Xenazine (tetrabenazine) is a medicine that Lundbeck Pharmaceuticals developed to treat one of the symptoms of Huntington’s disease known as chorea. Chorea refers to the involuntary and uncontrollable dance-like movements that affect people with Huntington’s disease. It has been approved by the U.S. Food and Drug Administration (FDA) since 2008.

How Xenazine works

Xenazine works by reducing the amount of dopamine in the brain of patients with Huntington’s disease. Dopamine is a neurotransmitter or chemical messengers that transmit signals between nerve cells. It is thought that chorea is caused by an increase in the activity of dopamine.

Xenazine reduces the amount of dopamine in the brain in two ways. The first is by blocking the action of a group of proteins called vesicular monoamine transporters (VMATs), which are responsible for putting dopamine and other neurotransmitters inside vesicles in nerve cells, where they remain stored until the moment they are released. When dopamine is released from the vesicles in one neuron, it spreads to and affects other nearby neurons. Xenazine binds to VMATs and stops them from storing excessive dopamine inside vesicles, which would affect other neurons upon release.

The second mode of action of Xenazine is by blocking dopamine receptors on the neurons that receive the signal that is being transmitted. Xenazine prevents dopamine from binding to the receptors and passing the signal to other neurons.

Xenazine in clinical trials

Xenazine’s approval by the FDA was based on the results of the Phase 3 TETRA-HD trial (NCT00219804) conducted by the Huntington Study Group. This was a multicenter, placebo-controlled study in 84 patients with Huntington’s disease who could still walk. Of these, 54 received Xenazine up to a maximum dose of 100 mg/day, and 30 received placebo. Results showed that Xenazine decreased the severity of chorea by 5 units on the total maximal chorea score of the Unified Huntington Disease Rating Scale (UHDRS). UHDRS evaluates the clinical features and course of Huntington’s disease through four parameters: motor function, cognitive function, behavioral abnormalities, and functional capacity. The decrease in patients treated with placebo was of only 1.5 units. However, this study also found serious adverse effects associated with Xenazine treatment, including one suicide and increased suicidal thoughts and depression. This led authorities to consider Xenazine contraindicated for suicidal or depressed patients.

Patients who completed this study were invited to participate in an extension study for up to 80 weeks to assess the long-term safety and effectiveness of Xenazine. Participants received the best individual dose or a maximum of 200 mg/day of Xenazine. Of the 75 participants included in the extension study, 45 completed the 80 weeks treatment period with Xenazine. Results showed a sustained significant reduction of 4.6 units on the total maximal chorea score on the UHDRS. Adverse effects related to Xenazine included depression, delusions with associated previous suicidal behavior, somnolence, depression, parkinsonism, and akathisia, which is the inability to sit still due to uncontrollable movements.

To investigate if Xenazine reduces the problems of impulsivity that are common in patients with Huntington’s disease, a Phase 4 trial (NCT02509793) was initiated in July 2015. This study expects to include around 20 participants in the Methodist Neurological Institute, in Texas. Participants will be given up to a maximum of 75 mg/day of Xenazine over three to five weeks. The best dose will be determined based on adverse effects and subjective effectiveness.

 

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