VMAT-2 Inhibitors for TD Compared in Meta-Analysis, Not Head-to-Head

Christoph Correll, MD

A systematic review and meta-analysis of studies distinguished between the vesicular monoamine transporter-2 (VMAT-2) inhibitors for tardive dyskinesia (TD), in absence of available head-to-head comparative trials.

Despite this common mechanism of action, researchers advised that pharmacological factors, efficacy, and safety should be considered when selecting a VMAT-2 inhibitor to treat TD.

Researchers, led by Christoph Correll, MD, professor of psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, said this due to the fact that any preference of 1 VMAT-2 is “currently based on individual medication properties, rather than on head-to-head comparison trials, which are still lacking.”

Two VMAT-2 inhibitors have been approved by the US Food and Drug Administration (FDA) for TD: deutetrabenazine (Austedo) and valbenazine (Ingrezza), and a third has been used off-label for this condition while approved for Huntington's chorea, tetrabenazine).

Their shared mechanism of action is attributed to the VMAT-2 reversible inhibition which blocks release of neurotransmitters, including dopamine, into the synaptic cleft.

While there are only observational, albeit promising, studies of tetrabenazine use for TD, Correll and colleagues note that the very short serum half-life of the agent produces large peak-to-trough variations in serum levels which have been linked to adverse effects. The occurrence of akathesia, and somnolence, as well as potential for depression and suicidality prompted the FDA to require black box warnings on the approved labeling for patients with Huntington's chorea.

The reviewers find that the VMAT-2 inhibitors which are approved for TD have demonstrated advantages over tetrabenazine in either pharmacokinetics (deutetrabenazine) or in both pharmacokinetics and pharmacodynamics (valbenazine).

They both have evidenced prolonged half-life with reduced peak-trough variations compared to tetrabenazine, and valbenazine is not metabolized to products which affect off-target receptors.

Correll and colleagues screened trials for double-blind, randomized, placebo-controlled design, and found 2 acute, 12-week trials with deutetrabenazine and 4 acute 4- or 6-week trials with valbenazine. Each agent consistently outperformed placebo in the primary measure of reduction in total Abnormal Involuntary Movement Scale (AIMS) scores.

There were less consistent results between patient-rated global impression-based response and clinical global impression for deutetrabenazine, and for clinical global impression change for valbenazine.

Neither drug was significantly superior to placebo in the following secondary measures, which were assessed in one, but not both drugs: deutetrabenazine on the modified Craniocervical Dystonia Questionnaire (mCDQ-24) and Patient Global Impression of Change (PGI-C) response; and for valbenazine on the Clinical Global Impression, TD (CGI-TD).

The researchers conclude that there is high-quality evidence supporting the agents which have been approved for TD, noting the most effective dose ranges of 24-35 mg for deutetrabenazine and 40-80 mg for valbenazine.

Correll considered data from extension phases of the acute trials as well as their safety profiles in a discussion with MD Magazine®.

"Importantly, the efficacy seems to progress further beyond the acute 6-12 weeks, as treatment continues for up to 1 year, both in patients with schizophrenia or schizoaffective disorder, and with mood disorders," Correll said.

Both VMAT-2 inhibitors are safe, at least in the studied, psychiatrically stable patient populations, Correll noted, as neither of the 2 agents seem to have an increased risk for depression or suicidality in stable patients with TD, according to the meta-analysis.

While other reviewers have not argued that the approved agents have demonstrated efficacy in treating TD, there has been concern expressed about their cost. The Institute for Clinical and Economic Review (ICER) issued an Affordability and Access Alert

in December 2017, indicating that pricing appears more appropriate to the rare disease market of Huntington's than to TD.

"Unfortunately, applying a rare-disease pricing strategy to therapies used to treat a much more common, chronic condition creates unsustainable financial barriers for patients and the health care system," wrote Dan Ollendorf, PhD, Chief Scientific Officer of ICER.

The study, "Treatment of tardive dyskinesia with VMAT-2 inhibitors: a systematic review and meta-analysis of randomized controlled trials," was published online in Drug Design, Development and Therapy.