Fintepla Earns FDA Approval for Treatment of Seizures in Dravet Syndrome
Note: This story was updated June 26, 2020, to note that the high dose of Fintepla used in the Phase 3 trials was 0.7 mg/kg/day rather than 0.8, as well as some differences in secondary outcome measures from what was reported on the trials’ webpages.
The U.S. Food and Drug Administration (FDA) has approved Zogenix‘s Fintepla (fenfluramine, formerly ZX008), an anti-seizure therapy, for use by patients 2 and older who have Dravet syndrome.
With Fintepla’s commercial launch planned for July, Zogenix has established Zogenix Central, a support service to assist patients who begin treatment, as well as their caregivers and medical teams.
“Having a new FDA-approved treatment option is so important because it improves our ability to optimize each patient’s treatment,” Mary Anne Meskis, executive director of the Dravet Syndrome Foundation, said in a press release.
“Moreover, because families living with Dravet syndrome never know when the next seizure is going to occur, whether they will end up in the [emergency room], or what the consequences might be following the seizure, having a strong support program like Zogenix Central to reduce the strain on families is very welcome. This will allow family members to remain focused on providing the best care of their loved one with Dravet,” she said.
Fintepla is an oral, low-dose fenfluramine solution originally developed as an appetite suppressant. It blocks the reuptake of serotonin, an important neurotransmitter (a chemical messenger that allows communication between nerve cells). Recent research also has suggested that Fintepla may act on sigma receptors — a type of cell membrane receptor commonly found in nerve cells.
Fintepla labeling will include a warning that the medication is associated with valvular heart disease and pulmonary arterial hypertension.
Because of these risks, patients using Fintepla must be monitored via echocardiogram before treatment, every six months during treatment, and once more, three to six months after treatment, for the possibility of cardiac abnormalities.
Because of these considerations, the FDA required the therapy be made available only through a restricted drug distribution program, under a risk evaluation and mitigation strategy (REMS). This means that healthcare providers prescribing Fintepla and pharmacies distributing it must be specially certified and that patients receiving the medication be enrolled in the REMS. Under the terms of this strategy, both prescribers and patients must adhere to the mandated cardiac monitoring in order to receive Fintepla.
Because of Fintepla’s low risk of abuse or misuse, the U.S. Drug Enforcement Administration classified the medication as a schedule 4 controlled substance, which restricts its distribution.
Fintepla’s approval has been in the works for some time.
Evidence from small studies and 30 years of compassionate use in Belgium had suggested that low-dose daily fenfluramine could lower the frequency of epileptic seizures without causing the cardiac problems that had been observed at higher doses.
The FDA extended its review period for Fintepla’s new drug application (NDA) in February, in order to review additional data that Zogenix had submitted in response to an FDA request. The FDA initially refused the NDA for Fintepla, citing several critical issues, including the failure to include non-clinical studies that addressed chronic administration of Fintepla’s active compound, fenfluramine hydrochloride. The agency also claimed that one of the clinical datasets included in that application was incorrect.
The new NDA, which was the basis for Fintepla’s approval, included chronic toxicity studies, complementing earlier data from two identical Phase 3 clinical studies, ZX008-1501 (NCT02682927) and ZX008-1502 (NCT02826863), and interim results from an ongoing open-label extension study (NCT02823145).
One trial is being conducted in the U.S. and Canada, and the other at different sites in Europe, Australia and Japan. This last trial is still recruiting participants; more information is available here.
Each Phase 3 trial enrolled patients ages 2 to 18, and compared two dosages of Fintepla — 0.7 mg/kg/day and 0.2 mg/kg/day — to placebo. Treatment time occurred over a 14-week period, including an initial two-week titration period to the final dosage.
The trials’ primary outcome was to assess high dose Fintepla’s effectiveness to lower the frequency of participants’ convulsive seizures — hemiclonic, tonic, clonic, tonic-atonic, generalized tonic-clonic, and focal seizures with clearly observable motor signs — compared to placebo.
Secondary outcomes included the same change in seizure frequency on the lower dose, the proportion of subjects that experienced greater than 50% reduction in convulsive seizure frequency, the proportion of subjects that experienced greater than 75% reduction, the longest seizure-free interval on either dose, changes in seizure severity, and the safety and tolerability of Fintepla.
Results from both trials showed that Fintepla significantly reduced monthly seizures among children and young adults with Dravet syndrome, when given with other antiepileptic medications, as compared to placebo. Data from the open-label extension study showed that Fintepla provided significant and sustained relief from convulsive seizures in young children with Dravet syndrome, comparable to the effect observed among adults.
Importantly, these reductions were seen within three to four weeks of treatment and remained stable over the 14- to 15-week treatment periods.
“There remains a huge unmet need for the many Dravet syndrome patients who continue to experience frequent severe seizures even while taking one or more of the currently available anti-seizure medications,” said Joseph Sullivan, MD, director of the Pediatric Epilepsy Center of Excellence at the UCSF Benioff Children’s Hospitals and the principal investigator for Fintepla in Dravet syndrome.
“Given the profound reductions in convulsive seizure frequency seen in the FINTEPLA clinical trials, combined with the ongoing, robust safety monitoring that will be part of its use, I feel FINTEPLA will offer an extremely important treatment option for Dravet syndrome patients,” Sullivan said.
The most common side effects reported with Fintepla include: low appetite; drowsiness; sedation and lethargy; diarrhea; constipation; abnormal echocardiogram; fatigue or lack of energy; ataxia (lack of coordination), balance disorder, gait disturbance (trouble with walking); increased blood pressure; drooling, excessive salivating; fever; upper respiratory tract infection; vomiting; decreased weight; risk of falls; and status epilepticus (seizures).
“Fintepla offers an additional effective treatment option for the treatment of seizures associated with Dravet syndrome. The FDA will continue to work with companies on drug development for Dravet syndrome and other types of epilepsy,” said Billy Dunn, director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research, in an FDA press release.
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