BioWorld International Correspondent

LONDON - GW Pharmaceuticals Ltd. hit a regulatory roadblock in its attempts to register its cannabis derivative, Sativex, in spasticity in multiple sclerosis.

The company has produced statistically significant Phase III data showing efficacy in relieving muscle spasms, but UK regulators have told GW they are not convinced that the data are "clinically relevant."

The impasse leaves GW with the option of an appeal that will not be heard for six months or mounting another Phase III study that will take until the end of 2005 to complete.

Shares in the Salisbury-based company fell 35.5 pence to £1.06 when the delay was announced Friday. GW shares stood at £2.84 in April, but have fallen on previous delays in getting approval for Sativex, which was submitted in March 2003.

Stephen Wright, R&D director, said the decision by the Committee on Safety of Medicines (CSM) was contrary to earlier advice from the regulators and to the views of leading medical experts. Speaking in a teleconference, he said, "We feel the view of the CSM is not reflecting the clinical reality."

In the opinion of one independent expert, Mike Barnes, president of the World Federation of Neuro-rehabilitation, chairman of the Royal College of Physicians Rehabilitation Committee and a trustee of the Multiple Sclerosis Trust, said, "The clinical trials show that Sativex offers sustained benefit to many patients with spasticity due to multiple sclerosis who are otherwise unable to find relief for their condition."

At issue is the method GW used to assess spasticity relief. "We designed the trials along the line that experts suggested - that is, patient experience," Wright said. "In essence, this is subjective, and what the CSM wants is a non-subjective endpoint."

In the Phase III trial, 40 percent of patients experienced 30 percent or greater improvement in spasticity. The other approach to assessing spasticity, the Ashworth scale, is based on physicians' observations and, as such, also is subjective. In the Phase III, Ashworth scale assessments were in favor of Sativex but did not reach statistical significance.

Apart from having the support of medical experts, MS patient organizations also say assessment of benefits should be based on patients' experience. All the patients treated have elected to transfer to prescription use. "In other words, they are voting with their feet," Wright said.

Worth noting is that regulators persuaded GW to put aside positive results in five other Phase III trials to concentrate on getting approval in spasticity in MS in the first instance. As a result, none of the other trials were considered in the application.

GW also was optimistic because it succeeded in answering 45 out of 46 questions raised by the regulators after the initial review, resolving a range of quality and safety issues. On quality, Geoffrey Guy, GW's executive chairman, said, "This has been the most potentially challenging area, to attain appropriate quality for a botanical product."

With no outstanding quality or safety issues, GW now intends to appeal the CSM decision on efficacy with the Medicines Commission. It expects a wait of six months before the case is heard.

The company was in the process of setting up another Phase III study in MS, which now it will design to suit the CSM's requirements. However, Wright said the CSM is not clear about what the endpoint of the trial should be. "There is a degree of confusion; [CSM] has not caught up with advances in neuro-rehabilitation."

He added, there is "no obvious scientific answer" to the question of how to make objective measurements of reductions in spasticity. "In [its] absence we still feel a patient-oriented scale is the appropriate one to use."

GW also has filed for approval of Sativex in Canada, and said that to date it has not been made aware of any problems that will prevent approval there. The company has £16 million (US$31.1 million) in cash and a burn rate of £1 million per month.

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