|Year : 2017 | Volume
| Issue : 2 | Page : 84-87
Valbenazine: Drug review
Mahanjit Konwar, Nithya J Gogtay, Urmila M Thatte
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
|Date of Web Publication||8-Dec-2017|
Department of Clinical Pharmacology, Multispeciality Building, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400 012, Maharashtra
Source of Support: None, Conflict of Interest: None
Valbenazine is the first drug approved by the US Food and Drug Administration for the treatment of adults with tardive dyskinesia (TD) on April 11, 2017. It acts as a reversible inhibitor of vesicular monoamine transporter 2. It is available orally with a starting dose of 40 mg once daily which can be increased after 1 week to the recommended dose of 80 mg. Clinical trials showed positive outcomes in Abnormal Involuntary Movement Scale and Clinical Global Impression - Global Improvement of TD score with respect to placebo. Valbenazine has an acceptable safety and tolerability profile, the most common side effect observed is somnolence. However, long-term study is lacking, and more data are required to establish its full benefits and concomitant risks which can be missed in the recent trials.
Keywords: Schizophrenia, tardive dyskinesia, valbenazine
|How to cite this article:|
Konwar M, Gogtay NJ, Thatte UM. Valbenazine: Drug review. Ann Indian Psychiatry 2017;1:84-7
| Introduction|| |
Tardive dyskinesia (TD) is an iatrogenic disorder, insidious in nature but potentially serious and irreversible with a negative impact on quality of life. It has been more than 50 years since the term “TD” was first introduced, yet no Food and Drug Administration (FDA) approved drug was available for its treatment until recently.,, Valbenazine is a novel highly selective (vesicular monoamine transporter 2 [VMAT2]) inhibitor, first of its class to get approved by FDA for treatment of TD in adult population. This article provides a review of Valbenazine focusing on pharmacology, therapeutic efficacy, safety, and tolerability in treatment of TD.
| Pathophysiology of Tardive Dyskinesia|| |
No accepted mechanism is available for TD universally but believes it to be associated with multifactorial pathways. There are various hypotheses that had been proposed out of which three are leading; dopamine receptor hypersensitivity due to prolonged blockage of postsynaptic dopamine receptors, oxidative stress, and gamma-aminobutyric acid (GABA) depletion. Dopamine hypothesis states that with chronic dopamine receptor blockage, there is upregulation of dopamine receptors which leads to exaggerated response with dopamine in nigrostriatal pathway precipitating TD. With regard to the oxidative hypothesis, dopamine blockage leads to increased dopamine synthesis and metabolism and thereby increases the production of free radicals. Monoamine oxidase (MAO) which metabolizes dopamine itself causes lipid peroxidation that result in alteration of endogenous defense mechanism in the metabolically active dopamine-rich striatum leading to neurotoxicity and cell death. Involvement of GABA pathway in TD may be related to the damage of GABAergic neurons in the striatum by drugs which ultimately manifest symptoms of TD., Other mechanisms include altered synaptic plasticity, cholinergic deficiency, defective neuroadaptive signaling, and neurotoxicity. Various drugs that can precipitate TD on long-term use are shown in [Table 1].
| Rationale for Targeting Vesicular Monoamine Transporter|| |
VMAT (VMAT1 and VMAT2) belong to the solute carrier family, VMAT1 is found in the peripheral neuroendocrine cells whereas VMAT2 located in the monoaminergic neurons of peripheral as well as the central nervous system. They are responsible for uptake of cytosolic monoamines in the synaptic vesicles and take an important part in the regulation of neurotransmission. In pharmacology, there are distinct classes of inhibitors that inhibit VMAT. Reserpine blocks both the receptors VMAT1 and VMAT2 in a pseudoreversible manner whereas tetrabenazine (TBZ) and its metabolites reversibly inhibit VMAT2 sparing VMAT1. This leads to inhibition of cytosolic uptake of monoamines into synaptic vesicles. Approval of TBZ in the treatment of Huntington's Chorea have helped us to improve our understandings of receptors involved in TD. Valbenazine having similar metabolite as that of TBZ was also extensively studied in its role of inhibiting VMAT receptors.,
| Tardive Dyskinesia Management in the Recent Past|| |
Early screening and intervention for TD in schizophrenic patients with antidopaminergic agents is always a better choice in reducing the severity of TD. A slow tapering of the suspected antipsychotic drug is advised to prevent withdrawal reactions, along with switching to a different agent having less risk for TD is recommended. Several drugs, vitamins, and dietary supplements had been used to ameliorate the symptoms of TD of which none of them are FDA approved except branched chained amino acids for men.
VMAT2 inhibitors such as TBZ was originally approved by FDA for the treatment of chorea in Huntington disease but used off-label commonly for TD and other hyperkinetic movement disorder. However, considering the variable pharmacokinetics, shorter half-life and side effects such as somnolence, depression, akathisia, and Parkinsonism More Details the drug failed to establish its supremacy. Deutetrabenazine another VMAT approved by FDA for Huntington's Chorea had a longer half-life and shown lesser side effects as compared to TBZ, it has shown good efficacy in its phase 2 and phase 3 clinical trials in TD and is a potential drug candidate for the future. Valbenazine is a (+)-α-isomer of TBZ had been recently approved by FDA for TD.,
| Pharmacokinetics and Pharmacodynamic|| |
TD is suspected with antipsychotic agents due to their antagonistic action on dopamine receptors which led to supersensitivity of these receptors to dopamine. VMAT2 protein helps in transporting dopamine from the cytosol to the synaptic vesicles and thereby facilitating the synaptic storage and release. Valbenazine is converted to its active metabolite (+)-α-dihydrotetrabenazine ([+]-α-HTBZ) and blocks this receptor in a reversible way and hinders in these synaptic transmissions. Valbenazine and its active metabolite showed no appreciable affinity to other receptors such as adrenergic, muscarinic, serotonergic, dopaminergic, or histaminergic.,
Following oral administration, Valbenazine reaches its maximum plasma concentration by 0.5-1 h and steady-state plasma concentration within 1 week with an oral bioavailability of 49%. It undergoes extensive metabolism, it is hydrolyzed to its active metabolite [+]-α-HTBZ and by oxidative metabolism by CYP3A4/5. [+]-α-HTBZ got further metabolize in part by CYP2D6. The half-life of Valbenazine and its active metabolite [+]-α-HTBZ range from 15 to 22 h. It has food-drug interaction, high-fat meal decreases Cmax and AUC of Valbenazine by 47% and 13%, respectively. It is excreted in the urine and feces.,
| Clinical Efficacy|| |
Four phase 2 trials done with Valbenazine for the treatment of TD (NCT01267188, NCT01393600, NCT01733121, and NCT01688037), out of which only one was published (NCT01733121) in peer-reviewed literature and another (NCT01688037), where the study was further extended by 6 weeks, had been published as an abstract.
In the phase 2 trial by O'Brien et al. (NCT01733121), 102 individuals within aged 18-85 years were randomized to placebo or Valbenazine for 6 weeks. Valbenazine 25 mg/d was the starting dose which is increased by 25 mg to a maximum 75 mg based on efficacy and tolerability. Abnormal Involuntary Movement Scale (AIMS) score from the baseline at 6th week and Clinical Global Impression - Global Improvement (CGI)-TD score assessed by blinded site investigator was taken as the primary and secondary endpoint, respectively. AIMS score with patients in Valbenazine as compared to placebo, the reduction seen was significant (−2.6 vs. −0.2). Similarly, Valbenazine was superior on CGI-TD and PGIC scales. Regarding exploratory outcomes, Valbenazine showed improvement in TD, regardless of type of antipsychotic drugs used concomitantly. This study was extended for another 6 weeks, 80 individuals participated, where all individuals received Valbenazine 50 mg/d. At the end of 12 weeks, the AIMS score reduced to −5.8 from its baseline mean of 12.8 along with 54% of individuals responded to ≥50% AIMS reduction from baseline. The CGI-TD was also found to have improved by 61%.
In another phase 2 trial, 107 participants were randomized 1:1 with placebo and Valbenazine (50 and 100 mg/d for 2 weeks followed by 50 mg/d for another 4 weeks. The primary endpoint AIMS scores by on-site rater and LS mean stands at −2.5 and −3.3 for placebo and Valbenazine, respectively, which were not significant. However, on post–hoc analysis on AIMS score by blinded central video rater, it was statistically significant (P = 0.3) with change scores of −1.5 and −3.3 for placebo and Valbenazine, respectively.
The results of other two phase 2 trials were published in the media. In one of the trials (NCT01393600), a post hoc analysis needed to be done as the result of one of this site included in the study showed the incorrect and inconsistent application of efficacy assessment protocol and data were removed. Drug dose with 12.5 mg and 50 mg were studied in compared to placebo. Results showed Valbenazine 50 g/d to have a significant (P = 0.002) reduction in LS mean AIMS dyskinesia score as compared to placebo at week 2, however, Valbenazine 12.5 mg did not show any significance to placebo (P = 0.68). The AIMS score stands at 6.1, 9.9, and 10.3 for Valbenazine 50, 12.5 mg, and placebo, respectively (baseline mean was 14.9).,
The other phase 2a study (NCT01267188) was a dose titration study and assessed the safety and efficacy of three once-daily doses (12.5, 25, and 50 mg). Six patients were enrolled, the starting dose was 12.5 mg and it was increased after 4 days' interval to 25 and 50 mg depend on the patient's tolerability. After 12 days, the AIMS dyskinesia score was found to be-8.4 (change from baseline in mean) and it corresponds to a reduction of 41.3%. However, it was noted that after a washout period of 7 days, the individual's dyskinesia AIMS scores returned close to the baseline.,
The first phase 3 clinical trial (KINECT-3) was 6 week, randomized double-blind phase 3 trial. It includes patient with schizophrenia, schizoaffective disorder, or mood disorder with DSM diagnosis of TD induced by dopamine receptor blocker ≥ 3 months before screening along with a qualitative assessment of screening videos by external reviewers. It includes 234 individuals randomized to once daily placebo, Valbenazine 40 mg and Valbenazine 80 mg. Considering the primary endpoint of change in baseline to week 6 in the AIMS dyskinesia score for the Valbenazine 80 mg and placebo, a significant change of 3.2 and 0.1 were found for Valbenazine 80 mg and placebo group, respectively, which corresponds to an effect size of 0.90. Per-protocol analysis also showed a significance difference (P < 0.001) in the AIMS dyskinesia score reduction with Valbenazine 80 mg (23.7) and placebo (20.1). Similarly, Valbenazine 40 mg proved to be superior as compared to placebo in dyskinesia score improvement in both intent to treat population (−1.9 compared to − 0.1; P = 0.002) as well as in per-protocol analysis (−2.3 compared to − 0.1; P < 0.001). Number need to treat (NNT) for robust AIMS response were calculated and found to be 4 and 7 whereas number need to harm for treatment-emergent adverse reactions stand at 13 and −32 for Valbenazine 80 mg and Valbenazine 40 mg, respectively.
Kane J et al. further extended this trial, Valbenazine extension (VE) for 42 weeks followed by 4 weeks drug-free period to established additional efficacy data. Participants who received Valbenazine 40 and 80 mg continued the same dose whereas the placebo group was randomized to receive either Valbenazine 40 or 80 mg/day. A total of 198 individuals participated in the study, out of which 124 completed the VE for 42 weeks and 121 remained till drug-free follow-up period. The effect of Valbenazine at both of its dose continued to maintain its efficacy however, there was an increase in AIMS mean score from week 48 (40 mg 6.8; 80 mg 6.2) to week 52 (40 mg 8.4; 80 mg 9.8) which indicates TD symptoms returning to the baseline levels on discontinuation. In a similar manner, considering CGI-TD the responder's rate decreased from 48 weeks (40 mg 58.1%; 80 mg 73.7%) to 52 weeks (40 mg 33.3%; 80 mg 29.7%). 9).
The ongoing third phase 3b trial (NCT02736955) includes 75 patients who had completed NBI-98854-1304 (KINECT 3) or NBI-98854-1402 (KINECT 4) phase 3 study. It is extended up to 72 weeks, and its primary outcome measure includes safety and tolerability. Other outcomes that were studied were CGI-TD severity, patient satisfaction questionnaire and social functioning scale.
| Dosing, Safety, and Drug Interaction|| |
It is an oral drug with a starting dose of 40 mg/day with or without food which needs to be increased to the recommended dose of 80 mg/day after 1 week. In case of moderate and severe hepatic impairment, the recommended dose is 40 mg. Dose adjustment is not necessary for patients with mild-to-moderate renal impairment but not recommended in patients with severe renal impairment. Dose adjustment is not required for elderly patients. Similar results were seen regarding safety and effectiveness in age ≥65 years as compared to younger patients. Animal data showed increased incidence of stillbirth and postnatal pup mortality when administered in pregnant rats. It also showed Valbenazine and its metabolites excreted in breast milk. Valbenazine has not been studied effectively in pregnancy or in breastfeeding women and based on animal data it is not recommended.
The dose of Valbenazine is to be reduced when it is coadministered with CYP3A4 or CYP2D6 inhibitor; however, it is not recommended to use with drugs which acts as strong CYP3A4 inducers. Concomitant use of Valbenazine and MAO inhibitor is also avoided as there is a chance of increase monoamine neurotransmitters concentration in the synaptic cleft which can precipitate adverse reactions such as serotonin syndrome.
It can prolong QT interval, so caution is to be taken in patients with risk factors for QT interval prolongation or with drugs that prolong it. Long-term safety and tolerability of Valbenazine were studied in three trials KINECT, KINECT 3, and KINECT 4 and showed no notable hepatic and renal effects. Somnolence is the most common adverse reactions (5–11%) found in the clinical studies along with others such as anticholinergic effects, fall, gait disturbance, dizziness, headache, akathisia, nausea, vomiting, and arthralgia.,
TRIALS in Tourette syndrome
A phase 2 trial on the efficacy and safety of Valbenazine was carried on adults with Tourette syndrome had been completed. The prespecified primary outcome, i.e. Yale Global Tic Severity scale change from baseline was not met (P = 0.18) at 8-week study period. However, it showed significant improvement in the symptoms of Tourette syndrome was evident (P = 0.015, assessed by CGI scale).
Other two phase 2 studies were ongoing. One (NCT02679079) carried to establish the safety and efficacy in children and adolescents with Tourette syndrome, and the other (NCT02879578) carried to show safety and tolerability with Valbenazine in children, adolescent, and adult in Tourette syndrome.,
| Conclusion|| |
TD is a serious movement disorder which affects the quality of life of the patient and needs to be treated. Valbenazine is a novel VMAT2 inhibitor that has been recently approved for treatment of TD by the FDA. Clinical studies have shown positive benefits with Valbenazine in patients suffering from TD along with an acceptable safety and tolerability profile. However, it is to be noted that Valbenazine provides symptomatic relief but no permanent cure for TD. Hence, more studies need to be done to understand the pathophysiology of TD and to find a definitive treatment. Valbenazine had filled the long-standing gap in the management of TD, yet it needs to go a long way to establish its long-term benefits in the near future.
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Conflicts of interest
There are no conflicts of interest.
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