Gw phase li spasticity

Phase III Sativex® MS Spasticity Trial : 

11 March 2009 Phase III Sativex® MS Spasticity Trial Study GWSP0604 Preliminary Results

Study Rationale:Route to Regulatory Approval : 

2 Study Rationale:Route to Regulatory Approval In previous regulatory application, quality and safety data were sufficient to support approval Regulators identified a key outstanding efficacy issue Target MS patients have advanced disease and are treatment-resistant Hence, not all patients have capacity to respond Benefit seen in “responders” is masked by mean data across all patients Regulators wish to be able to identify Sativex responders in the first 4 weeks of treatment and to confirm that improvements gained by such responders over a further 12 week period is significantly greater than placebo “Post hoc” analyses of responders data in previous submission showed strong results (p=0.015) Regulators asked GW to re-confirm this in a prospectively planned study The regulators gave GW clear guidance on the design of the required study “Enriched design” First identify responders over a 4 week period, and then analyse the effect of Sativex vs placebo on those responders over a further period of 12 weeks

Study Design : 

3 Study Design General: Placebo-controlled, randomised, parallel group study Patients: People with Multiple Sclerosis and spasticity who have failed to gain adequate relief from existing anti- spasticity medication and who demonstrate a capacity to respond to treatment Duration: 4 weeks single blind Sativex followed by 12 weeks double blind randomised period Primary Endpoint: Mean change in spasticity measured on the 0-10 Numeric Rating Scale Secondary Endpoints: Responder Analysis, Spasm, Sleep, Patient & Physician Global Impression of Change, etc

GWSP0604Study Design : 

4 Double Blind Randomised Period GWSP0604Study Design End of treatment /withdrawal 12 weeks Sativex 12 weeks Placebo 7 day Baseline Period 4 wks Single Blind Sativex Phase A Phase B Notes: Patients must achieve >20% improvement to be randomised The dose taken remains stable from Phase A to Phase B

GWSP0604: Demographics : 

5 GWSP0604: Demographics Treatment-resistant MS patients with significant disability and unmet medical need

GWSP0604: Background Medication : 

6 GWSP0604: Background Medication All patients have previously failed to respond to anti-spasticity therapy and continue to take their pre-existing background medication throughout the study

GWSP0604: Responders in Single-Blind Period (Phase A) : 

7 GWSP0604: Responders in Single-Blind Period (Phase A) Entered Phase A = 573 Screened = 670 Responders @ >20% = 271 (47%) Non-responders = 302 (53%) Randomised (Phase B) = 241 Sativex = 124 Placebo = 117

GWSP0604: NRS Spasticity scores over time : 

8 GWSP0604: NRS Spasticity scores over time NRS spasticity score Mean 48% improvement in spasticity on Sativex over 16 weeks Phase A Phase B

GWSP0604: Primary Endpoint Phase B Change in Spasticity scores : 

9 GWSP0604: Primary Endpoint Phase B Change in Spasticity scores Deterioration in spasticity score p=0.0002 Baseline scores Sativex: 3.87 Placebo: 3.92

GWSP0604: Secondary Endpoint: Change in Sleep Disturbance scores : 

10 GWSP0604: Secondary Endpoint: Change in Sleep Disturbance scores Deterioration in sleep disruption Baseline scores: Sativex: 1.96 Placebo: 2.07 p<0.0001

GWSP0604: Secondary Endpoint Change in Spasm Frequency scores : 

11 GWSP0604: Secondary Endpoint Change in Spasm Frequency scores Deterioration in spasm frequency Baseline scores: Sativex: 5.61 Placebo: 5.29 p=0.005

GWSP0604: Secondary Endpoint Responder Analysis: ≥30% Response : 

12 GWSP0604: Secondary Endpoint Responder Analysis: ≥30% Response A responder is defined as the change from the original study baseline All patients had been refractory to other anti-spasticity treatments 92/124 Sativex patients showed a response of at least 30% following this treatment regimen p=0.0003 % of population

GWSP0604: Other Positive Secondary Endpoints : 

13 GWSP0604: Other Positive Secondary Endpoints Patient global impression of change in spasticity (p=0.023) Physician global impression of change in spasticity (p=0.005) Provides useful objective verification of response

Excellent Safety Profile:Adverse Events at > 3% : 

14 Excellent Safety Profile:Adverse Events at > 3% Improved safety profile resulted from modified dose titration regimen employed in the study

Randomised Withdrawal Study of Sativex® in MS Spasticity : 

11 March 2009 Randomised Withdrawal Study of Sativex® in MS Spasticity Study GWSP0702 Preliminary Results

Study Rationale: The Regulatory Perspective : 

16 Study Rationale: The Regulatory Perspective In previous application, GW presented substantial long term open label data in 444 patients exposed to Sativex for a mean of 455 days Represents 554 patient-years of exposure Long term open label data showed evidence of maintenance of efficacy and no new safety signals Long-term open-label studies are not regarded by EU regulatory agencies as providing robust evidence of the maintenance of efficacy in the long term UK MHRA: “A randomised withdrawal trial following a period of open label treatment in patients considered to be responders would provide such information and would satisfy the need for controlled long term efficacy data”.

GWSP0702:Study Design : 

17 Long Term Sativex Prescription Use Double Blind Randomised Open Label – Mean Duration 3.6 years 4 weeks Sativex (n=18) Placebo (n=18) GWSP0702:Study Design All patients demonstrated clinically relevant response to Sativex whilst on long term prescription use Study dosing determined by dose level used in long term prescription use Recruitment for study was a challenge due to reluctance of patients to risk coming off Sativex for 4 weeks

Slide 18: 

18 GWSP0702: Positive Primary Endpoint Time to Treatment Failure Test Chi-Square p-value Kaplan-Meier Log-Rank 6.160 0.013

GWSP0702: Secondary EndpointCarer Global Impression of Change - Functional Ability : 

19 GWSP0702: Secondary EndpointCarer Global Impression of Change - Functional Ability Carers identify difference in functional ability

GWSP0702: Secondary EndpointPatient Global Impression of Change : 

20 GWSP0702: Secondary EndpointPatient Global Impression of Change

Summary : 

21 Summary Phase III study results provide robust evidence of efficacy of Sativex in MS Spasticity Phase III study expected to meet regulatory requirements for approval as stated in previous regulatory application Randomised withdrawal study provides significant evidence of long term efficacy in a study design recommended by regulators Sativex continues to show an excellent safety profile, which is further improved in this new data Amended dose titration schedule reduces adverse event rate in early exposure In the last 6 months, GW has reported three positive Sativex studies incorporating a design modified from previous studies New approach is producing consistent positive results Regulatory submission to be made Q2 09