Clinical Neuropharmacology
`Vol. 25, No. 6, pp. 300–302
`© 2002 Lippincott Williams & Wilkins, Inc., Philadelphia
`
`Tetrabenazine Treatment for Huntington’s
`Disease-Associated Chorea
`
`William G. Ondo, Ron Tintner, Madhavi Thomas, and Joseph Jankovic
`
`Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
`
`Summary: Tetrabenazine (TBZ), a monoamine depleter and dopamine receptor
`blocker, is used to treat a variety of hyperkinetic movement disorders. The objective was
`to study the efficacy and tolerability of TBZ for chorea associated with Huntington’s
`disease (HD). Nineteen patients (12 female), mean age 56.3 ± 12.4 years (range 37–76
`years) diagnosed with HD were prospectively evaluated at initial and follow-up visits
`using a modified Abnormal Involuntary Movement Scale (AIMS). Patients were video-
`taped, and the randomized videotapes were rated with the motor subset of the AIMS by
`two investigators who were blinded to treatment assignment. Eighteen patients com-
`pleted and were rated after 5.9 ± 3.3 months (range 2–11) at a final mean TBZ dose of
`62.5 ± 37.4 mg/day (range 25–150). The blinded videotaped motor scores showed that
`15 were better on TBZ, 2 were better before TBZ, and 1 was unchanged (p < 0.001,
`Wilcoxon signed rank test). The mean score improved from 16.2 ± 4.8 to 12.8 ± 4.4.
`Adverse events included akathisia, insomnia, constipation, depression, drooling, and
`subjective weakness. All 18 of these patients have continued to take TBZ since comple-
`tion of the study. TBZ was well tolerated and resulted in a significant improvement in
`modified AIMS scores in HD patients. These results support the use of TBZ for chorea
`in patients with HD. Key Words: Huntington’s disease—Tetrabenazine—Chorea
`
`Tetrabenazine (TBZ) inhibits presynaptic dopamine
`release and blocks postsynaptic dopamine receptors. It
`has been used for decades to treat a variety of hyperki-
`netic movement disorders, including Huntington’s dis-
`ease (HD) (1–12). Nevertheless, relatively little con-
`trolled data have been reported. Furthermore, as a result
`of marketing and financial factors, the drug remains
`largely unavailable in the United States. We conducted
`a blinded trial comparing randomized videotapes to test
`the efficacy of TBZ for the treatment of HD associated
`chorea.
`
`METHODS
`
`Patients diagnosed with HD, who reported disability
`specifically due to chorea, were recruited from the Bay-
`lor College of Medicine Parkinson’s Disease Center
`and Movement Disorders. Many patients were refrac-
`
`Address correspondence and reprint requests to Dr. William Ondo,
`6550 Fannin, Suite 1801, Houston, TX 77030, USA. E-mail:
`wondo@bcm.tmc.edu.
`
`tory to other medical treatments, but this was not a spe-
`cific inclusion criteria. The diagnosis of HD was con-
`firmed by expanded CAG repeat testing in 17 patients
`and based on a typical clinical presentation with posi-
`tive testing in other family members in 2. Tetrabena-
`zine was obtained from the supplier (Cambridge
`Laboratories, London, UK) under one of the authors’
`(J.J.) claimed Investigational Exemption for a New
`Drug (IND).
`Patients underwent neurologic history and examina-
`tion, and signed informed consent forms. They were
`videotaped while sitting (whole body and facial close-
`up), talking, arms forward, and walking (approxi-
`mately 3 minutes). Tetrabenazine was then started at a
`dose of 12.5 mg twice daily (25 mg/day) and titrated up
`to a maximum of 50 mg three times a day (150 mg/day)
`in weekly increments. Patients were instructed to stop
`increasing the dose if they experienced satisfactory
`benefit at their current dose and/or if adverse events
`(AE) became troublesome. Patients were not allowed
`to change any other medicines during the study period.
`They were asked to return in approximately 4 months,
`
`300
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`Apotex Ex. 1020
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`Apotex v. Auspex
`IPR2021-01507
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`TETRABENAZINE TREATMENT FOR CHOREA
`
`301
`
`but this varied due to geographic constraints. During
`their re-evaluation, patients underwent global assess-
`ments (including caregiver input), AE assessments,
`neurologic examinations, and repeat videotaping. Any
`AE experienced during titration or at the clinic visit
`were reported.
`Upon completion of enrollment, the videotapes were
`edited, randomized, and coded. Two separate investi-
`gators (M.T., R.T.) who were not otherwise involved
`with patient management and who were blinded to
`treatment assignment rated the pre-TBZ and post-TBZ
`videos using the motor section of the AIMS (questions
`1–7) (13). The mean of the two scores was used for
`statistical analysis. Audio was not allowed, as this
`could have jeopardized blinding in several cases.
`Patient evaluations included the video randomized
`blinded motor subscore (1–7) of the AIMS, global im-
`pressions, and AE. The Wilcoxon signed rank test was
`used to compare pretreatment and posttreatment
`scores.
`
`RESULTS
`
`Nineteen patients (12 female), age 56.3 ± 12.4 (range
`41–76 years) were enrolled. One patient was lost to fol-
`low-up and is not otherwise included in the analysis.
`Patients had a mean of 43.0 ± 2.6 CAG repeats and had
`an 8.1 ± 5.3-year duration of HD symptoms (Table 1).
`The initial symptoms were chorea (10), psychiatric (5),
`balance difficulties (2), and loss of dexterity (1). The
`Mini Mental Status Examination (MMSE) at entry into
`the study averaged 24.5 ± 3.8. Thirteen of the 19 pa-
`
`tients had tried 21 total medications specifically for
`chorea prior to study entry. None of the medications
`were felt to be satisfactory to the patient.
`The patients were subsequently evaluated 5.9 ± 3.3
`months (range 2–11) after starting TBZ at a mean final
`dose of 62.5 ± 37.4 mg/d (range 25–150). Twelve pa-
`tients divided their total dose into three doses per day,
`and six patients took two doses per day. Patients sub-
`jectively rated themselves as markedly improved (7),
`moderately improved (7), mildly improved (3), and un-
`changed (1). No patient who completed the evaluation
`felt that his or her condition had worsened. The blinded
`videotaped motor subscores showed that 15 patients
`improved on TBZ, 2 were better before TBZ, and 1 was
`unchanged (p < 0.001, Wilcoxon signed rank test). The
`mean motor AIMS score improved from 16.2 ± 4.8 to
`12.8 ± 4.4. Adverse events included akathisia (3), in-
`somnia, constipation, depression, drooling, and subjec-
`tive weakness. No patient complained of motor slow-
`ing or any other Parkinsonian symptom. All AE, except
`one case of akathisia, which improved immediately
`upon reduction of the dose, were rated as mild. All 18
`patients have continued to take TBZ since completion
`of the study.
`
`DISCUSSION
`
`We report a single blinded trial of TBZ for the man-
`agement of chorea in 18 patients with HD. In our popu-
`lation, TBZ was an effective and well-tolerated
`treatment.
`Our results concur with those of open-label (1–9)
`
`TABLE 1. Patient demographics and treatment responses
`
`Sex
`
`F
`F
`M
`M
`F
`M
`F
`F
`F
`M
`M
`F
`F
`F
`F
`M
`F
`F
`mean
`s.d.
`
`Age
`
`42
`49
`66
`55
`76
`40
`58
`73
`62
`60
`46
`69
`55
`47
`41
`72
`65
`37
`56.2
`12.4
`
`Duration of
`HD SX (years)
`
`CAG
`repeat
`
`TBZ dose
`(mg/day)
`
`Previous
`chorea medicines
`
`3
`9
`8
`17
`8
`20
`2
`6
`12
`4
`1
`9
`13
`8
`3
`3
`13
`6
`8.1
`5.3
`
`46
`46
`41
`42
`41
`
`43
`40
`43
`
`42
`41
`43
`42
`44
`40
`44
`50
`43.0
`2.6
`
`25
`37.5
`25
`75
`37.5
`150
`75
`75
`50
`75
`75
`50
`150
`75
`50
`25
`50
`25
`62.5
`37.4
`
`tram
`
`hal, narc
`hal
`ris, hal, bac, alp
`
`ris
`hal, clon
`flu
`clon
`
`alp, val
`flu, lor
`
`flu
`val
`
`Subject
`response
`
`Moderate
`Marked
`Moderate
`Marked
`None
`Moderate
`Mild
`Marked
`Mild
`Moderate
`Marked
`Moderate
`Marked
`Moderate
`Mild
`Mark
`Moderate
`Mark
`
`Pre-TBZ
`aims
`
`Post-TBZ
`aims
`
`Delta
`aims
`
`11
`17.5
`15
`28
`21.5
`22
`12.5
`16.5
`22
`15.5
`8.5
`13.5
`15.5
`16
`16.5
`11
`12
`16.5
`16.2
`4.8
`
`8
`10.5
`12
`18
`19
`20.5
`9
`11.5
`18.5
`7.5
`13
`14
`5.5
`14
`16.5
`9.5
`9
`15
`12.8
`4.4
`
`3
`7
`3
`10
`2.5
`1.5
`3.5
`5
`3.5
`8
`−4.5
`−0.5
`10
`2
`0
`2.5
`3
`1.5
`3.3
`3.6
`
`alp = alprazolam, bac = baclofen, clon = clonidine, flu = fluphenazine, hal = haloperidol, lor = lorazepam, narc = various narcotics, ris = risperidone,
`tram = tramadol, val = valproate
`
`Clin. Neuropharmacol., Vol. 25, No. 6, 2002
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`302
`
`W. G. ONDO ET AL.
`
`and smaller, partially controlled and controlled trials
`(10–12). Tetrabenazine also compares favorably to
`other medications used to treat HD chorea (10–12) and
`has been reported to have synergistic effects when used
`in combination with the dopamine antagonist pimo-
`zide. (14) Furthermore, long-term data suggests that its
`benefit persists for a longer duration when used for HD
`compared to other hyperkinetic disorders (1,9).
`Adverse events were mild but generally similar to
`those previously documented. Specifically, no patient
`became Parkinsonian, and only one patient felt that
`mood worsened. This likely resulted from the relatively
`low doses used in our flexible dosing schedule. Patients
`with Huntington’s disease may also be less likely to
`experience typical TBZ associated AE because they
`have chorea, which intuitively lessens the risk of drug-
`induced Parkinsonism, and they are middle aged, rather
`than at age extremes. In our experience, that age group
`has the fewest AE. Tetrabenazine has never been re-
`ported to cause tardive dyskinesia (TD). This is particu-
`larly important because HD patients may be predis-
`posed to develop TD with typical dopamine antago-
`nists (12).
`Tetrabenazine, a benzoquinolizine derivative, de-
`pletes presynaptic dopamine, norepinephrine, and se-
`rotonin storage and antagonizes postsynaptic dopamine
`receptors. Oral absorption is relatively poor and erratic
`(15,16). The serum half-life after oral ingestion is ap-
`proximately 6 hours, but this is also highly variable
`(15,16). The drug subsequently undergoes first-pass
`metabolism to dihydrotetrabenazine (DTBZ), which
`appears to have similar pharmacologic activity. Serum
`levels of this compound are much higher than the par-
`ent compound, it is less protein bound, and the half-life
`is consistently around 10 hours. Therefore, it is possible
`that most of the clinical effects result from DTBZ. In-
`dividual response may also depend upon specific
`monoamine transporter types. (17)
`Potential shortcomings of our clinical design include
`the limitations of video rating, which tend to blunt
`subtle differences in movement. The chorea in HD is
`also variable and influenced by the immediate sur-
`roundings. Our experience is that HD patients gener-
`ally show less chorea when knowingly videotaped.
`This could lessen differences in the motor examina-
`tions and possibly weaken our results. The AIMS scale
`was predominately designed to evaluate TD and there-
`fore may under-represent extremity movements rela-
`tive to facial movements, again possibly blunting ap-
`parent efficacy. Our patients were largely referred from
`
`other neurologists after failing conventional treatment
`and therefore may be biased toward more severe cases.
`We only evaluated chorea and only in HD patients for
`whom it was a major feature of their disease. Chorea,
`however, represents only one feature of HD, and this
`may not be the major cause of disability. Therefore,
`these results should not be extrapolated to suggest that
`TBZ helps all HD patients. Finally, this was not a pla-
`cebo-controlled trial.
`Nevertheless, given the fairly consistent benefit and
`good tolerability shown in this study, we feel that TBZ
`should be considered for the symptomatic treatment of
`chorea in HD.
`
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