FDA News

FDA Approves First Drug for Treatment of
Chorea in Huntington’s Disease

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 Coté, 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
www.fda.gov/cder/regulatory/FDAAA/FR_QA.htm

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

 

For more information, contact:

FOR IMMEDIATE RELEASE August 18, 2008

Hereditary Disease Foundation 212.928.2121 cures@hdfoundation.org

 

FDA Approves First Drug for Huntington’s Disease

The U.S. Food and Drug Administration today approved tetrabenazine, the first drug approved for use in the United States to treat Huntington’s disease, a fatal, inherited neurodegenerative disorder for which there is no cure. The action comes after an advisory panel unanimously voted on December 5, 2007, to advise the FDA to make the medication available to treat the disease.

The drug is already widely used in Europe, Canada and Australia and New Zealand to treat one of the most disabling symptoms of Huntington’s disease—the involuntary writhing movements known as chorea. Chorea is one of the trademark symptoms of the disease, which directly affects about 30,000 people in the United States today; another 70,000 people who are alive today will be diagnosed with the disease. FDA has classified tetrabenazine as an “orphan drug,” since it is targeted to a disease that directly affects fewer than 200,000 people in the nation.

The pivotal study leading to the drug’s approval was done by the Huntington Study Group, based at the University of Rochester Medical Center, and was led by Rochester neurologist Frederick J. Marshall, M.D. That study, published in the journal Neurology in 2006, found that the medication cut down involuntary movements on average by about 25 percent, with many patients experiencing a greater improvement. Overall, patients who received the medication were six times more likely to be considered by their doctors to have improved considerably, compared to participants who received a placebo.

“This is a huge deal,” said Marshall. “Ninety percent of patients with Huntington’s disease have chorea, and many suffer terribly. It’s hard to describe the torment that these people undergo. We had several patients who experienced a dramatic improvement in their quality of life. Some patients who hadn’t been able to attend church for years were able to do so. Others were able to go out to a restaurant and have a meal for the first time in years. It’s impossible to over-emphasize what this has meant to some patients, who are able to reclaim part of the life that they have lost due to this disease.”

Marshall is part of a team of doctors, scientists and nurses at the University of Rochester Medical Center that treats people from more than 200 families from throughout the Northeast with the disease. He has treated patients with the disease since 1991.

“Patients and families with Huntington’s disease maintain a courageous hope for progress,” said Marshall. “On one hand, the FDA approval of tetrabenazine represents only a small step forward.  This medication helps patients control their movements better, but is not known to slow the underlying progression of the disease. On the other hand, the FDA approval represents a giant symbolic breakthrough, since tetrabenazine is the first drug ever approved in the United States for any aspect of Huntington’s disease. It is an honor to be part of the extended community of patients, families, and researchers trying to find a better way forward.”

His enthusiasm is echoed by patients, family members, and doctors and nurses nationwide.

“This is spectacular news,” said Nancy Wexler, Ph.D., Higgins Professor of Neuropsychology at Columbia University and president of the Hereditary Disease Foundation, which was started by her father one year after her mother was diagnosed with Huntington’s disease in 1967.

“Chorea is a major cause of disability and death in individuals with Huntington’s disease. It is devastating and affects all aspects of life. Chorea can prevent people with HD from walking, talking, working and watching television, and chorea often causes choking and falls. We are ecstatic that, through the approval of XENAZINE, people suffering from HD and their families will have the option to take the only drug developed specifically for treating the movements of Huntington’s disease. While we are still hopeful we can some day find a cure, the approval of XENAZINE is a breakthrough for the HD community.”

The drug does have some side effects, including the ability to worsen depression and occasionally to increase rigidity. Most critically, tetrabenazine does not produce tardive dyskinesia, another severe movement disorder. The drug does not slow the progression of the disease or stop the underlying disease process. But most neurologists feel that overall, the benefits of the drug far outweigh the side effects, especially considering that there has been no medication approved for the treatment of Huntington’s patients.

Huntington’s disease usually strikes people in their 30s and 40s, though some are affected as early as childhood, while others are not affected until their older years. The disease is caused by an expansion in a single abnormal gene which produces a protein called huntingtin. A hallmark of the disease is the death of brain cells known as medium spiny neurons, which are killed off by the mutant protein. The disease brings with it an array of difficulties besides chorea, including cognitive problems, changes in personality, and psychiatric problems like depression. As many as one-quarter of patients with the disease attempt suicide, and many suffer from progressive cognitive decline. Unlike Alzheimer’s disease, where patients usually lose their memory and insight into their disease at some point, most Huntington’s patients understand exactly what is happening to them throughout most of their illness.

Virtually everyone with the disease had a parent with the disease, and children of a person with Huntington’s have a 50 percent chance of inheriting the disease. Fifteen years ago the gene that causes the disease was identified by Wexler and colleagues, and now a simple blood test can tell people whether they will develop the disease or not. But since there is no way known to prevent the disease or slow its progression, and for other reasons as well, most people at risk for Huntington’s disease choose not to be tested.

Prestwick Pharmaceuticals of Washington, D.C. owns the rights to develop and sell tetrabenazine in the United States. The medication was originally developed in the 1950s to treat psychosis, but was quickly pushed aside by more effective medications. But doctors in the United Kingdom found it to be effective to treat the excessive involuntary movements of Huntington’s.

Much of the work that led to the approval of tetrabenazine was carried out by the Huntington Study Group, a non-profit, cooperative group of Huntington’s disease experts from medical centers throughout North America, Europe and Australia who are dedicated to improving treatment for persons affected by the disease. HSG is supported by the Hereditary Disease Foundation, the Huntington’s Disease Society of America, the Huntington Society of Canada, and the High Q Foundation.

The president of HSG is neurologist Ira Shoulson, M.D., a University of Rochester professor who is widely recognized for revolutionizing the way clinical trials are done for neurological conditions like Parkinson’s and Huntington’s diseases. The study of tetrabenazine would have been nearly impossible to do without the cooperation of doctors, nurses and patients across the nation, made possible through Shoulson’s groundbreaking work with HSG.

The Hereditary Disease Foundation (HDF) is a publicly-supported organization focusing on finding treatments and cures for Huntington’s disease. The HDF was founded in 1968 by Milton Wexler when his wife was diagnosed with the illness. The organization supports research, including the development of mouse models, preclinical testing, studies of protein-protein interactions, strategies for gene therapy, intercellular signaling in striatal neurons and the development and planning of clinical trials.

Further details are available on the website: www.hdfoundation.org, by email: cures@hdfoundation.org, or by phone: 212.928.2121.

Nancy S. Wexler, Ph.D.
Higgins Professor of Neuropsychology
Columbia University
1051 Riverside Drive, Unit 6, PI Annex 371
New York, NY 10032
212.543.5667, fax 212.543.6002
wexlern@pi.cpmc.columbia.edu
President, Hereditary Disease Foundation
212.928.2121, fax 212.928.2172
www.hdfoundation.org

Click here for Tetrabenazine Articles Archives

FDA Panel Vote Backs Prestwick's HD Drug

By Donna Young
Washington Editor

Federal advisers Thursday said that, despite its risks, the FDA should approve Prestwick Pharmaceuticals' Xenazine (tetrabenazine) as a treatment to control the involuntary jerky movements, known as chorea, associated with Huntington's disease.

Study results showed that there was a clear drug-related increase in significant adverse events, including parkinsonism, akathisia, depression and dysphagia, associated with Xenazine use.

About 15 percent of patients receiving the drug in one study experienced depression, compared with no patients in the placebo group, the FDA said. One study participant committed suicide while on Xenazine. But regulators noted that there is a high prevalence of suicide in Huntington's disease and that twice as many patients were randomized in the study to receive the drug.

The FDA's Peripheral and Central Nervous Systems Advisory Committee Thursday voted unanimously that the adverse effects associated with Xenazine did not outweigh the benefits of using the drug to control chorea.

Because some of the drug-related reactions also are symptoms of Huntington's disease itself, regulators expressed concern that a patient's physician may not be able to identify the adverse event as being drug-related.

Prestwick argued that because the response to Xenazine is rapid, often being observed within days, physicians and patients can determine if the efficacy achieved outweighs potential adverse effects of treatment. The firm contended that the adverse effects associated with Xenazine can be managed through careful titration and dose adjustment.

The committee agreed, stating the FDA's concerns about adverse effects could be remedied by adding statements in drug labeling noting that Xenazine should be started at the lowest dosage necessary to control chorea.

Study investigator Peter Como, associate professor of neurology, psychiatry and brain and cognitive sciences at the University of Rochester in New York, said that most physicians prescribing the drug, "If they know their patient well enough," would more than likely decrease the dosage if the prescriber recognized a progression in the disease. However, he told BioWorld Today, "Even the most expert clinicians with 100 percent confidence may not always be able to pick out" the natural disease progression from an adverse event.

While the FDA determined Xenazine was effective in treating Huntington's chorea, the agency was concerned about secondary outcomes of the supporting studies that showed that patients on placebo performed better in terms of motor function and behavior.

However, panelists unanimously agreed that the lack of a beneficial effect of Xenazine on numerous measures of function and cognition did not outweigh the drug's effectiveness in treating chorea.

Como said that the secondary outcomes identified in the study may be more of a result of the need for more sensitive scales to measure such outcomes.

There currently is no FDA-approved treatment for chorea associated with Huntington's disease, a fatal neurodegenerative disease marked by involuntary movements, cognitive decline and behavioral disruption that affects about 30,000 Americans.

Drugs that block dopamine transmission, neuroleptics or reserpine, currently are prescribed for the condition, but central and peripheral adverse effects, including a condition known as tardive dyskinesia that actually can be caused by use of such drugs, limit their use, said Nancy Wexler, president of the Hereditary Disease Foundation.

Thursday's recommendation to approve Xenazine, Wexler told BioWorld Today, is not only "fantastic," but an "historic" event for patients.

Approval of the drug not only will help U.S. patients gain access to Xenazine, but also will ensure that insurers cover the drug, said Wexler, who, along with her father, discovered the Huntington's disease gene.

Tetrabenazine initially was developed by Basel, Switzerland-based F. Hoffmann-La Roche in the mid-1950s as an antipsychotic drug to treat schizophrenia. However, it never gained widespread use for that condition and later was found to be effective in treating chorea, especially for patients with Huntington's disease.

The drug is approved for Huntington's disease in several European countries, including Germany and France, and also is approved in other nations outside the U.S. to treat organic movement disorders and tardive dyskinesia, noted Wexler, a professor of neuropsychology at Columbia University in New York.

She praised Prestwick for seeking U.S. approval of the product, which has been designated by the FDA as an orphan drug. "Patients in the United States will finally have a chance to use it," Wexler said.

The FDA is expected to take approval action on Xenazine in early 2008.

BioWorld Today December 7, 2007