Huntington Disease (HD)

Austedo^®(deutetrabenazine) and Austedo XR are oral vesicular monoamine transporter 2 (VMAT2) inhibitors that are indicated for the treatment of chorea associated with Huntington disease (HD) in adults.¹ Austedo was developed by Teva and approved by the US Food and Drug Administration (FDA) in 2017. Austedo has also been approved in China, Australia, Israel, Brazil, and South Korea.^1,2

The main active ingredient of Austedo is deutetrabenazine, an oral and highly selective deuterium-containing VMAT2 inhibitor that is related to tetrabenazine.^2,3 Tetrabenazine is a VMAT2 inhibitor that is also indicated for the management of chorea in HD. The deuteration of tetrabenazine in Austedo increases the plasma half-life of the drug and reduces the metabolic variability, therefore promoting efficient systemic exposure and allowing reductions in the dosing and frequency of administration.^3,4

Huntington disease is a rare, neurodegenerative disease characterized by the triad of motor, cognitive, and psychiatric dysfunction. Chorea is often the most noticeable and hallmark symptom, which can affect any muscle of the body, compromising daily living and potentiating injury.^3,4 The severity of chorea in patients with HD varies from twitches to generalized muscle contractions.⁴

Mechanism of Action

The mode of action of Austedo is not clear, but it is believed to involve the reversible depletion of monoamines (dopamine, serotonin, norepinephrine, and histamine) from the nerve terminals. Two circulating metabolites deriving from Austedo, α-dihydrotetrabenazine (HTBZ) and β-HTBZ, are reversible inhibitors of VMAT2, leading to decreased uptake of monoamines into synaptic vesicles and the depletion of monoamine stores.¹

Read more about HD pathophysiology

Administration of Austedo

The dose of Austedo for HD should be determined individually. The medication may be gradually increased until an optimal dose is reached that reduces chorea but maintains tolerability.¹

The recommended initial dose is 6 mg twice per day.¹ A new once-daily option, Austedo XR, was recently made available to patients with HD, with a recommended initial dose of 12 mg/day.⁵ Either option may be increased weekly by 6mg, up to a maximum daily dosage of 48 mg/day.¹

Get full prescribing information for Austedo at MPR

Adverse Effects

The most common adverse reactions reported following Austedo treatment include somnolence, diarrhea, dry mouth, and fatigue. Prolongation of the QTc interval, akathisia, parkinsonism, and hyperprolactinemia have also been reported.¹ 

Read more about HD treatment

Warnings and Precautions

As Austedo may increase the risk of depression and suicidal thoughts and behavior, it is contraindicated in patients with uncontrolled depression and/or suicidal ideation.¹

Austedo should not be prescribed for patients with hepatic impairment or for patients taking monoamine oxidase inhibitors (MAOIs) or reserpine.¹

Clinicians should routinely reevaluate their patient’s need for Austedo, by assessing its effect on chorea, as well as possible adverse effects. It may be difficult to distinguish between adverse reactions and disease progression. Pausing the medication or limiting the dosage may help clarify the decision.¹

Patients should be observed for signs of Neuroleptic Malignant Syndrome, a potentially fatal symptom complex associated with Austedo and other dopamine antagonists.¹ 

Read more about HD complications

Safety and Efficacy in Trials

The efficacy of Austedo was evaluated in 2 multicenter phase 3 clinical trials.⁴ First-HD (NCT01795859) was a phase 3 randomized, double-blind, placebo-controlled clinical trial involving 90 patients with HD.^2,3,6 Patients received either Austedo or a placebo, starting at 6 mg per day with a titration up to 8 weeks to reach the optimal effective dose. A 4-week maintenance period followed. The experimental therapy was administered 2 times per day. Of the 90 patients, 87 completed the study, and at 12 weeks, results showed improved motor signs with improved chorea control in patients receiving the treatment. The total maximal chorea mean scores decreased 4.4 points from baseline to maintenance treatment in the Austedo group, while in the placebo group, a decrease of 1.9 points was reported. Patient- and clinician-rated impressions of change were also improved. Austedo exhibited a favorable safety profile with mild adverse events; somnolence was the most common adverse event reported. In the Austedo group, 1 patient experience cholecystitis and agitated depression.³

A second phase 3 clinical trial, ARC-HD (NCT01897896), aimed to evaluate the long-term safety and tolerability of Austedo in the treatment of chorea in HD. The trial included 119 patients who completed the first double-blind study and underwent overnight conversion from tetrabenazine to deutetrabenazine.^2,7 This was an open-label, single-arm, 2-cohort study in which the dose of Austedo varied from 6 mg per day to 72 mg per day. Reduced chorea persisted over time, with no unexpected worsening after ceasing treatment.² 

Clinical Study of Austedo XR 

The efficacy of Austedo XR was determined in a recent relative bioavailability study in which the administration of Austedo XR tablets once per day was compared to Austedo tablets administered twice per day. Austedo XR was shown to be therapeutically equivalent to the twice-daily formulation.^1,5 

Read more about HD clinical trials

References

1. Austedo XR/Austedo. Prescribing information. Teva Pharmaceuticals; 2023. Accessed August 6, 2023.
2. Frank S, Testa C, Edmondson MC, et al; Huntington Study Group/ARC-HD Investigators and Coordinators. The safety of deutetrabenazine for chorea in Huntington disease: an open-label extension study. CNS Drugs. 2022;36(11):1207-1216. doi:10.1007/s40263-022-00956-8
3. Huntington Study Group. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA. 2016;316(1):40-50. doi:10.1001/jama.2016.8655
4. Heo YA, Scott LJ. Deutetrabenazine: a review in chorea associated with Huntington’s disease. Drugs. 2017;77(17):1857-1864. doi:10.1007/s40265-017-0831-0
5. Austedo^® XR (deutetrabenazine) extended-release tablets, new once-daily formulation of Austedo^®, now available in the U.S. News release. Teva Pharmaceuticals; May 15, 2023.
6. First time use of SD-809 in Huntington disease (First-HD). ClinicalTrials.gov. Updated September 20, 2017. Accessed August 6, 2023.
7. Alternatives for reducing chorea in Huntington disease (ARC-HD). ClinicalTrials.gov. Updated November 9, 2021. Accessed August 6, 2023.

Reviewed by Hasan Avcu, MD, on 8/9/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.