France 24 reports that the French government’s health ministry has announced its approval for limited use of Sativex, a cannabinoid mouth spray, for treatment of patients suffering from multiple sclerosis (MS). Sativex, developed and manufactured by the British company GW Pharmaceuticals, will be the first marijuana-based medicine to be made available in the country.
France 24 also notes that the drug still has a few more regulatory hurdles to negotiate before it is for sale by prescription. GW Pharmaceuticals says the next step in the regulatory process is to work with the French National Agency of Medicine and Health Products Safety (ANSM) to finalize any country-specific requirements. Following completion of this next step, it is then expected that France will issue a national marketing authorization. Launch timing in France is dependent on completion of subsequent national pricing and reimbursement procedures. Sativex will be commercialized in France by GW’s European partner, Almirall S.A., an international pharmaceutical company headquartered in Barcelona, Spain, that researches, develops, manufactures and commercializes its own R&D and licensed drugs with the aim of improving people’s health and wellbeing.
In October, 2013, GW Pharmaceuticals had announced the successful closing of the European Mutual Recognition Procedure (MRP) in France for Sativex oromucosal spray in the treatment of spasticity due to MS and a resulting recommendation for approval by the French authorities.
“The successful completion of this regulatory process for Sativex in France maintains our positive regulatory track record for Sativex, which is already approved in 22 countries, and provides further endorsement of the important role Sativex can play in meeting a substantial unmet need of people with Multiple Sclerosis,” says GW Pharmaceuticals Chief Executive Officer Justin Gover in a GW release. “We look forward to working with our partners, Almirall, towards the launch of Sativex in this important European country.”
Sativex is approved as a treatment for MS spasticity in 17 countries in Europe. The medicine is currently available on prescription in the UK, Spain, Germany, Canada, Denmark, Norway, Israel, Austria, Poland, Sweden, Italy and Finland with launches currently in preparation for a further 8 European countries, as well as Australia, New Zealand and Kuwait. The US license to Sativex is held by Otsuka Pharmaceutical Co. Ltd. in the United States and to Bayer HealthCare AG in the UK and Canada. GW Pharmaceuticals has signed a deal to have Novartis (makers of Gilenya) market Sativex in parts of Asia, the Middle East, Australia, New Zealand and Africa, so is moving ahead in those markets. .
In 2007 GW and Otsuka Phamaceutical entered into an exclusive agreement for Otsuka to develop and market Sativex in the United States. They received permission from the US regulatory authority and the FDA to directly enter late stage trials in the US. Results were released in March. The randomized, double-blind, placebo controlled study was concluded very encouragingly. Dr. Steven Wright, GW’s R&D director said, “We are very pleased to have successfully completed phase II of studies supporting the efficacy of Sativex in Cancer pain, we are now working closely with Otsuka in preparing to develop phase III development of Sativex in the United States.” The current US development program anticipates two more Phase III trials prior to a subsequent submission of a New Drug Application to the FDA.
In the United States, GW announced in August 2013 that it had opened a Phase 3 Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) to conduct a pivotal efficacy and safety clinical program to evaluate Sativex for the treatment of MS spasticity. GW expects the U.S. Phase 3 trial to commence in 2014. Sativex is also currently in Phase 3 clinical trials as a treatment for cancer pain. This represents the lead target indication for the product in the US.
Marijuana’s role as a medication is complex and controversial. It was used as a medication in the nineteenth and early twentieth centuries but was outlawed in most western countries in mid twentieth century. In Canada, the federal government has developed a medicinal marijuana program, which allows people who meet certain criteria to possess and use marijuana therapeutically. MS is among the conditions for which a permit can be applied. In some cases, Health Canada authorized medical marijuana grow-ops to provide marijuana to people who hold medical use permits.
Health Canada approval of Sativex on April 19, 2005, made Canada the first county in the world in which the cannabis-based spray is available as a prescribed treatment for MS-related pain. Health Canada approved Sativex with conditions, under its Notice of Compliance with Conditions (NOC/c) policy. This authorization reflects the promising nature of the clinical evidence which must be confirmed with further studies. Products approved under Health Canada’s NOC/c policy, have demonstrated promising benefit, are of high quality and possess an acceptable safety profile based on a benefit/risk assessment for the approved use.
In August 2007, GW also announced the approval (NOC/c) in Canada of Sativex as adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain.
Health Canada’s approval of Sativex was based on results from a small, four-week clinical trial carried out in Great Britain by GW Pharmaceuticals, the company that developed the drug. The study involved 66 people with MS at a research center in Britain. Participants had central neuropathic pain because of MS. Half of the group received Sativex in a spray dispenser and the other half received a sham (placebo) spray in a similar dispenser. The primary outcome measure was to measure the effectiveness of Sativex in relieving central neuropathic pain compared to placebo. Secondary measures included sleep disturbance, participants’ perception of their condition at the end of treatment and other quality of life assessments. Participants in the Sativex group used fewer sprays per day than did the placebo group. In addition, individuals in the treated group reported they experienced pain relief, had less sleep disturbance and felt their condition had improved.
The Multiple Sclerosis Society of Canada welcomed the approval of Sativex, which it says will provide people with MS and their physicians another choice in treating pain, which is a common symptom of the disease. “Having available another way to manage pain is encouraging news,” said Dr. William J. McIlroy, the society’s national medical advisor.
GW’s development of plant-derived cannabinoid therapeutics has a deep pipeline of additional cannabinoid product candidates, including two distinct compounds, GWP42004 and GWP42003, in Phase 2 clinical development for Type 2 diabetes and ulcerative colitis, respectively, and GWP42006 in Phase 1 clinical development for the treatment of epilepsy.
Sativex was developed by GW Pharmaceuticals in specific response to the MS population’s unmet need for a prescription cannabis-based medicine. Manufactured under a British Home Office license at an undisclosed location in the UK, it is indicated as add-on treatment for symptom improvement in patients with moderate to severe spasticity due to MS who haven’t responded adequately to other anti-spasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy.
Cannabinoids is the name given to more than 60 chemicals found in the marijuana plant. Cannabinoids appear to bind to receptor molecules on the surface of neurons in the brain and spinal cord. Through a complex process, cannabinoids appear to prevent neurons from becoming overactive, which leads to the neuropathic pain sometimes experienced in MS. Neuropathic pain results directly from damage to the nerves.
Sativex is a first in class endocannabinoid system modulator, containing active ingredients called ‘cannabinoids’ such as Tetranabinex and Nabidiolex, GW’s proprietary extracts of chemically and genetically characterized Cannabis sativa L. plants (hemp plants) grown and processed under strictly controlled conditions. The principal active components are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The exact mechanism of action in relieving neuropathic pain is not known. Cannabinoids react with cannabinoid receptors that occur naturally throughout our bodies, including in our brains. A receptor is a site on a brain cell where certain substances can stick or “bind” for a while. If this happens, it has an effect on the cell and the nerve impulses it produces, which causes a ‘dimming down’ of the symptoms of spasticity. In patients who respond to Sativex, it is this effect which helps to improve their symptoms of spasticity and to help them cope better with their usual daily activities.
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Sativex is a liquid solution supplied in small vials and delivered by an oromucosal or buccal spray (sprayed into the mouth either onto the inside of the cheek or under the tongue). It has a flexible dosing regime, which is particularly appropriate given the variable nature of both spasticity and multiple sclerosis from patient to patient.
The way in which cannabinoids such as THC exert their effects on the human body is known as their “mechanism of action,” and has recently become clearer with the discovery of two cannabinoid receptors CB1 and CB2 together with that of a chemical called “anandamide.” Anandamide is an endogenous ligand, which literally means that it occurs naturally within the body (endogenous) and is a binding agent or “ligand.” The full name of anandamide is arachidonoyl ethanol amide, but it was nicknamed anandamide after the Sanskrit word for bliss “ananda.” Anandamide has its effect by inhibiting cyclic AMP (part of the cellular energy generation process), through G-protein coupling in target cells, which cluster in areas of the central nervous system that mediate pain, memory, and other key functions.
GW says preliminary tests of pharmacology and behavioral activity support the similarity of anandamide to THC. Both anandamide and THC bind weakly to the cannabinoid type one (CB1) receptors, which are found in the brain and are called partial agonist, in contrast, cannabidiol (CBD) has little activity at CB1 but greater activity at the cannabinoid type 2 receptors (CB2) that are mostly located in the periphery, in lymphoid tissues. CB1 receptor distribution and THC binding affinity at CB1 differ between humans and rodents, which underscores the importance of conducting human clinical trials. Both THC and CBD are neuroprotective antioxidants that have been shown to inhibit NMDA-mediated excitotoxicity under conditions of traumatic head injury, stroke and degenerative brain diseases.
The company notes that discovery of the endocannabinoid system has provided new insights into a neuromodulatory scheme that may provide better explanations of, and treatments for, a wide variety of previously poorly treatable, often painful disorders.
GW has recently been demonstrated that CBD also stimulates vanilloid pain receptors (VR1), inhibits uptake of the anandamide, and weakly inhibits its breakdown. These new findings have important implications in elucidating the pain-relieving, anti-inflammatory, and immunodulatory effects of CBD.
The combination of THC, CBD and essential oils in cannabis-based medicinal extracts may produce a therapeutic preparation whose benefits are greater than the sum of its parts.
Other cannabis-based drugs include Marinol (dronabinol) and Cesamet (nabilone). Both are synthetic versions of THC in tablet form used primarily by people with cancer and AIDS to treat nausea related to certain treatments and to stimulate the appetite.
stopthedrugwar.org notes that advocates of raw, smoked medical marijuana worry whether approval of a cannabis-based medicines like Sativex could cut the legs out from under the medical marijuana. So will Sativex eliminate the need for Medical Marijuana? The answer is “no.” Sativex acts far more slowly than marijuana that is inhaled. According to the company’s official product information, peak blood levels aren’t reached for more than an hour and half – about as slowly as Marinol, that some doctors and patient’s consider unacceptably slow. Sativex is also costly in addition to the simple fact that most patients respond better to different strains of marijuana for different situations and conditions. Sativex is just a different form of medical marijuana, and patient’s and doctors should be able to decide what works best for each patient’s particular situation.
Various studies have revealed that marijuana contains more than 60 active compounds likely possessing distinctive therapeutic properties, including anti-cancer properties, anti-diabetic properties, neuroprotection, and anti-stroke properties of cannabinoids other than tetrahydrocannabinol (THC), the primary psychoactive compound of cannabis, which itself has valuable therapeutic effects. As BioNews Texas reported last August, research conducted by assistant professor of pharmaceutical sciences Dai Lu, PhD of Texas A&M University’s Health Science Center, focused on finding new types of chemotherapeutic drugs that both kill pancreatic cancer and suppress the cancer pain at the same time, has revealed that pancreatic cancer cells have more type 2 cannabinoid receptors than do healthy cells. These receptors belong to the biological system responsible for the effects of Tetrahydrocannabinol (THC), marijuana’s primary psychoactive agent. Consequently, THC-derived drug molecules that selectively activate this receptor can induce cancer cell death without affecting normal pancreatic cells as well as generating painkillers comparable to morphine’s pain-killing effect, but without the negative side effects and addiction potential associated with opioids.
Medical marijuana is now legal in 20 U.S. states. In California a simple doctor’s prescription has been all you’ve needed since 1996. More than a dozen other state legislatures, including those of Illinois, New York, and Pennsylvania, have recently considered medical marijuana bills, and voter initiatives on the issue are coming in at least three states.
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