State-of-the-art pharmacological approaches to reduce chorea in Huntington’s disease

ABSTRACT

Introduction Chorea is a common motor manifestation of Huntington’s disease (HD). Two vesicular monoamine transporter type 2 (VMAT-2) inhibitors have been approved by the FDA for treatment of HD chorea, and a third is currently being assessed in a phase 3 trial. Antipsychotic therapies are used off-label for treatment of chorea and can treat comorbid psychiatric symptoms. There is considerable clinical equipoise regarding the safe and effective treatment of chorea and comorbid symptoms in HD.

Areas covered: The authors review existing medications used to treat HD chorea in the United States of America (USA). Implications for common comorbid symptoms (e.g. psychiatric, metabolic) are also discussed. Available therapies vary widely in cost, dosing frequency, and off -target effects, both beneficial or negative.

Expert opinion: Treatment considerations for chorea should account for patient comorbidities. The authors recommend prospective, observational clinical effectiveness studies which can evaluate the long-term comparative effectiveness and safety of VMAT-2 inhibitors and antipsychotics in HD. Data regarding safety of dual therapy is another critical need. This is especially timely given the changing landscape of HD therapies which may increase cost burden and possibly extend both asymptomatic and symptomatic years for HD patients.

KEYWORDS:

• Huntington Disease
• chorea
• tetrabenazine
• antipsychotic Agents
• off-Label Use
• clinical decision-making

Article highlights

• VMAT-2 inhibitors are the only medications approved by the FDA to treat HD chorea

• Antipsychotics are commonly used to treat chorea in HD, but there is no consensus on which agents are safest and most effective

• There are little data to support use of other therapies for treatment of HD chorea, though deep brain stimulation (DBS) is a promising option.

• Comparativeness effectiveness studies are needed to determine which agents are safest and most effective for reducing chorea and comorbid HD symptoms (e.g. psychiatric symptoms).

• Now is the ideal time for these studies, as the emergence of possible disease-modifying therapies increases the likelihood that HD patients may live longer, and more patients will seek care in the coming years.

This box summarizes key points contained in the article.

Declaration of interest

JS Gibson has received resarch support from Teva Neuroscience. DO Claassen has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (grant No. R01 NS097783), the Griffin Foundation, the Michael J Fox Foundation and the Huntington’s Disease Society of America (HDSA). Dr Claaassen has also received pharmacmeutical grant suppport from AbbVie, Acadia, Biogen Idec, Bristol-Myers Squibb, Cerecour, Eli Lilly & Company, Lundbeck, Jazz Pharmaceuticals, Teva Neuroscience, Wave Life Sciences, and Vaccinex. He has also receivedid personal fees for consulting and advisory board participation from Acadia, Adamas, Lundbeck, Neurocrine and Teva Neuroscience. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

List of abbreviations

Huntington’s disease (HD)

vesicular monoamine transporter type 2 (VMAT-2)

Food and Drug Administration (FDA)

United States (US)

deep brain stimulation (DBS)

cytosine-adenine-guanine (CAG)

Medium Spiny Neurons (MSNs)

Globus Pallidus (GP)

United Huntington’s Disease Rating Scale Total Motor Score (UHDRS-TMS)

Quantitative motor (Q-Motor)

body mass index (BMI)

internal GP (GPi)

external GP (GPe)

Reviewer disclosures

One referee declares that they have participated in an indirect treatment comparison comparing 2 VMAT2 inhibitors in HD. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke [R01NS097783]; National Institute on Aging [K24AG064114].