Carisbamate for partial onset epilepsy September 2009 This technology summary is based on information available at the time of research and a limited literature search. It is not intended to be a definitive statement on the safety, efficacy or effectiveness of the health technology covered and should not be used for commercial purposes. The National Horizon Scanning Centre Research Programme is part of the National Institute for Health Research September 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Carisbamate for partial onset epilepsy Target group • Epilepsy: partial onset seizures with or without secondary generalisation in patients aged 16 and older. - First line adjunctive therapy for patients who may experience psychiatric, cognitive or behavioural issues with alternative treatments. - Second line adjunctive therapy after generic adjunctive therapies for those not experiencing psychiatric, cognitive or behavioural issues. Technology description Carisbamate (YKP-509; RWJ-333369; JNJ-10234094) is a neuromodulator with antiepileptic properties. Its exact mechanism of action is unknown but it appears to modulate neurotransmitters in a distinct manner from other antiepileptic drugs. Carisbamate is administered orally twice a day. The minimum effective dose and starting dose is 400mg per day. The dose range will be 400–1,200mg per day, administered in two doses. Carisbamate is also in phase II trials for neuropathic pain and essential tremour. Innovation and/or advantages Confidential. Developer Janssen-Cilag Ltd. Availability, launch or marketing dates, and licensing plans In phase III clinical trials. NHS or Government priority area This topic is relevant to The Long-term (Neurological) Conditions National Service Framework (2005). Relevant guidance • NICE technology appraisal. The clinical effectiveness and cost effectiveness of newer drugs for epilepsy in adults. March 20041. • NICE clinical guideline. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. October 20042. • HTA. A systematic review of the effectiveness and cost-effectiveness of neuroimaging assessments used to visualise the seizure focus in people with refractory epilepsy being considered for surgery. 20063. • SIGN. Diagnosis and management of epilepsy in adults. 20034. Clinical need and burden of disease Epilepsy is the most common serious neurological condition in the UK5 and is characterised by recurrent, unprovoked seizures (i.e. not an isolated event or due to an underlying acute reversible medical problem such as meningitis or alcohol withdrawal)6. An epileptic seizure is a brief disturbance of consciousness, behaviour, emotion, motor function and/or sensation that is due to abnormal electrical discharge in the brain2. Epilepsy is not usually diagnosed unless the person has had at least two unprovoked 1 seizures . 2 September 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Partial-onset seizures are classified as simple partial seizures and complex partial seizures, either of which may lead to secondary generalised tonic-clonic seizures. The defining element of simple partial seizures is a seizure with preserved consciousness and this group includes sensory, motor, autonomic, and psychic types. Many patients with complex partial seizures have an aura warning them of their seizure. Diagnosis is based on the repeated, stereotypic occurrence of the same experience supported in some cases by focal changes recorded by an electroencephalogram. About 1 in 200 of the population receives treatment for epilepsy and the lifetime prevalence is estimated to be between 2%-5%7. Epilepsy affects between 260,000 and 416,000 people in England and Wales. The reported prevalence increases with age, from 3.9 per 1,000 population at age 7 years to 4.9 per 1,000 population at 16 years2. Existing comparators and treatments Current NICE guidelines recommend monotherapy with an antiepileptic drug (AED) where possible1. • If the older drugs (such as sodium valproate and carbamazepine) do not stop seizures, or if there are side effects, one of the newer drugs can be tried. • Gabapentin, lamotrigine, levetiracetam, oxcarbazepine and topiramate can be given as monotherapy, or if they do not control seizures, in combination with another drug. • Clobazam, lacosamide, pregabalin, tiagabine, vigabatrin and zonisamide are used as combination therapy (adjunctive or add-on therapy) with another drug. Efficacy and safety Trial NCT00433667; NCT00425282; NCT00210522; carisbamate vs placebo; carisbamate vs placebo; carisbamate vs placebo; phase III. phase III. phase II. Sponsor Johnson & Johnson. Johnson & Johnson. Johnson & Johnson. Status Trial complete and Trial complete and Published9. published in abstract8. published in abstract7. Location EU, USA and other EU, USA, Canada and EU (inc UK), USA and countries. other countries. other countries. Design Randomised, double blind, Randomised, double blind, Randomised, double blind, placebo controlled. placebo controlled. placebo controlled. Participants n=565; aged ≥16; partial n=562; aged ≥16; partial n=537; adults; partial onset and onset epilepsy for ≥1yr; ≥3 onset epilepsy for ≥1 yr; seizures. schedule seizures per month, ≥3 seizures per month; Randomised to carisbamate inadequate response to ≥ 1 inadequate response to ≥1 1,600, 800, 300 or AED, and receiving 1-2 AED; receiving 1-2 AEDs. 1,600mg per day or AEDs. Randomised to Randomised to carisbamate placebo for a 4 week dose- carisbamate 400 or 200mg 400 or 200mg per day or titration period and 12 per day or placebo for 12 placebo for 12 weeks with week maintenance period. weeks with concomitant concomitant AEDs.. AEDs. Follow-up 12 weeks. 12 weeks. 12 weeks stable dose; 3 weeks post-treatment. Primary Seizure frequency. Seizure frequency. Seizure frequency. outcomes Secondary Seizure Severity Seizure Severity Safety and responder rate. outcome Questionnaire; responder Questionnaire; responder rate (≥50% reduction in rate. seizure frequency). 3 September 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Key results For carisbamate 400mg, For carisbamate 400mg, For 1,600, 800, 300, 200mg and placebo 200mg and placebo 100mg and placebo respectively (p value vs respectively (p value vs respectively (p value vs placebo): reduction in placebo): reduction in placebo): reduction in seizures 27% (p=0.009), seizures 21% (p=0.225), seizures 28.6% (p<0.001), 16% (p=0.678) and 15%; 22% (p=0.289), 15%; 20.9% (p=0.006), 24% responder rate 33% responder rate 24% (p<0.001), 15.4% (p=0.07) (p<0.001), 25% (p=0.098) (p=0.553), 23% (p=0.637), and 6.2%; responder rate and 18%. A greater 21%. 24.8% (p=0.004), 18.5% response observed in those (p=0.07), 23.6% (p=0.01), not taking concomitant 12.4% (p=0.01) and enzyme inducing AEDs. 10.1%. Adverse Most common (>10%) Most common (>10%) Carisbamate 1,600, 800, effects AEs carisbamate 400mg, AEs carisbamate 400mg, 300, 100mg and placebo (AEs) 200mg, placebo 200mg, placebo respectively: respectively: headache respectively: headache discontinuation due to AEs 12%, 13%, 12% and 14%, 13%, 15% and 19%, 12%, 6%, 5% and dizziness 13%, 9%, 7%. dizziness 12%, 4%, 7%. 8%. Dizziness (2%) and headache (2%) were most common AEs leading to withdrawal. Headache, dizziness, diplopia, vertigo, somnolence, nausea, vomiting, gait disturbance and abnormal coordination occurred more commonly in the 1,600mg group. Trial CARISEPY-3013, NCT00740623; CARISEPY-3007, NCT00563459; carisbamate vs placebo; phase III. carisbamate vs topiramate vs levetiracetam; phase III. Sponsor Johnson & Johnson. Ortho-McNeil Janssen. Status Ongoing. Ongoing. Location EU, USA and other countries. EU (inc UK), USA and other countries. Design Randomised, double blind, placebo Randomised, double blind, controlled controlled with open label extension. with open label extension. Participants n=600; aged ≥16; partial onset seizures, n=600; aged ≥16; partial onset seizures; and schedule receiving ≤3 AEDs. Randomised to monotherapy treatment failure; receiving carisbamate 800 or 1,200mg per day or ≤2 AEDs. Randomised to carisbamate placebo for 14 weeks. 400-1,200mg per day or topiramate 200- 400mg per day or levetiracetam 1,000- 3,000mg per day for 12 months (titration and dose maintenance phases). Follow-up 14 weeks; 4 weeks post-treatment. 12 months active treatment period. Primary Seizure frequency and responder rate. Time to discontinuation (all causes). outcome Secondary Reduction in secondarily generalised Cognitive and neuropsychiatric AEs, outcome seizures and safety. seizure rates, cognitive assessments, mood, behavioural and cognitive changes. Expected Confidential. To be confirmed. reporting date 4 September 2009 National Horizon Scanning Centre News on emerging technologies in healthcare Estimated cost and cost impact The cost of carisbamate is not yet known. The costs of some licensed drug treatments are10: Drug Dose 28 day cost Gabapentin 300-1,200mg 3 times daily £7.53-£7.76 Levetiracetam (Keppra) 250-1,500mg twice daily £27.72-£83.16 Lamotrigine 100-200mg daily in 1-2 divided doses £4.13-£5.45 Oxcarbazepine 600-2,400mg daily in divided doses £22.32-£88.44 Topiramate (Topamax) 100-400mg daily in 2 divided doses £31.40-£109.22 Potential or intended impact – speculative Patients ; Reduced morbidity Reduced mortality or increased ; Improved quality of life for length of survival – delete as patients and/or carers appropriate Quicker,