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FDA Approves First Drug For Chorea in Huntington Disease



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Results of a large multicenter placebo-controlled trial established that tetrabenazine was generally safe and tolerated for long-term use.

In August, the FDA approved tetrabenazine, or TBZ (Xenazine), as a treatment for chorea in people with Huntington disease (HD) — making it the first drug approved in the US for any symptom of the disease.

Manufactured by Prestwick Pharmaceuticals, Inc., TBZ was designated as an “orphan drug” — for a condition affecting fewer than 200,000 people in the US — by the FDA in 1999. For thirty years it has been used in Canada, Europe, and Australia to treat chorea in HD and similar movement disorders.

Tetrabenazine is a selective and reversible centrally-acting dopamine-depleting drug. The exact mechanism for the drug is unclear. But it is believed that it depletes dopamine content by inhibiting vesicular monoamine transporter 2, an enzyme found only in the brain.


The chorea associated with Huntington disease involves rapid, jerky, and unpredictable movements.Bickley, LS, Szilagyi, P. Bates Guide to Physical Examination and History Taking, 8th Ed. Philadelphia: Lippincott Williams & Wilkins 2003


TETRA-HD, the randomized, double-blind, placebo-controlled study that primarily led to the FDA approval, involved 84 patients at 16 sites around the country, and was conducted by the Huntington Study Group, a multi-center research consortium based at the University of Rochester Medical Center in New York. The study was published in 2006 in Neurology.

Led by Frederick J. Marshall, MD, assistant professor of neurology at the University of Rochester School of Medicine and Dentistry, TETRA-HD established that tetrabenazine was generally safe and well tolerated for long-term use. Sixty-nine percent of the TBZ-treated group had significant reduction of chorea. Compared to neuroleptic drugs, tetrabenazine did not interfere with cognition or gait, and did not cause tardive dyskinesia, Dr. Marshall said.

Joseph Jankovic, MD, professor of neurology and director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine in Houston, TX, has treated patients with tetrabenazine for over 30 years under an Investigational Exemption for a New Drug (IND) for hyperkinetic movement disorders such as chorea, tardive dyskinesia, tics, dystonia, and myoclonus.

The results of the longitudinal observational studies that he and his colleagues performed on more than a thousand patients with movement disorders were used to support the pivotal TETRA-HD study to obtain FDA approval.

Most important, Dr. Jankovic said, is that they have not observed tardive dyskinesia in any of the chronically treated patients, some of whom have been receiving tetrabenazine with continued benefits for years or decades.


The most common side effects of tetrabenazine include fatigue, depression, and nausea, but they are generally reversible when the dosage is reduced. Other serious adverse events that neurologists must watch out for are suicidal ideation, akathisia, and drug-induced parkinsonism.

The adverse event profile is consistent with the drug's known pharmacological mechanism of action — the drug decreases cerebral serotonin and norepinephrine levels, Dr. Marshall noted. He added that the challenge for physicians will be to weigh the adverse effects and “select only those patients for whom chorea is a truly troublesome feature of the illness, and to titrate tetrabenazine carefully.”

Although the prescription labeling contains a “black box” warning regarding the risk for suicidal thoughts and actions, when carefully monitored, Dr. Jankovic said, this side effect can be prevented or effectively treated.

About 30,000 people in the United States have HD, according to the NIH. Chorea is the most common symptom, affecting 90 percent of patients, and is also one of the most devastating symptoms of the illness, Dr. Marshall said.

Experts said that while tetrabenazine is not a cure for Huntington disease, it is an effective drug for chorea — and an advance over drugs available to date — as well as an important agent for potentially improving patients' quality of life.

For clinicians prescribing the drug, Dr. Marshall advised: “Because it can be difficult to differentiate possible side effects of tetrabenazine from underlying aspects of the illness itself, clinicians should have a low-threshold for lowering the dosage or discontinuing the drug to try to differentiate these two possibilities. The drug should be lowered or stopped as appropriate at signs of worsening side-effects; if gradually higher doses are not achieving efficacy, it is appropriate to reconsider the approach, and cyp2D6 genotyping (a liver enzyme involved in metabolism of the drug) is called for in those patients non-responsive to doses as high as 50 mg (divided).”


DR. JOSEPH JANKOVIC said that investigators have not observed tardive dyskinesia in any of the chronically treated patients, some of whom have been receiving tetrabenazine with continued benefits for years or decades.

There is a sub-population of individuals who do not metabolize the drug as efficiently, Dr. Marshall explained, and those who require relatively high dosages of tetrabenazine to achieve a clinical impact may belong to this group.

For more information on the drug, see the January 2005 article, “Drug for Treating Chorea in Huntington Disease on ‘Fast Track’ Status,” on


• Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2006;66(3):366–372.
    • Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Rev Neurotherapeutics 2006;6:7–17.
      • Frank S, Ondo W, Jankovic J, et al. A study of chorea after tetrabenazine withdrawal in patients with Huntington disease. Clin Neuropharmacol 2008;31:127–133.
        • Kenney C, Hunter C, Jankovic J. Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord 2007;22:193–197.