Out of the Pipeline Valbenazine for tardive dyskinesia Jonathan M. Meyer, MD Valbenazine espite improvements in the toler- Table 1 reduces tardive ability of antipsychotic medica- Fast facts about valbenazine tions, the development of tardive dyskinesia severity D Brand name: Ingrezza dyskinesia (TD) still is a significant area of with once-daily Class: VMAT2 antagonist concern; however, clinicians have had few dosing and Indication: Tardive dyskinesia treatment options. Valbenazine, a vesicu- Approval date: April 11, 2017 no CYP2D6 lar monoamine transport type 2 (VMAT2) Availability date: May 1, 2017 monitoring inhibitor, is the only FDA-approved medi- Manufacturer: Neurocrine Biosciences cation for TD (Table 1).1 By modulating Dosing forms: 40-mg and 80-mg capsules dopamine transport into presynaptic Recommended dosage: 40 mg in the vesicles, synaptic dopamine release is morning, increasing to 80 mg/d after 1 week decreased, thereby reducing the post- synaptic stimulation of D2 receptors and the severity of dyskinetic movements. In the pivotal 6-week clinical trial, val- does not have tetrabenazine’s kinetic limi- benazine significantly reduced TD sever- tations, adverse effect profile, or CYP2D6 ity as measured by Abnormal Involuntary monitoring requirements represents an Movement Scale (AIMS) ratings.2 Study enormous advance in the treatment of TD. completion rates were high (87.6%), with only 2 dropouts because of adverse Clinical implications events in each of the placebo (n = 78) and Tardive dyskinesia remains a signifi- 40-mg (n = 76) arms, and 3 in the 80-mg cant public health concern because of the group (n = 80). increasing use of antipsychotics for disor- Before the development of valbenazine, ders beyond the core indication for schizo- tetrabenazine was the only effective option phrenia. Although exposure to dopamine for treating TD. Despite tetrabenazine’s D2 antagonism could result in postsynap- known efficacy for TD, it was not avail- tic receptor upregulation and supersen- able in the United States until 2008 with sitivity, this process best explains what the sole indication for movements related underlies withdrawal dyskinesia.3 The to Huntington’s disease. U.S. patients often persistence of TD symptoms in 66% to Discuss this article at were subjected to a litany of ineffective www.facebook.com/ medications for TD, often at great expense. CurrentPsychiatry Dr. Meyer is a Psychopharmacology Consultant, California Department Moreover, tetrabenazine involved multiple of State Hospitals, Sacramento, California, Assistant Clinical Professor daily dosing, required cytochrome P450 of Psychiatry, University of California, San Diego, San Diego, California, and is Deputy Editor of CURRENT PSYCHIATRY. (CYP) 2D6 genotyping for doses >50 mg/d, Disclosure had significant tolerability issues, and a Dr. Meyer is a consultant to Acadia Pharmaceuticals, Neurocrine monthly cost of $8,000 to $10,000. The avail- Biosciences, Inc., Teva Pharmaceutical Industries; and is a speaker for Current Psychiatry Acadia Pharmaceuticals, Alkermes, Allergan, Merck, Osutka America, 40 May 2017 ability of an agent that is effective for TD and Inc., and Sunovion Pharmaceuticals. Out of the Pipeline 80% of patients after discontinuing offend- tor, while reserpine is an irreversible and ing agents has led to hypotheses that the nonselective antagonist of both VMAT underlying pathophysiology of TD might isoforms. Investigation of tetrabenazine’s best be conceptualized as a problem with metabolism revealed that it is rapidly neuroplasticity. As with many disorders, and extensively converted into 2 isomers, environmental contributions (eg, oxi- α-dihydrotetrabenazine (DH-TBZ) and dative stress) and genetic predisposition β-DH-TBZ. The isomeric forms of DH-TBZ might play a role beyond that related to have multiple chiral centers, and therefore exposure to D2 antagonism.3 numerous forms of which only 2 are signif- There have been trials of numerous icantly active at VMAT2.3 The α–DH-TBZ agents, but no medication has been FDA- isomer is metabolized via CYP2D6 and 3A4 approved for treating TD, and limited data into inactive metabolites, while β-DH-TBZ support the efficacy of a few existing med- is metabolized solely via 2D6.3 Because of Clinical Point ications (clonazepam, amantadine, and the short half-life of DH-TBZ when gener- Valbenazine ginkgo biloba extract [EGb-761]),4 albeit ated from oral tetrabenazine, the existence with small effect sizes. A medical food, of 2D6 polymorphisms, and the predomi- significantly consisting of branched-chain amino acids, nant activity deriving from only 2 isomers, reduced TD severity received FDA approval for the dietary a molecule was synthesized (valbenazine), as measured by management of TD in males, but is no that when metabolized would slowly AIMS, with a mean longer commercially available except from be converted into the most active isomer reduction of 30% compounding pharmacies.5 of α–DH-TBZ designated as NBI-98782 Tetrabenazine, a molecule developed (Table 2, page 42). This slower conversion in the mid-1950s to improve on the toler- to NBI-98782 from valbenazine (compared ability of reserpine, was associated with with its formation from oral tetrabenazine) significant adverse effects such as ortho- yielded improved kinetics and permit- stasis.6 Like reserpine, tetrabenazine subse- ted once-daily dosing; moreover, because quently was found to be effective for TD7 the metabolism of NBI-98782 is not solely but without the peripheral adverse effects dependent on CYP2D6, the need for geno- of reserpine. However, the kinetics of tetra- typing was removed. Neither of the 2 benazine necessitated multiple daily doses, metabolites from valbenazine NBI-98782 and required CYP2D6 genotyping for doses and NB-136110 have significant affinity for >50 mg/d.8 targets other than VMAT2.11 Receptor blocking. The mechanism that dif- Use in tardive dyskinesia. Recommended ferentiated reserpine’s and tetrabenazine’s starting dosage is 40 mg once daily with clinical properties became clearer in the 1980s or without food, increased to 80 mg after 1 when researchers discovered that transport- week, based on the design and results from ers were necessary to package neurotransmit- the phase-III clinical trial.12 The FDA granted ters into the synaptic vesicles of presynaptic breakthrough therapy designation for this neurons.9 The vesicular monoamine trans- compound, and only 1 phase-III trial was porter (VMAT) exists in 2 isoforms (VMAT1 performed. Valbenazine produced signifi- and VMAT2) that vary in distribution, with cant improvement on the AIMS, with a mean VMAT1 expressed mainly in the periph- 30% reduction in AIMS scores at the Week 6 eral nervous system and VMAT2 expressed endpoint from baseline of 10.4 ± 3.6.2 The mainly in monoaminergic cells of the central effect size was large (Cohen’s d = 0.90) for the nervous system.10 80-mg dosage. Continuation of 40 mg/d may Tetrabenazine’s improved tolerability be considered for some patients based on profile was related to the fact that it is a tolerability, including those who are known Current Psychiatry specific and reversible VMAT2 inhibi- CYP2D6 poor metabolizers, and those tak- Vol. 16, No. 5 41 Out of the Pipeline Table 2 Binding profile of tetrabenazine’s major metabolites (Ki nM - cloned human receptors) (R,S,S)-(-)-β-DHTBZ (S,S,S)-(-)-α-DHTBZ (S,R,R)-(+)-β-DHTBZ (R,R,R)-(+)-α-DHTBZ Receptor NBI-98772 NBI-98771 NBI-98795 NBI-98782 VMAT2 690 250 10 4.2 D2 53 180 >1,000 >1,000 D3 400 230 >1,000 >1,000 D4 79 >1,000 >1,000 >1,000 D5 590 >1,000 >1,000 >1,000 5-HT1A >1,000 750 >1,000 >1,000 5-HT2B 460 600 >1,000 >1,000 Clinical Point 5-HT7 6 71 >1,000 >1,000 Patients taking a-1A 980 >1,000 970 >1,000 strong 3A4 inhibitors a-2A 220 >1,000 >1,000 >1,000 Source: Reference 10 should not exceed 40 mg/d ing strong CYP2D6 inhibitors. Patients respectively, remained on antipsychotics.1,2 taking strong 3A4 inhibitors should not There were no adverse effects with an inci- exceed 40 mg/d. The maximum daily dence ≥5% and at least twice the rate of pla- dose is 40 mg for those who have moder- cebo in the phase-III trial.2 ate or severe hepatic impairment (Child- When data from all placebo-controlled Pugh score, 7 to 15). Dosage adjustment studies were pooled, only 1 adverse effect is not required for mild to moderate renal occurred with an incidence ≥5% and twice impairment (creatinine clearance, 30 to that of placebo, somnolence with a rate of 90 mL/min). 10.9% for valbenazine vs 4.2% for placebo. The incidence of akathisia in the pooled Pharmacologic profile, adverse analysis was 2.7% for valbenazine vs 0.5% reactions for placebo. Importantly, in neither study Valbenazine and its 2 metabolites lack was there a safety signal related to depres- affinity for receptors other than VMAT2, sion, suicidal ideation and behavior, or par- leading to an absence of orthostasis in kinsonism. There also were no clinically clinical trials.1,2 In the phase-II trial, 76% significant changes in measures of schizo- of participants receiving valbenazine (n = phrenia symptoms. 51) were titrated to the maximum dosage The mean QT prolongation for val- of 75 mg/d. Common adverse reactions benazine in healthy participants was (incidence ≥5% and at least twice the rate of 6.7 milliseconds, with the upper bound of placebo) were headache (9.8% vs 4.1% pla- the double-sided 90% confidence interval cebo), fatigue (9.8% vs 4.1% placebo), and reaching 8.4 milliseconds. For those taking somnolence (5.9% vs 2% placebo).1 In the strong 2D6 or 3A4 inhibitors, or known phase-III trial, participants were random- 2D6 poor metabolizers, the mean QT pro- ized 1:1:1 to valbenazine, 40 mg (n = 72), longation was 11.7 milliseconds (14.7 mil- valbenazine, 80 mg (n = 79), or placebo (n = liseconds upper bound of double-sided 76).