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INTRODUCTION

Lennox-Gastaut syndrome (LGS) is an electroclinical developmental and epileptic encephalopathy characterized by multiple seizure types (most notably, tonic seizures, ~56%), abnormal electroencephalogram with diffuse slow spike-and-wave complexes at <3 Hz, and cognitive impairment, leading to life-long disability[1-3]
Despite availability of 9 FDA/EMA-approved antiseizure medications (ASMs), most patients remain refractory
During the RCT LGS study (Part 1), patients treated with fenfluramine 0.7 mg/kg/day experienced a 26.5% median reduction in seizures associated with a drop vs 7.6% in the placebo group, with an estimated median difference of -19.9% (P=0.0013)4 In addition, children and young adults with LGS treated with fenfluramine were more likely to show clinically meaningful improvement in executive functioning[5]

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OBJECTIVE

To evaluate the long-term safety and efficacy of fenfluramine in patients with LGS in an open-label extension study (OLE)

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METHODS

Patients with LGS who completed a phase 3 randomized clinical trial (RCT) were eligible to enroll in the OLE study (NCT03355209) (Figure 1A)
Effectiveness and safety/tolerability were assessed at Months 1, 2, and 3, and thereafter at 3-month intervals
Standardized color Doppler echocardiogram (ECHO) assessed cardiac valve function/structure and any evidence of pulmonary arterial hypertension (PAH)

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RESULTS

Patients

A total of 247 patients had enrolled in the OLE as of October 19, 2020 (interim cut-off date) and had at least 1 dose of study drug and 1 month of diary data in the OLE (Figure 1A and Table 1)
83 (33.6%) patients withdrew; the most common reason for withdrawal was lack of efficacy (n=55; 22.3%; Figure 1B)

Fenfluramine Exposure (Table 2)

Effectiveness

FFA provided significant improvement in median frequency of seizures associated with a drop that was maintained through the first 12 months of the OLE (Figure 2)
At Year 1 of the OLE, median percentage reduction in all seizures not associated with a drop was -66.9% (P<0.0001)
Median percentage increase in days free of seizures associated with a drop was 44.6% compared to pretreatment baseline, for a median absolute change of 2 days per 28 days vs pretreatment baseline in the core RCT (P<0.0001)

Most patients (51.2%) responded with a clinically meaningful (≥50%) reduction in percentage of seizures after treatment for up to 1 year with fenfluramine; 25.3% of patients demonstrated profound (≥75%) reduction in frequency of seizures associated with a drop (Figure 3)

Nearly half of investigators (49.2%) and caregivers (48.8%) rated their patients as having clinically meaningful improvement on the CGI-I (ie, “Much Improved” or “Very Much Improved”; Figure 4)

Safety

The most common treatment-emergent adverse events (TEAEs) were decreased appetite and fatigue (Table 3)
- 12 patients (4.9%) experienced a TEAE that led to study discontinuation, most commonly fatigue or change in seizure presentation (n=3, 1.2% each)
- Weight changes from OLE baseline ranged from weight loss of 22.4% to weight gain of 34.4%
- Overall, body weight gain ≥7% of OLE baseline was reported at any visit for 32.4% of subjects and body weight decrease ≥7% was reported for 17.0% of patients
One patient death occurred; the cause was reported as aspiration pneumonia and was considered unrelated to study drug
Echocardiography revealed that no patient had developed VHD or PAH by the interim analysis cut-off date
- 2 patients in the LGS program demonstrated instances of mild aortic regurgitation (AR) without the presence of VHD
- Neither subject exhibited valvular morphological (or structural) changes, nor did findings progress to a higher grade of regurgitation
- One of these patients had 2 diagnostic transesophageal echocardiograms (TEEs—a method with higher resolution than standard transthoracic ECHO); both patients demonstrated absent AR and normal valve structure
- Both patients were examined by cardiologists, who concluded no VHD in either patient
- Rates of mild AR observed in the study (n=2/247; 0.8%) are consistent with those seen in the screening period prior to treatment with fenfluramine (n=3/335; 0.9%)
- Both patients continue to be treated with fenfluramine without development of VHD

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CONCLUSIONS

Patients with LGS experienced sustained (39.4%-51.8%) clinically meaningful reduction in frequency of seizures associated with a drop during treatment with fenfluramine for up to 1 year
At Year 1, the median percentage reduction in all seizures not associated with a drop was -66.9%
Fenfluramine was generally well tolerated with no observations of VHD or PAH during the OLE
Fenfluramine may be an important new treatment option with a novel mechanism of action for patients with LGS

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REFERENCES, ACKNOWLEDGMENTS, DISCLOSURES

REFERENCES

Cross JH, et al. Front Neurol. 2017;8:505.
Gastaut H, et al. Epilepsia. 1966;7(2):139-79.
Arzimanoglou A. Epilepsia. 2009;50(suppl 8):3-9.
Knupp KG, et al. Virtual American Epilepsy Society (AES) Annual Meeting; December 4-8, 2020.
Bishop KI, et al. Virtual American Academy of Neurology Annual Meeting; April 17-22, 2021.

ACKNOWLEDGMENTS

The studies described in this poster were sponsored by Zogenix, Inc. (Emeryville, CA, USA). Professional medical writing and editing were provided to the authors by Danielle Ippolito, PhD, CMPP, MWC, and Dolores Matthews, ELS, MEd, of PharmaWrite (Princeton, NJ, USA), and were paid for by Zogenix.

DISCLOSURES

KGK: Research grants, Zogenix, Pediatric Epilepsy Research Foundation during conduct of the study, Colorado Department of Public Health, West Therapeutics; other as DSMB member, Greenwich Pharmaceuticals, outside the submitted work. IES: Compensation, Zogenix during conduct of the study; other, Zynerba Pharmaceuticals, GW Pharmaceuticals, Ovid Therapeutics, Marinus, Ultragenyx; Personal fees and other compensation, UCB; Personal fees, GlaxoSmithKline, Eisai, BioMarin, Nutricia, Xenon Pharmaceuticals, outside the submitted work; Research funding, National Health and Medical Research Council, Health Research Council of New Zealand, National Institutes of Health, Zogenix. BC: Research funding, Brabant, Zogenix; Consultant, Brabant, Zogenix; Patent, ZX008. BC and the KU Leuven University/Antwerp University Hospital may benefit financially from a royalty arrangement that is related to this research if Zogenix is successful in marketing its product, fenfluramine. The terms of this arrangement have been reviewed and approved by the KU Leuven University/Antwerp University Hospital. JS: Research grants, Stoke, Marinus, Zogenix, Biopharm; Consultant/Advisor, Dravet Syndrome Foundation, Epygenix, Encoded, GW Pharmaceuticals, Asceneuron, Longboard Pharmaceuticals, Knopp Biosciences, Neurocrine; Stock options, Epygenix; Travel support, Zogenix; Reviewer, Epilepsy Study Consortium. KCN: No relevant disclosures. LL: Grants, personal fees, Zogenix during conduct of the study; Consultant/Speaker, Brabant, LivaNova, Ovid, UCB Pharma, Zogenix, Eisai, Shire, outside the submitted work. LL has a patent for ZX008 for the treatment of Dravet syndrome and infantile epilepsies assigned to his institution and licensed to Zogenix. LL and KU Leuven University/Antwerp University Hospital might benefit financially from a royalty arrangement that is related to this research if Zogenix is successful in marketing its product, fenfluramine. The terms of this arrangement have been reviewed and approved by KU Leuven University/Antwerp University Hospital. RG: Research grants, Zogenix during conduct of the study; Speaker/Consultant, Zogenix, outside the submitted work. SMZ: Research support, Zogenix; Advisory board, Zogenix. RN: Research funding, Eisai, GW Pharma, Novartis, Shire, Zogenix; Consultant/Advisor, Eisai, Biogen, GW Pharma, Novartis, Shire, Zogenix; Speaker, Advicenne, Eisai, BioMarin, GW Pharma, Novartis, Zogenix. KR: Research funding, Travel support, Consultant, Speaker, AFT Pharmaceuticals, Eisai Australia, Janssen-Cilag Pty, LivaNova Austrailia, Novartis, UCB, Zogenix International. SS, AA, ML, GMF, BSG, ARG: Stockowners, Employees, Zogenix, with patents pending. RD: Speaker, LivaNova, Eisai, Lundbeck; Investigator, LivaNova, Eisai, Global Pharmaceuticals, Lundbeck, Pfizer, UCB, Zogenix. AG-N: Personal fees or research grants, Arvelle Therapeutics, Bial, Biocodex, Eisai, Esteve, GW Pharma, GW Research, PTC Therapeutics, Sanofi, Stoke, UCB, Zogenix.

Presented at the 50th Annual Child Neurology Society Meeting, September 29-October 2, 2021, Boston, MA

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Author Information

Kelly G. Knupp[1], Ingrid E. Scheffer[2], Berten Ceulemans[3], Joseph Sullivan[4], Katherine C. Nickels[5], Lieven Lagae[6], Renzo Guerrini[7], Sameer M. Zuberi[8], Rima Nabbout[9], Kate Riney[10], Svetlana Shore[11], Anupam Agarwal[11], Michael Lock[11], Gail M. Farfel[11], Bradley S. Galer[11], Arnold R. Gammaitoni[11], Ronald Davis[12], Antonio Gil-Nagel[13]

[1]Children’s Hospital Colorado, Aurora, CO, USA; [2]University of Melbourne, Austin Hospital and Royal Children’s Hospital, Melbourne, Victoria, Australia; [3]Department of Paediatric Neurology, Antwerp University Hospital, Antwerp, Belgium; [4]University of California San Francisco Weill Institute for Neurosciences, Benioff Children’s Hospital, San Francisco, CA, USA; [5]Mayo Clinic, College of Medicine, Division of Child and Adolescent Neurology, Rochester, MN, USA; [6]Member of the European Reference Network EpiCARE; Department of Paediatric Neurology, University of Leuven, Leuven, Belgium; [7]Pediatric Neurology and Neurogenetics Unit, Anna Meyer Children’s Hospital, University of Florence, Florence, Italy; IRCCS Fondazione Stella Maris, Pisa, Italy; [8]Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, United Kingdom; [9]Department of Pediatric Neurology, Reference Centre for Rare Epilepsies, Necker-Enfants Malades Hospital, Université de Paris, Imagine Institute, Paris, France; [10]Neuroscience Unit, Queensland Children’s Hospital, South Brisbane, QLD, Australia; School of Clinical Medicine, University of Queensland, St Lucia, QLD, Australia; [11]Zogenix, Inc., Emeryville, CA, USA; [12]Neurology and Epilepsy Research Center, Orlando, FL, USA; [13]Hospital Ruber Internacional, Madrid, Spain

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FINTEPLA (fenfluramine) provides clinically meaningful reduction in frequency of seizures resulting in a drop in patients with Lennox-Gastaut syndrome for up to 1 year: interim analysis of an open-label extension study

Kelly G. Knupp[1], Ingrid E. Scheffer[2], Berten Ceulemans[3], Joseph Sullivan[4], Katherine C. Nickels[5], et al.

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