ZX008’s mechanism of action may avoid the side effects caused by other antiepileptic treatments, preclinical research suggests. The potential treatment is also being studied in a series of pivotal clinical trials.
A study based on this research, “Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors” was published in the journal Oncotarget.
Low-dose fenfluramine has been used as an add-on to other therapies by Dravet patients in Belgium for more than two decades under a long-term and open-label study, the company reports. This real world experience has demonstrated the compound can reduce the frequency of seizures.
Several Phase 3 clinical trials are underway in the U.S. and Europe testing different doses of ZX008, its safety and its absorption by the body. One such trial (NCT02826863), taking place across Europe and in Australia, is currently recruiting patients ages 2 to 18.
The therapy has been given an orphan drug designation in the U.S. by the FDA and in Europe by EMA, which offers developmental incentives to companies. Recently, the drug also received breakthrough therapy designation by FDA.
Researchers, however, do not know exactly how ZX008 works. Initially, the medication was thought to increase the levels of serotonin (a nerve cell messenger) in the brain, but recent studies suggest a different mechanism.
To better understand its active ingredient, fenfluramine hydrochloride, researchers conducted several molecular analysis using laboratory assays, as well as mouse models of Dravet syndrome.
Results revealed that ZX008 inhibits the activity of neuronal cell receptors called glutamate NMDAR (N-methyl-D-aspartate receptors); excessive activity by these receptors is known to be key in seizure initiation.
ZX008 is thought to prevent the entry of calcium ions into nerve cells, lowering their over-excitability and reducing seizure episodes. ZX008 also activates serotonin receptors, which is thought to contribute to the overall antiepileptic action.
This therapeutic compound might benefit Dravet patients because it works in ways that differ from existing treatments. Selective inhibitors of NMDAR have had disappointing results in clinical trials due to side effects.
According to the researchers, because ZX008 seems to work in a different manner, it may circumvent these side effects and help to improve patients’ quality of life.
“Our study provides molecular support for the use of mixed drugs such as fenfluramine [ZX008] to diminish the incidence and extent of seizures promoted by the overactivity of NMDARs,” they concluded.