Cardiovascular safety of low-dose fenfluramine in Dravet syndrome: a review of its benefit-risk profile in a new patient population

Abstract

Objective: Dravet syndrome (DS) is a rare, treatment-resistant epilepsy syndrome for which current treatment regimens are often ineffective. Fenfluramine is currently in development for treatment of DS, based on reports in the 1980s and 1990s of its anti-epileptic activity in pediatric patients with intractable epilepsy. However, fenfluramine was withdrawn from global markets in 1997 following reports of its association with pulmonary hypertension and heart valve disease in adult patients treated for obesity. This review was conducted to assess cardiac safety of fenfluramine when used at lower doses for treatment of DS.

Methods: Pubmed was searched for clinical studies of fenfluramine in obese adults who reported incidence of heart valve disease. These data were reviewed against published results from Belgian patients with DS who have been treated with low-dose fenfluramine for up to 28 years.

Results: Nine controlled studies of fenfluramine and related compounds (dexfenfluramine and/or phentermine) which assessed incidence and severity of cardiac valve disease in 3,268 treated patients and 2,017 control subjects have been reported. Mild or greater aortic valve regurgitation was found in 9.6% of treated patients compared with 3.9% of control subjects, and moderate or greater mitral valve regurgitation was found in 3.1% of treated patients and 2.5% of control subjects. Nineteen DS patients have been treated for up to 28 years with 10–20 mg/day fenfluramine, with no clinical signs or symptoms of cardiac valve disease or pulmonary hypertension. Slight and clinically unimportant changes in valve structure have been seen on echocardiography in five patients at some time during the observation period.

Conclusions: A different benefit-risk relationship appears to be emerging when fenfluramine is used at low doses for extended periods in young patients with DS. Continued cardiac assessments during ongoing Phase 3 clinical trials will provide additional safety information for this potential new and effective treatment.

Keywords:

• Epilepsy
• heart valve disease
• cardiac valvulopathy
• pulmonary hypertension

Transparency

Declaration of funding

This study was funded by Zogenix, Inc.

Declaration of financial/other relationships

BC, AS, MP, MK, and LL have received honoraria for consulting and advisory board services from Brabant Pharma and Zogenix, Inc. FM and BP have nothing to disclose. AG is an employee of Zogenix, Inc. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Previous presentations

The summary of the echocardiographic findings in patients with Dravet syndrome who have been treated with fenfluramine is based on data that were presented at the 2016 meeting of the American Epilepsy Society in Houston, TX.

Acknowledgments

Professional medical writing and editing was provided by Edward Weselcouch of PharmaWrite (Princeton, NJ), which was funded by Zogenix, Inc. (Emeryville, CA).

Notice of correction

Please note that Table 2 has been corrected since the article was first published online (31 July 2017)