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Dose Patterns for Long-Term Deutetrabenazine Treatment in Patients With Tardive Dyskinesia by Baseline AIMS Item 8 Score
- Hadas Barkay, Stacy Finkbeiner, Amanda Wilhelm, Jessica Alexander, Nayla Chaijale, Mark Forrest Gordon
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- Journal:
- CNS Spectrums / Volume 27 / Issue 2 / April 2022
- Published online by Cambridge University Press:
- 28 April 2022, pp. 239-240
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Introduction
The mechanism of tardive dyskinesia (TD) is complex and not well understood. Dopamine-receptor blockade in the nigrostriatal pathway may lead to a hyperdopaminergic state that can interfere with mechanisms of movement control, leading to TD. Medications for the treatment of movement disorders, including TD, typically require fine-tuning of doses to optimize control of abnormal movements; however, doses are often not titrated sufficiently. The vesicular monoamine transporter 2 inhibitor deutetrabenazine is an FDA-approved treatment for TD in adults. This post hoc analysis examined dosing patterns in patients with TD according to baseline Abnormal Involuntary Movement Scale (AIMS) item 8 score, a clinician-rated global judgment of the overall severity of abnormal movements.
MethodsPatients who completed the pivotal 12-week studies, ARM-TD and AIM-TD, were eligible to enroll in the 3-year, open-label extension study. Deutetrabenazine was initiated at 12 mg/day and titrated in a response-driven manner on a weekly basis in intervals of 6 mg/day for 6 weeks, up to a maximum dose of 48 mg/day, based on dyskinesia control and tolerability. Further dose adjustments during the long-term maintenance period were permitted on a weekly basis. Subgroups were defined by AIMS item 8 scores of either 0/1/2 or 3/4 at baseline. Total daily dose categories and treatment exposure over time were evaluated in each subgroup.
ResultsA total of 336 patients were included in the analysis (baseline AIMS item 8 scores 0/1/2, n = 117; scores 3/4, n = 219). At week 15, the proportions of patients by deutetrabenazine total daily dose (mg) for scores 0/1/2 and 3/4, respectively, were: <24, 10% and 3%; ≥24 to ≤36, 41% and 48%; >36 to ≤48, 49% and 49%. At week 54, proportions by total daily dose (mg) for scores 0/1/2 and 3/4, respectively, were: <24, 11% and 4%; ≥24 to ≤36, 42% and 41%; >36 to ≤48, 46% and 55%; >48, 1% and 0. Similar patterns were observed at weeks 106 and 145 across total daily dose categories. For scores 0/1/2, mean ± SE total daily dose (mg) at weeks 15, 54, 106, and 145, respectively, was 36.9 ± 1.04 (n = 108), 37.1 ± 1.22 (n = 90), 37.7 ± 1.32 (n = 76), and 37.9 ± 1.44 (n = 64). For scores 3/4, mean ± SE total daily dose (mg) at weeks 15, 54, 106, and 145, respectively, was 39.2 ± 0.65 (n = 186), 39.8 ± 0.75 (n = 150), 40.3 ± 0.88 (n = 112), and 40.5 ± 0.99 (n = 97).
ConclusionDosing decisions in the treatment of TD are individualized, as treatment response is likely driven by complex factors. Findings from this analysis suggest that in order to achieve adequate control of TD symptoms, patients benefit from response-driven titration of deutetrabenazine to doses >24 mg/day, regardless of the baseline severity of abnormal movements assessed by AIMS item 8. These results highlight the importance of patient-driven titration of deutetrabenazine until adequate movement control is achieved, while maintaining safety/tolerability in the treatment of TD.
FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Deutetrabenazine Reduces Severe Tardive Dyskinesia Movements in a 3-year Open-Label Extension Trial
- Nayla Chaijale, Joseph Bona, Hadas Barkay, Amanda Wilhelm, Mark Forrest Gordon
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, p. 156
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Background
There are no established treatment guidelines for tardive dyskinesia (TD) based on movement severity. The 12-week ARM-TD and AIM-TD studies in TD patients with baseline Abnormal Involuntary Movement Scale (AIMS) total score (items 1–7) ≥6 showed clinically significant improvements in AIMS score with deutetrabenazine versus placebo. Patients who completed these studies were eligible for the open-label extension (OLE) trial. This post-hoc analysis evaluated deutetrabenazine in TD patients with severe movements.
MethodsSubgroups were defined by upper quartile of baseline total AIMS score (local rating). Endpoints were: change and percent change from baseline in AIMS score, and percent of patients achieving ≥50% AIMS reduction from baseline.
Results337 patients were analyzed. The upper quartile of baseline total AIMS score was 14. Subgroups were defined as >14 and ≤14 at baseline, respectively (n=64 vs 273); data are presented at Week 145 (n=40 vs 120). Mean treatment duration was 880.5 and 760.8 days. Mean±SE daily doses were 41.1±1.6mg and 38.9±1.0mg. Mean±SE change from baseline in AIMS score was –11.0±0.8 versus –5.1±0.3; percent change from baseline was –60.1%±3.6% versus –55.9%±3.0%. More patients with AIMS score >14 had ≥50% AIMS reduction (73% vs 65%). Less patients discontinued (38% vs 51%); reasons included withdrawal by subject (16% vs 25%), adverse event (3% vs 11%), and lost to follow-up (6% vs 7%). Withdrawal due to lack of efficacy was uncommon (5% vs 2%).
ConclusionsPatients with baseline total AIMS score >14 had clinically meaningful reductions in AIMS score, suggesting deutetrabenazine has long-term benefit in these patients.
FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Long-Term Safety and Efficacy of Deutetrabenazine in Younger and Older Patients With Tardive Dyskinesia
- Martha Sajatovic, Amanda Wilhelm, Stacy Finkbeiner, Hadas Barkay, Nayla Chaijale, Nicholas Gross, Mark Forrest Gordon
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 10 May 2021, pp. 157-158
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Background
Tardive dyskinesia (TD) is an involuntary movement disorder that is more prevalent in older patients. However, there is limited information on TD treatment for this population. In two 12-week pivotal trials (ARM-TD and AIM-TD), TD patients demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) score with deutetrabenazine versus placebo.
MethodsPatients who completed ARM-TD or AIM-TD enrolled in an open-label extension (OLE) study. This post hoc analysis assessed change and percent change from baseline in AIMS score, response rates for ≥50% AIMS improvement, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety in younger (<55 years) and older (≥55 years) patients.
ResultsThis analysis included 119 younger and 218 older patients enrolled in the OLE. Data presented at Week 145 (mean±SE): total deutetrabenazine dose was 39.4±1.39mg/day and 39.5±1.04mg/day in younger and older patients, respectively. Changes from baseline in AIMS score were –6.7±0.62 and –6.5±0.47, respectively (percent changes of –61.4%±4.10% and –54.6%±3.01%). The majority of younger and older patients achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%) and achieved ≥50% AIMS response (76% and 62%). Deutetrabenazine was generally well tolerated in both groups. Exposure-adjusted incidence rates (incidence/patient-years) were <0.01 and 0.02 for akathisia, 0.07 (both) for somnolence and sedation, 0.04 and 0.11 for parkinson-like events, and 0.06 and 0.09 for depression in younger and older patients, respectively.
ConclusionsDeutetrabenazine treatment was associated with sustained improvements in AIMS score and was well tolerated in both younger and older TD patients.
FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Comparison of Safety and Tolerability of Deutetrabenazine During Titration and Maintenance in Patients with Tardive Dyskinesia
- Amanda Wilhelm, Karen E. Anderson, Hubert H. Fernandez, Hadas Barkay, Nayla Chaijale, Alexander F. Send, Juha-Matti Savola, Mark Forrest Gordon
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- Journal:
- CNS Spectrums / Volume 26 / Issue 2 / April 2021
- Published online by Cambridge University Press:
- 30 April 2021, p. 164
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Background
Deutetrabenazine is approved to treat tardive dyskinesia (TD) in adults and is titrated weekly by 6 mg/day, from 12 to 48 mg/day, based on dyskinesia control and tolerability. This analysis compared the safety of deutetrabenazine during titration versus maintenance.
MethodsSafety was assessed during titration versus maintenance using integrated data from two 12-week placebo-controlled studies (ARM-TD and AIM-TD) and the open-label extension study. Rates were compared for overall and serious adverse events (AEs), AEs leading to discontinuation, treatment-related AEs, common AEs (≥4%), and specific AEs (parkinsonism, suicidal ideation, akathisia, restlessness).
ResultsIn titration versus maintenance, AE rates with placebo (n=130) were: overall, 43.1% vs 25.4%; serious, 4.6% vs 2.3%; leading to discontinuation, 3.1% vs 0; treatment-related, 26.9% vs 10.0%. For placebo, common AEs during titration were somnolence, headache, nausea, fatigue, and dry mouth; none occurred during maintenance. In titration versus maintenance, AE rates in fixed-dose deutetrabenazine 12–36 mg (n=216) were: overall, 33.3–38.9% vs 22.2–29.2%; serious, 2.8–6.9% vs 0–1.4%; leading to discontinuation, 2.8–5.6% vs 0; treatment-related, 8.3–16.7% vs 8.3–13.9%. For fixed-dose deutetrabenazine, common AEs during titration were headache, diarrhea, nasopharyngitis, depression, hypertension, and dry mouth; headache was the only common AE during maintenance. In titration versus maintenance, AE rates with flexible-dose deutetrabenazine (n=168) were: overall, 49.4% vs 32.7%; serious, 3.6% vs 2.4%; leading to discontinuation, 2.4% vs 0.6%. For flexible-dose deutetrabenazine, the only common AE during titration was somnolence; none occurred during maintenance. Rates of parkinsonism, suicidal ideation, akathisia, and restlessness were low and comparable in titration and maintenance.
ConclusionsDeutetrabenazine was well-tolerated, with AE rates similar to placebo during both phases; AE rates were higher during titration and decreased during maintenance.
FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel