Valbenazine

• CAT Number: I000166
• CAS Number: 1025504-45-3
• Molecular Formula: C24H38N2O4
• Molecular Weight: 418.57
• Purity: ≥95%
• Target: VMAT2
• Solubility: 10 mM in DMSO
• Storage: 3 years -20C powder
• InChI: InChI=1S/C24H38N2O4/c1-14(2)9-17-13-26-8-7-16-10-21(28-5)22(29-6)11-18(16)19(26)12-20(17)30-24(27)23(25)15(3)4/h10-11,14-15,17,19-20,23H,7-9,12-13,25H2,1-6H3/t17-,19-,20-,23+/m1/s1
• InChIKey: GEJDGVNQKABXKG-CFKGEZKQSA-N
• SMILES: N[C@@H](C(C)C)C(O[C@H]1[C@H](CC(C)C)CN2CCC3=CC(OC)=C(OC)C=C3[C@@]2([H])C1)=O

Valbenazine (CAT: I000166) is a prodrug of the (+)-α isomer of tetrabenazine, a selective vesicular monoamine transporter 2 (VMAT2) inhibitor. It is primarily used for the treatment of tardive dyskinesia, a movement disorder characterized by involuntary muscle movements, often caused by long-term use of certain psychiatric medications. Valbenazine works by reducing the release of dopamine in the brain, helping to control abnormal movements. As a prodrug, valbenazine is converted into the active form (tetrabenazine) in the body. By inhibiting VMAT2 function, it modulates dopamine signaling and helps alleviate the symptoms of tardive dyskinesia.

Reference

1. Clin Schizophr Relat Psychoses. Summer 2017;11(2):113-119. doi:
10.3371/CSRP.OFGR.071717.

Valbenazine for Tardive Dyskinesia.

Freudenreich O, Remington G.

Tardive dyskinesia (TD) remains a clinical concern for any patient who receives
an antipsychotic. While the overall risk of developing TD is lower with newer
antipsychotics compared to older agents, a significant number of patients who
require long-term treatment will develop TD. Recently, valbenazine (brand name
Ingrezza) became the first drug to be approved by the FDA specifically for the
treatment of TD. In this New Drug Review, we summarize the basic pharmacology and
clinical trial results for valbenazine. Valbenazine is a modified metabolite of
the vesicular monoamine transporter 2 (VMAT-2) inhibitor tetrabenazine, which is
approved for the treatment of the hyperkinetic movement disorder, Huntington/’s
disease. In short-term clinical trials, valbenazine at a dose of 80 mg/day
improved TD, with an effect size that is clinically significant (d=0.90). The
effect size for the 40-mg/day dose was lower (d=0.52). Compared to tetrabenazine,
valbenazine has better clinical characteristics (i.e., once-a-day dosing, better
short-term side effect profile). However, only long-term experience in routine
clinical populations can delineate valbenazine/’s full benefits, optimal dosing,
and risks not identified during short-term registration trials.

2. Int J Clin Pract. 2017 Jul;71(7). doi: 10.1111/ijcp.12964. Epub 2017 May 12.

Valbenazine for tardive dyskinesia: A systematic review of the efficacy and
safety profile for this newly approved novel medication-What is the number needed
to treat, number needed to harm and likelihood to be helped or harmed?

Citrome L(1).

Author information:
(1)New York Medical College, Valhalla, NY, USA.

OBJECTIVE: The objective of this systematic review was to describe the efficacy,
tolerability, and safety of valbenazine for the treatment of tardive dyskinesia
(TD).
DATA SOURCES: The pivotal registration trials were accessed by querying
http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the
search terms /’valbenazine/’ OR /’NBI-98854/’, and by also querying the EMBASE
(Elsevier) commercial database for clinical poster abstracts, and by asking the
manufacturer for copies of posters presented at congresses. Product labeling
provided additional information.
STUDY SELECTION: All available clinical reports of studies were identified.
DATA EXTRACTION: Descriptions of the principal results and calculation of number
needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous
outcomes were extracted from the available study reports and other sources of
information.
DATA SYNTHESIS: Valbenazine, a reversible inhibitor of Vesicular Monoamine
Transporter Type 2 (VMAT2), received approval for the treatment of TD in adults
based on a clinical trial development programme that included three 6-week
parallel group, randomised, placebo-controlled studies, including one Phase III
trial described in product labeling. The recommended dose for valbenazine is
80 mg/d. The percentage of responders in the Phase III acute study, as defined by
≥50% reduction from baseline in the Abnormal Involuntary Movement Scale
dyskinesia score was 40.0% for valbenazine 80 mg/d vs 8.7% for placebo, yielding
a NNT of 4 (95% CI 3-6). As pooled from available data, discontinuation rates
because of an adverse event were 2.9% for valbenazine-treated patients vs 1.6%
for placebo-treated patients, resulting in a NNH of 76 (ns). The only adverse
event that met the threshold of incidence ≥5% for valbenazine and a rate of ≥2
times than that observed with placebo was somnolence (somnolence, fatigue,
sedation), with rates of 10.9% for valbenazine (all doses) vs 4.2% for placebo,
resulting in a NNH of 15 (95% CI 9-52). An additional warning and precaution is
that valbenazine can prolong the ECG QT interval, however, the valbenazine
product label does not contain any bolded boxed warnings or contraindications.
CONCLUSIONS: Valbenazine is presently the only US Food and Drug
Administration-approved agent specifically indicated for the treatment of TD.
Valbenazine is about 15 times more likely to result in a response than in a
discontinuation because of an adverse event. Head-to-head comparisons with other
VMAT2 inhibitors among patients with TD in the /’real world/’ are needed.