Fintepla’s Potential Dual Mechanism of Action May Explain Effectiveness at Reducing Seizures in Dravet Syndrome

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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In addition to promoting the release of serotonin, a brain chemical typically associated with feelings of well-being and happiness, Fintepla (fenfluramine) also seems to control the activity of sigma-1 receptors found on the surface of nerve cells, a study has found.

This dual mechanism of action is likely responsible for the deep and sustained effectiveness of the medication at reducing the frequency of seizures in children and young adults with Dravet syndrome, researchers noted.

Results of the study,“Fenfluramine acts as a positive modulator of sigma-1 receptors,” were published in the journal Epilepsy & Behavior.

Fintepla, formerly known as ZX008, is a low-dose oral solution of fenfluramine hydrochloride currently being investigated as a potential add-on therapy to reduce the frequency of seizures in patients with Dravet. Fintepla is being developed by Zogenix.

Previous data from several Phase 3 clinical trials (NCT02682927NCT02826863, and NCT02926898) showed that when administered in combination with other anti-epileptic medications, Fintepla reduced the monthly frequency of convulsive seizures in children and young adults with Dravet compared to a placebo.

An open-label extension study (NCT02823145) also showed that children and young adults with Dravet treated with Fintepla for at least one year experienced significant improvements in cognition, behavior, and emotion control.

“Fenfluramine’s known pharmacological profile as a potent serotonin (5-HT) releaser (…) is likely insufficient to fully explain its clinical efficacy in seizure frequency reduction or its positive cognitive profile, [since other] 5-HT-acting agents, unlike fenfluramine, have inconclusive or inconsistent effects in reducing seizure frequency associated with Dravet syndrome,” the researchers wrote.

Previous studies have suggested that Fintepla also might control the activity of sigma receptors — receptors found on the surface of nerve cells that are associated with seizures.

To explore potential additional mechanisms of action that could explain the effects of Fintepla at reducing seizures and improving cognition, including its effects on sigma receptors, investigators at Zogenix and their collaborators performed a series of biochemical and cellular experiments.

They started by using radioligand binding assays — a type of test used to characterize receptors and determine their distribution within the body — to evaluate the affinity of Fintepla and norfenfluramine, its major metabolite, to bind to 47 brain receptors that previously had been associated with seizures, including sigma receptors.

Findings showed that Fintepla and norfenfluramine were able to bind to more than 30% of sodium channels, beta 2-adrenergic, muscarinic M1, serotonergic 5-HT1A, and sigma receptors.

To evaluate the effects Fintepla and norfenfluramine on the activity of these receptors, investigators then performed a series of cellular function assays.

Specific receptor functional assays revealed that sigma-1 receptors were the only type of receptors in which Fintepla had a positive effect (stimulation) and norfenfluramine had a slight negative effect (inhibition).

Researchers then turned to mouse models to investigate if the effects of Fintepla on sigma-1 receptors might reduce learning impairments in spatial and non-spatial memory tasks triggered by treatment with dizocilpine, a NMDA-receptor antagonist (which means that it blocks the receptor’s activity).

Of note, NMDA receptors are found at specific junctions between nerve cells (synapses) that respond to the chemical messenger glutamate and make nerve cells more likely to fire an electrical signal.

Findings revealed that when used alone, Fintepla had a dose-dependent anti-amnesic effect in animals displaying learning deficits triggered by treatment with dizocilpine.

Additionally, investigators found that low doses of Fintepla boosted the effects of PRE-084, a sigma-1 receptor agonist (which means it increases the receptor’s activity), and that all these effects were blocked by NE-100, a sigma-1 receptor antagonist.

Altogether, these findings confirmed that Fintepla had a positive modulatory effect on sigma-1 receptors.

“In conclusion, our research suggests that fenfluramine’s mechanism of action likely extends beyond previously characterized serotonergic modulation and may include a dual mechanism of action that involves [sigma-1] receptor modulation,” the researchers wrote.

“This novel mechanism of action may be responsible for the profound and long-lasting efficacy as well as executive function improvement demonstrated in [P]hase 3 clinical trials of fenfluramine in the treatment of seizures in children and young adults with Dravet syndrome,” they added.