Investigation of Cannabidiol (CBD) as a Potential Therapeutic Product

Alice P. Mead JD GW Pharmaceuticals Cannabis Summit April 17, 2016

Disclosures

• Ms. Mead is an employee and shareholder in GW Pharmaceuticals, which researches and develops cannabis-derived prescription medications.

GW Pharmaceuticals

• Founded in in the UK in 1998 by Dr Geoffrey Guy and Dr Brian Whittle;

Specialists in development of plant-based pharmaceuticals, controlled substances and drug delivery systems;

Goal was to develop a range of prescription medications derived from components or combinations of components of the cannabis plant; developed in accordance with modern medical standards.

• GW has become a world leader in development of plant-derived cannabinoid therapeutics;

• First product Sativex® approved in 28 countries (ex-US) for MS spasticity, CBD:THC 1:1;

• Research programs in broad range of disease areas;

• Collaborations with 36 universities around the world;

• In the U.S., an investigational CBD product finishing Phase 3.

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Manufacture of Epidiolex®: extraction of pure CBD and removal of THC

CBD Bot Raw Mat

CBD Bot Drug Sub

Final Product

Pure CBD

Purification Process to remove THC

Bulk Solution Production

Filling, Capping & Labelling

Processing of plant material into CBD extract

CO2 Extraction

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Importing Standardized Cannabis-derived Extracts into the US for Research

• Standardized pharmaceutical-quality cannabis extract preparations containing CBD may imported into the US;

• Such preparations are not subject to the exclusive “national agency” control requirement of the Single Convention;

• Since 2006, over 100 research sites around the US have been licensed by DEA to conduct research with such imported preparations;

• Individual researchers may import them directly, or a central distributor may be licensed as an importer and then distribute to research sites via DEA Form 222.

What is CBD?

• Cannabis plant is unique source of >100 cannabinoid molecules;

• Only THC is known to cause notable psychoactive effects;

• CBD and THC are the primary cannabinoids;

• Unlike THC, CBD does NOT bind to the CB1 or CB2 receptors, at therapeutic concentrations1;

This is why CBD is not psychoactive like THC;

• Until recently, was virtually bred out of modern cannabis

1 El-Alfy AT et al. Pharmacol Biochem Behav. 2010;95:434-442

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Treatment-Resistant Childhood Epilepsy: Significant Unmet Need

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Response to AEDs in patients with newly diagnosed epilepsy3

US CHILDREN WITH EPILEPSY

PHARMACORESISTANT EPILEPTICS1,4

466,000

30% SEIZURES THAT PERSIST, DESPITE MULTIPLE AED TREATMENT2

MEDICATION RESISTANT PATIENTS 140,000

REFRACTORY EPILEPSY COMPOSED OF MULTIPLE SYNDROMES

[1] Sander JW, Epilepsia. 1993;34(6):1007. [2] Picot et al, 2008 ; (3) Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319. (4) Kwan P, Brodie MJ, CNS Spectr. 2004;9(2):110

little change to this statistic over last 15 years

Seizure-free with 1st drug

Seizure-free with 2nd drug

Seizure-free with 3rd or multiple drugs

Pharmacoresistant epilepsy

47%

13%

4%

36%

Treatment-Resistant Childhood Epilepsy: Spectrum of Rare Disorders

DRAVET SYNDROME

TUBEROUS SCLEROSIS COMPLEX

Many different types of epilepsy syndromes, seizures and causes, including

FIRES

LENNOX-GASTAUT SYNDROME

DUP15q SYNDROME

CDKL5

DOOSE SYNDROME

GLUT 1 TRANSPORTER

DEFICIENCY

ANGELMAN’S SYNDROME

STXBP1/OHTAHARA SYNDROME

WEST SYNDROME (INFANTILE SPASM)

AICARDI SYNDROME

RASMUSSEN SYNDROME

68% of patients being treated with Epidiolex in latest expanded access data have conditions other than Dravet and LGS

UP TO 5% OF ALL CHILDHOOD EPILEPSIES IN FIRST YEAR OF LIFE2

3 TO 4% OF CHILDHOOD EPILEPSY1

[1] Trevathan et al, 1997; [2] Dravet et al, 2012 9

Clinical Program for Epidiolex

• The GWPCARE Clinical Trial program will enrol >500 patients with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS).

• GW is conducting 11 additional Epidiolex Phase I and II trials including a complete assessment of abuse potential.

• NDA submission planned for end 2016.

• Program in Tuberous Sclerosis just started.

• Other syndromes are under consideration for development

Dravet Syndrome Phase 3 Trial Results

• Primary endpoint achieved with high statistical significance (p=0.01)

• Secondary efficacy endpoints reinforced the overall effectiveness

• 120 patients (average age: 10, 30% <6 years)

• On average, Epidiolex administered as 8th AED in treatment regime Average of 3 concomitant AEDs, previously tried and failed average of >4

• Median baseline convulsive seizure frequency was 13 per month

• Epidiolex was generally well tolerated in this study 84% of patients on Epidiolex reported AEs as mild or moderate

SAEs: 10 on Epidiolex, 3 on placebo

Only 8 Epidiolex patients discontinued treatment due to AEs vs 1 on placebo

• Epidiolex has both Orphan Drug Designation and Fast Track Designation from the FDA

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Expanded Access Programs (EAPs)

• Open-label study for patients (primarily children) with treatment-resistant epilepsy (TRE) including Dravet (DS) and Lennox-Gastaut (LGS) with 6 state-initiated programs.

• Mean age 11.8 yrs, range 4 mos-46 yrs

• N=313 exposures, 261 ≥ 3 months

• N=234 evaluable for efficacy after 12 weeks

47% had > 50% reduction in total seizures

Seizure-free at 3 months- 9% in total patients, 13% in DS

LGS (N=14): 71.1% median reduction in atonic seizures

• Most common AEs: somnolence-23%, diarrhea-21%

• Discontinuations: AEs-4%, LOE-12%

• Related SAEs-5%

Devinsky et al, Poster presented at AES 2015 Annual Mtg, Philadelphia, PA

Securing FDA Approval for a Cannabis-Derived Product

• FDA has issued a Guidance for Industry on Botanical Drug Products;

• Sets forth the pathway for developing complex botanical materials into prescription medications;

• Rigorous CMC (chemistry, manufacturing and controls) requirements;

• Still need RCTs.

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FDA Approval cont.

• Herbal material must be grown under rigorous conditions to produce standardized and reproducible starting materials;

• May need to incorporate an extract (“Botanical Drug Substance”) or a purified cannabinoid into an appropriate delivery system;

• However, an inhaler is being developed in Israel, which uses granules of cannabis; has been tested in an 8-patient study;

FDA Approval cont.

• What about highly standardized plant material that is milled and encapsulated or “juiced” cannabinoids in acid form, e.g., THCA, CBDA, that are developed into a dosage form?

• Other new technologies are also emerging;

• NOTE: Cannabinoids are lipophilic, degrade with heat, light and time, acid form may require decarboxylation; developing precise and stable dosage forms can be challenging.

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The Importance of the FDA Process

• Provisions developed over the past 100 years to protect patient health and safety;

• Standardized by composition and dosage;

• Administered like other pharmaceutical products;

• Clinical and preclinical studies ensure physicians have appropriate prescribing information;

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The FDA Process cont.

• Reimbursed by health insurance;

• Prescription only; patients obtain only through monitored health care sources, i.e., pharmacy;

• 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;

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BUT….

• Process takes years and success is not certain; most products fail;

• Development is extremely expensive;

• Product will be given marketing authorization only for the specific formulation and the particular medical condition studied in the trials.

THANK YOU !!

ALICE MEAD JD apm@gwpharm.com

415-987-9679 cell 415-388-9057 W