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Huntington Disease (HD)

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Ingrezza

Ingrezza® (valbenazine) is selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is indicated for the treatment of chorea associated with Huntington disease (HD) in adult patients. It has a simple dosing schedule, with 1 capsule given once daily without any requirement for titration. It was developed by Neurocrine Biosciences and approved by the US Food and Drug Administration (FDA) on August 19, 2023.1

Ingrezza only treats the chorea associated with HD, not the underlying cause of involuntary movements, nor any other symptoms of HD, including cognitive or psychiatric dysfunction. The safety and efficacy of Ingrezza in children have not been established.2

HD is a rare, neurodegenerative disease defined by motor abnormalities (chorea, dystonia, hypokinesia), cognitive impairment, and neuropsychiatric symptoms such as depression, irritability, and apathy. The average age of onset is 35 to 45 years of age, but the disease can also manifest in children and older people. The condition progresses slowly over a period of 15 to 20 years.3 Most patients with HD have chorea, an abnormal involuntary movement disorder characterized by sudden, unpredictable, and irregular movements. Chorea can affect different body parts and impair speech, swallowing, and motor coordination.1 

Mechanism of Action

Although the exact mechanism of action of Ingrezza in treating chorea in patients with HD is unknown, it is believed to be mediated by the reversible inhibition of VMAT2, a transporter that controls the absorption of monoamine from the cytoplasm to the synaptic vesicle for storage and release.1 Ingrezza has a selective target action on VMAT2 to stop dopamine release, a brain chemical that helps control movement. It is thought to lessen excessive dopamine signaling, which could result in a decrease in involuntary movements.1

Ingrezza inhibits human VMAT2 with no discernible binding affinity for VMAT1, dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic, or muscarinic receptors.4 

Read more about HD pathophysiology

Administration

Ingrezza is available as 40-mg, 60-mg, and 80-mg capsules.4 The initial dose to treat chorea in patients with HD is 40 mg once daily. To reach the recommended dose of 80 mg once daily, the dose should be increased by 20 mg every 2 weeks. Ingrezza can be given both with and without food. Patients with moderate or severe hepatic impairment should take 40 mg once daily. Additionally, for people who are known to be poor metabolizers of CYP2D6, the recommended dosage is 40 mg once daily.4

Ingrezza is the only selective VMAT2 inhibitor that provides a potent initial dosage that can be modified by a patient’s health care provider according to response and tolerability without the need for a difficult titration process.1 

Get full prescribing information for Ingrezza at MPR

Adverse Effects

The most common adverse reactions reported in patients with HD (>5%) were drowsiness or lethargy, fatigue, hives, rash, insomnia, and restlessness. Less common adverse effects included diarrhea, nausea, and back pain.4    

Read more about HD treatment

Warnings and Precautions

Ingrezza may result in serious adverse reactions in patients with HD, including increased depression and suicidal thoughts or actions.2 Patients should be monitored for signs of new or increasing depression, suicidal ideation, and other unexpected changes in behavior. The use or discontinuation of Ingrezza should be carefully considered against these factors.4

Hypersensitivity and sudden swelling or angioedema have also been reported with the first dose or subsequent doses of Ingrezza. Angioedema can cause swelling of the face, lips, throat, and other parts of the skin. It can also cause breathing or swallowing difficulties, as well as hives. Throat swelling can be fatal.2

Ingrezza can also cause heart rhythm problems referred to as QT prolongation or increased QT interval. QT prolongation symptoms include a slow, fast, or irregular heartbeat, dyspnea, fainting, and dizziness. Ingrezza should be avoided in patients with congenital long QT syndrome or arrhythmias related to prolonged QT interval.2,4

Neuroleptic malignant syndrome (NMS) is a serious illness that can result in death. Ingrezza should be discontinued if this is noted.2,4

Abnormal movements or Parkinson-like movements have been noted following the administration of Ingrezza, including stiffness, shaking, and difficulty walking, moving, or maintaining balance. The dosage should be reduced or discontinued in such cases.2,4

As Ingrezza can cause sedation or somnolence, a patient’s ability to drive a vehicle or operate hazardous machinery may be impaired. These activities should be discontinued until the effects of Ingrezza are known.4

Read more about HD complications

Safety and Efficacy in Trials

The FDA approval of Ingrezza follows many comprehensive clinical studies, including the pivotal KINECT-HD phase 3 study and the ongoing KINECT-HD2 open-label extension trial, providing robust evidence of its efficacy.1 

KINECT-HD is a randomized, double-blind, phase 3 placebo-controlled investigation (NCT04102579)5 that examines the drug’s safety and tolerability in patients with HD and the effectiveness of Ingrezza as a once-daily treatment to lessen HD-related chorea. The trial enrolled 128 people between the ages of 18 and 75 years with motor-manifest HD and enough chorea symptoms to meet study protocol requirements. The primary efficacy endpoint for KINECT-HD was the Unified Huntington Disease Rating Scale (UHDRS) Total Maximal Chorea (TMC) score. The TMC score decreased by 3.2 units on average throughout treatment with Ingrezza, showing an improvement in chorea with high statistical significance. The clinical global impression of change (CGI-C) response status and patient global impression of change (PGI-C) response status were the secondary objectives and showed statistically significant improvements in TMC score. Adverse events that developed during treatment were generally consistent with Ingrezza’s known safety profile. Ingrezza-treated patients showed no signs of suicidal behavior or worsening suicidal ideation.1 

KINECT-HD2 is an ongoing open-label study (NCT04400331)6 assessing the long-term safety, tolerability, and maintenance of effects of Ingrezza. More than 150 patients between the ages of 18 and 75 years who have been diagnosed with motor-manifest HD and who have enough chorea symptoms to meet research protocol requirements will participate in the 156-week study. Antipsychotic medications are permitted while participating in the trial.1 

Read more about HD clinical trials

References

  1. Neurocrine Biosciences announces FDA approval of Ingrezza® (valbenazine) capsules for the treatment of chorea associated with Huntington’s disease. Neurocrine Biosciences, Inc; August 18, 2023.
  2. Ingrezza® (valbenazine) capsules. Ingrezza. Accessed September 5, 2023.
  3. Craufurd D, MacLeod R, Frontali M, et al; Working Group on Genetic Counselling and Testing of the European Huntington’s Disease Network (EHDN). Diagnostic genetic testing for Huntington’s disease. Pract Neurol. 2015;15(1):80-84. doi:10.1136/practneurol-2013-000790
  4. Ingrezza. Prescribing information. Neurocrine Biosciences, Inc; 2023. Accessed September 6, 2023.
  5. Efficacy, safety, and tolerability of valbenazine for the treatment of chorea associated with Huntington disease (KINECT-HD). ClinicalTrials.gov. September 25, 2019. Updated October 5, 2022. Accessed September 5, 2023.
  6. Open-label rollover study for continuing valbenazine administration for the treatment of chorea associated with Huntington disease. ClinicalTrials.gov. May 22, 2020. Updated November 2, 2022. Accessed September 5, 2023.

Reviewed by Kyle Habet, MD, on 9/6/2023.

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