Sativex - Investigational Cannabis-Based treatment for Pain and Multiple Sclerosis
Developed by GW Pharmaceuticals, Sativex is a whole plant medicinal cannabis extract indicated for the relief of multiple sclerosis (MS) symptoms and the treatment of severe neuropathic-related cancer pain.
Bayer has secured exclusive rights to market Sativex in the UK, and has the option to extend this to other countries in Europe and countries such as Canada. In December 2005, GW Pharmaceuticals entered into an agreement with Almirall Prodesfarma, under which Almirall can market Sativex throughout Europe, except in the UK.
Sativex received regulatory approval for treatment of neuropathic pain associated with MS in Canada in 2005. 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 II / 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 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 cancer patients (Phase II/III) was initiated in January 2011.
In June 2010, GW Pharmaceuticals announced that Sativex had been approved by the UK's Medicines and Healthcare products Regulatory Agency (MHRA). The company subsequently launched the drug in the market. GW Pharmaceuticals received a £10m milestone payment from Bayer.
In July 2010, GW Pharmaceuticals received approval for Sativex for treating MS-related spasticity in Spain. In March 2011, Sativex was launched in Spain by GW Pharmaceuticals' marketing partner Almirall. GW Pharmaceuticals received £2.5m milestone payment from Almirall.
GW Pharmaceuticals filed for regulatory submissions in other European countries in the second half of 2010.
In March 2011, it announced the successful completion of the European Mutual Recognition Procedure (MRP) for Sativex, leading to the drug's approval in Italy, Denmark, Germany, Sweden, Czech Republic and Austria. Sativex is expected to be launched in these countries in 2012.
Sativex was launched in Denmark and Germany in July 2011. It was approved in Sweden in December 2011 and it is expected to be launched in the first half of 2012. In Sweden, the drug will be marketed by Almirall.
In November 2010, Sativex was approved by New Zealand's regulatory authority MedSafe.
In April 2011, GW Pharmaceuticals entered into a licensing agreement with Novartis Pharma to market Sativex in Australia, New Zealand, Asia (excluding Japan, China and Hong Kong), the Middle East (excluding Israel/Palestine) and Africa. Under the terms of the agreement, Novartis made a $5m upfront payment to GW Pharmaceuticals and additional payments upon achievement of approval and commercial milestones. GW Pharmaceuticals is planning to submit regulatory applications in these countries.
In November 2011, GW Pharmaceuticals filed a regulatory application for expanding the marketing authorisation for Sativex in additional European member countries. It has submitted an application under the MRP to cover ten more countries. The MRP process is expected to be completed by mid-2012.
Estimates suggest that 10-30% 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 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. This represents 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 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 not smoked, but administered by means of a spray into the mouth. 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 per year.
The composition of Sativex is protected by patents in both the US and Europe.
In 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 authorities.
The company used to sub-contract the manufacturing of Sativex. The facility, which has capacity to provide Sativex for 25,000 patients annually, is used to produce the drug for the European commercial launch. GW Pharmaceuticals expects to increase capacity in line with demand.
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 earlier registration trial data. Again, treatment with Sativex produced a statistically significant improvement over placebo in spasticity, the primary endpoint, (p<0.05).
Other secondary endpoints, such as the Ashworth scale, also favoured Sativex over placebo. Overall, the data showed that Sativex produced 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 has also announced positive results of a Sativex Phase III MS study in 572 UK patients with spasticity.
The results showed that when compared to placebo, Sativex reduced the mean NRS score for spasticity significantly by 3.01 points from the 6.91 baseline.
Treatment of severe neuropathic pain
Neuropathic pain, which is frequently chronic, arises when neurones in the brain or peripheral nervous system become hypersensitised 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 no available drug 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.
In November 2010, GW Pharmaceuticals commenced a Phase III programme of Sativex for the treatment of cancer pain. The programme was launched on the basis of positive data from a Phase IIb trial announced in March 2010. It includes two Phase III trials funded by Otsuka which enrolled 380 patients across Europe, North America, Latin America and Asia. The first trial commenced in December 2010 and the second in June 2011.
In Europe alone there are some 500,000 MS patients on top of the four million experiencing neuropathic pain. This fact, together with a market poorly served by currently available drugs, presents an excellent opportunity for Sativex.