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78700004

New Medicines

FinteplaDravet syndrome - low-dose formulation

Information

Fintepla
New formulation
Zogenix
Zogenix

Development and Regulatory status

Launched
Launched
Launched
December 2021
Yes
Yes
May 22Currently Fintepla is available in the UK from Zogenix under a Free of Charge (FoC) programme (or privately), in advance of NICE guidance being issued [28].
Dec 21Fintepla 2.2mg/ml oral solution available in the UK. 60ml=£901.44; 120ml=£1802.88; 360ml=£5408.65 [27].
Nov 21No date has yet been announced for publication of final NICE guidance for fenfluramine; launch presumably delayed as company waits for a decision [26].
May 21FDA revoked the breakthrough therapy designation in Jun 19 as two therapies (stiripentol and cannabidiol) were approved for this indication and the administrative criteria for designation were no longer met [25].
Feb 21Launched in Germany under a controlled access program requested by the European Medicines Agency [25].
Jan 21Zogenix is delaying UK launch until it knows the outcome of the NICE appraisal [24].
Dec 20Approved in EU [23]
Nov 20Fintepla has been available in the US since Jul 20 [22].
Oct 20Recommended for EU approval by CHMP - the full indication is "for the treatment of seizures associated with Dravet syndrome as an add-on therapy to other anti-epileptic medicines for patients 2 years of age and older. The medicine should be initiated and supervised by physicians experienced in the treatment of epilepsy. It should be prescribed and dispensed according to a controlled access programme" [21].
Jun 20Approved in US for treatment of seizures associated with Dravet syndrome in patients age 2 and older [19].
Nov 19FDA accept NDA and priority review for fenfluramine oral solution for treatment of seizures associated with Dravet Syndrome [17].
Nov 19Zogenix have asked NICE to reschedule their appraisal to better align with the regulatory process. Assume launch may be delayed until NICE guidance is published [16].
Apr 19FDA has refused to fully review the marketing application as the company had not submitted certain non-clinical studies to allow the assessment of chronic administration [13]
Mar 19EU Marketing Authorisation Application validated by EMA [14].
Feb 19Zogenix announce submission of NDA to EMA and completion of rolling NDA submission to FDA [12].
Nov 18Zogenix begins submission of a New Drug Application (NDA) for rolling review by the US FDA for low dose fenfluramine for treatment of seizures associated with Dravet syndrome. Study 1501 and 1504 form the clinical basis for the rolling NDA submission [11].
Feb 18FDA Breakthrough Therapy Designation for ZX008 in Dravet Syndrome. ZX008 is designated as an orphan drug in the US and Europe for Dravet syndrome and has received Fast Track designation in the US for Dravet syndrome [9].
Sep 17Zogenix announces intention to submit regulatory applications in USA and Europe for Dravet syndrome in H2 2018 [8].
Oct 15US FDA request additional information prior to the proposed PIII program. Zogenix has responded with the requested information required to initiate the clinical program and expects that the PIII clinical studies for Dravet syndrome will commence during Q4 of 2015 [5].
May 15Marketing authorization application targeted for the 4th quarter of 2016 [3].
Oct 14Company plans to start two PIII studies (of 40 to 60 Dravet syndrome patients per study) in Q2 2015 in the US and Europe, with top line results potentially available in the H1 2016 [2].
Jan 14Brabant has met with the FDA and European regulatory authorities to discuss the Phase III clinical program for Brabafen. The Phase III clinical trials will be based on the previously announced results of the longer than 19-year ongoing, prospective observational study using low-dose fenfluramine to treat Dravet Syndrome patients [1].

Category

Indirect-acting sympathomimetic which usually depresses rather than stimulates the CNS. Fenfluramine appears to stimulate the release of serotonin and selectively inhibits its reuptake resulting in increased CNS serotonin
Dravet Syndrome is a rare and extremely severe form of refractory epilepsy with a distinctive and complex electroclinical presentation thought to be caused by a gene defect causing abnormal functioning of a sodium channel in the brain. Children with Dravets Syndrome experience severe fever-related seizures in the first year of life. Other seizure types typically arise later, e.g. myoclonus and status epilepticus, resulting in severe cognitive and developmental impairment [1]
Dravet syndrome - low-dose formulation
Oral

Further information

Yes

Trial or other data

Sep 20In Study 3 (n=143), the addition of fenfluramine (0.7mg/kg/day) to the existing antiepileptic medication regimen was associated with a 64.8% RR in mean monthly convulsive seizures vs placebo (73.7% vs 7.6% respectively; p<0.0001) [20].
Dec 19PIII NCT02682927 and NCT02826863 (n=119) are published in The Lancet; fenfluramine 0.7 & 0.2mg/kg showed a 62.3% & 32.4% greater reduction in monthly convulsive seizure frequency vs placebo (p<0.0001 & p=0.0209 for difference respectively). Adverse effects included decreased appetite, diarrhoea, lethargy, and somnolence [18].
Oct 19Pooled PIII RCT data (n=206) reported that fenfluramine, as an adjunctive treatment, reduced median baseline monthly frequency of generalised tonic-clonic seizures by 80%, 64%, and 48% in the fenfluramine 0.8, 0.5, 0.2 mg/kg/day groups, respectively, vs 10% in the placebo group [15].
Jul 18Zogenix reveal top-line results from a second trial of ZX008. Study of ZX008 as adjunctive therapy to stiripentol in children and young adults reported a 54.7% greater reduction in mean monthly convulsive seizures compared to placebo [10].
Sep 17Zogenix reports top-line results from NCT02682927 and NCT02826863 trials [8].
Jan 17NCT02682927 is a PIII placebo-controlled RCT to assess efficacy, safety and PK of ZX008 used as adjunctive therapy for uncontrolled seizures in 130 paediatric and young adult subjects with Dravet syndrome. Subjects will be randomized (1:1:1) to receive either ZX008 (0.2 mg/kg/day, 0.8 mg/kg/day; maximum dose: 30 mg/day) or placebo. Randomization will be stratified by age group (under 6 years, 6 to 18 years). After a 14 day titrtuion period, subjects will continue treatment at their randomly assigned dose for a further 12 weeks. The study started Jan 16 and Feb 17 is the estimated primary completion date [7].
Dec 15The company plans to start its PIII programme for ZX008 imminently, with top-line results expected in 2016. The programme will consist of two randomized, double-blind placebo-controlled studies, each enrolling 105 patients, and will include two dose levels of ZX008 (0.2mg/kg/day and 0.8mg/kg/day, up to a maximum daily dose of 30 mg). One study will be conducted primarily in the US and Canada, and the other will be a multi-national study, conducted primarily in Europe. The primary endpoint will be the change in frequency of convulsive seizures. The key secondary endpoints include 40% and 50% responder analyses and convulsive seizure-free interval [6].
Jul 15Following feedback received from the US FDA, Zogenix announced that it would push back its PIII clinical trial for ZX008 for Draver syndrome by about three months. This will allow for enrolment of an additional 105 pts in both PIII trials. The baseline observation period will last 8 wks, followed by a 2-wk titration period. In addition, Zogenix indicated it will hold an optional, long-term, open label extension study [4].
May 15Low-dose fenfluramine (ZX008) is designated as an orphan drug in both the US and EU for the treatment of Dravet syndrome. New efficacy data demonstrate sustained efficacy and tolerability of ZX008 as an adjunctive therapy for pts with Dravet syndrome. The data, which were presented at European Paediatric Neurology Society Congress 2015 includes 10 pts with Dravet syndrome who were treated with low-dose fenfluramine (10 mg to 20 mg per day) and followed up for 5 yrs from 2010-2014. At least 80% of pts achieved a greater than or equal to 75% reduction in the frequency of seizures and 3 pts (25%) were seizure-free for 5 yrs whilst five pts (42%) were seizure-free for 2- 4 yrs. Low-dose fenfluramine was well tolerated, with the most common adverse events being transient loss of appetite and fatigue/somnolence and there were no discontinuations due to adverse events. Zogenix intends to initiate PIII trials during Q2 of 2015 [3].
Oct 14Zogenix, Inc. acquired Brabant Pharma. The acquisition includes worldwide development and commercialization rights to Brabafen [2].
Jan 14Brabant recently reported two-year follow-up data to the ongoing 19-year observational study. These data showed that 92% of Dravet patients taking low-dose fenfluramine were either seizure-free or had greatly reduced seizure frequency. On average Dravet patients were seizure-free for 6-years in the 19-year study and the average treatment period was over 13 years. [1]

Evidence based evaluations

FinteplaLennox-Gastaut syndrome - low-dose formulation

Information

Fintepla
Licence extension / variation
Zogenix
Zogenix

Development and Regulatory status

None
Pre-registration (Filed)
Approved (Licensed)
Mar 22The FDA has approved and granted paediatric exclusivity for fenfluramine as an oral solution for Lennox-Gastaut syndrome in pts aged two years and older. This decision was based on positive results of the PIII trial (NCT03355209) [10]
Jan 22Currently pre-registration in the EU [9].
Nov 21Zogenix plans to file for LGS in the EU by end of 2021 [8].
Sep 21Filed in US [7].
Sep 20Zogenix is working to gather additional data required to support a supplemental New Drug Application (sNDA) in the US, including two-year carcinogenicity data from our non-clinical study in rats and additional safety data from our ongoing open label extension study. Based on its clinical development plan and written feedback received from the FDA in Sep 20, the company expects to submit the sNDA in Q2 2021. Expect EU filings to follow, although not stated [6].
Jul 19Has orphan drug status in EU & US [3].

Category

Indirect-acting sympathomimetic which usually depresses rather than stimulates the CNS. Fenfluramine appears to stimulate the release of serotonin and selectively inhibits its reuptake resulting in increased CNS serotonin
Lennox-Gastaut syndrome is estimated to occur in 0.1-0.28 people per 100,000 and is believed to account for 1-4 percent of all cases of childhood epilepsy. The annual incidence in children is estimated to be 2 per 100,000 children. Onset of Lennox-Gastaut syndrome is usually between 2-7 years with a peak onset between 3 to 5 years [1].
Lennox-Gastaut syndrome - low-dose formulation
Oral

Further information

Yes

Trial or other data

May 22May 22: PIII RCT (NCT03355209; n=263) found fenfluramine 0.7mg/kg/dose significantly reduced frequency of drop seizures vs placebo (26.5% vs 7.6%; p=0.001). More patients in the 0.7-mg/kg/d fenfluramine group achieved a ≥50% response (25% vs. 10% vs placebo; p=0.02) [11].
Feb 20PIII trial met its primary objective of demonstrating that FINTEPLA at a dose of 0.7 mg/kg/day was superior to placebo in reducing the frequency of drop seizures, based on the change between baseline and the titration and maintenance treatment period (p=0.0012) in patients with LGS [5].
Sep 19Collection of primary outcome data in PIII trial (NCT03355209) is expected to complete Dec 19 [4].
Jun 19PIII trial (NCT03355209) is recruiting [2].
Nov 17PIII trial to assess the efficacy and safety of fenfluramine low dose (0.2 mg/kg/day and 0.8 mg/kg/day, up to a maximum daily dose of 30 mg) as an adjunctive therapy for the treatment of uncontrolled seizures in children and adults up to age 35 years, with Lennox-Gastaut syndrome starts (ZX008-1601; NCT03355209). The trial will enrol 263 patients in the US, Australia, Spain, the Netherlands, Denmark, Belgium and Canada, Japan, France, Germany, Italy, Mexico, Mexico, Poland, Austria and Sweden. The primary endpoint of the trial is the change in the number of seizures that result in drops between baseline and the combined titration and maintenance periods at the 0.8 mg/kg/day dose compared to placebo [2].

Evidence based evaluations