Dr. Geoffrey W. Guy Executive Chairman GW Pharmaceuticals plc, UK NIH, 21 April 2005

1. Dr. Geoffrey W. GuyExecutive ChairmanGW Pharmaceuticals plc, UK NIH, 21 April 2005

2. 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

3. Sativex: Public Health Rationale 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

4. 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 system

5. 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-psychotic Anti-oxidant, Neuroprotective, Immunomodulator • Other Cannabinoids • CBC (Cannabichromene) • CBG (Cannabigerol) • CBN (Cannabinol) • THC-V / CBC-V (Propyl derivatives)

6. 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

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

8. 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

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

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

12. 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

13. Quality

14. 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)

15. 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) Strip dried plants from stems Mill dried plant to defined particle size Apply BRM specification QC & Release Botanical Raw Material (BRM; contains: THCA + CBDA) Control of Starting Materials: GAP Cultivation

17. GMP Extraction Storage of BRM under appropriate conditions Selection of batch of stored BRM for extraction QC sampling / Release Controlled decarboxylation of BRM QC / In process control Primary Extraction of BRM under controlled conditions Further processing of Primary Extract under controlled conditions Apply macro / micro appearance Secondary Extract – Botanical Drug Substance (BDS) Apply BDS specification QC & Release BDS (contains: THC + CBD)

18. Storage of BDS under appropriate conditions Selection of batch of stored BDS for formulation QC sampling / Release Dissolve BDS in Solvent 1 Add Solvent 2 Dissolved BDS in vehicle Add Flavouring Mix final bulk solution QC / In process control Filter & fill final bulk Solution – Botanical Drug Product (BDP) Apply BDP specification QC & Release BDP (contains: THC + CBD) GMP Manufacture

19. 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

20. 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

21. 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

22. Product Portfolio PRODUCT INDICATION Pre-clin Phase I Phase II Phase III Submit Approval Sativex 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 THCPost-operative Pain Chronic Pain THC-V Neurotherapeutics Methadone Drug Dependency Diamorphine Drug Dependency

23. Safety & Efficacy:Clinical Program

24. Clinical Trials 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

25. Positive Findings in Phase II & III Studies

26. Positive Findings in Phase II & III Studies

27. Phase III Trial: Peripheral Neuropathic Pain • 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 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. Nurmikkoto the American Academy of Neurology (AAN), Miami, FL, USA09-16 April 2005, and IASP, Sydney, 21-26 August 2005

28. V1 Day 0 V2 Day 7 V3 Day 14 V4 Final Day 42 Study Entry Randomisation& DoseIntroduction SATIVEX® Open Label Extension Study GWEXT0102 4 weeks steady state Completion / Withdrawal Titration Period 1 week Baseline No Treatment Placebo 1 week 1 week 4 weeks Randomised Treatment Period (5 weeks) Phase III Trial: Study DesignPeripheral Neuropathic Pain

29. Peripheral Neuropathic PainStudy Dosing

30. Peripheral Neuropathic Pain:Improvement in NRS Pain Score from BL

31. Peripheral Neuropathic Pain:NRS Pain Scores: Responder Analysis

32. Peripheral Neuropathic Pain:Total PDI Score - Improvement from BL

33. 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, Italy Abstract 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

34. SATIVEX® Phase III Trial: Central Neuropathic Pain in MS: Dosing

35. Central Neuropathic Pain in MSImprovement in NRS Pain Scores from BL Scale = BS11 Scale 0-10 p-value obtained using ANCOVA, ITT

36. 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

37. Neuropathic Pain in MS Study Reduction in Sleep DisturbanceWeek 4 Analysis Scale = 0-10: 0 = did not disrupt10=completely disrupts p=-value obtained using ANCOVA, ITT

38. 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. Johnsonto IASP, Sydney 21-26 August 2005.

39. Phase III Trial: Cancer PainPain Scores (ITT)

40. Phase III Trial: Cancer Pain Responder Analysis (ITT)

41. Safety:Adverse Event (AE) Type • The Adverse Events likely to be present on Product Label are as follows: • Ear & Labyrinth disordersVertigo • 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 disordersDisturbance in attention, dizziness, somnolence. • Psychiatric disorders Disorientation, euphoric mood, dissociation. • Respiratory, thoracic and mediastinal disordersPharyngitis • 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)

42. Safety & Efficacy:Long Term Data

43. 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

44. 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

45. Multiple Sclerosis SymptomsLong Term Data

46. Multiple Sclerosis SymptomsLong Term Data Dosing Data

47. PainLong Term Data Dosing Data CBM 1:1

48. Preliminary Long Term Data Intoxication Scores n=137

49. Investigation of A Cannabinoid Withdrawal Syndrome: Experiences with Sativex® 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” Budney AJ et al. Review of the validity and significance of cannabis withdrawal syndrome. Am J Psychiatry 2004;161(11):1967-77.

50. 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