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 neuralpsychology 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.