Therapeutic Spotlight: Assessments of Emerging Therapies for Tardive Dyskinesia

By Xcenda

Tardive dyskinesia (TD) is a medication-induced disorder that is characterized by abnormal, involuntary movements of facial muscles, extremities, and trunk, as well as respiratory movements (eg, irregular breathing rhythms). We examine the demand for effective management of TD and its evolution in the context of increasing recognition of the importance of patient-centered factors and quality-of-life considerations.

HTA Quarterly | Late Summer 2018

Therapeutic Spotlight: Assessments of Emerging Therapies for Tardive Dyskinesia

By Kim Riggs, MPH; Anuja Kanaskar, PharmD; Kristen Migliaccio-Walle 

Tardive dyskinesia (TD) is a medication-induced disorder that is characterized by abnormal, involuntary movements of facial muscles, extremities, and trunk, as well as respiratory movements (eg, irregular breathing rhythms). TD is typically associated with dopamine-blocking medications such as first- and second-generation antipsychotics used to manage conditions such as schizophrenia, bipolar disorder, and mood disorders. In the context of seeking effective management for psychiatric conditions such as these, TD has historically been accepted as a relatively minor inconvenience relative to the benefits that treatment affords. The demand for effective management of TD has evolved in the context of increasing recognition of the importance of patient-centered factors and quality-of-life considerations. Nevertheless, effective management of TD has been lacking with no treatment options indicated for TD until the recent approval of vesicular monoamine transporter 2 (VMAT2) inhibitors. 

Burden of Disease

The most common symptoms involve oral and facial movements, such as protruding and twisting tongue, chewing movements, lip pouting, puckering or smacking, retraction of mouth corners, bulging of cheeks, blepharospasm, ticks, stereotypy, and tremor. These symptoms range in severity, and, unlike other medication-induced movement disorders, symptoms of TD remain present for at least 1 month following medication discontinuation. In some cases, full remission of symptoms is possible, particularly when TD is detected early and medication is immediately discontinued. However, symptoms are permanent and irreversible for a majority of patients, despite discontinuation of causative medications. As a consequence, there is significant humanistic burden associated with TD as evidenced by poorer self-reported quality of life and greater social withdrawal in patients with symptoms compared to those without. Humanistic burden associated with TD also increases with symptom severity. Among those taking antipsychotic medications, the average global TD prevalence rate is approximately 25%. Higher rates of both prevalence and incidence of TD have been found in patients using first-generation antipsychotics relative to second-generation antipsychotics. TD prevalence rates also vary by region, with lower rates found in Asia (compared to the US and other regions).

Treatment Landscape

Management of TD has remained largely unchanged since the 1980s, with experimental and off-label use of therapies such as clonazepam, Ginkgo biloba, amantadine, and propranolol to manage symptoms. Physicians have also utilized non-pharmacological approaches, such as discontinuing medications, switching from first- to second-generation antipsychotics, administering botulinum toxin injections, or performing surgical therapy. Recently, the introduction of VMAT2 inhibitors has been considered groundbreaking and has renewed interest in TD, a condition with significant unmet need. While VMAT2 inhibitors have been approved in the US and Europe for treatment of Huntington’s disease, it wasn’t until 2017 that INGREZZA (valbenazine, Neurocrine Biosciences, Inc.) and AUSTEDO (deutetrabenazine, Teva Pharmaceutical Industries Ltd.) were approved by the US Food and Drug Administration (FDA) to treat adults with TD, representing the only 2 treatments officially approved for TD globally. 

Treatment Spotlight: VMAT2 Inhibitors

VMAT2 inhibitors modulate the pre-synaptic packaging and release of dopamine into the nerve cell synapse and help to offset movement-related side effects of antipsychotic drugs and other dopamine receptor blocking agents (DRBAs).

AUSTEDO™ (deutetrabenazine) Overview

AUSTEDO is the first and only FDA-approved product to treat both chorea associated with Huntington’s disease and TD. AUSTEDO is administered twice daily as an oral tablet for both indications. The 2017 FDA approval of AUSTEDO for TD was based on two 12-week, randomized, double-blind, placebo-controlled trials that included a total of 335 adult patients with TD. Both trials met their primary efficacy endpoint—the Abnormal Involuntary Movement Scale (AIMS) total score. AUSTEDO was determined to have an adequate safety and tolerability profile in patients with TD, although it received a black box warning from the FDA for use in patients with Huntington’s disease. 

INGREZZA™ (valbenazine) Overview

INGREZZA was approved by the FDA as an oral capsule administered once daily for the treatment of TD based on a 6-week randomized, double-blind, placebo-controlled trial in 234 (enrolled) adult patients with moderate to severe TD. The trial met its primary efficacy endpoint, demonstrating greater reduction (ie, improvement) on therapy in the AIMS total score. The safety and tolerability of INGREZZA were established in 3 placebo-controlled studies that included 445 adult patients with moderate to severe TD. 

XENAZINE® (tetrabenazine) Overview

Tetrabenazine is approved in both the US and Europe for treatment of Huntington’s chorea. Tetrabenazine has commonly been used off-label to treat TD but is not yet approved for this indication. 

Reimbursement Spotlight

As VMAT2 inhibitors are still emerging treatment options for TD, it is not surprising they haven’t been formally evaluated by many prominent HTAs and regulatory agencies at the global level. However, in the US, the 2017 approval of AUSTEDO and INGREZZA prompted the Institute for Clinical and Economic Review (ICER), a US-based, independent, non-profit institution, to review the effectiveness and economic value of both newly approved TD treatments (valbenazine and deutetrabenazine) and those pending FDA approval (tetrabenazine). The report concluded the evidence regarding the effectiveness of valbenazine and deutetrabenazine was “promising but inconclusive” and the effectiveness of tetrabenazine was “unclear due to insufficient evidence.” Furthermore, ICER expressed concern regarding the cost-effectiveness of valbenazine and deutetrabenazine, noting their economic model analyses indicated the listed wholesale acquisition cost (WAC) of these products would not commensurate with their benefits. Incremental cost-effectiveness ratios ranged from $752,080 per quality-adjusted life-year gained (QALY) for valbenazine (vs placebo) to $1.1 million per QALY for deutetrabenazine. ICER also estimated the cost to achieve fewer TD symptoms in a year, which was $71,448 with valbenazine and $104,573 with deutetrabenazine.

Figure 1 illustrates the results of ICER’s threshold analyses which estimated that valbenazine would require a discount of 85%–90% and deutetrabenazine a discount of 90%–93% to fall within the commonly accepted range of incremental cost-effectiveness values ($100,000–$150,000 per QALY). The resulting optimal benchmark price ranges are shown in the shaded bands of each bar.


Figure 1. Costs and Benchmark Price Ranges for Valbenazine and Deutetrabenazine

In budget impact analyses, ICER estimated that 15% and 21% of the treatment-eligible patient population could be treated with valbenazine at the current WAC price (with and without discount, respectively) without crossing ICER’s annual budget impact threshold of $915 million (note, this report was completed prior to ICER updating this annual affordability threshold to $991 million). Similar estimates were calculated for deutetrabenazine for which approximately 14% and 20% could be treated. 

Concerns by patients and patient advocates were noted by ICER in terms of lack of clarity as to how the introduction of the VMAT2 inhibitors may impact the overall approach to treating the underlying condition that causes TD. The general sense was that there is presently little known or understood about this and that, consequently, the full impact of these novel therapies on quality of life in particular may be undervalued.

It is still unclear how payers will perceive ICER’s evidence report on TD treatments. Over the next few years, it will be interesting to note how often these TD medications are prescribed to patients in need of a treatment for this debilitating disorder, despite the high price tag.


The article should be referenced as follows: 

Riggs K, Kanaskar A, Migliaccio-Walle K. Assessments of emerging therapies for Tardive Dyskinesia. HTA Quarterly. Late Summer 2018. Sept. 12, 2018.

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