SATIVEX. London New Drugs Group APC/DTC Briefing Document. June 2010

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1 Page 1 London New Drugs Group APC/DTC Briefing Document SATIVEX Contents Summary 1 Background 5 Sativex 5 Controlled drug status 5 Dose and administration 6 Precautions 6 Drug interactions 6 Excipients 6 Current Guidelines 7 Clinical Efficacy 7 Phase III spasticity in MS study 7 Phase III withdrawal study 10 Longer term use 11 Budget impact model 12 References 13 Appendix 1 14 Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: Med.info@nwlh.nhs.uk Further copies of this document are available from URL: Summary The drug and the review Sativex is a cannabis-based medicine which contains delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) in an oromucosal spray. The regulatory submission for Sativex for the treatment of spasticity due to MS was filed in the UK in May Sativex has been available on a named-patient basis in the UK since December The purpose of this review is to evaluate the data supporting the use of Sativex to treat MS-related spasticity. Background Multiple Sclerosis (MS) affects the white matter of the central nervous system (brain and spinal cord), causing almost any neurological symptom. Spasticity is a common symptom, with prevalence ranging from 21-85%. Patients with MS-related spasticity have an increased stiffness or tightness in their muscles, which can affect their movement. They may also suffer with spasms. Current NICE guidelines (2003) recommend that pharmacological treatment for spasticity associated with MS should be treated with either baclofen or gabapentin. If these are ineffective, or not tolerated, then tizanidine, diazepam, clonazepam or dantrolene can be used. Sativex is a Schedule 1 controlled drug under the Misuse of Drugs Act and will remain so until approved by the MHRA. Once it is approved, the Home Office intends to reschedule Sativex to Schedule 4. The open general licence issued by the Home Office means that doctors and pharmacists do not need to contact the Home Office before prescribing and dispensing Sativex. Patients who want to travel abroad and need to take Sativex with them must first check with the appropriate authorities of the destination whether it is legal for them to take Sativex into that country. Literature The following databases were searched: Medline: sativex.af, [*CANNABIDIOL/ OR *TETRAHYDROCANNABINOL/] AND *MULTIPLE SCLEROSIS/, [*CANNABIDIOL/ OR *TETRAHYDRO PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 Embase: Sativex.af AND *MULTIPLE SCLEROSIS/. IDIS: "CANNABINOIDS " and Disease(s): "SCLEROSIS, MULTIPLE 340." Abstracts for the two, as yet unpublished, pivotal trials were obtained from Bayer and a presentation from GW Pharmaceuticals on the two trials was obtained. The MHRA Public Information Report and studies for the original application were obtained. Efficacy studies Following discussions with the MHRA regarding trial design a marketing application was withdrawn in The regulatory authorities wanted to be able to identify Sativex responders in the first 4 weeks of treatment and confirm that improvements gained over a further 12 weeks was significantly greater than those seen with placebo. A new study was required that would have an enriched design to identify responders, and then analyse the effects of Sativex vs. placebo. Phase III spasticity in MS study 572 patients with spasticity due to MS were enrolled in a 4-week, single-blind treatment period (Phase A) to determine response to Sativex. 272 patients (48%) had 20% reduction in spasticity scores and were classed as responders. Of these, 241 entered the 12-week, double-blind, phase B and were randomised to treatment with either Sativex (n=124) or placebo (n=117). The primary endpoint was the mean change from pre-randomisation baseline in the spasticity numerical rating scale (0=none, 10=worst). The changes were (placebo, positive figure indicates a deterioration) and (Sativex), p= Sleep disturbance worsened in the placebo group (by ~0.6 on the numerical rating scale) but improved in the Sativex group (by ~0.2) (p<0.0001). The frequency of spasms was maintained by Sativex from baseline, but increased in the placebo group by ~2.5/day (p=0.005). Significantly more patients treated with Sativex than with placebo showed a 30% response from the original study (pre-treatment phase A) baseline: 74% vs. 50%, p= Withdrawal study Patients using Sativex entered this five-week placebo-controlled, parallel group, randomised withdrawal study. All patients had demonstrated clinically relevant responses to Sativex whilst on long-term prescription use. After a 7-day baseline period where the subjects continued with Sativex at their current effective dose level, they ceased Sativex and were randomised. They were randomised to Sativex (n=18) or placebo (n=18) and to continue with the current effective dose identified at the start of the baseline period for the next 4 weeks The primary endpoint was time to treatment failure. Time to treatment failure was significantly in favour of Sativex (p=0.013). Eight Sativex patients (44.4%) and 17 (94%) placebo patients were classed as treatment failures. 16 (89%) of placebo patients withdrew vs. 3 (17%) of Sativex patients. Withdrawal of Sativex precipitated significant worsening in spasticity. Adverse events which may have been caused by withdrawal of Sativex have not yet been published. Long term use 137 patients continued with Sativex treatment after a 6week double-blind and 4 week open-label study. These patients perceived to have had a benefit from treatment and continued taking it, mimicking clinical practice. 73 of these patients had completed at least one year of follow-up. The benefits seen in the primary symptoms (spasticity, spasm, pain and bladder) after the initial 10 weeks were maintained throughout the year.

3 Page 3 Safety Dizziness, fatigue, somnolence, nausea, dry mouth, urinary infection, vertigo were reported in phase A (single-blind Sativex) of the phase III study; somnolence, dry mouth, euphoric mood and vertigo were more common with Sativex treatment than placebo in phase B. No withdrawal syndrome was evident from the small withdrawal study, but worsening of spasticity symptoms and functional ability were seen. In other studies (from the 2006 licensing application), one of the most frequently reported adverse events was a sore mouth (20% in the open-label phase continuation study). CNS events, such as fatigue, dizziness, somnolence, impaired balance, disturbance of attention and lethargy occurred in more patients treated with Sativex than placebo. Critical evaluation MS is a long-term condition: there is limited evidence of maintenance of efficacy with long-term Sativex treatment. The studies have not yet been fully published and currently available data is poorly reported, with few comparisons between Sativex and placebo given. Phase B of the phase III spasticity study shows that Sativex is able to maintain the improvements in spasticity achieved with Sativex and continue to improve sleep disturbances and spasms. Responses were based on the subjective numerical rating scale. The clinical significance of the differences in spasticity and sleep symptoms between placebo and Sativex is not clear. The combined data from phases A and B show that Sativex is associated with a statistically significant improvement in health outcome and physical and daily functioning, but lack of data from the placebo group make it difficult to assess whether this translates to a clinically significant improvement. Whilst withdrawal of Sativex can lead to worsening of spasticity symptoms, if other withdrawal symptoms did occur these have not been reported in the abstract/pharmaceutical company presentation. Potential benefits over existing technologies Patients in the spasticity study had failed to respond to antispasticity therapy but 74% of those treated with Sativex for 16 weeks showed a 30% response (change in spasticity numerical rating score) from baseline. It is not documented whether the patients were titrated to the maximal tolerated/therapeutic doses of the original antispasticity medications before using Sativex. Potential disadvantages over existing technologies No head-to-head studies with other treatments for spasticity of MS were identified, so there is a lack of evidence suggesting that Sativex could be used in place of currently recommended treatments. Sativex is an oromucosal spray that contains alcohol: the spray should be directed to a different part of the oromucosa each time it is administered. Use has been associated with a sore mouth in 20% of patients. The median dose in clinical trials is 8 sprays per day. Doses of > 12 sprays per day are not recommended. The legal status of Sativex may vary between countries (as already mentioned): this may limit travel. Not all patients will respond to Sativex; a 4-week trial period has been suggested to monitor response. A 15 minute gap between sprays is required.

4 Page 4 Estimated cost per population There are approximately 100,000 patients with MS in the UK, and of these, 84% (84,000) are affected with spasticity. Of these, 28,500 have either moderate (17%) or severe/total (17%) spasticity and 21,134 will use medication (69% and 79% respectively). Combination therapy is used by 33% of patients with moderate and 46% of patients with severe/total spasticity (11,567) It is assumed that 50% of these (5,784) will use Sativex. This equates to approximately 9 users per 100,000. If 9 patients were treated for 1 month, and 4 continued on therapy, the annual cost per 100,000, assuming a dose of 8 sprays/day and a cost per spray of , would be in the range of 11,500 28,700. Issues for consideration The trial data for the 2009 licence application are not yet fully published: the data that are published do not give an indication of the clinical significance of the changes in symptoms seen with Sativex treatment compared with placebo treatment, or how the side effect profile of Sativex compares with that of placebo. There are no data comparing Sativex with other treatments for spasticity. A trial period of 4 weeks is required to assess response to Sativex: not all patients will respond. There should be a 15 minute gap between sprays: for patients taking the average of 8 sprays a day (given in 2 divided doses), administration will take one hour. MS is a long term condition: the main trial was 12 weeks long. Currently Sativex is a Schedule 1 drug (with some restrictions lifted), but this is due to be changed to Schedule 4 when it is approved by the MHRA. The cost of Sativex is significantly more than that of the treatments recommended by NICE for spasticity.

5 Page 5 Background Multiple sclerosis (MS) is a disease that affects the white matter of the central nervous system (CNS, brain and spinal cord). 1 There are three main clinical types: 1 Relapsing-remitting: clearly defined disease relapses with full recovery or some after-effects upon recovery. Periods between relapses are characterised by a lack of disease progression. About 80% of patients have relapsing-remitting disease at onset. Secondary progressive: initial relapsingremitting course followed by progression with or without occasional relapses, minor remissions and plateaux. About 50% of people with relapsing-remitting MS develop secondary progressive MS during the first 10years of their illness. Primary progressive: disease progression from onset with occasional plateaus and temporary minor improvements. About 10-15% have primary progressive disease at onset. Patients with MS, as well as those with stroke, head injury and spinal cord injury, commonly experience spasticity. 1;2 Surveys in patients with MS have reported rates ranging from 21% to 85%. 1;2 Patients with MSrelated spasticity have an increased stiffness or tightness in their muscles which can affect their movement. They may also suffer with spasms. The intensity of the symptoms is variable, but consequences include pain and sleep disturbance, and interference in mobility, exercise, physical endurance and activities of daily living, discomfort or pain, sleep disturbance. 3 Sativex Sativex is a cannabis-based medicine which contains 27mg/mL delta-9- tetrahydrocannabinol (THC) and 25mg/mL cannabidiol (CBD) in an oromucosal spray (5.5mL). 4;5 This formulation is said to bring out the therapeutic benefits of cannabinoids while at the same time minimise adverse and unwanted effects such as intoxication, sedation or psychotropic effects. 6 The regulatory submission for Sativex for the treatment of spasticity due to MS was filed in the UK (to the MHRA) in May Sativex is already available in Canada (for cancer pain and neuropathic pain associated with MS) and since December 2005 has been available on a namedpatient basis in the UK. 4;6 Cannabinoids act via specific cannabinoids (CB) receptors. 5 CB 1 and CB 2 receptors are found predominantly at nerve terminals. A role of this receptor may be to modulate neurotransmitter release and prevent development of excessive neuronal activity in the CNS. Sativex has been researched and developed by GW Pharmaceuticals and will be marketed by Bayer HealthCare. Controlled drug status Sativex is a Schedule 1 controlled drug under the Misuse of Drugs Act and will remain so until approved by the MHRA. 4;7 Once it is approved, the Home Office intends to reschedule Sativex (but not cannabis) to Schedule 4. The current open general licence issued by the Home Office means that doctors and pharmacists are not required to contact the Home Office before prescribing or dispensing Sativex. Prescription requirements for Sativex include: 4;8 Medical condition for which it is prescribed Name and address of the prescribing doctor, signed and dated Drug description of x packs each containing 4x5.5mL vials of Sativex Oromucosal Spray. GW Pharmaceuticals is required to record the initials, date of birth, medical condition and gender of patients, as well as the prescribers name and address, for Home Office purposes; without this information, orders for Sativex will not be processed. 4 The legal status of Sativex will vary between countries. Patients who want to travel abroad and need to take Sativex with them, must first check with the appropriate authorities of the destination whether it is legal for them to take Sativex into the country. 5 Storage (safe custody requirements) Whilst Sativex is classed as a Schedule 1 controlled drug, safe custody requirements apply. The unopened spray containers must be refrigerated. 4;5 The Home Office requires that Sativex should be stored in a locked refrigerator (where available), prior to dispensing. Otherwise it should be kept in a refrigerator out of view to

6 Page 6 the public and in an adequately secure location. Pharmacists do not need to record Sativex in their CD registers. 4 Once the spray has been opened, refrigeration is not necessary but avoid temperatures over 25 C. The opened spray has a shelf life of 28 days. 5 Schedule 4 drugs do not require safe custody requirements, records in the CD register and prescription requirements. 8 Dose and administration A titration period is required to reach the optimal dose. The number and timings of sprays will vary between patients. Sativex should be sprayed either under the tongue or on to the inside of the cheek: the spray should not be inhaled. 9 The dose should then be increased by one spray per day, according to responsible and tolerability. 5 There should be at least a 15 minute gap between sprays. Patients should be told that it may take up to two weeks before the optimal dose is found. Following the titration period, patients should be advised to continue using the optimal dose: for many this is 8-9 sprays a day, but up to 12 sprays can be used. Re-titration may be necessary if the severity of the patient s condition changes, if concomitant medications are changed or if troublesome adverse events occur. 5 Sativex is not recommended for use in children under 18 years of age, and frequent review of its use in the elderly is recommended. Sativex should not be used in patients with a known or suspected history of schizophrenia or psychotic illness, severe personality disorder or any other significant psychiatric disorder other than depression associated with the underlying condition. Sativex spray should be directed at different sites of the oromucosal surface each time it is used. Application site reactions such as oral pain and discomfort, dysgeusia (taste distortion), mouth ulceration and mouth/throat irritation have been reported. Two cases of possible leukoplakia (thick white plaques that develop inside the mouth, may be pre-cancerous) were seen but not confirmed histologically; a third case was unrelated. 5 Precautions and Adverse reactions 5 Mild to moderate dizziness is common in the first few weeks of treatment. Patients with a history of epilepsy or seizures should be treated with Sativex with caution. Sativex should not be used in patients with serious cardiovascular disease, because cannabinoids can cause tachycardia and hypotension. In healthy volunteers no clinically relevant changes in QTc, PR or QRS intervals were seen. The effects of Sativex may be prolonged or exaggerated in patients with hepatic or renal impairment; no studies have been carried out in this patient population. Animal studies have shown that cannabinoids can affect spermatogenesis. There is insufficient experience of the use of Sativex in human pregnancy. Men and women of childbearing potential should use reliable contraception for the duration of Sativex treatment and three months after. Sativex should not be used by breast-feeding mothers; in animal studies considerable levels of cannabinoids were found in breast milk. No withdrawal-type symptoms have been seen after abrupt withdrawal of long-term Sativex. The likely effects are expected to be transient disturbances of sleep, emotion or appetite in some patients. Self-reported levels of intoxication are low. Drug interactions 5 No clinically apparent drug interactions have been seen with drugs metabolised by the cytochrome P450 enzyme system. There may be an additive effect on sedation and muscle relaxing effects if Sativex is used concurrently with hypnotics, sedatives and other drugs with potential sedating effects. Sativex may interact with alcohol, affecting co-ordination, concentration and the ability to respond quickly. Excipients 5 Sativex contains ethanol (alcohol), 50% v/v: each 100microlitre spray contains up to 0.04g of alcohol. Most patients respond at doses up to and including 12 sprays per day which would contain less than 0.5g of ethanol. A 125mL glass of wine (12% v/v) contains approximately 12g of alcohol.

7 Page 7 Current Guidelines NICE Guidelines for the management of MS in primary and secondary care (2003) have the following recommendations for the spasticity and spasms: 1 Consider if the spasms/spasticity are a significant problem or a contributing factor to the current clinical state. Causative factors such as pain and infections should be treated. Neurophysiotherapy assessment and advice should be sought. Initial pharmacological treatment should be with baclofen or gabapentin. If baclofen or gabapentin are not effective or if side effects are not tolerated, tizanidine, diazepam, clonazepam or dantrolene can be used. Intramuscular botulinum toxin can be considered for localised hypertonia that is not responding to other treatments. Intrathecal baclofen and phenol injections are other invasive treatments that can be used. Clinical efficacy The two pivotal studies on which the licence application is based have not yet been published. Data come from conference abstracts, posters and a presentation from GW Pharmaceuticals Data from the trials submitted for the 2006 licence application are in appendix 1. Phase III spasticity in MS study In previous regulatory applications, the quality and safety data were sufficient to support approval but Sativex was ineffective. 11 The MS patients targeted had advanced disease and may have been treatment-resistant, so not all patients have the capacity to respond to Sativex. The benefits seen in responders may have been masked by mean data across all patients. The regulatory authorities sought to identify Sativex responders in the first 4 weeks of treatment and confirm that improvements gained by such responders over a further 12 week period was significantly greater than that seen with placebo. 11 The regulators gave clear guidance on the design of the required study: it would have an enriched design and identify responders, initially over a 4-week period and then analyse the effect of Sativex vs. placebo on those responders over a further 12 week period. Ambler et al 10 and Montalban et al 12 assessed the efficacy and safety of Sativex in treating spasticity in MS in a placebo-controlled, randomised, parallel group, two phase study. Patients were enrolled if they had failed to gain adequate relief from existing antispasticity medication. 11 The average age of the enrolled patients was 48.5 years and 60% were female. 11 The type of MS was as follows: primary progressive (16%), secondary progressive (50%), remitting/relapsing (32%) and progressive relapsing (2%). The average duration of MS was years, with spasticity for just over 7 years on average. The mean baseline spasticity numerical rating score (NRS)(range 0=none to 10=worst) was The patients were taking a variety of background medication: baclofen (57%), tizanidine (19%), benzodiazepines (17%), others such as gabapentin, dantrolene and botulinum (12%) and disease modifiers (53%). All had previously failed to respond to antispasticity therapy and

8 Page 8 continued to take their pre-existing background medication throughout the study. The study was carried out in two phases. Phase A: identification of responders 10;12 In the 4-week, single-blind phase A, responders to Sativex were identified ( 20% reduction in spasticity scores on a 0-10 NRS, n=272/572, 48%). 10;12 The 20% threshold was based on previous trial data. 12 The mean NRS spasticity score fell from 7 to 4 (indicating improvement). 11 Of these responders, 241 then entered the 12-week double-blind, randomised, placebo-controlled phase B. A total of 19 patients withdrew from phase A due to adverse events (AE) (these were not detailed in the conference abstract). In total, 268 of 572 patients (47%) reported at least one adverse event in phase A, including the 10-day up-titration period, the most common being dizziness (14%). Phase B: placebo-controlled treatment phase Patients were randomised to 12 weeks of treatment with either Sativex (n=124) or placebo (n=117). The baseline spasticity scores were 3.87 (Sativex) and 3.92 (placebo). The mean dose of Sativex was 8.3 sprays/day. The mean duration of MS was 13.3 years (range ) in the MS group and 11.8 years (range 1.5 to 37.6) in the placebo group. The mean duration of spasticity was 8.6 years (range ) and 6.7 years ( ) respectively. 10 The primary endpoint of phase B was the mean change from pre-randomisation baseline in spasticity numerical rating scale (NRS). After 12 weeks, the change in the spasticity score was in the placebo group (deterioration, NRS score 4.73) and in the Sativex group (improvement, NRS score 3.83), p= There were a number of secondary endpoints (change from pre-randomisation, phase B baseline). 10 Sleep disruption NRS: treatment difference was -0.88, p< in favour of Sativex. Sleep disturbance worsened in the placebo group (increase from the baseline Phase B value of 2.07 on the numerical rating scale of 0-10 by ~0.6) but improved in the Sativex group (decrease from the baseline Phase B value of 1.96 on the NRS by ~0.2). 11 Frequency of spasms: At baseline (phase B) the frequency of spasms were 5.61 (Sativex) and 5.29 (placebo) [per day]. After 12 weeks of treatment the frequency was virtually unchanged in the Sativex group but had increased by ~2.5/day in the placebo group (p=0.005). 11 Responders: Significantly more patients treated with Sativex (74% 10 vs. 50% 11, p=0.0003) showed a 30% response at the end of phase B from the original study baseline (phase A) and were classed as responders, though note that half of the patients treated with placebo were classed also as responders. PGIC and SGIC: The treatment differences in the PGIC and SGIC (see figure 1 for explanations, p9) were both in favour of Sativex (1.96, p=0.005 and 1.70, p=0.023 respectively). Barthel ADL Index: The treatment difference between the two groups in the Barthel ADL index was 2.04 (p=0.0067, in favour of Sativex. The maximum score for this index can be either 20, or 100, depending on the scoring system used, see figure 1, p9. It would be useful to see changes for each assessment because a difference of 2.04 may not be clinically significant). Motricity Index: Non-significant treatment differences were seen for arm (- 1.92, p=0.630) and leg (0.97, p=0.439). 10m walk: There was a non-significant treatment difference in the timed 10m walk (-3.34, p=0.069). Non-significant treatment differences were seen in the SF-36 questionnaire (physical functioning domain). It is clear from phase A that not all patients respond to Sativex. Of those that do respond, treatment differences rather than changes from baseline limited have been published, and while some are statistically significant in favour of Sativex, the clinical significance is unclear.

9 Page 9 Table 1: Results of the PIII study Sativex (n=572) Placebo Phase A (4 weeks) Spasticity NRS (baseline) 7 - Spasticity NRS (endpoint) ~4 - Phase B (12 weeks) N=124 N=117 Spasticity NRS (baseline) Spasticity NRS (change) Spasticity NRS (endpoint) 3.83, p= Sleep disturbance NRS (baseline) Sleep disturbance NRS (change) -0.2 (1.76), p< (2.13) 30% response from Phase A baseline 74%, p= % Figure 1: Rating scales (Modified) Ashworth Scale: Measures resistance during passive soft-tissue stretching. Each joint is tested up to 3 times. Scale: 0=no increase in tone, 1=slight increase in tone, 2=more marked increase in tone, 3=considerable increase in tone, 4=affected parts rigid in flexion or extension. 15 Barthel Activites of Daily Living: 10 items that measure a persons daily functioning daily living and mobility, such as bathing, grooming (score 0=unable, 5=independent), feeding, dressing, bowels, bladder, toilet use, stairs (score 0=unable, 5=some help/occasional accident, 10=independent), transfers (bed to chair), mobility on level surface (score 0=unable, 5=major help, 10=minor help, 15=independent). (Scores 0=15, max score 100; 0, 5, 10, 15 may be replaced by 0, 1, 2, 3, max score 20).. 16 Physician, Carer and Subject Global Impression of Change (PGIC, CGIC, SGIC): Measures improvements. Scores range from 1=very much improved to 7=very much worse. 17 Motricity Index: Measures muscle power in pinch and various joints. 0=no movement, 9=palpable movement, 14=movement seen, 19=full range of movement, 22=normal power. 18;19 Numerical rating scale: a verbal analogue scale asking patients to rate their stiffness on a scale of 0 (none) to 10 (worst). 3 QoL EQ-5D: Measures health outcome. Designed for self-completion, takes a few minutes to complete. Evaluates mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Measured on a visual analogue scale (0=worst imaginable health state, 100=best imaginable health state). 20 QoL SF-36 Role Physical: A 36-item survey that measures 8 domains of health: physical components: physical functioning, role limitations due to physical health, bodily pain, general health, [mental components: perceptions, vitality, social functioning, role limitations due to emotional problems and mental health]. Score: 0=poorest health, 100=best health. 21

10 Page 10 Adverse events Almost half (47%) of patients reported at least one adverse event (AE). 10 In phase A, the most common AE was dizziness, which occurred in 14% of patients. Of the 241 phase B patients, 66 (53%) on Sativex and 57 (49%) on placebo reported at least one AE. 10 Most of the AEs were mild-moderate. One patient experienced treatment (Sativex)- related suicidal ideation, which resolved within 5 hours. No differences in mood between the two groups were noted. Eight patients in the Sativex group withdrew due to an adverse event. The most common adverse events were Nervous System disorders (Sativex 9% vs. placebo 5%), including headache (1% vs. 3% respectively) and somnolence (3% vs. 0, respectively); GI disorders (Sativex 8% vs. placebo 6%), including diarrhoea (0% vs. 3%, respectively) and dry mouth (3% vs. 1%); Psychiatric disorders (Sativex 7% vs. placebo 2%), including euphoric mood (3% vs. 1%); Vertigo (5% vs. 1%). The pattern of CNS side effects suggest that some unblinding is possible and the potential for bias. The MHRA stated, in response to the previous licence application, that if a compelling treatment effect can be shown it might be concluded that the possibility of unblinding might not represent a major concern. 14 To summarise: Analysis of this study is limited by the way the data are reported. Phase A informs that not all patients will respond to Sativex: this was in response to a request by the regulatory authorities. Phase B shows that both Sativex and placebo maintain the improvements in spasticity and provide continued improvements in sleep disruption and frequency of spasm. The number of responders to medication at the end of both phases was significantly higher than seen with placebo, but over half of those treated with placebo were responders at the 30% level of response: this could be due to a positive placebo effect or a long-lasting effect of Sativex. The combined data from both phase A and B suggest that Sativex is associated with a statistically significant improvement in health outcome and physical and daily functioning. It remains to be reported but it is possible that placebo has a similar effect. Adverse events occurred at a higher rate in the Sativex group. Phase III withdrawal study 13 In the previous licensing application, GW Pharmaceuticals presented long-term openlabel data in 444 patients treated with Sativex for a mean of 455 days. 11 This data showed evidence of maintenance of efficacy and no new safety concerns. However, the EU regulatory authorities do not regard longterm open-label studies as providing robust evidence of the maintenance of efficacy in the long-term, especially when there is such a marked placebo effect. The UK MHRA stated that 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. Notcutt et al assessed the maintenance of efficacy after long-term treatment with Sativex for spasticity in MS in a five week, randomised withdrawal study. 13 Eligible patients (those currently using Sativex) entered a 7 day open-label treatment phase and were then randomised to either treatment with Sativex (n=18) or placebo (n=18, withdrawal group). Dosing at the patient s current effective dose was continued. Patients had suffered with spasticity on average 12.7 years (±9.14) and been using Sativex for an average of 3.6 years (±2.04). The mean study doses were 7.3 (Sativex) and 9.2 (placebo) per day. Patients could drop out at any time and return to their own supplies of prescribed Sativex. The primary endpoint was time to treatment failure, which was defined as: withdrawal without completing the 28-day randomised treatment period, worsening of spasticity, or an increase in anti-spasticity/diseasemodifying medication after randomisation. Only two patients in the placebo group and 15 in the Sativex group completed the 4 week study. Eight Sativex patients (44.4%) were classified as treatment failures (three of these had withdrawn from the study), compared with 17 (94.4%) on placebo (16 of these had withdrawn from the study, nine due to adverse events). The time to treatment failure was significantly in favour of Sativex (p=0.013; Hazard ratio=0.335; 90% CI: 0.162, 0.691). Secondary endpoints included: spasticity severity 0-10 Numeric Rating Scale (0-10 NRS),

11 Page 11 Sleep Disruption 0-10 NRS, Modified Ashworth Scale (MAS), Timed 10m walk, Motricity Index, and Carer and Subject s Global Impression of Change (CGIC & SGIC). All secondary endpoints (except the MAS) showed trends in favour of Sativex, reaching statistical significance in the SGIC and CGIC (functional ability) scales (i.e. a greater worsening on placebo; p=0.017 and respectively). Note that for the CGIC (functional ability) about half of the patients treated with Sativex were assessed having minimally worse functional ability and about 30% had no change, whilst over 60% of patients treated with placebo were assessed as much worse. For the SGIC, about 30% of patients treated with Sativex showed no change, or were minimally worse, and just under 30% were assessed as much worse. Around 50% of patients treated with placebo were assessed as much worse and around 10% as very much worse. This small study shows that withdrawal of Sativex treatment precipitated significant worsening in spasticity in patients switched to placebo, as demonstrated by the large number of patients who withdrew from the study. Maintenance of long-term efficacy was demonstrated with Sativex compared with placebo in this randomised-withdrawal setting. No evidence of a withdrawal syndrome was seen in those patients who stopped Sativex, despite a prolonged period on the medication. Long term use Wade et al evaluated 137 patients who had completed an initial six week randomised, placebo-controlled study, followed by a four week open-label phase which continued into an extension study. 22 Study entry was staggered over a number of months. Throughout the extension study patients recorded the number of sprays used each day and how MS symptoms and intoxication levels using a visual analogue scale were each week. Primary symptoms (spasticity, spasms, tremor, bladder problems and pain) were assessed every 8 weeks. The mean duration of study participation was 434 days ( days, until data collection) for the 79 patients who continued Sativex and 225 days (range ) for the 58 who stopped treatment. Sixty two patients who had used Sativex for at least one year and who had a stable dose for at least 2 weeks were asked to participate in a planned abrupt interruption of study medication; 25 agree to do so. Further details are in Appendix 1. The primary symptoms of a cohort of 73 patients who had completed at least one year of treatment and had contributed data at each time point were assessed. The large reductions seen at 10 weeks (i.e. following the acute study) were maintained over one year of treatment: VAS scores at 10 weeks and at 66 weeks: pain, 31.9 and 26.4; spasm 30.7 and 26.7; spasticity, 34.2 and 31.0; bladder, 29.5 and 23.4 respectively. The most frequently occurring side effects were oral pain (20.4%), dizziness (14.6%), diarrhoea (12.4%), nausea (10.9%), oral mucosal disorder (8.8%) and bad taste (8%). Other side effects included fatigue, headache, somnolence and dry mouth in 6.6% of patients, constipation and vomiting in 5.8%, tooth discolouration, weight loss (5.1%), impaired balance, disturbed attention, lethargy, loose stools and raised GGT (4.4%). Note that the 137 patients who continued into the extension study did so because they had perceived to have had some benefit from the initial study treatment; the authors state that this is representative of clinical practice, where only patients who consider a treatment beneficial will continue taking it.

12 Page 12 Budget impact model 23 The proposed price of Sativex is likely to be in the range of 0.90 to 2.24 per dose. It is likely that Sativex will be used as add-on treatment for patients who have not gained adequate relief of symptoms from one or more oral therapies or where these therapies have resulted in intolerable side effects, and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy. The annual cost of consultations associated with the general management of spasticity was reported to be 894 per patient in The proportion of patients with MS likely to be eligible for Sativex treatment is estimated as follows: 100,000 patients with MS in the UK 84,000 (84%) are affected with spasticity 17% have moderate, 17% have severe/total spasticity: 28,560 69% with moderate and 79% with severe/total spasticity use medication: 21,134 35% of patients with moderate and 46% with severe/total spasticity use combination therapy with >1 agent: 11,567 Assume 50% of these as eligible for Sativex treatment: 5,784. If 5,784 patients with MS use Sativex, out of a UK population of 61 million, this equates to approximately 9 users per 100,000. If nine patients were treated for 1 month and the four patients continued on treatment, the annual cost per 100,000 population, assuming a dose of 8 sprays/day, would be in the range of 11,500-28,700. Table 2: Costs of NICE-recommended drugs for spasticity Drug Indication and dose 24 Drug Tariff (March 2010) 25 Baclofen Gabapentin Tizanidine Diazepam Dantrolene Chronic severe spasticity due to MS: 5mg orally tds increased to a maximum of 100mg/day. Not licensed for the treatment of spasticity but doses of mg/day (300mg tds 900mg tds (300mg + 600mg)) have been used. 26 Spasticity associated with MS: 2mg/day increased to up to 24mg/day in 3-4 divided doses, max 36mg/day. Muscle spasm of varied aetiology: 2-15mg/day increased to maximum 60mg/day. Chronic severe spasticity of voluntary muscle: 25mg daily, increased to maximum 100mg qds; usual dose 75mg tds. Baclofen (generic): 84x10mg tablets = 1.55 Cost/month (max 100mg/day): 5.16 ( 67/year) Gabapentin (generic) 100x300mg = x600mg = Cost/month ( mg/day): ( /year) Tizanidine (generic): 120x2mg = x4mg = Cost/month (24mg-36mg/day): ( /year) Diazepam (generic): 28x2mg = 97p 28x5mg = 99p 28x10mg = 1.00 Cost per month (2mg-60mg/day): 97p- 6 ( /year) Dantrium: 100x25mg caps = x100mg caps = Cost per month (75mg tds 100mg qds) = ( /year) The use of intrathecal baclofen is mainly as a last line therapy in few patients. It is rarely used in the UK: in 1998 only 60 patients with MS had a continuous intrathecal baclofen infusion. 1 In 2000, the estimated cost per quality adjusted life year (QALY) was 20,000.

13 Page 13 This document reflects the views of the London New Drugs Group and may not reflect those of the reviewers. Bayer Healthcare have commented on this review. Reference List (1) Multiple sclerosis. National Clinical Guideline for diagnosis and management in primary and secondary care. November National Collaborating Centre for Chronic Conditions Accessed via: on 11/03/10. (2) Hutchinson B. What is spasticity and what causes it? MS in focus 2008; 12:6-8. (3) Jarrett L. Evaluating and measuring spasticity. MS in focus 2008; 12:9-11. (4) Unlicensed Cannabis based medicine - Sativex Oromucosal Spray. Prescriber / Pharmacy Statement - December GW Pharmaceuticals. (5) Named Patient SATIVEX(R) Physician Product Information. Last updated: 10 September GW Pharmaceuticals. (6) Almirall announces filing Sativex regulatory submission. Accessed via: Press_release_regulatory_submission_final.pdf on 11/03/10. (7) Sativex (R) (delta-9-tetrahydrocannabinol, cannabidiol). Letter from Medical Information. 01/02/2010. Bayer Healthcare Ltd and Bayer Schering Pharma. (8) Medicines, Ethics & Practice. A guide for pharmacists and pharmacy technicians. Number 33, July Section Controlled Drugs. Royal Pharmaceutical Society of Great Britain Accessed via: on 17/03/2010. (9) Package leaflet: Information for the user. Sativex (R) Oromucosal spray. 10 September GW Pharma Ltd. (10) Ambler Z, Davies P, Gasperini C et al. A two-phase study of Sativex in the relief of spasticity due to multiple sclerosis: phase A single-blind response assessment followed by phase B double-blind, randomised, placebo-controlled, parallel-group study. 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS). Dusseldorf, Germany September.: (11) Phase III Sativex MS Spasticity trial. Preliminary results. 11 March GW Pharmaceuticals. Accessed via: on 11/03/10. (12) Montalbán X, Wright S Trial period for new symptomatic treatments: lessons learnt from a Sativex in MS spasticity clinical trial. 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS). Dusseldorf, Germany September: (13) Notcutt W, Davies P, Langford R et al. Results of a randomised withdrawal study of subjects with spasticity due to multiple sclerosis who were receiving long-term Sativex. 25th Congress of the European Committee for the Treatment and Research in Multiple Sclerosis (ECTRIMS). Dusseldorf, Germany September.: ectrims2009/ (14) Public Information Report on Sativex Oromucosal Spray. MHRA. Accessed via: on 12/03/10.

14 Page 14 (15) Testing Spasticity: The Modified Ashworth Scale. Levine, P. Accessed via: physical-therapy.advanceweb.com/editorial/content/editorial.aspx?cc= on 10/03/2010. (16) Barthel Index. Based on: Mahoney Fl, Barthel DW:Functional evaluation: the Barthel Index. Md State Med J 14:2, University of Dundee. Accessed via: on 11/03/10. (17) Clinical Global Impression (CGI). Servier Laboratories Limited Accessed via: on 11/03/10. (18) Collin C, Davies P, Mutiboko IK et al. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007; 14: (19) Motricity Index (MI). Chartered Society of Physiotherapy. Accessed via: on 11/03/10. (20) What is EQ-5D? EuroQol Group. Accessed via: on 11/03/10. (21) SF-36 Health Survey. International Quality of Life Assessment (IQOLA) Project. Accessed via: on 11/03/10. (22) Wade DT, Makela PM, House H et al. Long-term use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler 2006; 12: (23) Sativex(R) Oromucosal Spray. Budget Notification document for NHS decision makers. October Bayer Healthcare Ltd and Bayer Schering Pharma. (24) British National Formulary, 59th edition. March Ed. Martin J. British Medical Association and Royal Pharmaceutical Society of Great Britain. Accessed via: (25) Department of Health, Welsh Assembly Government. National Health Service England and Wales. Drug Tariff March TSO, London., prescriptions (26) DrugDex monograph: Gabapentin. Therapeutic uses (4.5.AA Spasticity). Klasco RK (Ed): MICROMEDEX System. Thompson Micromedex, Greenwood Village, Colorado (18/03/2010) (27) Wade DT, Makela P, Robson P et al. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004; 10:

15 Page 15 Appendix 1: Clinical efficacy: Other studies The studies by Wade et al 27 and Collins et al 18 were submitted to the MHRA for the 2006 marketing authorisation application. Neither study was considered suitable. Study design Primary outcomes Results Comments 6 week randomised double-blind, placebocontrolled parallel-group study. 27 Dose titrated from 1 spray/day to maximum 48/day. Then active medication for 4-weeks, then open-label phase (see below). Primary symptom score (PSS) of 5 target symptoms: spasticity (n=37), spasms (n=38), bladder problems (n=32), tremor (n=13) or pain that was not obviously musculoskeletal (n=36). Power calculation: at least 65 patients to show a 10% shift in VAS score compared with placebo. VAS: 0=no problem, 100=very bad. Change in PSS: (Sativex) vs (placebo), difference =-5.93, p= Change in VAS (spasticity): (Sativex) vs (placebo), difference = , p=0.001 No statistically significant differences between Sativex and placebo for other symptoms. Pain and tremor improved to greater extent with placebo (differences: and +3.75) If pain removed from PSS, difference between Sativex and placebo was statistically significant Dizziness occurred in 32.5% (Sativex) vs. 12.5% (placebo). Disturbed attention (8.8%) disorientation (7.5%), feeling drunk (5%), vertigo (6.3%) all occurred in Sativex- but not placebo-treated patients. Results suggest Sativex may be effective for spasticity symptoms. Study limitations: Combining scores from different symptoms as the primary outcome assumes that each symptom is equal in terms of its response to Sativex. VAS has been validated for measuring pain and was felt to be an appropriate tool for the other symptoms, but the clinical significance of any changes is unknown. The number of patients with each individual symptom was small. The large placebo effect for pain may be explained by the patient group recruited, mostly by selfreferral, who had not received any specialist review or treated for neuropathic pain previously. There was no check to see if other forms of cannabis were taken The titration period took up to 4 weeks of the 6- week double-blind phase, which may not have given enough time post-titration for the full effect to be seen. Study design Main results Adverse events Comments Open-label phase continuation of study above (n=137) plus planned withdrawal after 1 year (n=25) 22 Aim: assess maintenance of effects, safety and tolerability. Mean study duration: 434 days (range , n=79). 58 patients withdrew (adverse events, n=17; other reasons, n=41). VAS scores after one year (n=73) (baseline, week 10, last visit): Pain (68.1, 31.9, 26.4 week 66). Spasm (65.1, 30.7, 26.7 week 66). Spasticity (69.5, 34.2, 31.8 week 82). Bladder (65.6, 29.5, 23.5 week 74) No patients with tremor as primary symptom continued treatment. Number of sprays/day: ~11. Planned withdrawal (up to 14 days, n=25) 5 resumed treatment (marked symptoms). Symptoms reported as: much worse (28%), worse (40%), no change (20%) and better (12%). Symptoms returned over 5-10 days. Withdrawal-type symptoms in 11 patients: interrupted sleep (16%), hot and cold flushes (16%), tiredness (16%), low mood (12%), decreased appetite (8%), emotional liability (4%), vivid dreams (4%) and intoxication (4%). Treatment-related adverse events: Most common: sore mouth (20.4%), 8 patients had visible change in oro-mucosa. Fatigue, somnolence, impaired balance, disturbed attention and lethargy occurred in <7% of patients. Serious adverse events: 33 in 22 patients but 28 in 19 patients unrelated to Sativex. 5 related to Sativex: seizures (n=2, causing aspiration pneumonia and death in 1), loss of balance causing ankle injury (n=1), vomiting (n=1) and diarrhoea (n=1). Study suggests that symptom relief attained after 10 weeks of Sativex treatment was maintained for up-to or over a year without any increase in dose. There was a high withdrawal rate (42%) and difficult to keep track of patients (137 continued in extension study, 92 were followed for at least one year on medication, 79 continued on treatment, 58 stopped treatment but some of these had used Sativex for >1 year). The way the patients were selected (those who thought they had benefitted from the initial 10 weeks of treatment) may limit the generalisability of the results, though in clinical practice patients who do not consider a treatment beneficial may not continue taking it. No consistent withdrawal syndrome was seen in the patients who agreed to take part in the sudden withdrawal, but they may not be a representative sample.

16 Page 16 Study design Outcomes Results Comments 6 week, doubleblind, randomised parallel-group study to study efficacy, benefits and adverse events of Sativex in 189 patients with spasticity due to MS 18 Primary outcome: Change from baseline in severity of spasticity based on a daily diary assessment on a 0-10 numerical rating scale. Secondary outcomes: change from baseline in composite score of Ashworth Scale, mean daily spasm score and Motricity Index and Patients GIC. Responder analysis: reduction in NRS spasticity score of 30% and 50% of their initial score. Primary analysis on intention-to-treat (ITT) population (n=184, Sativex 120, placebo 64). NRS spasticity scores (ITT): Adjusted mean change: (Sativex) vs (placebo), treatment difference 0.52, p=0.048 (95% CI, , ). 30% reduction: 40% (Sativex) vs. 21.9% (placebo), difference 18.1%, p=0.014, (95% CI 4.73, 31.52). 50% reduction: 17.5% (Sativex) vs. 9.4% (placebo), difference 8.1%, p=0.189, 95% CI -1.73, Previous exposure to cannabis: change in NRS: (Sativex) vs (placebo), p= Improved global impression of change: 57% (Sativex) vs. 48% (placebo). Differences in the mean changes from baseline to endpoint in Ashworth scale, spasm frequency and Motricity Index (arms and legs) were not statistically significant but favoured Sativex. Adverse events CNS side effects were more common in the Sativex group (dizziness. 32.3% vs. 10.8%, impaired balance 7.3% vs. 1.5%, disturbance in attention, 3.2% vs. 0% and blurred vision, 3.2% vs. 0%). The possibility of bias from unblinding due to treatment AEs cannot be discounted. 7 serious adverse events (AEs), 4 (Sativex, 3.2%) and 3 (placebo, 3.2%). Only 1 considered possibly treatmentrelated (vomiting, Sativex group). Withdrawals due to AEs: 6 (Sativex, 4.8%) and 2 (placebo, 3.1%). Comments Sativex was more effective than placebo in reducing spasticity, though the clinical significant of a difference of 0.5 on a 0-10 scale can be questioned. There was an increase in muscle power in legs, suggesting that reduction in spasticity was not gained at the cost of increasing weakness. The MHRA did not consider that this pivotal trial satisfied the requirements of the CHMP with respect to a successful application: statistical evidence should be considerably stronger than p<0.05, the estimated size of treatment benefit should be clinically viable and all important endpoints should show similar findings. 14 Data from a second pivotal trial was necessary.