =

Bes

t P

oss

ible

100

= W

ors

t P

oss

ible

1 year

Multiple Sclerosis SymptomsLong Term Data Dosing Data

Study GWMS0001 EXT - Number of Sprays per Day of CBM 1:1Patients Ongoing at Visit 14 (Week 74)

0

4

8

12

16

20

24

18 26 34 42 50 58 66 74

Study Week

Sp

rays

per

Day

(+

/- S

E M

ean

)

Mean

Median

n=80 n=80

1 year

Note: Error bars represent +/- standard error

PainLong Term Data Dosing Data

CBM 1:1

Preliminary Long Term Data Intoxication Scores

Intoxication Scores (Clinic Visits)

010

2030

4050

6070

8090

100

BL 6 10 18 26 34 42 50 58 66 74 82

Study Week Number

VA

S In

toxi

catio

n S

core

(0-1

00m

m)

Sativex

Placebo

Placebo toSativex

Placebo Crossover to Sativex

n=137

Budney criteria:• Suggested definition of syndrome of ≥4 symptoms:

anger or aggression, decreased appetite or weight loss, irritability, nervousness or anxiety, restlessness, sleep difficulties or strange dreams, chills, depression, stomach pain, shakiness, sweating

plus “evidence that these symptoms produced clinically significant distress or dysfunction”

Investigation of A Cannabinoid Withdrawal Syndrome: Experiences with Sativex®

Budney AJ et al. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 2004;161(11):1967-77.

Budney AJ et al. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 2004;161(11):1967-77.

Effects of Cessation of Treatment with Sativex® in patients on long-term treatment

•Aim:– To assess whether abrupt discontinuation of Sativex® cannabis based

oromucosal medicine from long-term multiple sclerosis (MS) patients would result in a consistent withdrawal syndrome

•Methods– Subjects had completed at least one year of therapy, and had a stable

medical regimen for at least 2 weeks– Invited to discontinue Sativex® suddenly for 2 weeks with option to continue

an additional 2 weeks– At end of withdrawal, subjects rated MS symptoms as ‘much worse’, ‘worse’,

‘no change’, ‘better’, or ‘much better’– New symptoms were monitored– Subjects then opted to resume Sativex® or discontinue it

•Sample Size– N= 62 screened (33 declined to participate - i.e. refused to discontinue

Sativex®)– 3 were deemed unsuitable by PI– N= 26 enrolled, n=25 produced evaluable data

Effects of Cessation of Treatment with Sativex® (continued)•Results

– Efficacy• 26 patients (80%) completed 2 weeks of Sativex® abstinence, 25 with evaluable data• A total of 22 patients (88%) returned to treatment with Sativex® overall

– 5 patients (20%) resumed Sativex® during the 2 weeks due to MS symptom recurrence– 7 patients (28%) opted for a 2nd 2-week abstinence - 5 of these (71%) then resumed long-term Sativex®

– 2 remained off of Sativex® due to lack of symptom worsening– 1 further withdrawal due to house move out of the area

• 17 patients (68%) reported that their symptoms were “Worse or “Much Worse” off treatment (Global Assessment)

• 17 patients (68%) reported that 2 or more symptoms had worsened off treatment (VAS Scores)

• A total of 22 patients (88%) returned to treatment with Sativex® overall• Mean Sativex® dose was 13 sprays/day (35.1 mg THC + 32.5 mg CBD)

– Safety• No consistent withdrawal syndrome with symptom clusters or time of onset and remission was

detected• 13/24 (54%) patients had no withdrawal-type symptoms• Of 11 (46%) patients with some withdrawal symptoms, none met Budney criteria

•Conclusion• Abstinence from Sativex® was associated with re-emergence of MS-related symptoms in 7-10

days• No rebound phenomena were observed

Summary

• Pharmaceutical development program according to internationally recognised standards

• Therapeutic window achieved through cannabinoid ratios, drug delivery and predictable self-titration

• Substantial clinical data to confirm safety and efficacy• No tolerance to beneficial therapeutic effects• Apparent tolerance to side effects

– Adverse Events Diminish over time– Mean intoxication scores are low even during dose-titration– Mean intoxication scores diminish over time

• No identified withdrawal syndrome seen after abrupt cessation

• No evidence of diversion/abuse to date• First regulatory approval granted in Canada

Long Term Extension DataSymptom VAS Scores (Clinic Visits) in Patients Ongoing at 1 Year

0

10

20

30

40

50

60

70

80

BL 6 10 18 26 34 42 50 58

Study Week Number

Pain (n=44)

Spasm (n=48)

Spasticity (n=67)

BladderProblems (n=57)

Tremor (n=24)

VA

S S

core

(0-

100m

m)

0 =

Bes

t P

oss

ible

100

=W

ors

t P

oss

ible

Long Term DataMS Symptom VAS Scores

Long Term DataDosing

Median No. of Sprays per Day of Sativex

0

4

8

12

16

20

24

18 26 34 42 50 58 66 74

Study Week

Spr

ays

per

Day n=80 n=80

1 year