Despite the fact that there are no quality or safety issues standing in the way of approval for GW Pharmaceuticals' MS spasticity treatment Sativex, and clinical efficacy data showing promising and statistically significant results, the Medicines and Healthcare products Regulatory Agency (MHRA) has requested an 'enriched design' study be carried out focussing on specific patients who respond to the treatment. MS specialist Professor Mike Barnes of the University of Newcastle criticised the regulator's "bureaucratic approach," claiming it is "regrettable and unnecessary…that the regulators require GW to generate further data to show what we already know - that Sativex is a safe and efficacious treatment for people with MS." The stumbling block in the approval process has been caused by the fact that Sativex is intended for patients who have exhausted all other treatment options, which means that some subjects simply lack the ability to respond to the drug, or any other MS treatment. "That translates in a clinical trial setting into a situation where…patients who do respond [are] masked by the lack of response in those patients who simply don't have the capacity to respond," explained Stephen Wright, R&D director at GW. As such, the MHRA has asked GW to carry out confirmatory studies looking only at patients showing a response to Sativex, and to identify the level in response in this set of subjects. Although the company carried out analysis of existing data through which responders were found to be easily identifiable, as well as 62 per cent more likely to achieve a meaningful response than on placebo, the MHRA has put its foot down and demanded more data be generated before the drug can be approved. "Analyses show we can very reliably identify responders after four weeks of treatment," said Wright. "From the regulator's point of view that is very encouraging, but from a technical point of view they have a requirement that those analyses be carried out in a prospective way rather than in a 'post-hoc' analysis." GW had planned to carry this type of study further down the line anyway, and as such is already well-prepared to carry out the confirmatory study. The first patients should be able to enter the trial in October this year, with completion expected in around 12 months time. The company has two options for resubmission in the EU following the decision to withdraw its application last week. A second pivotal Phase III trial of Sativex for the treatment of MS neuropathic pain is due to complete in early 2008, which could lead to a regulatory filing around that time. As the outstanding issue regarding efficacy in responders relates to an indication of MS spasticity, it should not affect the pain application. Should GW not submit an application for the neuropathic pain indication, the company's next opportunity is to submit for MS spasticity in the second half of 2008 following completion of the additional study. "It's quite clear from our discussions with [the MHRA] that this enrichment study, providing it's positive, will result in the approval of Sativex," said Wright. Sativex is GW Pharmaceutical's first product, and is being developed for approval in four target indications: MS spasticity, MS neuropathic pain, cancer pain and peripheral neuropathic pain. The treatment is based on extracts taken from the widely-used recreational drug cannabis, and applied as an oro-mucosal spray to the mouth. It is based on a combination of two well-characterised cannabinoids (chemical compounds found only in the cannabis plant), delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD). THC has been shown to have analgesic, anti-spasmodic, anti-tremor, anti-inflammatory, appetite stimulant and anti-emetic properties, while CBD has shown anti-inflammatory, anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective and immunomodulatory effects. In April 2005 GW received approval for Sativex in Canada, for use as an adjunctive therapy for the relief of neuropathic pain in patients with MS. The company also expects Canadian approval for the relief of cancer pain in the near future. In the US, cancer pain is the lead indication for Sativex, with the first patients entering pivotal late stage trials next month. While the drug is yet to be approved anywhere outside Canada, the company has already licensed Sativex to Bayer Healthcare for the Canadian and UK markets and Almirall Prodesfarma for the rest of Europe, as well as Otsuka for the US market. Together, these agreements have generated $51m (€37m) in signature fees, up to $376m in milestone payments, and 'significant' long term supply price provisions.