1. Finding the Medicine in
Marijuana
Alice P. Mead
GW Pharmaceuticals
Presentation to the 2012 Nevada Marijuana Summit
October 1, 2012

2. Myth: Who Killed Marijuana?
 Marijuana was widely used as a medicine
until the federal government killed it with
the Marijuana Tax Act in 1937
2

3. Fact
 Crude marijuana extracts and tinctures
couldn’t compete with modern opiates and
new synthetic medicines
3

4. Modern History
 In 1839, William B. O’Shaughnessy
introduced European world to
therapeutic properties of cannabis
 There was increased medical use of oral
extracts and tinctures (not smoked!)
in Europe and North America
4

5. Different Paths of Opiates and Cannabinoids
 During the 1800s, the active ingredient in opium—
morphine—was identified and isolated.
 Other opiates and synthetic medicines rapidly
followed
 Opium was not smoked for medical purposes
 The paths of medicinal opioid development and
recreational use of smoked herbal opium became
clearly distinct
5

6. Smoked opium vs. modern opiates
6

7. Different Paths cont.
 BUT, the active ingredients in cannabis remained unknown
 Lack of standardization in preparations ; high variability in
clinical response
 Oral cannabis products fell out of favor with the medical
profession
 Smoked recreational cannabis became a focus of
governmental restriction and prohibition
 Marijuana Tax Act of 1937 = cannabis products even less
attractive as a treatment option
7

8. Different Paths cont.
 In 1964, THC identified as the primary psychoactive
cannabinoid and synthesized
 Still very limited follow-up scientific research interest
 In 1960s, recreational use of smoked cannabis increased; some
users accidentally re-discovered its therapeutic properties
 The medical and recreational forms—smoked—were merged
8

9. • Had technology been more advanced in the early
1900s, cannabinoid medicines would have
developed as did opiates and there might be no
“medical marijuana” controversy today.
9

10. Research/Technology Breakthrough
 In the early 1990s, two cannabinoid receptors, CB1 and
CB2, were identified and cloned
 Endogenous cannabinoids identified, e.g., anandamide
 This clarified the mechanism of action of cannabinoids,
legitimated research
 Scientific interest in cannabinoids greatly increased
 In 20 years, a huge body of preclinical data has developed
 This is how new medications begin!
10

11. The Importance of the FDA Process
• Provisions developed over the past 100 years to
protect patient health and safety
promotes quality, safety and efficacy of
medications;
supported by all major medical organizations
• The US must require all controlled substance
medications to go through the FDA process in order
to satisfy its international treaty obligations
• GW is a pharmaceutical company and accordingly is
firmly committed to meeting all FDA requirements
11

12. The Modern Medication Approach…
…is very important (part 1):
• Products required to meet standards of modern medicine
• Standardized by composition and dosage
• Delivered like other pharmaceutical products; not smoked;
• Clinical and preclinical studies ensure physicians have
appropriate prescribing information
• Prescription only; patients obtain only through monitored
health care sources, i.e., pharmacy
12

13. The Modern Medication Approach…
…is very important (part 2):
• Reimbursed by health insurance
• Registration/inspection ensures that manufacturing process
conducted in accordance with validated quality control tools
Manufacturers accountable for defective products
• Promotional activities of manufacturers limited
• Products dispensed under the supervision of licensed health
care providers, e.g., physicians, pharmacists
13

14. Justification for Products like Sativex
“Medical marijuana” does not fit into the modern
medical paradigm - (part 1)
• Composition ( % of THC) of herbal cannabis varies significantly
depends on strains, cultivation and storage, etc.
“laboratories” often cannot replicate results
• Modern cannabis bred to exhibit (only) high levels of THC
no meaningful levels of other cannabinoids such as CBD
• Delivery systems (smoked/vaporized, baked goods, teas) do
not provide a standardized dose
• Contamination with microbes, heavy metal, and pesticides a
real possibility.
14

15. Justification cont.
“Medical marijuana” does not fit into the modern
medical paradigm - (part 2)
• Distribution does not take place within regulated supply
chain for pharmaceuticals
“collectives” and “cooperatives”
• No collection of adverse event or efficacy data
impossible to know who is really benefiting or being harmed
• Medical advice being given by untrained and unlicensed individuals
broad efficacy claims
often no meaningful physician supervision
no labelling with risk information or instructions for use
• Patients cannot obtain health insurance coverage
15

16. This is how it works….
• Who the “patients” are:
• How they get “medical information:
• The doctors:

17. The “Medical Marijuana” Manufacturing
Process
17

18. MYTHS
• The federal government is suppressing
research into cannabis
• It is impossible to take a product made from
the cannabis plant through the FDA process
18

19. Is the federal government suppressing
research?
• In the past 12 years, the FDA/DEA have licensed at least 12 human
studies investigating smoked/inhaled cannabis for therapeutic use;
NIDA provided the herbal cannabis for those 12 studies.
• FDA/DEA have also allowed research involving a cannabis-derived
medication;
this study had over 30 research sites in the US and another 60 in 10 other
countries.
DEA permitted importation of the product.

20. Suppressing research cont.
• Advocates claim that it is impossible to develop a cannabis-based
medication in the U.S. because the DEA will not authorize a second
source of cannabis besides the U. of Mississippi.

21. Manufacture/Cultivation in the US?
• Under international policies of past 85 years, the US
imports, rather than cultivates, psychoactive herbal
material; finished products are manufactured in US.
• Finished cannabis-derived product can be imported
into the US for research or for commercial use
without the need to cultivate cannabis in US.
21

22. Seeking FDA approval
• Herbal material grown by clones under rigorous conditions,
ideally computer controlled greenhouses, to produce
standardized starting materials
The US imports, rather than cultivates, psychoactive herbal material and
manufactures finished products in US
• Need to extract the components and incorporate into an
appropriate delivery system;
No precedent for administering any crude herbal material in a manner that
reliably achieves a reproducible dose, produces no carcinogens
22

23. FDA approval cont.
• Sponsor must manufacture and test product in accordance
with FDA “Guidance for Industry: Botanical Drug Products”
Guidance allows some leniency in early research; by Phase 3 /NDA, all
NCE standards must be met
Blinded, placebo-controlled large clinical studies must examine
specific medical condition in specific population
Sponsor must conduct abuse liability testing and prepare risk
management plan/REMS
23

24. MYTH
• Cannabis obtained from dispensaries is much
cheaper than what would be produced by
pharmaceutical companies
24

25. FACTS
• The average patient usage is 1.8-3 grams per day, but there is quite
a range. Patients who vaporize cannabis or incorporate it into
baked goods use much more
• The average price is $11-15 per gram (28 grams in an ounce), but
the range of costs is wide. Prices of up to $50 per gram have been
recorded;$35 is not unusual.
• An average daily use of 2.2 grams times $11 per gram equals $726
per 30-day month
• The range (at 2.2 grams/day) in price is $726-$2,310 per month
• If a patient uses more than 2.2 grams, as many do, the monthly
cost is huge!
25

26. There is more to cannabis than THC!
• Over 60 cannabinoids in total, each with their own--often
complementary—pharmacology, e.g., CBDV, THCV, CBG, CBN,
CBC, etc., for different medical conditions
Only THC is psychoactive
Multiple extracts can be blended to form new products
Likely research targets: oncology, epilepsy, inflammation, metabolic
disorder/diabetes, psychiatric disorders, substance abuse, etc.
• There are also other non-cannabinoid active components,
e.g., terpenes, flavonoids
• Real issue is whether plant extracts can be adequately
characterized and standardized
GW have shown that they can and have been!
26

27. More than THC cont.
• Cannabis used centuries ago would have involved a
1:1 CBD:THC ratio
• THC (tetrahydrocannabinol):
is analgesic, anti-spasmodic, anti-tremor, anti-
inflammatory, appetite stimulant, anti-emetic
• CBD (cannabidiol):
does not bind with strong affinity to CB1 cannabinoid
receptor, but does bind to other receptors in the body;
is anti-inflammatory, analgesic, anti-convulsant, anti-
psychotic, anti-oxidant, neuroprotective;
reduces the negative effects of THC
has been bred out of modern herbal cannabis!
27

28. Research Takes Time!
• Improved technology and discovery of
endocannabinoid receptor system means that we
are only at the early stages of developing modern
medications, i.e., numerous preclinical studies,
gradually moving into clinical trials, etc.
• At some point soon, will be same distinction as there
is with smoked opium (recreational use only) and
modern opiate medications
28

29. GW’s Cannabinoid Pipeline
29

30. International Clinical Research
30 clinical trials involving over 3500 patients in 12 countries
Canada
Colombia
South Africa
Finland
UK
India
Spain
France
Germany
Poland
Italy
Czech Rep
Belgium
Chile
Argentina Australia
30

31. Advisors and Collaborators:
• Prof Roger Pertwee
• Prof Vincenzo Di Marzo
• Prof Raphael Mechoulam
• Prof Mike Cawthorne
• Prof Jimmy Bell
• Prof Clive Page
• Prof Tamas Biro
• Prof Dave Kendall
• Prof Yasmin Hurd
• Prof Daniela Parolaro
• Prof Ruth Ross
• Prof Mauro Maccarone
• Pro Fernadez-Ruiz
• Dr Ben Whalley
• Dr Marilyn Huestis
• Dr Manuel Guzman
• Dr Guillermo Velasco
• Dr Cristina Sanchez
• Dr Pepe Martinez-Orgado
• Dr Angelo Izzo
• Dr Alistair Nunn
• Dr Saoirse O’Sullivan
• Dr Sabatino Maione
• Dr Barbara Costa
Etc….
International Academic Network
31

32. Challenges ofDeveloping Cannabinoid
Medication: Quality andManufacturing
Demands

33. Terminology & Quality Standards
Botanical Raw Material
(BRM)
Botanical Drug Substance
(BDS)
Botanical Drug Product
(BDP)
Stage 1
Stage 2
Stage 3
GAP
(Good Agricultural
Practice)
GMP
(Good Manufacturing
Practice)
Note: Above terms are all taken from FDA botanical guidelines
Plants grown, harvested, dried and
leaves and flowers removed
BRM milled and treated to
produce concentrated extract
BDS used with ethanol and propylene
glycol to produce oro-mucosal spray
33

34. Tightly Controlled Indoor Environment
34

35. BRM: Control of Starting Materials
• Uniform Genetics
• Precise Propagation Timings
• Tightly Controlled Temperature
• Near Uniform Light Intensity
• Automated Irrigation
• Automated Irrigation
• Bespoke Growth Medium
• Tightly Controlled Plant Nutrition
• ‘Organic’ Pest/Disease Prevention
• Attention to detail by trained staff
Controlled genetics
and standardized
environment to
produce consistent
starting material
uniform mature crop
35

36. Growing on a Commercial Scale
36

37. GMP Extraction and Manufacture
Storage 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)
Further processing of Primary Extract
under controlled conditions
Apply BDS specification
QC sampling / Release
QC / In process control
Apply macro / micro appearance
BRM → BDS BDS → BDP
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)
Mix final bulk solution
Apply BDP specification
QC sampling / Release
Add Solvent 2
Add Flavouring
QC / In process control
Storage of
BDS under
appropriate
conditions
(cold room)
37

38. Supercritical CO2 Extraction
• Low temperature (30°
Celsius)
• Retains cannabinoids
• Retains most terpenoids
• Retains little pigment or
chlorophyll
• Waxy ballast removed by
“winterization” (chilling in
ethanol solution)
• Ready for liquid dose
forms
38

39. BDS: Highly Characterised and Complex
Analysis to determine the
extract standardisation:
• Principal Cannabinoids
THC, CBD
• Minor Cannabinoids
CBC, CBG, CBN, THCV, CBDV,
THCA, CBDA, CBO, CBE, CBCV, CBL
• Terpenoids
• Carotenoids
• Fatty Acids
• Sterols
• Vitamins
• Triglycerides
• Waxes 39
CBD Content Between Batches
Extract Characterisation

40. Batch Reproducibility
Chromatographic image of multiple batches of a THC BDS over laid
40

41. Sativex® (USAN: nabiximols)
• Each ml contains:
38-44 mg and 35-42 mg of two extracts
from Cannabis sativa L. corresponding to
27 mg delta-9-tetrahydrocannabinol and
25 mg cannabidiol
• Excipients:
Ethanol anhydrous
Propylene glycol
Peppermint oil (0.05%)
• Pharmaceutical form:
Oromucosal solution in spray container
• Extraction solvent: Liquid carbon dioxide
• Each 100 microlitre spray contains:
2.7 mg delta-9-tetrahydrocannabinol
(THC) and 2.5 mg cannabidiol (CBD)
contains up to 0.04 g alcohol self titration
41

42. Sativex® is not Cannabis
“Medical Marijuana” Cannabis Based Medicine – Sativex®
Product
Development
Clinical
Evaluation
Raw Material
Production
None
None
Grown in uncontrolled,
unregulated conditions
resulting in variability
Herbal cannabis is
predominantly grown
for high potency of THC
only
World class academic / scientific research
programme
Regulated pre-clinical and clinical evaluation
to prove Efficacy, Safety and Quality
Consistent materials due to highly controlled
growing conditions, growing medium and
documentation.
Sativex® is made from an extract of cannabis
plants containing a ratio of 1:1 THC and CBD
as well as other active cannabinoids.
Plants are bred specifically to consistent
cannabinoid profile and potency
42

43. Sativex® is not Cannabis
Medical Marijuana Cannabis Based Medicine – Sativex®
Manufacturing
Process
Process is not
registered or regulated
in any way
Dried material
packaged in basic
packaging materials
Manufactured to Good Manufacturing
Practices (GMP) in regulated facilities to
processes that are registered with the
competent authorities and inspected
regularly
Results in a quality, consistent and safe
product made to the highest pharmaceutical
industry standards
43

44. Safe for the Patient to Use
“Medical Marijuana” Cannabis Based Medicine – Sativex®
Delivery system
Supervision by
Patient’s Treating
Physician
Security of Supply
Smoked, inhaled or
consumed orally
“Recommending”
physician may not be
involved in patient’s care;
treating MD may not be
aware of patient’s use
Medical advice given by
untrained personnel.
Limited control on
provision to patients.
Easily diverted to non-
medical use; no reliable
records kept
None
Novel delivery system, oromucosal spray
Approved medicine is prescribed by registered
physician with access to full product information
to make an informed decision
Patient Leaflet supplied with every pack
National controls on prescribing and safety
monitoring
Secure distribution route from manufacture to
patient.
Packaging designed to protect the product from
contamination, adulteration, diversion and
counterfeiting 44

45. Sativex® GMP Manufacturing Process
Uniform plants grown in
controlled conditions
Fully automated
GMP manufacturing
Highly controlled
drying conditions
Fully automated
GMP labelling & packing
GMP packaging, includes
product information,
tamper evidence and
anti-counterfeit features
Highly controlled
Extraction process
45

46. Taking the Difficult Pathway
Why not just make a pure, synthetic medicine?
• Pharmaceutical companies believed for some time that medications should
comprise a single chemical that would bind potently to a single receptor or
other target
• The industry has been met with limited success as well as many failures as a
result of highly potent/specific compound development
THC agonist– therapeutic doses often unachievable due to psychoactivity
Market withdrawal of rimonibant instigated a wave of terminated programmes
Peripheral restriction associated with side effects
Modulation of endocannabinoid concentrations inefficacious
• Very difficult to develop ECS modulators, yet we continue - why?
Endocannabinoids are altered and participating in most pathological conditions
46

47. A New Paradigm For Drug Development
• Old development model is failing: Increasing support within the
industry for a different approach, where in a molecule works on
multiple targets or multiple molecules work in synergy together
e.g., new Gilead 4-in-1 AIDS drug
• “Multi-target” concept should be
revisited
Without need for high potency
• Extracts are developed as a single
pharmaceutical entity (single active)
Not considered combination products
• Compounds from same plant often
interact/synergize with each other
Not just additive effect on targets
3 µM 1 µM 0.3 µM 0.1 µM
potent &
selective
chemical space
for target X
chemical space
for target Z
chemical space
for target Y
Target area of
current drug
discovery
desirable area for
multi-target approach
poly-
pharm.
in vitro potency
47

48. CentralNervousSystem/safetyissues

49. 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 in inhaled route
• Limitations of oral route
• Poor aqueous solubility
Predictable maintenance of acceptable risk / benefit 49

50. MYTHS
• In order that patients can titrate
their doses, cannabis must be
inhaled (smoked or vaporized);
• Vaporization addresses all the
problems with smoking.
50

51. FACT
• WRONG!
• Inhalation is not the best delivery system, at least for
patients with chronic conditions
51

52. Therapeutic Window - Solutions
• Cannabinoid ratios widen window
CBD may counter 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 metabolism
• 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 52

53. Dose-normalised comparison of THC Levels from
Smoked Cannabis (33.8mg THC) with nabiximols
(Sativex) (12.5 sprays containing 33.8mg THC)
53
0
20
40
60
80
100
120
140
160
180
0 60 120 180 240 300 360
THCplasmalevel(ng/ml)
Time (minutes)
Smoked
Cannabis
(33.8mg THC)
Sativex (Dose
normailsed to
33.8mg THC)

54. Intoxication
• Sativex rarely produces intoxication outside of early-
on dose titration
• After titration, Sativex intoxication scores are in
single digits out of 100 on Visual Analogue Scales,
with no significant difference from placebo
• Mild psychoactive effects noted in patients have not
been labelled as desirable
54

55. 0
10
20
30
40
50
60
70
80
90
100
BL 6 10 18 26 34 42 50 58 66 74 82
VASIntoxicationScore
(0-100mm)
Study Week Number
Sativex
Placebo
Placebo to Sativex
Placebo
Crossover
to THC:CBD
Intoxication
Wade DT et al. Mult Scler. 200755

56. Cognitive Assessments
• Short-term cognitive impairment predicts long-term cognitive impairment
• Cognitive impairment may predict functional outcomes
i.e. retaining good cognitive performance is good for function
• Many medications may cause cognitive impairment
Three Tests Performed:
1. Sternberg Test (Short-Term Memory)
No significant effect of Sativex at any dose level
Marinol significantly different from placebo at 40 mg dose (p=0.01)
2. Divided Attention (Simultaneous performance of different tasks)
No negative impact of Sativex on divided attention
High dose Marinol significantly greater times logged than placebo
3. Choice Reaction Time (Measures accuracy of responses)
No significant effect of Sativex or Marinol on any of the parameters assessed
56
Unlike Marinol, at single doses of 4 sprays, 8 sprays and 16 sprays,
Sativex does not produce short-term cognitive impairment

57. No Tolerance or Dose Escalation
• Tolerance a common problem with use of opioids
• In over 1500 patient-years of experience, no dose escalation
or tolerance has been observed
Long term extension studies in MS and peripheral neuropathic pain
show stable/decreased doses after months/years of administration
Patient registry data confirms
• Sudden withdrawal of medication in MS patients taking it for
over one year produced a gradual re-emergence of symptoms
in 7-10 days, but no withdrawal syndrome or side effects
requiring treatment.
• No signals of abuse or diversion in 7 yrs of prescription use
57

58. 0
4
8
12
16
20
24
18 26 34 42 50 58 66 74
SpraysperDay
Study Week
Median
n=80
n=80
1 year
Tolerance – Sativex Sprays Per Day
Dosing Remains Stable in Long-Term
Wade DT et al. Mult Scler. 200758

59. Vaporization: safety issues
• Vaporization does not remove all toxic byproducts and resolve
safety issues:
• Vaporizers vary significantly in quality and features, none FDA
approved;
• If temperature can be set up to 200-230°C, toxic combustion
products will be produced;
• Even at lower temperatures, some tars produced, and delivery of
cannabinoids becomes very inefficient;
• Uncertain whether all microbes destroyed;
• Content of vapor determined by underlying
quality/contamination of herbal material;
• More ammonia may be inhaled because no loss
in side stream smoke.
59

60. Other Regulatory Issues

61. Controlled Substances Act
• DEA must register (license) clinical and preclinical
research sites and importer/manufacturer using a
Schedule I product
this can, and has been done before - prior Phase IIb study
involved 30+ research sites and an importer
• After FDA approves New Drug Application (NDA),
product can be moved out of Schedule I
FDA approval constitutes “currently acceptable medical
use in the US” for that product, a necessary criterion for
Schedules II and III.
61

62. Would Cannabis be Rescheduled?
• If a cannabis-derived product were FDA approved,
cannabis itself would not be moved to Schedule II
• Opium and coca leaves are in Schedule II but there
were modern medications derived from them on the
market when CSA enacted
• Differential scheduling is currently in place for
cannabinoids and other substances:
Marinol (Schedule III) vs. THC (Schedule I)
Xyrem (Schedule III) vs. GHB (Schedule I)
62

63. What Would Rescheduling of Herbal Cannabis
Achieve?
• FDA does not approval bulk substances/ active
ingredients for direct prescriptive use
• Even if “cannabis” itself were moved to Schedule II,
a specific cannabis or cannabis-based product
would need FDA approval to be available by
prescription
• But: would be huge symbolic victory for cannabis
advocates;
further fuel state initiatives—allowing physicians to
prescribe under state law?
63

64. The Disadvantages of Giving Herbal Cannabis a
“free pass”
• By creating an exception for cannabis, we are
preventing the development of quality, safety and
efficacy data that would allow it to become broadly
accepted as a true medication
• The vast majority of patients want a product that is
standardized by composition and dose and about
which their physicians can offer meaningful advice
64

65. What Do Modern Cannabis-Derived or
Cannabinoid Products Get Us?
• Process governed by science
• Patients will have legitimate prescriptions and health
care insurance coverage
• Products distributed and dispensed through
monitored drug supply channels
• Data from controlled clinical studies available to
physicians
• Products standardized by composition and dose
• Medication administered in appropriate dosage form
• Manufacturers accountable for quality
65

66. What is Coming in the Future?
• Many more products comprising different
cannabinoids and/or cannabinoid ratios, perhaps
both botanically- and synthetically-derived
• It takes time! Improved technology and discovery of
endocannabinoid receptor system means that we
are only at the early stages of developing a range of
modern medications, i.e., numerous preclinical
studies, gradually moving into clinical trials, etc.
66