The Mechanism of Action (MOA) of Valbenazine for the Treatment of Tardive Dyskinesia (TD)

Thank you for contacting Neurocrine Biosciences to request information regarding the mechanism of action (MOA) of valbenazine (VBZ), also known as NBI-98854, for the treatment of Tardive Dyskinesia (TD).

INGREZZA is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of adults with tardive dyskinesia.

The etiology and pathophysiology of TD have not been fully elucidated. One leading hypothesis implicates the post-synaptic dopamine D2 receptor upregulation that may result from exposure to dopamine receptor blocking agents (DRBAs), such as first- and second-generation antipsychotics and the gastric motility agent metoclopramide. This upregulation of D2 receptors is thought to result in post-synaptic dopamine hypersensitivity with the subsequent, aberrant neurotransmission manifesting as the abnormal, involuntary movements of TD.1

The MOA of VBZ in the treatment of TD is unknown, though its pharmacology has been well characterized. VBZ is a selective vesicular monoamine transporter 2 (VMAT2) inhibitor.2,3 VMAT2 is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synaptic cleft.2,3 It is believed that by inhibiting VMAT2 from packaging dopamine into synaptic vesicles for subsequent release, thereby reducing the dopamine available for binding to upregulated D2 receptors.2,3,4

This letter and the enclosed material are provided in response to your unsolicited medical information inquiry. Please feel free to contact Neurocrine Medical Information at (877) 641-3461 or medinfo@neurocrine.com if you would like to request additional information.

References

  1. Sayers AC, Burki HR, Ruch W, et al. Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias: effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia. 1975;41(2):97-104.
  2. Grigoriadis D, Smith E, Hoare SRJ, et al. Pharmacologic characterization of valbenazine (NBI-98854) and its metabolites. J of Pharmacology and Experimental Therapeutics. 2017; 361:454-461.
  3. Grigoriadis D, Smith E, Madan A, et al. Pharmacologic Characteristics of Valbenzaine and its Metabolites. Clinical Pharmacology in Drug Development. September 2016:43. Presented at the 2016 annual meeting of the United States Psychiatric and Mental Health Congress. October 20 – 23, 2016; San Antonio, Texas.
  4. Patel J, Mooslehner KA, Chan PM, et al. Presynaptic control of striatal dopamine neurotransmission in adult vesicular monoamine transporter 2 (VMAT2) mutant mice. J Neurochem. 2003;85(4):898-910.

MED-MI-TD-US-0019

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