Horizon Scanning Research November 2015 & Intelligence Centre

Fenfluramine for Dravet syndrome – first line

LAY SUMMARY

Dravet syndrome is a very rare form of epilepsy that begins in childhood. Prolonged seizures begin in the first year of life and the overall development of children with this disease is often severely affected. This briefing is based on information Fenfluramine is a new drug given as a tablet for the treatment of available at the time Dravet syndrome. Fenfluramine is being studied to see whether it of research and a improves the symptoms of Dravet syndrome and that it is safe to use limited literature for children with this disease. search. It is not intended to be a If fenfluramine is licensed for use in the UK, it could be a new definitive statement treatment option for children with Dravet syndrome and may improve on the safety, the quality of life of children and their families. At the moment, there efficacy or are no drugs that treat the underlying causes of Dravet syndrome. effectiveness of the health technology covered and should NIHR HSRIC ID: 9860 not be used for commercial purposes or commissioning without additional information.

This briefing presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.

NIHR Horizon Scanning Research & Intelligence Centre, University of Birmingham. Email: [email protected] Web: www.hsric.nihr.ac.uk Horizon Scanning Research & Intelligence Centre

TARGET GROUP

• Dravet syndrome (severe myoclonic epilepsy of infancy); in children aged 2 to 18 years – first line.

TECHNOLOGY

DESCRIPTION

Fenfluramine (ZX008) is a serotonin receptor agonist being developed for the treatment of children with Dravet syndrome, a rare and severe form of myoclonic epilepsy. Dravet syndrome is a clinically diagnosed syndrome; however, 80% of those diagnosed have a mutation in the sodium channel gene, SCN1A. Serotonin-releasing drugs such as fenfluramine may have an effect on epileptic activity in the brain. Fenfluramine is administered orally at 10-30mg per day on an ongoing, continuous basis.

Fenfluramine does not currently have Marketing Authorisation in the EU for any indication.

INNOVATION and/or ADVANTAGES

If licensed, fenfluramine will offer an additional oral treatment option for children with Dravet syndrome, who currently have few effective therapies available.

DEVELOPER

Brabant Pharma Ltd. (subsidiary of Zogenix Inc).

AVAILABILITY, LAUNCH OR MARKETING

Fenfluramine is a designated orphan drug in the EU and USA and is currently in phase III clinical trials.

PATIENT GROUP

BACKGROUND

Dravet syndrome, also known as severe myoclonic epilepsy of infancy, is a neurodevelopment disorder beginning in infancy that is characterised by intractable seizures1. The development of affected children is typically on track during the first year of life; however, progressive developmental arrest begins to emerge in the second year of life2. Patients with Dravet syndrome typically experience their first seizure at 5 to 8 months of age3. This is usually a clonic, generalised, or unilateral seizure triggered by fever3, sometimes lasting for 15 to 30 minutes, or longer4. Within weeks to months, patients experience additional febrile seizures and then begin to exhibit temperature-independent seizures, including tonic, myoclonic, atypical absence, focal, generalised clonic, or generalised tonic–clonic seizures3,4. Complex partial seizures can be triggered by sudden changes in body temperature: usually as a result of getting cold after a shower or batha.

a Patient group personal communication.

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Children with Dravet syndrome are often photosensitive4; this is seen in approximately 50% of cases5.

Patients with Dravet syndrome are at higher risk of febrile seizures, prolonged status epilepticus, and of SUDEP (sudden unexplained death in epilepsy) and have a wide range of associated conditions, which all need to be properly treated and managed2. These associated conditions include: behavioural and developmental delays, movement and balance disorders, orthopaedic disorders, delayed language and speech issues, growth and nutrition issues, sleep disturbance, and chronic infections6. Dravet syndrome places a heavy emotional burden on families who report that once seizures become more manageable it is the associated co-morbidities that are the most emotionally and physically demanding aspect of the diseaseb.

A major contributor to the cause of Dravet syndrome has been found to be mutation or deletion of the SCN1A gene, found in around 80-85% of patients1,7. SCN1A mutations are also associated with other forms of epilepsy, including intractable childhood epilepsy with generalised tonic-clonic seizures and severe multifocal epilepsy of infancy1. Mutations in the PCDH19 gene (also seen in female restricted epilepsy with intellectual deficit), are thought to account for about 5% of Dravet syndrome cases in girls7. However, expert opinion suggests that some medical professionals dispute that the epilepsy observed in these cases can be attributed to Dravet syndromec.

Seizures tend to be difficult to control throughout childhood and learning disabilities persist and are usually severe4. As the condition progresses most children become unsteady on their feet (ataxic)4. Usually by the age of 14-16 years the seizures tend to become less frequent, though moderate to severe cognitive impairment and intractable epilepsy into adulthood is common4,7.

NHS or GOVERNMENT PRIORITY AREA

This topic is relevant to: • NHS England. 2013/14 NHS Standard Contract for Paediatric Neurosciences: Neurosurgery. E09/S/a. • NHS England. 2013/14 NHS Standard Contract for Paediatric Neurosciences: Neurology. E09/S/b. • NHS England. 2013/14 NHS Standard Contract for Paediatric Neurosciences: Neurodisability E09/S/c. • NHS England. 2014/14 NHS Standard Contract for Paediatric Neurosciences: Neurorehabilitation. E09/S/d. • NHS England. 2013/14 NHS Standard Contract for Children’s Epilepsy Surgery Service (CESS). E09/S/e

CLINICAL NEED and BURDEN OF DISEASE

The worldwide incidence of Dravet syndrome is estimated to be less than 1 in 40,000 live births; in the UK this is estimated to be 1 in 28,000 live births7. Expert opinion suggests it is likely that the incidence of Dravet syndrome is underestimated, particularly in areas of the world where premature mortality is highc. The prevalence of Dravet syndrome is estimated to be between 1 in 20,000 to 1 in 40,000 population8. If these figures were generalisable to

b Patient group personal communication. c Expert personal communication.

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England, there could be between 1,350 and 2,700 patients with Dravet syndromed. Myoclonic seizures appear between the age of 1 and 5 years in 85% of children with Dravet syndrome9. Between 15-25% of patients with Dravet syndrome have a family history of febrile convulsions or epilepsy9. The rate of Dravet syndrome-related mortality is estimated to be 14-20%10. The causes of death vary and include SUDEP, status epilepticus, infection, and drowning10.

The population likely to be eligible to receive fenfluramine could not be estimated from available published sources.

PATIENT PATHWAY

RELEVANT GUIDANCE

NICE Guidance

• NICE guideline. The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care (CG137). January 2012. • NICE quality standard. The epilepsies in children and young people (QS27). February 2013. • NICE advice. Partial seizures in children and young people with epilepsy: zonisamide as adjunctive therapy (ESNM37). March 2014.

Other Guidance

• Scottish Intercollegiate Guidelines Network. Diagnosis and management of epilepsies in children and young people (SIGN81). March 2005.

CURRENT TREATMENT OPTIONS

Currently, treatment for Dravet syndrome consists mainly of antiepileptic medications to help control seizures1. These include sodium valproate, levetiracetam, topiramate, clonazepam, clobazam and zonisamide1,4,e. Stiripentol is also licensed for use in combination with clobazam and valproate as adjunctive therapy of refractory generalised tonic-clonic seizures in children, and occasionally adults, with Dravet syndrome11,e. Expert opinion suggests that there is little published evidence regarding the effectiveness of these drugs in the treatment of Dravet syndromee. They are used due to theoretical, animal model and anecdotal human datae.

While Dravet syndrome is largely refractory to common antiepileptic drugs, ketogenic diet therapy has recently been used in the management of Dravet syndrome and related severe myoclonic epilepsies2,12. In one study, 65% of patients with Dravet syndrome treated with a ketogenic diet experienced a greater than 50% reduction in seizure frequency13. However, expert opinion advises that a ketogenic diet cannot be considered to be more effective than the use of anti-epileptic medicationse.

d Assuming the population of England to be approximately 54 million (ONS population estimates for UK, England and Wales, Scotland and Northern Ireland, mid-2014). e Expert personal communication.

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Many patients with Dravet syndrome experience prolonged seizures (status epilepticus) that require emergency intervention6. In these circumstances rescue medication such as diazepam, midazolam or paraldhydef will be administered6.

Children with Dravet syndrome should also receive physical, occupational, speech and social therapies9. Surgery is not indicated in most patients with Dravet syndrome9. From a patient perspective, difficulties can arise in the diagnosis of the condition, access to specialist care, and qualification for respite and therapy servicesf.

EFFICACY and SAFETY

Not reported.

ESTIMATED COST and IMPACT

COST

The cost of fenfluramine is not yet known.

IMPACT - SPECULATIVE

Impact on Patients and Carers

 Reduced mortality/increased length of survival  Reduced symptoms or disability

 Other: expert opinion suggests that seizure  No impact identified control, even late in life, could improve cognition of patientsg.

Impact on Health and Social Care Services

 Increased use of existing services  Decreased use of existing services

 Re-organisation of existing services  Need for new services: expert opinion suggests that cardiac monitoring may be required, for example by cardiology review, ECG or echocardiographyg.

 Other.  None identified

Impact on Costs and Other Resource Use

 Increased drug treatment costs  Reduced drug treatment costs: expert opinion suggests that if fenfluramine were effective, it could result in a decline in the use of other anti-epileptic drugs (e.g. stiripentol) which can be very expensiveg.

 Other increase in costs.  Other reduction in costs.

 Other: unknown drug treatment costs.  None identified

Other Issues

f Patient group personal communication.

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 Clinical uncertainty or other research question  None identified identified: expert opinion suggests that approximately 85% of children with Dravet syndrome will survive to adulthood. As the indication states that fenfluramine will be for the treatment of Dravet syndrome in children there is uncertainty regarding whether this drug will be available for adults with this diseaseg.

REFERENCES

1 Dravet Syndrome UK. What is Dravet syndrome? www.dravet.org.uk/what-is-dravet-syndrome/ Accessed 2 October 2015. 2 Boison D. Dravet in the dish: Mechanisms of hyperexcitability. Epilepsy Currents 2014;14(5):279- 280. 3 Chopra R and Isom L. Untangling the Dravet syndrome seizure network: The changing face of a rare genetic epilepsy. Epilepsy Currents 2014;14(2):86-89. 4 Epilepsy Action. Dravet syndrome. www.epilepsy.org.uk/info/syndromes/severe-myoclonic- epilepsy-in-infancy Accessed 2 October 2015. 5 Dravet C and Guerrini R. Dravet Syndrome (Topics in Epilespy). 2011. 1st Edition. Paris: John Libbey. 6 Dravet Syndrome Foundation. What is Dravet syndrome? www.dravetfoundation.org/dravet- syndrome/what-is-dravet-syndrome Accessed 2 October 2015. 7 Orphanet. Dravet syndrome. www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=33069 Accessed 2 October 2015. 8 Dravet Syndrome Foundation. Spanish and European Dravet syndrome population estimates. www.dravetfoundation.eu/wp-content/uploads/2013/12/Spanish-and-European-Dravet-syndrome- population-estimates.pdf Accessed 6 October 2015. 9 Epilepsy Foundation. Dravet Syndrome. www.epilepsy.com/learn/types-epilepsy- syndromes/dravet-syndrome Accessed 2 October 2015. 10 Genton P, Velizarova R, and Dravet C. Dravet syndrome: The long-term outcome. Epilepsia 2011;52(2):44-49. 11 Joint Formulary Committee. British National Formulary. BNF for Children October 2015. BMJ Group and Pharmaceutical Press. www.medicinescomplete.com 12 Dressler A, Trimmel-Schwahofer P, Reithofer E et al. Efficacy and tolerability of the ketogenic diet in Dravet syndrome – comparison with various standard antiepileptic drug regimen. Epilepsy Research 2015;109:81-89. 13 Laux L and Blackford R. The ketogenic diet in Dravet syndrome. Journal of Child Neurology 2013;28(8):1041-1044.

g Expert personal communication.

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