Fintepla Reduces Seizure Frequency in Dravet Children Who Respond Poorly to Diacomit Combo Regimens, Phase 3 Trial Shows
Fintepla (fenfluramine) reduced the frequency of convulsive seizures in children and adolescents with Dravet syndrome who responded poorly to treatment regimens that included Diacomit (stiripentol), Phase 3 trial results show.
The findings were reported in a study, “Fenfluramine for Treatment-Resistant Seizures in Patients With Dravet Syndrome Receiving Stiripentol-Inclusive Regimens,” published in JAMA Neurology.
Dravet syndrome is a severe type of epilepsy that usually manifests during the first year of life and is characterized by convulsive seizures that may contribute to intellectual disability as well as impairments in motor control, behavior, and cognition.
Standard of care treatments for Dravet include anti-seizure medications, such as Depacon (sodium valproate) and Onfi (clobazam), which are sometimes used in combination with adjunctive therapies such as Diacomit.
Diacomit, marketed by Biocodex, is a new type of anticonvulsive medication that has been shown to reduce the frequency of seizures in patients with Dravet, especially when administered in combination with other antiseizure medications, or with dietary interventions such as the ketogenic diet (low-carbohydrate, high-fat diet).
“Despite treatment with stiripentol-inclusive antiepileptic drug (AED) regimens, 38% of patients were reported to present with weekly seizures [more than three per month],” the researchers wrote. “Given the risks of sudden unexpected death in epilepsy, cognitive deficits, and other neurological consequences putatively caused at least in part by poorly controlled seizures, there remains an urgent unmet need for treating [Dravet syndrome].”
Fintepla, formerly known as ZX008, is a low-dose oral solution of fenfluramine hydrochloride that is currently being investigated as a potential add-on therapy to reduce the frequency of seizures in patients with Dravet. The experimental therapy is being developed by Zogenix.
Previous data from two Phase 3 trials (NCT02682927 and NCT02826863) showed that when administered in combination with other antiepileptic medications, Fintepla reduced the monthly frequency of convulsive seizures in children and young adults with Dravet compared to a placebo.
However, patients receiving a combination therapy containing Diacomit were excluded from this analysis due to data unavailability.
In the new study, investigators reported the findings from another Phase 3 trial (NCT02926898) focused on evaluating the safety and effectiveness of Fintepla when used as an add-on therapy in patients with Dravet receiving antiepileptic drug regimens containing Diacomit.
The double-blind, placebo-controlled trial enrolled children and adolescents, ages 2–18, with a confirmed diagnosis of Dravet, who were receiving a combination of antiepileptic medications that had to include Diacomit plus Onfi or Depacon, to control their seizures.
After a period of six weeks to establish baseline seizure frequency, participants were randomly assigned to receive either Fintepla at a daily starting dose of 0.2 mg/kg/day in two equal doses with a gradual titration period of three weeks (up to 17 mg/kg), or a placebo.
Following this initial titration period, patients continued treatment for an additional 12 weeks at their assigned doses.
The study’s main goal was to assess changes in the mean monthly frequency of convulsive seizures from the beginning of the study until the end of the treatment period, which included the titration and maintenance phase.
From the 115 patients who were screened for eligibility, 87 were randomized to both treatment groups (43 to Fintepla and 44 to the placebo), and 77 completed the study.
At baseline, participants were having on average 25 convulsive seizures per month. Findings revealed that Fintepla reduced the monthly frequency of seizures by 54% compared to placebo.
In addition, more than half of the patients treated with Fintepla (54%) had a clinically meaningful reduction — a reduction of at least 50% — in the monthly frequency of convulsive seizures, whereas 5% of those treated with a placebo achieved the same outcome.
Adding Fintepla to other antiepileptic medications also increased the longest period that patients remained seizure-free compared to the placebo (median of 22 versus 13 days).
Common adverse events were more frequent among patients receiving Fintepla compared to placebo, and included decreased appetite (44% versus 11%), fatigue (26% versus 5%), diarrhea (23% versus 7%), and fever (26% versus 9%). No cases of valvular heart disease or pulmonary arterial hypertension (PAH) were reported during the study.
“Fenfluramine demonstrated statistically significant and clinically meaningful efficacy in this Phase 3 trial in patients with [Dravet syndrome] currently receiving a stiripentol-containing [antiepileptic drug] regimen without the development of valvular heart disease or PAH,” the researchers wrote.
Therefore, they added, “fenfluramine may represent an important, effective new treatment option for patients with [Dravet syndrome] and seizures inadequately controlled on stiripentol-inclusive AED regimens.”