FDA approves tetrabenazine

The FDA approves the first drug specifically for Huntington's Disease, tetrabenazine for chorea.

The U.S. Food and Drug Administration has approved tetrabenazine for the treatment of chorea in Huntington’s Disease. Tetrabenazine is marketed by Prestwick Pharmaceuticals, Inc., in Canada; Prestwick also has marketing rights in the United States.

Tetrabenazine (TBZ) is a dopamine depleter. It works by inhibiting the vesicular monoamine transporter 2 (VMAT2). Neurons are connected to each other by synapses and communicate through chemical signals called neurotransmitters. VMAT2 is responsible for regulating how much of the neurotransmitter is released across the synapse.

Since TBZ also reduces serotonin and norepinephrine, although to lesser degree than dopamine, depression is a potential side effect. In a 2006 Lighthouse interview, former Prestwick CEO, Kathleen Clarence-Smith, M.D., Ph.D., recommended that TBZ be titrated up to the individual patient’s correct dose to avoid the potential side effects of depression, Parkinsonism, and sedation. About sixty percent of HD patients are already taking antidepressants. If depression occurs with TBZ, it can be treated by prescribing an antidepressant, increasing the dosage of an antidepressant the patient is already taking, or reducing the dosage of TBZ.

Tetrabenazine was first approved as a treatment for chorea in movement disorders in the United Kingdom in 1971 and in Canada in 1995. Prestwick filed a New Drug Application with the FDA in September, 2005.

TBZ is the first drug ever approved in the United States for the treatment of a Huntington’s Disease symptom. Another ‘first’ was the inclusion of an HD family advocate on an FDA committee. Karen Milek, HDSA’s 2003 HD person of the year, served on the Advisory Committee that recommended approval of tetrabenazine,.

Huntington’s Disease family advocates played a large role in getting the FDA to act. Letter writing campaigns were organized by Dr. Nancy Wexler of the Hereditary Disease Foundation and Barbara Boyle of the Huntington’s Disease Society of America. Two hundred family members from around the country turned out for an advisory committee meeting on December 6, 2007 in Beltsville, Maryland and over a dozen spoke about the disabling effects of chorea and the importance of treating this symptom. Educating the FDA on the negative effect that chorea has on the quality of life was key to the decision.

The FDA had two sets of concerns. The first was the risk of depression and suicidal thoughts. The second was a trend toward a worsening of mood, cognition, and functional capacity. The trend was not statistically significant which means that the results might have occurred by chance. Still, it does suggest that the patient, family, and doctor should continue to monitor the patient's response to the drug on an ongoing basis.

The Advisory Committee recommended approval of TBZ in December of 2007. Approval was delayed while the FDA and Prestwick worked on a Risk Evaluation and Mitigation Strategy (REMS) so that the rikss of taking the drug do not outweigh the benefits. Patients and their families should read the materials included with TBZ and discuss anything they don't understand with their pharmacist and doctor.

Personally, before giving TBZ to one of my loved ones, I would make sure that he/she was already on an antidepressant and I would stay home with him or her while they adapted to the drug or arrange for a family member or aide to be there.

I think that the FDA made the right decision. Although TBZ carries risks, individual patients vary in symptoms and responses to medication. As individuals, they have different ideas about quality of life issues. Some members of the HD community have reported good experiences with the drug while others have been unhappy with the results. Some individuals want their chorea treated and others are not bothered by it. Patients, family members and doctors can discuss the drug and decide if they want to try it and if they do so, can decide if continuing to take the drug is the right choice.

There are some lessons for the HD community from the TBZ experience. First, we need to educate ourselves about any drug that is under review for approval. I've talked to some HD family members at recent HD related events who were confused about what this drug is being approved for. It has been approved as a treatment for chorea, a symptom of Huntington's Disease. It was not tested for nor approved as a treatment of the underlying disease itself. That needs to be understood as do the good results in reducing chorea and the potential side effects. It's also a good idea to look at the studies that were done, as we do here on the Lighthouse (see the references below). In educating ourselves, we need to know 1) what any drug is expected to do, 2) what the evidence is for its effectiveness and safety is, and 3) and what the potential side effects are.

Second, we need to make our voices heard during the review process. Huntington's has no approved treatments for the disease itself. TBZ is the first approved treatment for a symptom of the disease, chorea. Although other symptoms such as depression are treated, the drugs prescribed were tested in other patient populations and their use in HD is considered off-label. In the next few years, we are likely to see more new drug applications, some for symptoms, some for the disease. Drugs have side effects, even the safest drugs. Those side effects have to weighed against the potential benefit. We need to tell the FDA how we balance the equation.

References and Resources:

C. Kenney and J. Jankovic. “Tetrabenazine in the treatment of hyperkinetic movement disorders.” Expert review of neurotherapeutics. 2006 Jan;6(1):7-17. Lighthouse coverage: Baylor study

Huntington Study Group, (Marshall F, primary author). “Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial.” Neurology 2006;66:366-372. Lighthouse coverage: HSG study

FDA News Release

Prestwick’s December 6, 2007 Briefing Document for the FDA and the public: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4328b1-02-Prestwick.pdf

Prestwick website: http://www.prestwickpharma.com/




Marsha L. Miller, Ph.D.
HD community members speaking to an FDA Advisory Committee about TBZ, December 6, 2007
FDA Approves First Drug for Treatment of Chorea in Huntington’s Disease
Food and Drug Administration
The U.S. Food and Drug Administration has approved Xenazine (tetrabenazine) for the treatment of chorea in people with Huntington’s disease. Chorea is the jerky, involuntary movement that occurs in people with this disease.

Xenazine is a new drug and is the first treatment of any kind approved in the United States for any symptom of Huntington’s disease. Currently there are no other drugs that are FDA-approved to treat chorea.

Serious side effects reported with use of Xenazine include depression and suicidal thoughts and actions. Xenazine should not be used in patients who are actively suicidal or in patients with untreated depression. Concerns about the risk of suicide are heightened in all patients with Huntington’s disease.

“Xenazine represents hope for patients and families dealing with this difficult disease,” said Timothy Cot?, M.D., M.P.H., director of FDA’s Office of Orphan Products Development. “For the first time, there is a treatment that can help patients with this disease gain some quality of life.”

Huntington's disease is a rare, inherited neurological disorder affecting about 1 in 10,000 people in the United States. The disease results from genetically programmed degeneration of brain cells. The deterioration causes uncontrolled movements, loss of intellectual faculties, and emotional disturbance. Huntington’s disease is passed from parent to child through a gene mutation. Each child of a parent with the disease has a 50 percent chance of inheriting the mutation.

About 30,000 people in the United States have Huntington’s disease and another 200,000 are at risk of developing the condition. Symptoms commonly develop between ages 30 and 50. The disease progresses slowly and a person may live for another 15-20 years after the onset of symptoms.

Xenazine decreases the amount of dopamine available to work at relevant synapses in the brain. Dopamine is a chemical that communicates between certain nerve cells in the brain. In patients with Huntington’s disease, this system is overactive and results in the abnormal movements called chorea. Xenazine decreases the amount of dopamine available to interact with certain nerve cells, thereby decreasing the involuntary movements.

The effectiveness and safety of Xenazine was established primarily in a randomized, double-blind, placebo-controlled multi-center clinical trial. Patients treated with Xenazine had a significant improvement in chorea compared to patients treated with placebo. Other studies provided additional support for this effect.

The most common side effects reported by patients using Xenazine in clinical trials include insomnia, depression, drowsiness, restlessness and nausea.

While the drug has been shown to decrease chorea in the short-term, it also showed slight worsening in mood, cognition, rigidity, and functional capacity in clinical trials. Health care professionals and family members of patients taking the drug should pay attention to all of the facets of the disease.

Xenazine has been approved with a required Risk Evaluation and Mitigation Strategy (REMS) to ensure that the benefits of the drug outweigh its risks, particularly the risks of depression and suicidal thoughts and actions. REMS is a strategy to manage a known or potential serious risk associated with a drug or biological product.

The REMS includes educational materials for prescribers, pharmacists and patients (and their caregivers) to help minimize adverse effects associated with Xenazine. It also includes a Medication Guide, which informs patients and their caregivers about the risks of depression, suicidal thoughts and actions, and other side effects. The FDA requires that the Medication Guide be handed out with every prescription for the drug dispensed.

Xenazine was granted orphan drug designation by the FDA. A drug is eligible for orphan drug designation if it is intended to treat a disease or condition that affects less than 200,000 people in the United States. A drug is also eligible for orphan drug designation if it is intended to treat a disease or condition that affects more than 200,000 people in the United States, but there is no reasonable expectation that the cost of developing and making available a drug for the disease or condition will be recovered from sales of the drug.

Xenazine is manufactured by Prestwick Pharmaceuticals, Inc., Washington, D.C.

For more information:

FDA: Questions and Answers on Risk Evaluation and Mitigation Strategies: http://www.fda.gov/cder/regulatory/FDAAA/FR_QA.htm

FDA: Office of Orphan Products Development www.fda.gov/orphan

National Institute of Neurological Disorders and Stroke: Huntington's Disease Information: Page www.ninds.nih.gov/disorders/huntington/huntington.htm

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