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Introduction

  • Lennox-Gastaut syndrome (LGS) is a treatment-resistant developmental and epileptic encephalopathy (DEE) with multiple seizure types and high rates of morbidity and mortality[1] 

  • FFA has demonstrated sustained, clinically meaningful reduction in monthly convulsive seizure frequency (MCSF) in patients with Dravet syndrome[2,3] 

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Objective

  • To evaluate the safety and efficacy of fenfluramine (FFA) in patients with LGS in a double-blind, randomized placebo-controlled trial (RCT; NCT03355209) 

 

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Methods

Patients 

  • Patients aged 2-35 years (inclusive) with Epilepsy Study Consortium (ESC)-confirmed diagnosis of LGS entered the RCT (Figure 1; Figure 2) 

  • Key inclusion criteria

    • Onset of seizures at ≤11 years old 

    • Multiple seizure types, including countable motor seizures that result in drops (defined as generalized tonic-clonic, tonic, clonic, atonic, focal), including ≥8 seizures associated with a drop within 4 weeks of inclusion 

    • Abnormal cognitive development 

    • Abnormal electroencephalogram with abnormal background activity accompanied by a slow spike and wave pattern <2.5 Hz 

  • Primary endpoint

    • To compare the percentage change from baseline in seizures associated with a drop in the 0.7 mg/kg/day FFA group vs placebo (Figure 3)

      • Seizures associated with a drop were defined as ESC-confirmed seizures of the following type that result in drops for each participant at a subject level: generalized tonic-clonic, secondary generalized tonic-clonic, tonic, atonic, and tonic-atonic seizures 

  • Key secondary endpoints

    • Percentage change from baseline in drop seizure frequency in the 0.2 mg/kg/day FFA group vs placebo 

    • ≥50% responder rate for all treatment groups 

    • Clinical Global Impression of Improvement (CGI-I) for all treatment groups 

  • Safety outcomes

    • Frequency of adverse events among placebo and FFA treatment groups 

    • Standardized color Doppler ECHO to monitor cardiac valve structure/function and pulmonary arterial hypertension at screening, during treatment, and post-treatment 

  • Statistical analysis

    • Hodges-Lehmann estimate of median percentage reduction from baseline in monthly drop seizure frequency during the combined titration and maintenance periods (T+M); non-parametric rank ANCOVA 

    • Control of statistical analyses for multiplicity using a gatekeeping approach, where primary and key secondary endpoints were arranged in a hierarchy and tested sequentially

 

 

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Results

Patients (Figure 2; Table 1) 

 

Efficacy (Figures 3 through 5; Table 2) 

Safety 

  • Most common adverse events (≥10%) included decreased appetite, somnolence, fatigue, vomiting, diarrhea, irritability, seizure, and pyrexia (Table 3) 

  • No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed in any patient at any time during the study

    • One subject (0.7 mg/kg/day) had an end of study ECHO read as mild aortic regurgitation, but subsequent diagnostic transesophageal ECHO revealed absent aortic regurgitation and a normal aortic valve 

  • One subject death due to SUDEP was reported as unrelated to study drug in the FFA 0.7 mg/kg/day group 

Effect on Seizures Associated With a Drop Relative to Recently Reported LGS RCTs 

  • With multiple approved treatment options for LGS, patients who choose to enter clinical trials likely represent the most refractory cases 

  • This can be illustrated in 2 ways:

    • A relatively consistent reported placebo-adjusted difference in frequency of seizures associated with a drop was observed in the 4 most recently completed trials (Figure 6) 

    • The large number of prior medications patients have been exposed to, with recently completed trials reporting medians of 6-8 with maximum numbers of 20-28 

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Conclusions

 

  • The current phase 3 study in LGS met its primary endpoint, with FFA 0.7 mg/kg/day demonstrating significant improvement in frequency of seizures associated with a drop (estimated median difference [Hodges-Lehmann EMD] from placebo: -19.9%) 

  • FFA was highly effective in reducing generalized tonic-clonic seizures (GTCs) by 46% and 58% in the 0.7 and 0.2 mg/kg/day FFA groups, respectively, compared to worsening of 3.7% in the placebo group

    • GTCs are a primary risk factor for sudden unexpected death in epilepsy (SUDEP) and are associated with a 10-fold increased risk of SUDEP[4] 

  • FFA offers a treatment option for patients with LGS that has comparable efficacy for seizures associated with a drop and a different mechanism of action compared with other commonly used AEDs[5-7] 

    • FFA may be a particularly advantageous choice for LGS patients experiencing GTCs 

  • FFA was generally well tolerated, and VHD or PAH was not observed 

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References/ Acknowledgments/ Disclosures

REFERENCES 

  1. Cross JH, et al. Front Neurol. 2017;8:505. 

  2. Lagae L, et al. Lancet. 2020;394(10216):2243-54. 

  3. Nabbout R, et al. JAMA Neurol. 2020;77(3):300-08. 

  4. Sveinsson O, et al. Neurology. 2017;89(2):170-7. 

  5. Devinsky O, et al. N Engl J Med. 2018;378(20):1888-97. 

  6. Thiele E, et al. Lancet. 2018;391(10125):1085- 96. 

  7. Takeda Pharmaceutical Company, Ltd. https://www.takeda.com/newsroom/ newsreleases/2020/. Accessed September 3, 2020. 

 

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, of PharmaWrite, LLC (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. 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/ Travel support, Zogenix; Consultant/Advisor, Dravet Syndrome Foundation, Epygenix; Reviewer, Epilepsy Study Consortium. KCN: No relevant disclosures. IM: Grants/Personal fees (honoraria, travel support), Zogenix during conduct of the study, GW Pharmaceuticals, Dravet Syndrome Foundation, Greenwich, INSYS, Neurelis, NeuroPace, Tuberous Sclerosis Alliance, Ultragenyx, Visualase, outside the submitted work. LL: Grants, personal fees, other, Consultant/Speaker, Zogenix during conduct of the study; other, Consultant/Speaker, LivaNova; Grants, other, Consultant/Speaker, UCB; other, Speaker, Shire, Speaker, Eisai, 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 support, Zogenix. KR: No relevant disclosures. SS, AA, GM, ML, GMF, BSG, ARG: Personal fees, Stockowner, Employees, Zogenix; with patents pending. RD: Speaker, LivaNova, Eisai, Lundbeck; Investigator, LivaNova, Eisai, Global Pharmaceuticals, Lundbeck, Pfizer, UCB, Zogenix. AG-N: Investigator, Speaker, Advisory Board Member, Bilal, Eisai, Esteve, UCB, GW Pharmaceuticals, GW Research, Zogenix, Stoke Therapeutics, Sanofi, Arvelle; Personal fees, Bilal, GW Pharmaceuticals, Zogenix, Stoke Therapeutics, Eisai, Esteve. 

 

Previously presented at the Virtual American Epilepsy Society (AES) Annual Meeting, December 4-8, 2020 

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