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Phase III Sativex® MS
Spasticity Trial
Study GWSP0604
Preliminary Results
11 March 2009
Study Rationale:
Route to Regulatory Approval
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In previous regulatory application, quality and safety data were sufficient to
support approval
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Regulators identified a key outstanding efficacy issue
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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
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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
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Study Design
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General:
Placebo-controlled, randomised, parallel group study
Patients:
People with Multiple Sclerosis and spasticity who
have failed to gain adequate relief from existing antispasticity 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
GWSP0604
Study Design
Phase A
Phase B
12 weeks Sativex
End of
treatment
/withdrawal
12 weeks Placebo
7 day
Baseline
Period
4 wks
Single Blind
Sativex
Double Blind Randomised Period
Notes: Patients must achieve >20% improvement to be randomised
The dose taken remains stable from Phase A to Phase B
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GWSP0604: Demographics
Age (yrs)
48.5 years
Gender – Male
40%
Female
60%
Type of MS
Primary Progressive
16%
Secondary Progressive
50%
Remitting/Relapsing
32%
Progressive Relapsing
2%
Duration of MS
12.14 years
Duration of Spasticity
7.17 years
Mean Baseline Spasticity (0-10 NRS)
7.04
Baseline EDSS
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Treatment-resistant MS patients with significant disability and
unmet medical need
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GWSP0604: Background Medication
Medication
6
%
Baclofen
57%
Tizanidine
19%
Benzodiazepines
17%
Others (gabapentin, dantrolene, botulinum
toxin)
12%
Disease modifiers
53%
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)
Screened = 670
Entered Phase A = 573
Responders @ >20% = 271
(47%)
Non-responders = 302
(53%)
Randomised (Phase B) = 241
Sativex = 124
7
Placebo = 117
GWSP0604:
NRS Spasticity scores over time
7.5
Phase A
Phase B
7
NRS spasticity score
6.5
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5.5
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LO
CF
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Mean 48% improvement in spasticity on Sativex over 16 weeks
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Sativex
Placebo
GWSP0604: Primary Endpoint
Phase B Change in Spasticity scores
0.6
0.4
p=0.0002
0.2
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LO
CF
Deterioration in spasticity score
0.8
-0.2
-0.4
Baseline scores
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Sativex: 3.87
Placebo: 3.92
Sativex
Placebo
GWSP0604: Secondary Endpoint:
Change in Sleep Disturbance scores
0.6
0.4
p<0.0001
0.2
Sativex
Placebo
CF
LO
-0.2
-0.4
-0.6
Baseline scores:
10
12
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10
9
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5
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3
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Deterioration in sleep disruption
0.8
Sativex: 1.96
Placebo: 2.07
GWSP0604: Secondary Endpoint
Change in Spasm Frequency scores
2.5
2
1.5
p=0.005
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0.5
CF
LO
-0.5
-1
Baseline scores:
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Deterioration in spasm frequency
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Sativex: 5.61
Placebo: 5.29
Sativex
Placebo
GWSP0604: Secondary Endpoint
Responder Analysis: ≥30% Response
p=0.0003
80%
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A responder is defined
as the change from the
original study baseline
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All patients had been
refractory to other antispasticity treatments
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92/124 Sativex patients
showed a response of at
least 30% following this
treatment regimen
70%
% of population
60%
50%
40%
30%
20%
10%
0%
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Sativex
Placebo
GWSP0604:
Other Positive Secondary Endpoints
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Patient global impression of change in spasticity (p=0.023)
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Physician global impression of change in spasticity (p=0.005)
– Provides useful objective verification of response
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Excellent Safety Profile:
Adverse Events at > 3%
Adverse Event
Phase A period of
Study SP0604
(n=573)
Guidance from
previous MS studies
(n=663)
Dizziness
13%
32%
Fatigue
6%
12%
Somnolence
5%
8%
Nausea
4%
12%
Dry Mouth
4%
8%
Urinary Infection
3%
9%
Vertigo
3%
4%
Improved safety profile resulted from modified dose titration
regimen employed in the study
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Randomised Withdrawal
®
Study of Sativex in MS
Spasticity
Study GWSP0702
Preliminary Results
11 March 2009
Study Rationale:
The Regulatory Perspective
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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
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Long term open label data showed evidence of maintenance of efficacy and no
new safety signals
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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
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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
Sativex (n=18)
Long Term Sativex Prescription Use
Placebo (n=18)
Open Label – Mean Duration 3.6 years
Double Blind Randomised
4 weeks
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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
GWSP0702: Positive Primary Endpoint
Time to Treatment Failure
Kaplan-Meier Plot: Time to Treatment Failure
Placebo
1
Sativex
Probability of Failure
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
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0
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Kaplan-Meier
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Test
Log-Rank
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Days on Treatment
Chi-Square
6.160
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p-value
0.013
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GWSP0702: Secondary Endpoint
Carer Global Impression of Change
- Functional Ability
70
p=0.001
% of Carers in each category
60
50
40
Sativex
Placebo
30
20
10
0
Very much
Much
better
better
19
Minimally
better
No change
Minimally
worse
Much
worse
Very much
worse
Carers identify difference in functional ability
GWSP0702: Secondary Endpoint
Patient Global Impression of Change
60
p=0.0172
% of patients in each category
50
40
Sativex
30
Placebo
20
10
0
Very much Much better
better
20
Minimally
better
No change
Minimally
worse
Much worse Very much
worse
Summary
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Phase III study results provide robust evidence of efficacy of Sativex in MS
Spasticity
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Phase III study expected to meet regulatory requirements for approval as
stated in previous regulatory application
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Randomised withdrawal study provides significant evidence of long term
efficacy in a study design recommended by regulators
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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
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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
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Regulatory submission to be made Q2 09