Nature Reviews | Drug Discovery

cis rac–1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one; C19H27NO3; Mr = 317.43

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fresh from the pipeline

Tetrabenazine Michael R. Hayden, Blair R. Leavitt, Uma Yasothan and Peter Kirkpatrick Tetrabenazine

In August 2008, tetrabenazine (Xenazine; Ovation Pharmaceuticals/Biovail) was approved by the US FDA for the treatment of chorea associated with Huntington’s disease. This makes it the first treatment to be approved in the US for a symptom of this neurodegenerative disorder.

Huntington’s disease, an inherited neurological disorder that affects approximately 1 in 10,000 people in the United States, is characterized by progressive motor dysfunction, cognitive decline and psychiatric disturbances1. It is caused by a CAG repeat expansion in the HD gene, which results in an expanded polyglutamine sequence in the encoded protein huntingtin (HTT)1,2. The initial consequences include degeneration of medium spiny neurons in the striatum, which is important in the control of movement1,2. The movement disorder in Huntington’s disease consists of abnormal involuntary movements (chorea or dystonia), and impairment of voluntary movement1. Motor symptoms can also include rigidity, bradykinesia, eye movement abnormalities and gait dysfunction1.

The molecular mechanisms underlying the pathogenic effects of mutant HTT are being elucidated2,3, but so far, no treatments have been proven to delay the onset or halt the progression of Huntington’s disease4. However, treatment of chorea associated with Huntington’s disease with drugs that decrease dopaminergic neurotransmission can improve the quality of life for patients with the disease. Neuroleptics such as haloperidol have been used for this purpose for many years, but are associated with extrapyramidal side effects4. Tetrabenazine (FIG. 1), a monoamine-depleting agent, has also long been available as a treatment for such disorders in countries including the UK, Canada and Australia4–8. In August 2008, it was also approved in the US.

Basis of discoveryTetrabenazine was first introduced in the 1960s as an antipsychotic. Although it was not widely used in this respect, it was found to be beneficial in hyperkinetic movement disorders, and it also seemed not to be associated with extrapyramidal side effects that are characteristic of neuroleptics4–7. This provided the rationale for its use in the treatment of chorea associated with Huntington’s disease. However, until recently, there had been no randomized, double-blind, placebo-controlled trials demonstrating its efficacy specifically for this indication.

Drug propertiesThe precise mechanism underlying the antichorea effects of tetrabenazine is not clear. However, it is thought to be related to depletion of monoamines from nerve terminals due to the ability of tetrabenazine to reversibly inhibit the human vesicular monoamine transporter 2 (VMAT2)9–11. This transporter is responsible for the translocation of monoamines such as dopamine from the cytoplasm into synaptic vesicles for storage and subsequent release9,10.

Clinical dataThe safety and efficacy of tetrabenazine as a treatment for the chorea associated with Huntington’s disease was studied

in a randomized, double-blind, placebo-controlled trial involving 84 ambulatory patients with a diagnosis of Huntington’s disease based on family history, neurological exam and genetic testing10,11. The duration of treatment was 12 weeks, including a 7-week dose titration period and a 5- week maintenance period, followed by a 1-week washout period10,11. The dose of tetrabenazine was started at 12.5 mg per day and was titrated upwards in 12.5 mg increments at weekly intervals until satisfactory control of chorea was achieved, until intolerable side effects occurred, or until a dose of 100 mg per day was reached10,11. The primary efficacy outcome was the change from baseline in the chorea score of the Unified Huntington’s

Disease Rating Scale10,11. On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for seven different parts of the body, and the total score ranges from 0 to 28.

Overall, treatment with tetrabenazine resulted in a reduction of 5.0 units in chorea severity compared with a reduction of 1.5 units for treatment with placebo10,11. Tetrabenazine-treated patients were more likely to have any given degree of improvement in chorea score than patients receiving placbeo10,11. For example, about 50% of tetrabenazine-treated patients had a 6-point or greater improvement compared with 7% of placebo-treated patients10,11. Tetrabenazine was also superior to placebo with regard to the secondary efficacy outcome of physician-rated Clinical Global Impression (CGI) Global Improvement Scale, with an adjusted effect size (improvement) of –0.7 CGI units on this 7-point scale11.

Tetrabenazine can amplify the increased risk of depression and suicidal thoughts and behaviour already seen in patients with Huntington’s disease. The drug label contains a black-box warning highlighting this risk10.

IndicationsTetrabenazine is approved by the FDA for the treatment of chorea associated with Huntington’s disease10. ▶

Figure 1 | Tetrabenazine. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter 2 (VMAT2), with a K

i

value of ~100 nM, resulting in reduced uptake of monoamines such as dopamine into synaptic vesicles and depletion of monoamine stores9,10. Human VMAT2 is also inhibited by dihydrotetrabenazine, the major circulating metabolite of tetrabenazine10.

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AnAlysis | huntIngton’s DIsease▶

Box 1 | Market for antichorea therapy for huntington’s disease

Analysing the market for antichorea therapy for huntington’s disease is Uma yasothan, ims health, london, UK.

huntington’s disease, a hereditary neurodegenerative disorder that affects more than 15,000 people in north America, typically onsets between 35 and 45 years of age, although symptoms can develop in those aged younger than 20 or older than 60 (ReF. 13). the average lifespan after onset of disease is 10–20 years.

tetrabenazine (Xenazine; ovation pharmaceuticals/Biovail), a monoamine-depleting agent that has been in clinical use in several countries for decades, was approved in the Us for the treatment of chorea associated with huntington’s disease in August 2008. it is in a unique situation as the first fDA-approved treatment for this indication, launching into a market with no other approved competitor presence currently and none anticipated in the next few years. moreover, tetrabenazine has 7-year market exclusivity owing to its approval in the orphan disease category. in addition, prescriber comfort for tetrabenazine could be anticipated to be high given its extensive previous clinical use for chorea associated with huntington’s disease in non-Us markets.

ims data show that sales of tetrabenazine in european and Canadian markets in 2007 were Us$9 million and $5.5 million14, respectively. With the Us huntington’s disease market valued at $600 million and an estimated 90% of patients with huntington’s disease suffering from chorea, analysts’ estimate peak annual sales for tetrabenazine of $150 million15. furthermore, tetrabenazine might also have potential for use in hyperkinetic disorders, for which it is currently in clinical trials.

Analysing issues in the treatment of Huntington’s disease are Blair R. leavitt, M.D., C.M., Associate Professor, Department of Medical Genetics and Michael R. Hayden, M.D., Professor of Medical Genetics, Centre for Molecular Medicine and Therapeutics, University of British Columbia, Canada.

Chorea in Huntington’s disease was historically treated by manipulating dopaminergic neurotransmission using typical neuroleptics. Haloperidol was considered first-line therapy, although no adequately controlled clinical trials were performed confirming its effectiveness. Treatment with typical neuroleptics carries considerable risk of adverse events, and some patients develop extrapyramidal side effects. Neuroleptics can also exacerbate cognitive impairment, rigidity, bradykinesia and dysphagia in advanced disease, and their use should be time-limited and carefully monitored. These side effects mimic the symptoms associated with natural progression of the disease, and so care must therefore be taken to distinguish them from each other.

The standard treatment options for chorea in Huntington’s disease now include the atypical antipsychotics — which are unlikely to cause extrapyramidal symptoms, but are associated with other side effects such as weight gain — and/or tetrabenazine. However, other therapeutic strategies are occasionally used for reducing chorea, including benzodiazepines and the NMDA (N-methyl-d-aspartate) antagonist amantadine. In our opinion, the medical treatment of the involuntary movement

disorder in Huntington’s disease is only indicated when chorea has a significant impact on daily function.

The trial data published by the Huntington Study Group demonstrated that tetrabenazine was clinically effective in suppressing involuntary movements in Huntington’s disease over a 12-week period11, thereby supporting the clinical experience of many clinicians in Canada and around the world1,4. A secondary analysis also suggested that the suppression of chorea by tetrabenazine may have functional benefit, as indicated by a significant improvement on the CGI Global Improvement Scale. However, no properly controlled study has assessed whether suppression of chorea in Huntington’s disease has functional benefit, and the lack of correlation between functional decline and the progression of chorea in Huntington’s disease has been noted12.

The most common dose-dependent adverse effects of tetrabenazine are drowsiness, insomnia and akathesia. extrapyramidal side effects occur with tetrabenazine, but less frequently than with typical neuroleptics. There are no published reports of neuroleptic malignant syndrome caused by tetrabenazine, although this remains a theoretical risk. The most serious potential adverse events caused by tetrabenazine are depression and suicide, and the frequent co-morbidity of depression and chorea limits the clinical utility of tetrabenazine in Huntington’s disease. longitudinal studies of tetrabenazine treatment are needed to assess the long-term benefits or risks.

Clinical experience indicates that tetra benazine is most effective in suppressing

chorea when slowly titrated to the maximally tolerated dose. Tetrabenazine dose should be individualized and frequently re-evaluated, as patients may require dose reduction with advancing disease. The functional benefit of suppressing chorea has not been definitively demonstrated, and the potential for rare serious adverse effects (including depression and suicide) must be carefully weighed against the potential benefit when initiating symptomatic therapy with tetrabenazine.

At present, there are no treatments that can alter the progression of Huntington’s disease. However, several agents aimed at achieving this goal are currently being investigated in ongoing randomized placebo-controlled studies, including creatine, coenzyme Q10 and minocycline.

Blair R. Leavitt and Michael R. Hayden are at the Centre for Molecular Medicine and Therapeutics,

Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue,

Vancouver, British Columbia V5Z 4H4, Canada.

Uma Yasothan is at IMS Health, 7 Harewood Avenue, London NW1 6JB, UK.

Peter Kirkpatrick is at Nature Reviews Drug Discovery.

e-mails: mrh@cmmt.ubc.ca; UYasothan@de.imshealth.com; p.kirkpatrick@nature.com

doi:10.1038/nrd2784

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3. Graham, R. K. et al. Cleavage at the caspase 6 site in huntingtin is required for motor dysfunction, neurodegeneration and excitotoxicity in Huntington Disease. Cell 125,1179–1191 (2006).

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5. Quinn, G. P., Shore, P. A. & Brodie, B. B. Biochemical and pharmacological studies of RO1-9569 (tetrabenazine), a non-indole tranquilizing agent with reserpine-like effects. J. Pharmacol. Exp. Ther. 127, 103–109 (1959).

6. Dalby, M. A. Effect of tetrabenazine on extrapyramidal movement disorders. BMJ 2, 422–423 (1969).

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12. Frank, S. et al. Functional decline due to chorea in Huntington’s disease. Neurology 62, A204 (2004).

13. National Institute of Neurological Disorders and Stroke (NINDS). Huntington’s disease: hope through research. NINDS web site [online],

<http://www.ninds.nih.gov/disorders/huntington/detail_huntington.htm#130613137> (2008).

14. IMS MIDAS (2007).15. Gibbs, L. NewCrest Biovail Research Report (New Crest,

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