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

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(Schoonjans AS, et al. 2017). Fenfluramine is currently in a Phase 3 clinical trial for Dravet syndrome sponsored by Zogenix, Inc. While primarily used in the 1980s and 1990s for obesity, there were reports of it reducing seizures in the pediatric epilepsy population. It was withdrawn from the market in 1997 due to reports of pulmonary hypertension and heart valve disease in patients undergoing treatment for obesity but has been used in a small group of patients with Dravet syndrome at a low dose for up to 28 years with limited effects on the heart. Obviously, cardiac safety is important in evaluating a potential new drug for epilepsy, and the current clinical trial includes cardiac monitoring as part of the protocol, the results of which will be available upon study completion. In the meantime, the authors of this study reviewed the literature to assess cardiac safety when used at a low dose. The authors found 9 controlled studies on fenfluramine and its related compounds involving 3268 patients (with 2017 controls) and several uncontrolled studies.

Reports in adult obesity, where doses of fenfluramine ranged from 50 to 160 mg/day (roughly 0.7-2.0 mg/kg/day based on an obese adult female with a BMI of 30.0 in the U.S.), often in combination with phentermine, described pulmonary hypertension and aortic or mitral valve regurgitation. This caused the FDA to estimate the prevalence of valvular disease at 33% after exposure to fenfluramine or dexfenfluramine. Subsequent studies have shown the prevalence to be closer to 20% or below when treated with high-dose fenfluramine. In the original FDA report, the relative risk of severe valvulopathy was 9.2 in patients taking 60 mg/day or more of fenfluramine compared with patients taking less than 40 mg/day. The authors note that the original reports did not control for pre-existing valve disease, which would not be unexpected in the obese adult population.

In the Dravet syndrome population, two cohorts of Belgian patients have been treated for an extended period. The first, a group of 12 patients who began treatment before 2010 and have been treated with a mean dose of 0.34 mg/kg/day for a mean of 17 years have had echocardiograms performed at least annually since 2010. Most have seen significant seizure reduction and none has seen any clinical symptoms of heart valve dysfunction or pulmonary hypertension. Slight thickening of valves has been seen at some point in five patients, but 8/10 had no changes in structure on the most recent echocardiogram.

The second cohort, involving 9 patients who began treatment after 2010, was assessed for cardiac function at baseline and again at 3, 6, and 12 month intervals throughout treatment. After the first report, initial dose was 0.24 mg/kg/day and patients had been treated for a median of 1.5 years with 75% major motor seizure reduction and no heart valve abnormalities had been found. At the 5 year mark, one patient had a minor abnormality on echocardiogram that was stable at follow-up and determined unlikely to be related to fenfluramine. No symptoms of PPH have been observed in any patient. The authors stress that the current study of fenfluramine in Dravet syndrome utilizes lower doses than those described in the original reports of pulmonary hypertension and valvular abnormalities and that cardiac function remains a top priority for the study.

Because Dravet syndrome can be such a life limiting illness, the benefit of this treatment may outweigh the risk, providing a different outcome than that found in evaluating the benefit-risk ratio in adult obesity.

Schoonjans AS, Marchau F, Paelinck BP, Lagae L, Gammaitoni A, Pringsheim M, Keane MG, Ceulemans B. Cardiovascular safety of low-dose fenfluramine in Dravet syndrome: a review of its benefit-risk profile in a new patient population. Curr Med Res Opin. 2017 Jul 13:1-21. doi: 10.1080/03007995.2017.1355781. [Epub ahead of print] PubMed PMID: 28704161.
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