Tetrabenazine News

HD Lighthouse Contributing Editor's Comment: Two recent scientific papers provide encouraging news about the use of the drug tetrabenazine (TBZ) for chorea in Huntington’s. Though this drug has been used elsewhere in the world (Australia, Canada, England, Europe), and at Baylor College of Medicine in Texas for many years, it awaits FDA approval for general use in the United States. The two publications discussed below provide evidence that TBZ significantly decreases chorea and can improve quality of life for HD people, but also can have potentially serious side-effects that need to be closely monitored by a doctor.

Expert Review

In Expert Review of Neurotherapeutics (January 2006), Dr. Christopher Kenney and Dr. Joseph Jankovic from Baylor College of Medicine review the results of several TBZ clinical studies and trials performed over the years. In all these trials, the majority of participants showed moderate to marked (68%–97%) reduction of chorea for extended periods of time. The authors go on to report that among hundreds of their patients treated at Baylor between 1979 and 2004, 80% have experienced a complete or marked improvement.

Though these studies provide evidence to support TBZ use, most were not placebo controlled (some trial participants receive no active drug) or double-blind (neither doctor nor patient knows whether placebo or active drug is received). As such, more evidence was needed to support FDA approval. The Huntington Study Group (HSG) and Prestwick Pharmaceuticals worked together in TETRA-HD to provide the type of evidence that will more strongly support FDA approval of this drug for chorea. Also very important, the authors included “quality of life” measures. This may be the first HSG study to formally address this very important aspect of drug benefit.

The entire HD community salutes all of the 84 HD people who participated in TETRA-HD. Likewise we owe gratitude to HSG for this elegantly designed short study that has delivered results important to HD people. Lastly, we thank Prestwick Pharmaceuticals for its persistence and financial support.

TETRA-HD

In February 14, 2006 issue of the journal Neurology, Dr. Frederick Marshall and HSG colleagues published results of TETRA- HD, a rigorously controlled clinical trial of TBZ in subjects who had significant chorea. In this 12 week study, 54 people received TBZ, while 30 got placebo. Chorea measures were compared for these two study groups at the outset (without any drug), and at week 12 (with stable dosages for at least 6 weeks), and again at one week after stopping the drug. The authors report that 69% of the tetrabenazine-treated group had significant benefit. When expressed as a total group measure, chorea decreased by 25% in the TBZ group. While this percentage is significant, the degree of benefit is not as great as that reported in other studies. And, as in other studies, chorea benefit ended abruptly when the drug was stopped.

Though change in chorea was the primary outcome measure in TETRA-HD, there was also significant improvement in the Clinical Global Improvement (CGI) scale. CGI is a 7 point scale commonly used to assess treatment response of drugs such as antidepressants. A score of 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 =minimally worse, 6 = much worse, 7 = very much worse. Using this scale, patients who received TBZ were six times as likely to be considered by their doctors to have improved considerably compared to those who received placebo.

Further analysis showed that, compared to neuroleptic drugs (like Haldol and Risperdal), tetrabenazine did not interfere with cognition or gait, and did not cause tardive dyskinesia (involuntary repetitive movements), or blunting of personality. And no change in swallowing ability occurred, as had been suggested in earlier studies.

Side Effects

This drug has significant side effects. The most common is fatigue and sleepiness. A more serious side effect is injury from falls. Though falls are the result of many factors, benefit from TBZ may encourage enthusiastic return to activities previously lost. As such, the newly treated person should use caution and “relearn” safe motor limits.

The most serious side effect is depression. Though the drug’s intended effect is to decrease dopamine levels, it also decreases serotonin and nor-epinephrine levels. Huntington’s people start out with lowered levels of these neurotransmitters, which are critically important in sustaining a good mood. Further decreasing these neurotransmitter levels can precipitate or worsen depression which can come quickly and be profound. Of concern, suicide was reported in this, and earlier studies. A very strong medical argument can be made for taking dual-action (serotonin- and nor epinephrine-enhancing) antidepressants alongside tetrabenazine.

As with any successful drug that has significant side effects, it is essential that doctors work closely with patients and families, to adjust TBZ dosage and to assess frequently for side effects.

Prestwick Pharmaceuticals is in process of seeking FDA approval for tetrabenazine, and hopes to market it in the U.S. before the end of 2006. However, many HD people are already using this drug (manufactured by Prestwick), which can be obtained legally from Canada with a U.S. prescription.

Comment

There is a definite divide in the HD community (both patient/family and doctor) as to whether chorea “should” be treated. As tetrabenazine approaches FDA approval, it becomes vitally important to address this issue from all perspectives. More to follow . . .
--LaVonne Veatch Goodman, M.D.
Posted to the HDL: 25 Feb 2006

Dr. Frederick Marshall

Drug aimed at Huntington's eases chorea, the disease's hallmark feature A drug widely available in Europe and Canada – but not the United States – dramatically eases one of the most disabling symptoms of Huntington’s disease, involuntary writhing movements known as chorea, according to a study in the Feb. 14 issue of the journal Neurology.

The medication, tetrabenazine, is currently being reviewed by the U.S. Food and Drug Administration. If approved, the medication would be the first authorized by the agency expressly for the treatment of Huntington’s disease, which affects about 30,000 people in the United States.

In a randomized, controlled study conducted in 84 patients at 16 sites around the nation, doctors found that the medication cut down involuntary movement on average by about 25 percent, with many patients experiencing a greater improvement. Overall, patients who received the medication were six times as likely to be considered by their doctors to have improved considerably, compared to participants who received a placebo.

“Neuroleptic drugs like haloperidol (Haldol) are currently in widespread use in the United States to suppress chorea, but the effect of these drugs on chorea has never been studied in a systematic way, and they have a number of troublesome side effects, such as blunting of personality, loss of voluntary movement, and hindering balance. Our study showed that tetrabenazine, when appropriately dosed, can decrease chorea without causing those side effects,” said Frederick J. Marshall, M.D., a neurologist at the University of Rochester Medical Center who led the study conducted by the Huntington Study Group. The study was funded by Prestwick Pharmaceuticals of Washington, D.C., the company that owns the rights to develop and sell the medication in the United States.

Tetrabenazine 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, and it is approved for use in several nations. In the United States, tetrabenazine is designated as an “orphan drug” by the FDA since it’s targeted to a disease directly affecting fewer than 200,000 people in the nation.

The symptom that tetrabenazine treats – involuntary, writhing movements of the limbs, face, and sometimes the entire body – is the hallmark symptom of Huntington’s disease, an inherited neurodegenerative disorder that worsens as brain cells known as medium spiny neurons are killed off by a mutant protein. The disease brings with it an array of other difficulties as well, 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.

The disease usually strikes people in their 30s and 40s, though some patients are affected as early as childhood, while others aren’t affected until their older years. 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. Thirteen years ago the gene that causes the disease was identified by scientists, 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, many patients decline the test, instead waiting to see if they develop symptoms like the ones they witnessed in a parent. Patients usually live for 15 to 20 years after the onset of symptoms.

Viewed simply, in some ways Huntington’s disease is the opposite of Parkinson’s disease, where damage to the neurons that produce dopamine hinders a person’s ability to move and cause other symptoms. In Huntington’s, too many dopamine signals result in random, uncontrollable movements. Tetrabenazine inhibits a molecule known as vesicular monoamine transporter 2 (VMAT2), an action that ultimately blocks the release of dopamine.

“This is not a wonder drug for Huntington’s. It doesn’t address the psychiatric or cognitive problems, for instance. But there are some patients for whom chorea is clearly a devastating feature of the illness.” said Marshall, an associate professor of Neurology who is chief of the University’s Geriatric Neurology Unit. “Easing chorea could help patients with tasks they normally struggle with, such as eating, driving, grooming, and walking.

“As a physician, I have no doubt that this medication can be very helpful to some patients. If the drug is approved, physicians will need to work closely with patients and their caregivers to adjust the dosage safely. About a quarter of patients reported sedation, fewer than 10 percent of patients had motor restlessness, and fewer than 5 percent had motor slowing or depressed mood. Side effects generally resolved with downward adjustment of the dosage. Of concern, one patient committed suicide during the study. Because of the high rate of suicide attempts in patients with Huntington’s disease, all patients deserve close follow-up.”

The study 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 Huntington’s Disease Society of America, the Hereditary Disease Foundation, the Huntington Society of Canada, and the High Q Foundation. More information is available at www.Huntington-Study-Group.org.

HSG is based at the University of Rochester Medical Center, which is home to one of the world’s top groups of doctors specializing in Huntington’s disease. The study was run through the Department of Neurology’s Clinical Trials Coordination Center, where physicians design and conduct large multi-site studies of potential new treatments for diseases like Parkinson’s disease, Huntington’s disease, and neurological disorders related to HIV.

Marshall is part of a team of doctors, scientists and nurses that treats people from more than 200 families from throughout the Northeast with the disease. He also specializes in the treatment of patients with Parkinson’s and Alzheimer’s diseases.

“There’s something compelling about this disease,” said Marshall. “I feel very close to my patients with Huntington’s disease. I’m inspired by them. To a person, they are courageous and compassionate. Even in the face of something as difficult as Huntington’s disease, my patients preserve a sense of dignity and grace.

“These are people who live every day with the burden of knowing that there is not yet a cure, and that their closest loved ones are themselves at 50/50 risk of getting the disease. Many of them grew up caring for a parent or a sibling with the illness, so they are fully aware of the symptoms and signs of the disease as it progresses. Yet, even in the face of this, they maintain optimism and a sense of humor. It is an honor to be part of the extended community of patients, families, and researchers trying to find a better way forward.”

Abstract

Background: Tetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type 2 vesicular monoamine transporter. Open-label reports indicate TBZ is effective in treating chorea.

Objective: To examine the safety, efficacy, and dose tolerability of TBZ for treating chorea in Huntington disease (HD).

Methods: The authors randomized 84 ambulatory patients with HD to receive TBZ (n = 54) or placebo (n = 30) for 12 weeks. TBZ was increased over 7 weeks up to a maximum of 100 mg/day or until the desired antichoreic effect occurred or intolerable adverse effects supervened. The primary outcome was the change from baseline in the chorea score of the Unified Huntington's Disease Rating Scale (UHDRS)

Results: TBZ treatment resulted in a reduction of 5.0 units in chorea severity compared with a reduction of 1.5 units on placebo treatment (adjusted mean effect size = –3.5 ± 0.8 UHDRS units [mean ± SE]; 95% CI: –5.2, –1.9; p < 0.0001). There was also a significant benefit on ratings of clinical global improvement. There were five study withdrawals in the TBZ group and five serious adverse events (SAEs) in four subjects (drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer) compared with one withdrawal and no SAEs in the placebo group.

Conclusion: Tetrabenazine (TBZ), at adjusted dosages of up to 100 mg/day, effectively lessens chorea in ambulatory patients with Huntington disease. TBZ should be dosed individually based on ongoing assessment of possible adverse side effects.

The Review:

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

Tetrabenazine, a dopamine-depleting agent first synthesized half a century ago, was initially developed for the treatment of schizophrenia. Although psychotic disorders have since been treated more successfully with other neuroleptic medications, many studies have shown this drug to be effective in the treatment of hyperkinetic movement disorders (hyperkinesias). Hyperkinesias are neurologic disorders characterized by abnormal involuntary movements such as chorea associated with Huntington's disease, tics in Tourette's syndrome and stereotypies in tardive dyskinesia. Recently, clinical trials investigating tetrabenazine for the treatment of chorea associated with Huntington's disease found the drug to be safe and efficacious, making approval by the US Food and Drug Administration for this indication a distinct possibility.

Tracked on the Lighthouse:
tetrabenazine

Source: Neuology 2006;66:366-372

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