Presented as par t o f a Sc ient i f ic Exh ib i t dur ing the 69th Annual Meet ing of the Amer ican Epi lepsy Soc iety, December 4-8, 2015, Ph i lade lph ia

History of the Use of Low-dose Fenfluramine in Pediatric Epilepsy

Presented as par t o f a Sc ient i f ic Exh ib i t dur ing the 69th Annual Meet ing of the Amer ican Epi lepsy Soc iety, December 4-8, 2015, Ph i lade lph ia

History of the Use of Low-dose Fenfluramine in Pediatric Epilepsy

REFERENCES 10. Clemens B. Epilepsy Res. 1988;2:340-3.

11. Aicardi J, et al. Arch Neurol. 1988;45:923-5.

12. Boel M, Casaer P. Neuropediatrics. 1996;27:171-3.

13. Casaer P, Boel M. Epilepsia. 2002;43:205-6.

14. Ceulemans B, et al. Epilepsia. 2012;53:1131-9.

DISCLOSURESMedical writing assistance provided by Latoya M. Mitchell, PhD, CMPP, of PharmaWrite, LLC (Princeton, NJ), along with editorial and graphic art support, were funded by Zogenix, Inc.

REFERENCES 1. Dravet C, et al. Adv Neurol. 2005;95:71-102.

2. Schoonjans A-S, et al. Ther Adv Neurol Disord. 2015;8:328-38.

3. Dravet C. Vie Méd. 1978;8:543-8.

4. Dravet Syndrome Foundation. 2015. http://www.dravetfoundation.org/dravet-syndrome/medical-information/treatment. Accessed December 1, 2015.

5. Bonnycastle DD, et al. Br J Pharmacol Chemother. 1957;12:228-31.

6. Gastaut H. Presse Méd. 1984;13:2024-5.

7. Aicardi J, Gastaut H. N Engl J Med. 1985;313:1419.

8. Gastaut H, Zifkin BG. Ann Neurol. 1987;22:414-5.

9. Gastaut H, et al. J Autism Dev Disord. 1987;17:391-406.

DISCLOSURESMedical writing assistance provided by Latoya M. Mitchell, PhD, CMPP, of PharmaWrite, LLC (Princeton, NJ), along with editorial and graphic art support, were funded by Zogenix, Inc.

1978 1984 1996 20121985 1988 20021987

Charlotte Dravet

Dravet Syndrome f Dravet syndrome is a rare, severe, therapy-resistant epileptic

syndrome, first described by Charlotte Dravet in 1978,1 that affects an estimated 1 in 20,000 to 40,000 children2,3

f Children with Dravet syndrome are developmentally normal infants at the time of first occurrence of recurrent seizures which are usually provoked by a fever2

f Diagnosis of Dravet syndrome is based on clinical presentation including the child’s age at seizure onset, evolution of seizure types, electroencephalographic (EEG) features, and developmental course2

f Patients with Dravet syndrome most commonly present with seizures before 7 months

– The seizures have longer duration (>10 minutes), occur more frequently (often ≥5 in infancy), and consist of hemiconvulsions, myoclonic seizures, or focal seizures

– Around 2 years of age, developmental arrest becomes evident, and multiple other therapy-resistant seizure types begin to appear

f Approximately 75% of patients have genetic evidence of Dravet syndrome2

– The most common mutation is in the SCN1A gene, which encodes for a subunit of the voltage-gated sodium channel Nav1.1

Treatment of Dravet Syndrome f Dravet syndrome is resistant to common epileptic drugs f Rational adequate maintenance therapy is initiated using

antiepileptic drugs (AEDs) with avoidance of specific sodium channel-blocking agents such as lamotrigine, carbamazepine, and phenytoin, which aggravate symptoms of Dravet syndrome

f Anticonvulsants that have been useful for chronic seizure management in Dravet syndrome include clobazam, clonazepam, levetiracetam, stiripentol, topiramate, and valproic acid4

– Stiripentol has been effective in some patients with Dravet syndrome when used in combination with valproic acid and clobazam; stiripentol is not FDA approved

Fenfluramine and Epilepsy f Fenfluramine (3-trifluoromethyl-N-ethylamphetamine)

was originally developed as an appetite suppressant and is believed to act through serotonergic mechanisms2

f Early preclinical experiments by Bonnycastle et al. suggested that elevated serotonin in the CNS modifies epilepsy5

Henri Gastaut

Henri Gastaut, “Efficacy of Fenfluramine for the Treatment of Compulsive Behavior Disorders in Psychotic Children”6

f Dr. Gastaut described the use of fenfluramine in 3 children – ages 9, 10, and 11 – with self-induced syncopes

f Treatment with 30-60 mg/day of fenfluramine resulted in disappearance of the syncopes and lessened their autistic behavior

Marc Boel Paul Casaer

Marc Boel and Paul Casaer, “Add-on Therapy of Fenfluramine in Intractable Self-induced Epilepsy” in Neuropediatrics12

f Study of 11 institutionalized children (mean age 8 years) with severe seizures that were refractory to standard AEDs

f All patients had generalized tonic-clonic seizures; additional myoclonic seizures occurred in 5 patients

f Fenfluramine was given in doses between 0.5 mg/kg/day and 1 mg/kg/day as add-on therapy to their currently used antiepileptic medication(s)

f Improvement in seizure control was observed within 2-3 weeks of starting fenfluramine

– 7 of 11 patients became seizure-free and in the other 4 patients, a greater than 75% decrease in seizure frequency was observed

f Importantly, 5 of these patients were subsequently determined to have Dravet syndrome13

f “The results of this add-on therapy with fenfluramine indicate that this drug could have significant antiepileptic activity in a selected group of young patients with idiopathic or symptomatic generalized epilepsy”

Berten Ceulemans Lieven Lagae

Berten Ceulemans, Marc Boel, Katrien Leyssens, Carolin Van Rossem, Pieter Neels, Philippe G. Jorens, and Lieven Lagae, “Successful Use of Fenfluramine as an Add-on Treatment for Dravet Syndrome” in Epilepsia14

f This retrospective study reports the clinical outcome of 12 patients with Dravet syndrome after the addition of fenfluramine to their treatment

f Patients were seen twice a year and treatment efficacy, based on an individualized seizure diary, AED changes, and side effects were noted

f Patients underwent a full clinical examination, a yearly cardiac examination, and routine blood examination

f A total of 7 out of 10 patients were seizure-free for at least a year by the time of the last visit; 1 patient had a 75% reduction in seizure frequency

– 2 patients had no response to fenfluramine, yet their parents did not want to stop fenfluramine for fear of provoking status epilepticus; 1 patient stopped because of the lack of efficacy; and 1 patient discontinued fenfluramine and remained seizure-free

f No evidence of clinically important cardiac valve disease was found f “In this small exploratory and retrospective study, remarkably good results

were reported on the use of fenfluramine as an add-on medication for controlling seizures in patients with Dravet syndrome”

Current and Upcoming Clinical Trials f In Belgium, the prospective clinical study of patients with Dravet syndrome

treated with low-dose fenfluramine was initiated in 2010 and is ongoing2 f In the United States, there are several available, active, or recruiting clinical

trials in Dravet syndrome investigating various treatments such as STP and cannabidiol

f Two identical clinical trials investigating the use of 2 fixed doses of fenfluramine hydrochloride oral solution as adjunctive therapy in children and young adults with Dravet syndrome are being planned and sponsored by Zogenix, Inc. in the United States and Canada (initiation in late 2015) and in a multinational study primarily in Europe (initiation in 2016)

f Table 1 presents a summary of studies on fenfluramine in epilepsy2

Jean Aicardi

Jean Aicardi and Henri Gastaut, “Treatment of Self-induced Photosensitive Epilepsy with Fenfluramine” in the New England Journal of Medicine7

f A year later, Dr. Aicardi along with Dr. Gastaut wrote a letter to the editor describing the successful treatment of 3 patients with intractable self-induced photosensitive epilepsy, each using 60 mg fenfluramine daily

Béla Clemens, “Dopamine Agonist Treatment of Self-induced Pattern-sensitive Epilepsy. A Case Report” in Epilepsy Research10

f A 5.5-year-old boy developed excessive pattern sensitivity in addition to generalized seizures; bilateral myoclonia and impaired consciousness, frequently developing into generalized tonic-clonic seizures, were also present

f The patient demonstrated a partial response to bromocriptine mesylate (5 mg, thrice daily), VPA, and carbamazepine and a more complete response when fenfluramine (10 mg, twice daily) was added to his previous treatment regimen

Jean Aicardi, Henri Gastaut, Jeanne Misès, “Syncopal Attacks Compulsively Self-induced by Valsalva’s Maneuver Associated with Typical Absence Seizures. A Case Report” in Archives of Neurology11

f Case report of a 7-year-old patient with both compulsively self-induced apneic syncopes and true epileptic absence seizures

f At 11 years, the patient was treated with fenfluramine hydrochloride (60 mg/day)

– The apneic attacks disappeared within 48 hours and there was marked improvement in behavior

Paul Casaer and Marc Boel, “Fenfluramine as a Potential Antiepileptic Drug” in Epilepsia13

f In a letter to the editor, Casaer and Boel follow up their previous study with an additional 22 patients (11 boys, 11 girls) with severe tonic-clonic seizures before the add-on therapy of fenfluramine (dose between 0.25 and 1 mg/kg/day)

f Seizures were completely controlled in 6, and there was a 90% improvement in seizure rate in 10 of the 22 patients

f “We conclude that in young patients with intractable epilepsy and self-induced seizures fenfluramine should be considered as add-on therapy”

Henri Gastaut, Benjamin Zifkin, and Marcel Rufo, “Compulsive Respiratory Stereotypies in Children with Autistic Features: Polygraphic Recording and Treatment with Fenfluramine” in the Journal of Autism and Developmental Disorders9

f Gastaut and colleagues studied syncope due to compulsive respiratory stereotypies (CRS) in 8 patients ages 6 to 15 years with autistic features

f Patients were treated with 1.5-3 mg/kg per day of fenfluramine alone or, in some cases, as adjunctive therapy to VPA and CLB; VPA alone; phenobarbital and CLB; carbamazepine and CLB; phenobarbital and phenytoin; or phenobarbital, carbamazepine, and CLB

f Fenfluramine treatment resulted in 7 out of 8 patients achieving a temporary or permanent reduction in frequency of CRS2

f Reported side effects in patients included dose-related sedation and reduction in appetite with weight loss

f “A double-blind placebo-controlled trial of fenfluramine seems warranted in such patients”

Henri Gastaut and Benjamin G. Zifkin, “Antiepileptic Effects of Fenfluramine: Pilot Study” in Annals of Neurology8

f A study of 33 patients with severe childhood-onset epilepsy where patients received 0.5-1.5 mg/kg/day of fenfluramine in addition to their usual medication

f There was a 50% or greater reduction in seizure frequency in 46% of patients with generalized epilepsy, both idiopathic and symptomatic

f “Although fenfluramine does not seem promising as a primary antiepileptic drug, it may be an effective complementary drug in severe epilepsy, especially in generalized epilepsy not suitable for operation, or in refractory seizure disorders with childhood psychosis”

Table 1. Summary of Studies of Fenfluramine in Epilepsy

Citation Study type N Age (years)

Primary diagnoses

Fenfluramine dose

Results

Gastaut6 Case series 3 9–11 Self-induced syncopes

30–60 mg/day Elimination of the self-induced syncopes and improvement in autistic behavior

Aicardi and Gastaut7

Case series 3 14–20 Self-induced photosensitive epilepsy

60 mg/day Reduction in seizure frequency

Gastaut et al.9

Case series 8 6–15 Compulsive respiratory stereotypies in children with autistic features

1.5–3 mg/day 7 of 8 had a temporary or permanent reduction in frequency of compulsive respiratory behavior

Gastaut and Zifkin8

Pilot study 33 NR Intractable epilepsy

0.5–1.5 mg/kg/day

≥50% reduction in seizure frequency in 46% of patients

Clemens10 Case report 1 5.5 Self-induced photosensitive epilepsy

20 mg/day in 2 doses

100% reduction in seizure frequency

Aicardi et al.11 Case report 1 11 Self-induced syncopes

60 mg/day Dramatic reduction in self-induced syncopes and apneas. Improvement of behavior.

Boel and Casaer12

Case series 11 0.5–15.5 Intractable self-induced epilepsy

0.5–1 mg/kg/day

>75% to 100% reduction in seizure frequency

Casaer and Boel13

Case series 22a 1–12b Intractable self-induced epilepsy

0.25–1 mg/kg/day

100% reduction in 6 patients90% reduction in 10 patientsNo effect in 6 patients

Ceulemans et al.14

Retrospective case series

12c 1–16d Dravet syndrome

0.12–0.90 mg/kg/day

7 patients were seizure free during the last year1 patient had a 75% reduction in seizure frequency2 patients had no response1 patient stopped due the lack of efficacy 1 patient stopped and was controlled with another drug

NR, not reported;aIncludes 11 patients previously reported by Boel and Casaer.12

bRefers only to the 16 patients with a positive response to treatment.cIncludes 5 patients from the study of Boel and Casaer12 who were subsequently diagnosed with Dravet syndrome following genetic testing.dAge at starting fenfluramine.