Cannabinoids and Cannabis-Based Medicines
Only in the last two decades, a natural cannabinoid receptor system has been discovered in the human body. It is by interacting with these receptors that cannabinoids exert many of their pharmacological effects. The discovery of the cannabinoid receptor system has sparked renewed interest in the therapeutic potential of cannabinoids by providing important new targets for drugs. There are at least two types of cannabinoid receptors in mammalian tissues, CB1 and CB2. CB1 receptors are present in the brain and spinal cord and in certain peripheral tissues. CB2 receptors are expressed primarily in immune tissues. There is preliminary evidence to suggest that additional cannabinoid receptor types may exist. The cannabinoid system also interacts with many other neurotransmitter/neuromodulator systems, such that cannabinoids affect almost every body system.
GW has conducted considerable research into CBD (cannabidiol), a non-psychoactive cannabinoid. CBD has anti-inflammatory, analgesic, anti-psychotic, anti-convulsant, and other properties. It is also believed to mitigate many of the side effects of THC. GW has also commenced a clinical development programme of its novel cannabinoid product, delta-9-tetrahydrocannabivarin (THCV). THCV has shown promise in pre-clinical studies as a potential treatment for obesity, diabetes and related metabolic disorders. A range of other cannabinoid molecules are undergoing early research evaluation.
GW is interested in researching as many of the cannabinoids as possible. We are also interested in some of the non-cannabinoid contents. There are some ingredients in cannabis that have very potent pharmacological activity but which are not cannabinoids.
To date, GW has completed clinical trials in over 3,000 patients, including over 20 Phase II and Phase III trials. These trials are conducted around the world and have included patients with a range of different medical conditions, including multiple sclerosis, cancer pain, neuropathic pain, and rheumatoid arthritis. For more information on the target therapeutic areas for Sativex and the clinical trials completed to date. please click here
GW's clinical trials programme is being carried out by a team of pharmaceutical professionals experienced in drug development and, in particular, the development of plant-based medicines and drug delivery systems. GW's team is also supported by a number of prominent scientific advisers in this field in Europe and North America. In general, each step in developing a pharmaceutical product must be tested under a range of conditions including extremes to simulate error. The test methods themselves need to be validated across the range of values expected. A development programme for regulatory approval has three main objectives: QUALITY, SAFETY and EFFICACY. QUALITY relates to consistency of the product throughout production and in its final presentation and packaging. This will also include long term testing of stability in order to establish an acceptable shelf life. The starting material will need to be tested for contaminants (which should be absent) such as pesticide and fungicide residues, fungal and microbial toxins, heavy metals, etc. Each test is performed many times. SAFETY Regulatory authorities require evidence from controlled studies and in depth critical review of the literature by experts in order to assess safety. GW has embarked upon this costly and time consuming undertaking to be able to provide sufficient evidence of appropriate quality to satisfy the regulatory authorities. The safety of the drug in clinical usage is continually monitored throughout the entire clinical development programme as well as following regulatory approval. EFFICACY Prior to submission of a dossier for regulatory approval there are three phases of clinical research:
Phase I. These are studies generally in healthy volunteers where the safe dose range of the drug is established. Phase I programmes are typically run in dedicated clinical pharmacology departments which do nothing but early-phase safety studies. Subjects may be exposed to increasing doses of the drug whilst all bodily functions are closely observed and blood samples taken to assess blood levels of the drug. Sometimes subjects are asked to perform tasks (e.g. exercise) or, more appropriately for cannabis-based medicines, batteries of intensive cognitive and psychometric function testing. The data from these studies assists in establishing appropriate dosage schedules to be used in the Phase II studies.
Phase II. These studies are generally carried out in small groups of patients. Usually specific aspects of the patient's condition are studied to demonstrate the effect, if any, of the drug on defined endpoints and to establish a dose/response relationship if present. In these studies the clinical endpoints are validated for their use in larger studies (i.e. are we asking the right questions or doing the right test to best evaluate the therapeutic value of the drug under test). Some drugs which are seemingly similar may require very different measures of efficacy. We suspect cannabis may well be one that requires very close attention to the clinical endpoints.
Phase III. Having established an acceptable dose range and validated the clinical endpoint in a range of conditions and having shown therapeutic benefit in the smaller Phase II studies then larger scale studies are undertaken. Hundreds of patients may be entered into each study and may receive active or placebo or active and placebo in a random order. Sub groups of responding patients are identified and so are interactions with other medicines that the patient may take. Special target patient groups will be studied at this time - young, old, renal impaired etc.
GW's first product, Sativex, is administered as a measured dose oral (oro-mucosal) spray that is absorbed by the lining of the patient’s mouth. This method of administration enables patients to titrate (adjust) their dose to achieve symptom relief without incurring an unacceptable degree of side effects.
One of the cannabinoids in Sativex is THC whereas the other principal cannabinoid is CBD, a non-psychoactive molecule. Evidence suggests that CBD may modulate many of the unwanted effects of THC. Hence, through the incorporation of CBD and the utilization of an oromucosal spray delivery system which is administered through careful self-titration (dose adjustment) and which keeps THC from entering the blood too rapidly., most patients are able to separate the thresholds for symptom relief and intoxication, the 'therapeutic window', so enabling them to obtain symptom relief without experiencing a 'high'. Patients emphasise that they seek to obtain the medical benefits without intoxication. There is no evidence from Sativex clinical trials that patients obtain a high akin to that sought by recreational cannabis users.
All of GW’s non-Sativex cannabinoid research focuses on cannabinoid molecules other than THC. These other molecules are not psychoactive.
GW has never endorsed or supported the idea of distributing or legalizing crude herbal cannabis for medical use. In both our publications and presentations, we have consistently maintained that only a cannabinoid medication--one that is standardized in composition, formulation, and dose, administered by means of an appropriate delivery system, and tested in properly controlled preclinical and clinical studies--can meet the standards of regulatory authorities around the world, including those of the FDA. These criteria are also mandatory if the modern medical model—informed patients working with, and being advised by, knowledgeable physicians to identify appropriate treatment options--is ever to be attained with a cannabinoid medication.
We have also repeatedly stressed that these regulatory processes provide important protections for patients, and we believe that any cannabinoid medication must be subjected to, and satisfy, such rigorous scrutiny.
In GW's opinion, smoking is not an acceptable means of delivery for a medicine. We believe that patients wish to use a medicine that is legally prescribed, does not require smoking, is of guaranteed quality, has been developed and approved by regulatory authorities for use in their specific medical condition and is dispensed by pharmacists under the supervision of their doctor.
The national regulatory processes of the UK, US, and other countries have been developed over the past century to protect patient health and safety. GW believes that all medicines should undergo these review and approval processes before they are made available to patients.
Sativex, like other medications in development, undergoes rigorous controlled clinical trials to examine its safety and efficacy.
We believe our program demonstrates that it is possible to develop a cannabis-derived medication in accordance with modern medical criteria, and therefore, that is the approach that should be taken, as is the case with all other medications prescribed for serious medical conditions.
Sativex is a cannabinoid pharmaceutical product standardized in composition, formulation, and dose, administered by means of an appropriate delivery system, which has been, and continues to be, tested in properly controlled preclinical and clinical studies. Crude herbal cannabis in any form--including a crude extract or tincture--is none of those things.
We believe that most patients and most physicians should accept only a product that meets the standards of modern medicine. Since the company’s founding in 1998, GW has consistently maintained a single objective: to develop modern medicines that satisfy international standards for quality, safety, and efficacy, while also meeting the medical needs of seriously and chronically ill patients.
Moreover, GW has conducted its program exclusively in accordance with the parameters of modern medical and pharmaceutical practice.
GW is entirely focused on creating cannabinoid medications that can be made available on prescription to patients 1) whose conditions have been shown to benefit from such medicines and 2) who wish to obtain their medical treatment from their physicians in accordance with the standards of modern medical practice.
GW's cannabinoid medications are derived from standardised extracts of proprietary cannabis plant varieties bred to exhibit a pre-determined content of cannabinoids. These extracts are incorporated into pharmaceutically-appropriate drug delivery technologies and then undergo pre-clinical and clinical testing prior to submitting applications to national regulatory authorities.
Cannabinoids are a group of chemical compounds found only in the cannabis plant. Different cannabinoids appear to have different pharmacological effects. Over 60 different cannabinoids have so far been identified but the role and importance of many of these has yet to be fully understood. Cannabinoids known to have pharmacological effects of therapeutic relevance include Delta-9 Tetrahydrocannabinol (THC), Cannabidiol (CBD), Cannabinol (CBN), Cannabichromene (CBC), Cannabigerol (CBG) and Delta-9-tetrahydrocannabivarin (THCV). Certain cannabinoids have been shown to have analgesic, anti-spasmodic, anti-convulsant, anti-tremor, anti-psychotic, anti-inflammatory, anti-cancer, anti-oxidant, anti-emetic and appetite-stimulant or appetite-suppressant properties.
GW uses plant material in order to extract the cannabinoids and other pharmacologically-active components from the plant. The extract is then formulated and incorporated into appropriate dosage forms. Each step is carefully quality-controlled and subject to strict Standard Operating Procedures, as well as international Good Manufacturing Practice standards.
GW utilizes the cannabis plant material solely to develop its cannabinoid pharmaceutical products. GW does not provide herbal cannabis to outside researchers.
GW's cannabis plants are grown under computer-controlled conditions in secure glasshouses at a secret location in the UK. GW has developed a highly sophisticated cultivation process to ensure plant material grown is of sufficient quality and consistency to be suitable for incorporation into pharmaceutical products.
Strict Standard Operating Procedures (SOPs) are followed to ensure non-contamination by chemicals, infestation or fungal growth, consistency of content, methods of harvest, drying, primary extraction, storage and onward consignment. Temperature, humidity, total light and photoperiod are all controlled by computer.
The facility is situated in the South of England but for clear security reasons we do not divulge the precise location.
The absolute requirement for a plant-based medicine from a regulatory point of view is "control of starting materials". A drug in its manufacture goes through many processes, each of which need to be monitored and strict quality controls applied. This process control and QC would be invalidated if the starting materials (i.e. the herbal materials) were of poor or inconsistent quality. Laboratory analysis of GW’s selected chemovar lines demonstrates that the cannabinoid ratios are very consistent. Such high levels of consistency are unusual in plants and are very important in applications made to medical regulatory authorities.
GW's foremost consideration therefore is the cultivation of highly consistent plants with defined cannabinoid ratios. Total yield of one or other cannabinoid is relatively less important than consistency. We have a number of chemovars (varieties characterised by their chemical content) chosen for their composition and morphological traits i.e. hybrid vigour and disease resistance.
GW cultivates cannabis in order to be able to control the starting materials for the in-house production of GW’s cannabinoid pharmaceutical products. GW does not distribute herbal cannabis to outside researchers or institutions.