No Signs of Heart Problems Over 3 Years With Fintepla in Children
Up to three years of treatment with the anti-seizure medication Fintepla (fenfluramine) did not result in any signs of valvular heart disease — damage to any of the heart’s four valves — or pulmonary arterial hypertension (PAH) in children with Dravet syndrome.
That’s according to new results from an ongoing, long-term Phase 3 open-label extension study evaluating Fintepla‘s use in more than 300 children with the rare epilepsy disorder.
“This study, which represents the largest, longest, and most rigorous examination of cardiovascular safety of [Fintepla] yet reported, found no cases of [valvular heart disease] or PAH,” the researchers wrote.
“These results, combined with [Fintepla’s] substantial antiseizure efficacy, support a strong positive benefit-risk profile for [Fintepla] in the treatment of Dravet syndrome,” the team added.
The findings, “Long-term cardiovascular safety of fenfluramine in patients with Dravet syndrome treated for up to 3 years: Findings from serial echocardiographic assessments,” were published in the European Journal of Paediatric Neurology.
Fintepla is an oral add-on therapy intended to be used in combination with other anti-epileptic treatments to reduce seizure frequency in patients with Dravet syndrome. Developed by Zogenix, the medication was approved by both the U.S. Food and Drug Administration and the European Commission in 2020. Both regulatory agencies approved the therapy’s use for people with Dravet, ages 2 and older.
Prior to its use as an anti-epileptic treatment, a higher dose of the active ingredient in Fintepla — fenfluramine — was marketed as a weight loss therapy.
Although reports of its anti-seizure properties began to emerge in the 1980s, the product was removed from the market in 1997 after heart problems were reported in some patients.
Specifically, some people taking Fintepla began experiencing valvular heart disease, in which any of the four heart valves become damaged or diseased, or a rare form of pulmonary hypertension known as PAH. In this condition, the blood pressure in the artery leading to the lungs from the heart, called the pulmonary artery, is elevated.
Active ingredient in Fintepla tied to heart problems
To assess the long-term efficacy and safety of Fintepla, Zogenix launched an open-label extension study (NCT02823145) in 2016. The study is evaluating Fintepla — specifically for long-term safety and tolerability, to include effects on heart function — in children and adolescents with Dravet.
Each of the participants had previously been enrolled in one of three Phase 3 trials of Fintepla: ZX008-1501 (NCT02682927), ZX008-1502 (NCT02826863), or ZX008-1504 (NCT02926898).
All children enrolled in the extension study were given Fintepla twice daily at a dose of 0.2 mg/kg per day, which was titrated up to a maximum dose of 0.7 mg/kg per day based on tolerability and effectiveness. For children also using Diacomit (stiripentol), an anticonvulsant medication, the maximum dose was 0.4 mg/kg due to potential interactions between the medications.
Echocardiography — a test that uses sound waves to produce an image of the heart — was used to monitor heart function and blood pressure in the pulmonary arteries. That test was performed at the study’s start, after four or six weeks, and every three months thereafter.
A previous interim analysis from the extension study showed that none of the 232 children then enrolled experienced signs of valvular heart disease or PAH after a median of 256 days (about 8.5 months) with a median daily dose of 0.41 mg/kg.
Here, the investigators provided an updated report from the trial, which now included 327 enrolled children who had received at least one dose of Fintepla by November 2020. The children ranged in age from 2 to 19, with a median age of 9, and 53.5% were male.
Treatment length ranged from 0.2 months (about a week) to 42.6 months (about 3.5 years), with a median treatment duration of 23.9 months (about two years). The participants were given a median dose of 0.44 mg/kg daily.
During the study course, 3,308 echocardiograms were performed, with a mean of 10.1 per patient. None of the children developed valvular heart disease, the data showed.
Some children did show signs of heart valve regurgitation — a condition in which blood leaks through the valve or moves through it in the wrong direction. However, these cases were considered mild, and none qualified as valvular heart disease.
PAH also was not observed in any of the children. The team noted, however, that because PAH is a rare condition, the relatively small sample size of the study precludes the ability to accurately estimate PAH risk.
Among the children, 77 (23.5%) were withdrawn from the study, with the most commonly cited reasons being lack of efficacy (44 children) or adverse events (six children).
“The results of this study extend and confirm previous results in this patient population showing no incidence of [valvular heart disease] or PAH in children and adolescents with Dravet syndrome who have been treated with [Fintepla],” the researchers wrote.
Reductions in seizure frequency are a secondary efficacy goal of the extension trial. A previous two-year interim analysis showed that most of the 330 then-enrolled participants (61.7%) experienced a clinically meaningful decrease in seizure frequency with Fintepla treatment.
This study was sponsored by Zogenix, and all six study authors are Zogenix employees.
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