Fintepla Unlikely to Cause Heart Valve Problems, PAH in Young Patients, Extension Study Finds

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by Joana Carvalho |

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Children with Dravet syndrome receiving Fintepla (fenfluramine) to control their seizures are unlikely to develop cardiac valvulopathy — a disease in which at least one of the four heart valves start to malfunction — or pulmonary arterial hypertension (PAH), according to interim data from a long-term extension study.

The study, “Cardiovascular safety of fenfluramine in the treatment of Dravet syndrome: Analysis of an ongoing long‐term open‐label safety extension study,” was published in the journal Epilepsia.

Dravet is a severe form of drug-resistant epilepsy that usually manifests in the first year of life, and is characterized by seizures that normally fail to respond to treatment with conventional anti-seizure medications.

In the 1980s, it was discovered that fenfluramine — a medicine originally approved to help obese patients lose weight — contained potent anti-seizure properties that could be helpful for patients with drug-resistant forms of epilepsy.

However, the medication was removed from the market in 1997, after some patients started experiencing cardiac valvulopathy, accompanied later on by a few cases of PAH.

Fenfluramine hydrochloride is a salt formulation that makes up the active ingredient of Zogenix’s Fintepla (formerly known as ZX008), an anti-seizure therapy that was recently approved in the U.S. to treat children with Dravet, ages 2 and older.

In this study, investigators at Zogenix and colleagues reported the findings of an interim analysis of an ongoing open-label long-term extension study (NCT02823145) evaluating the long-term safety of Fintepla in children and adolescents with Dravet.

The extension study enrolled 232 patients with Dravet, ages 2–18, who had previously participated and completed one of three Phase 3 trials of Fintepla (NCT02682927NCT02826863, and NCT02926898).

During the extension study, patients received increasing daily oral doses of Fintepla, ranging from 0.2 to 0.7 mg/kg, or 0.4 mg/kg for those also taking Diacomit (stiripentol).

Echocardiography — a test that uses sound waves to produce an image of the heart while it is pumping blood — was used to monitor the function of the patients’ heart valves, and measure blood pressure in their pulmonary arteries (the large blood vessels that connect the heart to the lungs). This test was performed on weeks 4 and 6, and every three months thereafter during the extension study.

The main goal of the echocardiography tests was to determine the number of patients who developed either cardiac valvulopathy or PAH while receiving Fintepla.

From the 232 children and adolescents (128 boys and 104 girls, with a mean age of 9.1 years) in the extension study, 22 (9%) withdrew by its interim cut-off date (March 13, 2018). Most withdrawals were due to the therapy’s lack of effectiveness, followed by patient and/or carer’s personal decision.

After being treated with Fintepla for a median of 256 days with an average daily dose of 0.41 mg/kg, none of the patients developed either cardiac valvulopathy or PAH.

In some patients, echocardiography tests identified signs of heart valve regurgitation — a condition in which blood either leaks through the valve or backs up through the valve in the wrong direction. However, most cases were mild and temporary, and did not qualify as cardiac valvulopathy.

Two patients also had abnormally high blood pressure (more than 35 mm Hg) readings in their pulmonary arteries. However, these incidents were isolated and not observed in following tests.

“Longitudinal echocardiography over a median 8.4 months of treatment with fenfluramine suggests a low risk of developing cardiac valvulopathy and PAH when used to treat pediatric patients with Dravet syndrome,” the researchers wrote.

“These results, taken together with the magnitude and durability of the positive effect on seizures previously reported in Phase 3 clinical trials in this severe pediatric‐onset, refractory epileptic encephalopathy, strongly suggest that significant benefits of fenfluramine for this patient population outweigh potential cardiac risks, which can be monitored via echocardiography,” they concluded.

Of note, three authors of the study received personal fees from Zogenix as current employees of the company, two others received personal fees and research funding from the company, and another was given honoraria for consulting and advisory board services.