scholarly journals Long-Term Efficacy and Safety of Deutetrabenazine for Chorea in Huntington’s Disease: Results From the ARC-HD Open-label Study

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 164-165
Author(s):  
Samuel Frank ◽  
Claudia M. Testa ◽  
David Stamler ◽  
Elise Kayson ◽  
David Oakes ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Rating Scale ◽  
Study Drug ◽  
Motor Dysfunction ◽  
Open Label ◽  
Entire Treatment Period ◽  
End Of Treatment ◽  
Pharmaceutical Industries

AbstractBackgroundChorea is a prominent motor dysfunction in Huntington’s disease (HD). Deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is FDA-approved for the treatment of chorea in HD. In the pivotal, 12-week First-HD trial, deutetrabenazine treatment reduced the Unified Huntington’s Disease Rating Scale (UHDRS) total maximal chorea (TMC) score versus placebo. ARC-HD, an open-label extension study, evaluated long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner for treatment of HD chorea.MethodsPatients who completed First-HD (Rollover) and patients who converted overnight from a stable dose of tetrabenazine (Switch) were included. Safety was assessed over the entire treatment period; exposure-adjusted incidence rates (EAIRs; adverse events [AEs] per person-year) were calculated. A stable, post-titration time point of 8 weeks was chosen for efficacy analyses.ResultsOf 119 patients enrolled (Rollover, n=82; Switch, n=37), 100 (84%) completed ≥1 year of treatment (mean [SD] follow-up, 119 [48] weeks). End of study EAIRs for patients in the Rollover and Switch cohorts, respectively, were: any AE, 2.6 and 4.3; serious AEs, 0.13 and 0.14; AEs leading to dose suspension, 0.05 and 0.04. Overall, 68% and 73% of patients in Rollover and Switch, respectively, experienced a study drug–related AE. Most common AEs possibly related to study drug were somnolence (17% Rollover; 27% Switch), depression (23%; 19%), anxiety (9%; 11%), insomnia (10%; 8%), and akathisia (9%; 14%). Rates of AEs of interest include suicidality (9%; 3%) and parkinsonism (6%; 11%). In both cohorts, mean UHDRS TMC score and total motor score (TMS) decreased from baseline to Week 8; mean (SD) change in TMC score (units) was –4.4 (3.1) and –2.1 (3.3) and change in TMS was –7.1 (7.3) and –2.4 (8.7) in Rollover and Switch, respectively. While receiving stable dosing from Week 8 to 132 (or end of treatment), patients showed minimal change in TMC score (0.9 [5.0]), but TMS increased compared to Week 8 (9.0 [11.3]). Upon drug withdrawal, there were no remarkable AEs and TMC scores increased 4.4 (3.7) units compared to end of treatment.ConclusionsThe type and severity of AEs observed in long-term deutetrabenazine exposure are consistent with the previous study. Efficacy in reducing chorea persisted over time. There was no unexpected worsening of HD or chorea associated with HD upon deutetrabenazine withdrawal.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

scholarly journals Evaluation of the Safety of Deutetrabenazine at Higher Doses to Treat Chorea in Huntington’s Disease

CNS Spectrums ◽  
2021 ◽  
Vol 26 (2) ◽  
pp. 162-163
Author(s):  
Samuel Frank ◽  
Christina Vaughan ◽  
David Stamler ◽  
David Oakes ◽  
Mat D. Davis ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Drug Exposure ◽  
Open Label ◽  
Titration Period ◽  
Open Label Extension ◽  
Pharmaceutical Industries ◽  
Post Hoc ◽  
Higher Doses

AbstractBackgroundIn the First-HD pivotal trial, the maximum deutetrabenazine dose evaluated to treat chorea associated with Huntington’s disease (HD chorea) was 48 mg/d, which is the approved maximum dose for this population. In ARC-HD, an open-label extension study evaluating the long-term efficacy and safety of deutetrabenazine to treat HD chorea, dosage ranged from 6 mg/d to 72 mg/d, with doses ≥12 mg/d administered twice daily. Doses in ARC-HD were increased by 6 mg/d per week in a response-driven manner based on efficacy and tolerability until 48 mg/d (Week 8). At the investigator’s discretion, further increases were permitted by 12 mg/d per week to a maximum of 72 mg/d. This post-hoc analysis evaluates the safety and tolerability of deutetrabenazine >48 mg/d compared to ≤48 mg/d to treat HD chorea in ARC-HD.MethodsPatient counts and safety assessments were attributed to patients when they received a dose of either ≤48 mg/d or >48 mg/d. For 9 selected adverse events (AEs), we compared AE rates adjusted for duration of drug exposure (as number of AEs/year) at ≤48 mg/d or >48 mg/d. The AE rates were determined after titration when participants were on stable doses of deutetrabenazine.ResultsAll 113 patients were exposed to doses ≤48 mg/d (177.1 patient-years) and 49 patients were ever exposed to doses >48 mg/d (74.1 patient-years). In patients taking deutetrabenazine >48 mg/d compared to ≤48 mg/d after the titration period, there were no apparent differences in exposure-adjusted AE rates.ConclusionsBased on clinical experience, some patients with HD may benefit from doses higher than 48 mg/d to adequately control chorea. These doses were tolerated without apparent increase in the exposure-adjusted rates of selected AEs after titration. This analysis does not address the occurrence of other AEs or whether adequate efficacy was achieved at lower doses, factors that may have influenced dose increases.FundingTeva Pharmaceutical Industries Ltd., Petach Tikva, Israel

Deep brain stimulation for Huntington's disease: long-term results of a prospective open-label study

2014 ◽  
Vol 121 (1) ◽  
pp. 114-122 ◽  
Author(s):  
Victoria Gonzalez ◽  
Laura Cif ◽  
Brigitte Biolsi ◽  
Sara Garcia-Ptacek ◽  
Anne Seychelles ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Open Label ◽  
Open Label Study ◽  
Label Study ◽  
Deep Brain

Object To date, experience of globus pallidus internus (GPi) deep brain stimulation (DBS) in the treatment of Huntington's disease (HD) has been limited to a small number of case reports. The aim of this study was to analyze long-term motor outcome of a cohort of HD patients treated with GPi DBS. Methods Seven patients with pharmacologically resistant chorea and functional impairment were included in a prospective open-label study from 2008 to 2011. The main outcome measure was the motor section of the Unified Huntington's Disease Rating Scale. The primary end point was reduction of chorea. Results Patients underwent MRI-guided bilateral GPi implantation. The median duration of follow-up was 3 years. A significant reduction of chorea was observed in all patients, with sustained therapeutic effect; the mean improvement on the chorea subscore was 58.34% at the 12-month follow-up visit (p = 0.018) and 59.8% at the 3-year visit (p = 0.040). Bradykinesia and dystonia showed a nonsignificant trend toward progressive worsening related to disease evolution and partly to DBS. The frequency of stimulation was 130 Hz for all patients. DBS-induced bradykinesia was managed by pulse-width reduction or bipolar settings. Levodopa mildly improved bradykinesia in 4 patients. Regular off-stimulation tests confirmed a persistent therapeutic effect of DBS on chorea. Conclusions GPi DBS may provide sustained chorea improvement in selected HD patients with pharmacologically resistant chorea, with transient benefit in physical aspects of quality of life before progression of behavioral and cognitive disorders. DBS therapy did not improve dystonia or bradykinesia. Further studies including quality of life measures are needed to evaluate the impact of DBS in the long-term outcome of HD.

Q07 Long-term safety and tolerability of pridopidine in patients with huntington's disease (HD): results of the mermaihd study open-label extension

2012 ◽  
Vol 83 (Suppl 1) ◽  
pp. A56.3-A57
Author(s):  
F Squitieri ◽  
B Landwehrmeyer ◽  
R Reilmann ◽  
A Rosser ◽  
J Garcia de Yebenes ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Open Label ◽  
Open Label Extension

ABPM Comparison of the Anti-Hypertensive Profiles of Telmisartan and Enalapril in Patients with Mild-to-Moderate Essential Hypertension

2002 ◽  
Vol 30 (6) ◽  
pp. 543-552 ◽  
Author(s):  
J Amerena ◽  
S Pappas ◽  
J-P Ouellet ◽  
L Williams ◽  
D O'Shaughnessy
Keyword(s):  
Blood Pressure ◽  
Essential Hypertension ◽  
Blood Pressure Monitoring ◽  
Study Drug ◽  
Pressure Control ◽  
Moderate Essential Hypertension ◽  
Open Label ◽  
Night Time ◽  
Once Daily

In this multicentre, prospective, randomized, open-label, blinded-endpoint (PROBE) study, the efficacy of 12 weeks' treatment with once-daily telmisartan 40–80 mg and enalapril 10–20 mg was evaluated using ambulatory blood pressure monitoring (ABPM) in 522 patients with mild-to-moderate essential hypertension. Patients were titrated to the higher dose of study drug at week 6 if mean seated diastolic blood pressure (DBP) was ≥ 90 mmHg. The primary endpoint was the change from baseline in ambulatory DBP in the last 6 h of the 24-h dosing interval after 12 weeks' treatment. Telmisartan and enalapril produced similar reductions from baseline in DBP and systolic blood pressure (SBP) over all ABPM periods evaluated (last 6 h, 24-h, daytime and night-time). Telmisartan produced a significantly greater reduction in mean seated trough DBP, measured unblinded with an automated ABPM device in the clinic, amounting to a difference of −2.02 mmHg ( P < 0.01). A significantly greater proportion of patients achieved a seated diastolic response with telmisartan than enalapril (59% versus 50%; P < 0.05), also measured with the same ABPM device. Both treatments were well tolerated. Compared with telmisartan, enalapril was associated with a higher incidence of cough (8.9% versus 0.8%) and hypotension (3.9% versus 1.1%). Therefore, telmisartan may provide better long-term compliance and, consequently, better blood pressure control than enalapril.

scholarly journals Objectively characterizing Huntington’s disease using a novel upper limb dexterity test

2021 ◽  
Author(s):  
Samuel Woodgate ◽  
Philippa Morgan-Jones ◽  
Susanne Clinch ◽  
Cheney Drew ◽  
Rebecca Playle ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Severity ◽  
Convergent Validity ◽  
Rating Scale ◽  
Objective Assessment ◽  
Prognostic Index ◽  
Transfer Task ◽  
Clinical Expertise ◽  
Clinical Scores

Abstract Background The Clinch Token Transfer Test (C3t) is a bi-manual coin transfer task that incorporates cognitive tasks to add complexity. This study explored the concurrent and convergent validity of the C3t as a simple, objective assessment of impairment that is reflective of disease severity in Huntington’s, that is not reliant on clinical expertise for administration. Methods One-hundred-and-five participants presenting with pre-manifest (n = 16) or manifest (TFC-Stage-1 n = 39; TFC-Stage-2 n = 43; TFC-Stage-3 n = 7) Huntington’s disease completed the Unified Huntington’s Disease Rating Scale and the C3t at baseline. Of these, thirty-three were followed up after 12 months. Regression was used to estimate baseline individual and composite clinical scores (including cognitive, motor, and functional ability) using baseline C3t scores. Correlations between C3t and clinical scores were assessed using Spearman’s R and visually inspected in relation to disease severity using scatterplots. Effect size over 12 months provided an indication of longitudinal behaviour of the C3t in relation to clinical measures. Results Baseline C3t scores predicted baseline clinical scores to within 9–13% accuracy, being associated with individual and composite clinical scores. Changes in C3t scores over 12 months were small ($$\Omega$$ Ω ≤ 0.15) and mirrored the change in clinical scores. Conclusion The C3t demonstrates promise as a simple, easy to administer, objective outcome measure capable of predicting impairment that is reflective of Huntington’s disease severity and offers a viable solution to support remote clinical monitoring. It may also offer utility as a screening tool for recruitment to clinical trials given preliminary indications of association with the prognostic index normed for Huntington’s disease.

scholarly journals Direct assessment of presynaptic modulation of cortico-striatal glutamate release in a Huntington’s disease mouse model

2018 ◽  
Vol 120 (6) ◽  
pp. 3077-3084 ◽  
Author(s):  
Ellen T. Koch ◽  
Cameron L. Woodard ◽  
Lynn A. Raymond
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Frequency ◽  
Glutamate Release ◽  
Presynaptic Receptors ◽  
High Frequency Stimulation ◽  
Presynaptic Modulation ◽  
Frequency Stimulation

Glutamate is the main excitatory neurotransmitter in the brain, and impairments in its signaling are associated with many neurological disorders, including Huntington’s disease (HD). Previous studies in HD mouse models demonstrate altered glutamate receptor distribution and signaling at cortico-striatal synapses, and some studies suggest that glutamate release is altered; however, traditional methods to study synaptic glutamate release are indirect or have poor temporal resolution. Here we utilize iGluSnFR, a modified green fluorescent protein reporter for real-time imaging of glutamate transmission, to study presynaptic modulation of cortical glutamate release in the striatum of the YAC128 HD mouse model. We determined that iGluSnFR can be used to accurately measure short- and long-term changes in glutamate release caused by modulation of extracellular Ca2+ levels, activation of presynaptic receptors, and high-frequency stimulation (HFS) protocols. We also confirmed a difference in the expression of HFS-induced long-term depression in YAC128. Together, this research demonstrates the utility of iGluSnFR in studying presynaptic modulation of glutamate release in healthy mice and disease models that display impairments in glutamate signaling. NEW & NOTEWORTHY We use iGluSnFR to directly assess presynaptic modulation of cortico-striatal glutamate release in brain slice and compare changes in glutamate release between wild type and a Huntington’s disease mouse model, YAC128. We observed reductions in glutamate release after low extracellular Ca2+ and activation of various presynaptic receptors. We also demonstrate a presynaptic mechanism of reduced glutamate release in high-frequency stimulation-induced long-term depression and show this to be altered in YAC128.

scholarly journals Early Motor Dysfunction and Striosomal Distribution of Huntingtin Microaggregates in Huntington's Disease Knock-In Mice

2002 ◽  
Vol 22 (18) ◽  
pp. 8266-8276 ◽  
Author(s):  
Liliana B. Menalled ◽  
Jessica D. Sison ◽  
Ying Wu ◽  
Melisa Olivieri ◽  
Xiao-Jiang Li ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Motor Dysfunction
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