Sativex - Investigational Cannabis-Based Treatment for Pain and Multiple Sclerosis

Developed by GW Pharmaceuticals, Sativex is a whole plant medicinal cannabis extract indicated for relief of symptoms of multiple sclerosis (MS) and for treatment of severe neuropathic-related cancer pain.

Bayer has secured exclusive rights to market Sativex in the UK with the option to extend this to other countries in Europe and countries such as Canada, where Sativex received regulatory approval in 2005 for treatment of neuropathic pain associated with MS. In December 2005, GW Pharmaceuticals entered into an agreement with Almirall Prodesfarma, under which Almirall can market Sativex throughout Europe, except for in the UK.

In August 2007, Canadian regulators approved Sativex as adjunctive analgesic treatment in adult patients with advanced cancer pain. Sativex and a related tetrahydrocannabinol (THC) medicine have been investigated in Phase III trials for the relief of cancer pain, an indication for which Bayer also has the option to market the drugs.

In February 2007, GW Pharmaceuticals also entered into a long-term research and development alliance on medicinal cannabinoids with Otsuka Pharmaceutical, which gave Otsuka exclusive rights to develop and market Sativex in the US. The companies will jointly oversee clinical development and regulatory activities in the US.

Having secured FDA approval to conduct trials of Sativex in patients with advanced cancer, whose pain is unrelieved by opioids, the companies are conducting the first US efficacy trial of Sativex in neuropathic-related cancer pain, having begun in 2007. The clinical spray trial of Sativex on a large number of volunteers (Phase III) is underway in the US and is scheduled for completion by the end of 2009.

On 16 July 2009, GW Pharmaceuticals received a licence for its new in-house Sativex manufacturing facility after passing a Good Manufacturing Practice inspection by the UK regulatory authority.

The company used to sub-contract the manufacturing of Sativex. The facility will be used to produce the drug for European commercial launch. The facility has a production capacity to treat 25,000 patients annually and is expected to increase capacity in line with demand.

Cannabis-based medicines

Estimates suggest that between 10% and 30% of MS patients in Europe smoke cannabis to ease the pain and disabling symptoms of the disease. This activity is illegal and patients run the risk of prosecution. In the UK, cannabis-based medicines were in fact outlawed in 1968 after legislation banned doctors from prescribing tincture of cannabis. This preparation contained high concentrations of the active THC psychotropic ingredient and was popular among recreational cannabis users.

The UK Government gave GW Pharmaceuticals special permission to investigate medicines derived from cannabis and has indicated that the law will be changed to allow doctors to prescribe them if approved by the MHRA. This would represent a major step forward for MS patients as for the first time they would have access to safe and effective cannabis-derived drugs on prescription.

Sativex is a cannabis extract containing tetranabinex (THC) and nabidiolex (cannabidiol – CBD) as its principal component. It does not contain the active substance found in recreational cannabis and so patients taking Sativex will not become intoxicated.

Sativex is administered by means of a spray into the mouth rather than smoked. A 100µl dose of Sativex spray contains 2.5mg CBD and 2.7mg THC. To meet demands for this innovative drug, GW Pharmaceuticals has increased production of cannabis at its fortified greenhouses to 60t/y.

Clinical trials on Sativex point to efficacy and safety

Phase III placebo-controlled trials in about 350 patients with MS have shown that administration of Sativex as a sublingual spray is a safe and effective treatment for symptom relief. Compared with placebo, significantly more patients in the Sativex treatment arm experienced reduced neuropathic pain, spasticity, and sleep disturbances.

Further Phase III data on 189 MS patients supports the earlier registration trial data. Again, treatment with Sativex produced a statistically significant improvement over placebo in spasticity, the primary endpoint, (p lt;0.05). Other secondary endpoints, such as the Ashworth scale, also favoured Sativex over placebo. Overall, these data have shown that Sativex produces treatment effects over and above those achieved with existing medications, which patients were allowed to continue while taking part in the Sativex trial.

Additional trials have been conducted to assess the effectiveness of Sativex in treating neuropathic pain and spinal cord injury. Results from three Phase III trials in patients with neuropathic pain showed that the addition of Sativex to standard therapy produced improvements over and above those obtained with existing medication. Patients in these trials had all failed to response to standard therapy and constituted a population with high clinical need.

GW Pharmaceuticals announced positive results of the Sativex Phase III MS study in patients with spasticity. The Phase III study was conducted on 573 patients in the UK. In May 2009, GW Pharmaceuticals filed a regulatory submission for spasticity treatment in the UK and Spain. The outcome is expected by the end of 2009 or early 2010. If approved in the UK and Spain, the drug's approval in all European countries can be expected by early 2010.

Treatment of severe neuropathic pain

Neuropathic pain, which is frequently chronic, arises when neurones in the brain or peripheral nervous system become hyper-sensitised and generate abnormal or prolonged impulses. There are many causes of neuropathic pain including diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, multiple sclerosis and cancer. Around 40% of cancer patients suffer some degree of neuropathic pain.

Severe neuropathic pain has proved difficult to treat and evidence suggests that none of the available drugs, mainly opioids, is effective in more than 50% of patients. Thus, it represents an area of significant unmet clinical need.

The encouraging data from the Sativex Phase III registration trials in multiple sclerosis patients suggest cannabis-derived medicines may have a valuable place in this sector of the pain market.

Marketing commentary

In Europe alone there are some 500,000 MS patients on top of the 4 million experiencing neuropathic pain. This fact, together with a market poorly served by currently available drugs, presents an excellent opportunity for Sativex if the encouraging results seen in multiple sclerosis are reproduced in other patient groups.

Now that Sativex has been approved for clinical use in Canada, for treatment of MS neuropathic pain and cancer pain, other countries including the UK and the US are conducting clinical trials of Sativex.

Sativex is not licensed in the UK but is prescribed to patients on a special basis. It is exported to about 22 countries across the globe.

On 16 July 2009, GW Pharmaceuticals received a licence for its new in-house Sativex manufacturing facility after passing a Good Manufacturing Practice inspection by the UK regulatory authority.

The company used to sub-contract the manufacturing of Sativex. The facility will be used to produce the drug for European commercial launch. The facility has a production capacity to treat 25,000 patients annually and is expected to increase capacity in line with demand.