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INGREZZA® (valbenazine) capsules for adults with tardive dyskinesia (TD) Home Logo

Mechanism of action and pharmacology of INGREZZA

INGREZZA is a uniquely selective VMAT2 inhibitor1,2

Tardive dyskinesia (TD)

Tardive dyskinesia

Huntington's disease (HD) Chorea

HD chorea

TD—an often persistent movement disorder induced by prolonged DRBA exposure4

TD Mechanism of Disease
  • 1 VMAT2 plays a key role in dopamine signaling
    • VMAT2 is a transporter protein found in presynaptic neurons of the CNS
    • VMAT2 packages monoamines (eg, dopamine) for release into the synaptic cleft
  • 2 TD is associated with prolonged exposure to DRBAs, including antipsychotics4
  • 3 Prolonged exposure to DRBAs can cause hypersensitivity in postsynaptic dopamine D2 receptors in areas that control motor function2

CNS, central nervous system; DRBA, dopamine receptor blocking agent; VMAT2, vesicular monoamine transporter 2.

MOA of INGREZZA® (valbenazine) capsules

TD Mechanism of Action
  • 1Selective inhibition of VMAT2 in presynaptic neurons, with no appreciable binding affinity for VMAT1, dopaminergic receptors, or serotonergic receptors2
  • 2INGREZZA is believed to provide reversible reductions of dopamine release into the synaptic cleft2
  • 3INGREZZA is believed to reduce the amount of dopamine available to hypersensitive postsynaptic dopamine D2 receptors1,2

CNS, central nervous system; DRBA, dopamine receptor blocking agent; VMAT2, vesicular monoamine transporter 2.

Neurodegeneration in the striatum leads to increased dopamine signaling that results in chorea5

HD Chorea Mechanism of Disease

DOPAMINE SIGNALING CYCLE:

  • 1 Dopamine is taken up into the cytosol of the presynaptic neuron through the DA transporter5
  • 2 Here, it is packaged into vesicles by VMAT2 or quickly broken down by enzymes5
  • 3 When the neuron is activated, vesicles full of dopamine fuse with the presynaptic membrane and dopamine is released into the synapse6

VMAT2, vesicular monoamine transporter 2.

Only INGREZZA® (valbenazine) capsules selectively inhibits VMAT2 to counteract increased dopamine signaling7,8

HD Chorea Mechanism of Action

HYPOTHETICAL DOPAMINE SIGNALING CYCLE WITH INGREZZA9

While the mechanism of action of INGREZZA is unclear, it is believed that:

  • 1 Dopamine is taken up into the cytosol of the presynaptic neuron through the DA transporter
  • 2 With INGREZZA blocking VMAT2, less dopamine is packaged into vesicles, and free dopamine is quickly broken down into the cytosol
  • 3 When the neuron is activated, vesicles with less dopamine fuse with the presynaptic membrane, reducing dopamine release into the synapse

VMAT2, vesicular monoamine transporter 2.

ONLY INGREZZA IS UNIQUELY SELECTIVE FOR VMAT2

When all you want is VMAT2 inhibition, all you need is INGREZZA. Only INGREZZA exclusively delivers one primary metabolite (+ α) for potent and selective inhibition of VMAT21-3,*

View full transcript
The Pharmacology of INGREZZA® (valbenazine) capsules, video
*

Based on in vitro VMAT2 binding affinity of dihydrotetrabenazine (HTBZ) metabolites and the primary active metabolite of INGREZZA, + α HTBZ. The clinical significance of in vitro data is unknown and is not meant to imply clinical outcomes.

Only INGREZZA: 100% on-target activity at VMAT23,7,8

Targeting VMAT2 with 100% of the highly selective + α metabolite3,7,8

VMAT2 isomer percentages
INGREZZA, Tetrabenazine, & Deutetrabenazine to isomer, chart

aData from single-center, phase 1, open-label crossover study following single dose of valbenazine 40 mg or deutetrabenazine 24 mg (n=18).7

bData determined in serum sample following tetrabenazine 25 mg (n=1).8

The clinical implications of in vitro data are unknown. These data do not imply superiority in efficacy or safety of any compound.

cAUSTEDO® and AUSTEDO XR® are trademarks of Teva Pharmaceutical Industries Ltd.

The primary metabolite of INGREZZA—+ α—has high affinity for VMAT2 and no appreciable
binding for off-target receptors3,7,8,10

Binding affinity, chart
Binding affinity, chart

The clinical implications of in vitro data are unknown. These data do not imply superiority in efficacy or safety of any compound.

dIn vitro data from 2 separate studies. All assays were performed in 1 to 3 independent experiments and in duplicate or triplicate.3,7

eData from single-center, phase 1, open-label crossover study following single dose of valbenazine 40 mg or deutetrabenazine 24 mg (n=18).7

fAUSTEDO® and AUSTEDO XR® are trademarks of Teva Pharmaceutical Industries Ltd.

THERAPEUTIC DOSE
FROM DAY 1

The only VMAT2 inhibitor that offers an effective starting dosage you can adjust based on response and tolerability1

EXPLORE DOSING

TREAT FIRST LINE WITH
VMAT2 INHIBITORS

VMAT2 inhibitors, like INGREZZA, are recommended as first-line treatment for TD11-13

VISIT TD GUIDELINES

REFERENCES:

  1. INGREZZA [package insert]. San Diego, CA: Neurocrine Biosciences, Inc.
  2. Harriott ND, Williams JP, Smith EB, Bozigian HP, Grigoriadis DE. VMAT2 inhibitors and the path to INGREZZA (valbenazine). Prog Med Chem. 2018;57(1):87-111.
  3. Grigoriadis DE, Smith E, Hoare SRJ, Madan A, Bozigian H. Pharmacologic characterization of valbenazine (NBI-98854) and its metabolites. J Pharmacol Exp Ther. 2017;361(3):454-461.
  4. Hauser RA, Factor SA, Marder SR, et al. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia. Am J Psychiatry. 2017;174(5):476-484.
  5. Coppen EM, Roos RA. Current pharmacological approaches to reduce chorea in Huntington’s disease. Drugs. 2017;77(1):29-46.
  6. Vesicular monoamine transporter 2 (VMAT2) inhibitors. In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Accessed March 10, 2023. https://www.ncbi.nlm.nih.gov/books/NBK548187/?report=reader.
  7. Brar S, Vijan A, Scott FL, et al. Pharmacokinetic and pharmacologic characterization of the dihydrotetrabenazine isomers of deutetrabenazine and valbenazine. Clin Pharmacol Drug Dev. 2023;12(4):447-456.
  8. Skor H, Smith EB, Loewen G, O’Brien CF, Grigoriadis DE, Bozigian H. Differences in dihydrotetrabenazine isomer concentrations following administration of tetrabenazine and valbenazine. Drugs R D. 2017;17(3):449-459.
  9. Stahl SM. Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other? CNS Spectr. 2018;23(4):239-247.
  10. Data on file. Neurocrine Biosciences, Inc.
  11. Keepers GA, Fochtmann LJ, Anzia JM, et al. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. American Psychiatric Association Publishing, 2020.
  12. Bhidayasiri R, Jitkritsadakul O, Friedman JH, Fahn S. Updating the recommendations for treatment of tardive syndromes: a systematic review of new evidence and practical treatment algorithm. J Neurol Sci. 2018;389:67-75.
  13. Caroff SN, Citrome L, Meyer J, et al. A modified Delphi consensus study of the screening, diagnosis, and treatment of tardive dyskinesia. J Clin Psychiatry. 2020;81(2):19cs12983.
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Important Safety Information

Depression and Suicidality in Patients with Huntington’s Disease: VMAT2 inhibitors, including INGREZZA, can increase the risk of depression and suicidal thoughts and

Important Information

INDICATION & USAGE

INGREZZA® (valbenazine) capsules and INGREZZA® SPRINKLE (valbenazine) capsules are indicated in adults for the treatment of tardive dyskinesia and for the treatment of chorea associated with Huntington’s disease.

IMPORTANT SAFETY INFORMATION

Depression and Suicidality in Patients with Huntington’s Disease: VMAT2 inhibitors, including INGREZZA and INGREZZA SPRINKLE, can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidal ideation, or unusual changes in behavior. Inform patients, their caregivers, and families of the risk of depression and suicidal ideation and behavior and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in patients with Huntington’s disease.