FormalPara Key Points

The findings of this post hoc analysis of the ARC-HD open-label study suggest that for some participants (42%) with chorea in Huntington disease who received a deutetrabenazine dosage above the approved maximum of 48 mg/d, higher dosages were not associated with increase of exposure-adjusted incidence rates of adverse events of interest.

Participants who took deutetrabenazine in ARC-HD were able to achieve a response [on the basis of total maximal chorea (TMC) score], regardless of their baseline score; however, those who switched from tetrabenazine required higher dosages of deutetrabenazine if they had high baseline TMC scores.

Titrating to higher dosages within the approved dose range (maximum dosage 48 mg/d) while closely monitoring for safety and tolerability can help ensure that participants receive the full benefit of treatment with deutetrabenazine.

1 Introduction

Huntington disease (HD) is a hereditary neurodegenerative disorder that affects motor and cognitive function and causes behavioral/emotional disturbances [1,2,3,4,5]. Chorea is the hallmark visible motor symptom of HD, affecting approximately 90% of adult patients over the course of their disease [6,7,8], and can potentially increase the risk of injury, cause social isolation, and impede daily function [2, 7, 8]. Currently, no treatment exists for the underlying disease process in HD, but chorea can be managed with approved treatments such as the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine, deutetrabenazine, or valbenazine [9,10,11], and off label with treatments as published in the scientific literature [12].

Deutetrabenazine, a novel, highly selective VMAT2 inhibitor, is approved by the United States Food and Drug Administration (US FDA) and countries such as Australia, Brazil, Israel, and China for the treatment of adults with chorea in HD or tardive dyskinesia (TD). The recommended maximum dosage is 48 mg/d (24 mg twice daily), or 36 mg/d (18 mg twice daily) if patients are poor metabolizers of cytochrome P450 2D6 (CYP2D6) or are receiving concomitant, strong CYP2D6 inhibitors [9, 13].

In the randomized, double-blind, placebo-controlled First Time Use of Deutetrabenazine in Huntington Disease (First-HD; ClinicalTrials.gov Identifier: NCT01795859) study [14], deutetrabenazine significantly improved motor signs as measured by Unified Huntington’s Disease Rating Scale® total maximal chorea (TMC) scores. Results from First-HD also demonstrated an overall improvement in quality of life compared with placebo, as measured by Patient Global Impression of Change (PGIC), Clinician Global Impression of Change (CGIC), and 36-Item Short Form–physical functioning subscale scores (SF-36) at 12 weeks, and had a comparable safety profile with placebo. The Alternatives for Reducing Chorea in Huntington Disease (ARC-HD; ClinicalTrials.gov Identifier: NCT01897896) open-label study [15] evaluated the long-term safety and efficacy of deutetrabenazine dosed in a response-driven manner up to 72 mg/d for the treatment of chorea in HD. ARC-HD comprised two cohorts: participants who switched overnight from tetrabenazine (the switch cohort) and those who were previously taking deutetrabenazine as part of the First-HD study (the rollover cohort). Deutetrabenazine maintained and improved chorea control with a favorable benefit–‍risk profile across the dosage range (6–72 mg/d) in both cohorts.

This post hoc analysis of the ARC-HD study was performed to investigate differences, if any, in deutetrabenazine safety and efficacy between dosages > 48 mg/d and ≤ 48 mg/d among participants who received higher dosages. This analysis can support decision-making on risk/benefit assessment when determining dose adjustments.

2 Methods

2.1 Study Design, Participants, and Interventions

ARC-HD was an open-label, single-arm, two-cohort, multicenter study. It was conducted from November 2013 to August 2017 at 37 sites in the USA, Canada, and Australia and consisted of two cohorts: the rollover cohort and the switch cohort. The study design and inclusion criteria for both studies have been described previously [14,15,16]. Briefly, the Rollover cohort comprised participants who had successfully completed First-HD [14], including participants randomly assigned to placebo and those randomly assigned to deutetrabenazine for 12 weeks. Key inclusion criteria for First-HD were age ≥ 18 years, HD diagnosis with at least moderate chorea (TMC score ≥ 8 and a total functional capacity [TFC] score ≥ 5), and no tetrabenazine use for ≥ 6 months prior to screening. Participants were required to have daily access to a caregiver, or a live-in caregiver in more advanced cases (TFC score 5–7). In ARC-HD, participants in the rollover cohort completed a 1-week washout period before initiating deutetrabenazine (6 mg/d), followed by re-titration for 8 weeks. Dosages could be titrated up or down in weekly increments of 6 mg/d up to 48 mg/d. After a dosage of 48 mg/d was reached, weekly changes of 6 or 12 mg/d [up or down, up to a maximum of 72 mg/d (36 mg twice daily)] were permitted at the investigator’s discretion to reach an optimal, individualized dosage on the basis of efficacy and tolerability. Dosages of 6 mg/d were administered once daily in the morning, and dosages ≥ 12 mg/d twice daily, approximately 10 h apart. If participants were receiving a strong CYP2D6 inhibitor (e.g., paroxetine, bupropion, or fluoxetine), the maximum dosage of deutetrabenazine was 42 mg/d (21 mg twice daily).

The switch cohort included participants with chorea in HD who enrolled in ARC-HD de novo and had been on a stable dosage of tetrabenazine with therapeutic benefit (although the benefit may have been suboptimal) for ≥ 8 weeks. These participants were converted overnight from tetrabenazine to deutetrabenazine. Initial deutetrabenazine dosages were calculated with a protocol-specified algorithm hypothesized to provide comparable systemic exposure to their previous stable tetrabenazine dosage [15, 16]. Participants in the switch cohort remained on their initial deutetrabenazine dosages for 1 week, after which dose adjustments could be made up to week 4, with an extended dose-adjustment period up to week 8. Similar to the rollover cohort, weekly adjustments (up or down) in increments of 6 mg/d up to 48 mg/d and of 6 or 12 mg/d up to 72 mg/d were permitted. For both cohorts, the stable-dose period was defined as week 8 through the last dose of study drug.

2.2 Safety Assessments

Safety and tolerability were assessed during in-clinic study visits and telephone study visits from the time informed consent was received through the end of follow-up (4 weeks after last dose of study drug) [15]. For this post hoc analysis, adverse events (AEs) of interest were evaluated using the following groupings of preferred terms: akathisia (including akathisia, hyperkinesia, psychomotor hyperactivity, restlessness, and agitation [preferred terms]), parkinsonism (including akinesia, bradykinesia, cogwheel rigidity, freezing phenomenon, hypertonia, masked facies, muscle rigidity, on and off phenomenon, parkinsonian crisis, parkinsonian gait, parkinsonian rest tremor, parkinsonism, Parkinson disease, and resting tremor [preferred terms]), fall, dysphagia (including aphagia and dysphagia [preferred terms]), somnolence, insomnia, anxiety, depression (including all preferred terms containing “depression”), and suicidality (including completed suicide, suicidal depression, intentional overdose, intentional self-injury, deliberate poisoning, self-injurious ideation, suicidal behavior, suicidal ideation, and suicide attempt [preferred terms]). Participant data (from both cohorts) were divided into two sets according to daily dosage: all participants, and participants who ever received dosages > 48 mg/d during the stable-dose period. AEs of interest reported during the stable-dose period (where dosages > 48 mg/d would be expected) were analyzed according to daily dosage (≤ 48 mg/d and > 48 mg/d) at the time of the AE report. Additionally, the temporal relationships (if any) between AE reports and dosage increases for participants who had dosage increases > 6 mg/d (at the discretion of the investigator) were evaluated.

2.3 Efficacy Assessments

In ARC-HD, changes in TMC and TMS scores from baseline to week 8 (titration period) and during the stable-dose period were evaluated [15]. Because baseline observations for participants who switched overnight from tetrabenazine to deutetrabenazine (switch cohort) were made while the participants were on different stable dosages of tetrabenazine, post hoc efficacy analyses were performed separately for the rollover and switch cohorts for the entire study period (titration and stable-dose periods). The lowest dosage needed for a TMC response (defined as ≥ 30% improvement from baseline in TMC score) was determined and plotted against baseline TMC score. Additionally, for each dosage level, the number of participants for whom that dosage was the lowest dosage sufficient to elicit a TMC response during the entire study period was assessed, and the cumulative proportions of participants who achieved a TMC response, by dose, were calculated. These analyses were also performed for participants with baseline TMC scores above and below the median value to determine whether there was a relationship between baseline TMC score and the dosage needed to achieve a TMC response.

2.4 Statistical Analysis

Exposure-adjusted incidence rates (EAIRs) for AEs reported during the stable-dose period (starting at visit 4/week 8) were used for analysis. EAIRs were calculated as the ratio of the number of individuals with the given AE divided by the total exposure time up to the end of follow-up (AEs per person-year) [17]. Comparisons between dosages are summarized as rate ratio (95% CI). The 95% CIs were calculated separately for each AE, assuming a uniform Poisson rate among participants while receiving the lower deutetrabenazine dosage and a different rate while receiving the higher dosage. Only participants who had baseline and post-baseline TMC scores were included in the efficacy analyses.

3 Results

3.1 Participants' Characteristics

In total, 136 participants were screened in the ARC-HD study, of whom 119 were administered the study drug (82 in the rollover cohort and 37 in the switch cohort); of those, 116 entered the stable-dose period. In the rollover and switch cohorts, 77 and 35 participants, respectively, had both baseline and post-baseline TMC scores and were included in the efficacy analyses. When comparing baseline characteristics between the two participants groups (all participants and those who had ever received dosages > 48 mg/day during the stable-dose period, respectively), the average (SD) ages of participants were 53.3 (12.0) and 50.5 (12.3) years, respectively. The majority of participants were male (56% and 57%), white (94% and 96%), and had normal body mass indexes (BMIs) (mean [SD]) at screening (25.2 [4.70] and 24.8 [5.1] kg/m2) (Table 1). The average (SD) ages of participants in the rollover and switch cohorts were 53.7 (12.3) and 52.4 (11.5) years, respectively. The majority of participants were male (rollover cohort, 55%, and switch cohort, 59%), white (93% and 97%), and had normal BMIs at screening (25.8 kg/m2 and 23.9 kg/m2) (Table 1). Overall, 100 participants (84%) completed ≥ 1 year of deutetrabenazine treatment, and 81 participants (68%; 56 in the rollover cohort and 25 in the switch cohort) completed the study [15].

Table 1 Baseline characteristics
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3.2 AEs of Interest

Of the 116 participants who entered the stable-dose period, 49 had ever received (at least once during the stable-dose period) a deutetrabenazine dosage > 48 mg/d. EAIRs for AEs of interest were compared in the following two analyses: (1) among all participants, when receiving ≤ 48 mg/d (exposure = 177.7 person-years) versus when receiving > 48 mg/d (exposure = 74.1 person-years) and (2) among participants who had ever received dosages > 48 mg/d, when receiving ≤ 48 mg/d (exposure = 37.9 person-years) versus > 48 mg/d (exposure = 74.1 person-years). In general, no apparent differences in EAIRs were observed for participants who received deutetrabenazine dosages ≤ 48 mg/d compared with > 48 mg/d among the full set of participants at the time of AE occurrence, or in those who ever received a dosage > 48 mg/d during the stable-dose period (Fig. 1). Among participants who ever received a dosage > 48 mg/d during the stable-dose period, the highest rate ratio observed was for akathisia (rate ratio, 2.56 [95% CI 0.29–121.14]), suggesting that akathisia might be more common when receiving dosages > 48 mg/d; however, the CI ranges reported are wide.

Fig. 1
figure 1

AE rates by daily dosage at AE onset. AE adverse event, EAIR exposure-adjusted incidence rate, NE not estimable, PY person-years, RR rate ratio. aArrows indicate upper limits of the CIs that extend beyond the x-axis range

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3.3 Safety for Participants with Dosage Increases of More Than 6 mg/d

After a daily dosage of 48 mg was reached, further weekly changes of 6 or 12 mg/d (up or down) were permitted at the investigator’s discretion, up to a maximum dosage of 72 mg/d (36 mg twice daily). Out of the 49 participants who were ever assigned daily dosages of > 48 mg/d, 37 participants received only dosage increases of 6 mg/d and 12 participants received a mixture of dosage increases (6 mg/d and > 6 mg/d); no participants received only > 6-mg/d increases. Two participants reported AEs (akathisia and insomnia) within 2 days of a dosage increase from 48 to 60 mg/d. In each of these cases, the investigator considered the AE to be at least possibly related to study drug, but not serious, and thus continued to increase the dosage by an additional 12 mg/d 5 days later, although the AEs were still present.

In a separate case, a participant reported intermittent gagging and intermittent insomnia (both considered possibly related to study drug but not serious) 13 and 41 days, respectively, after an increase from 42 to 48 mg/d; the dosage was further increased by 12 mg/d 46 days later, although the AEs were still present. A total of 26 days later, the participant reported additional intermittent worsening anxiety (considered possibly study-drug related but not serious), but the dosage was not adjusted further. Another participant’s dosage was increased from 30 to 48 mg/d on day 41 because of a dosing titration error (documented as a minor protocol deviation). No AEs were reported following this increase; however, the dosage was subsequently decreased by 12 mg/d 11 days later. The remainder of AEs (e.g., insomnia, somnolence, falls, depression, and irritability) that were reported as soon as 6 days after a 12-mg/d dosage increase were not considered serious and did not prompt a further dosage decrease, regardless of their duration or relationship to study drug.

3.4 Efficacy

Changes in efficacy, based on TMC response from baseline throughout the study (week 0 to week 145), were compared within the rollover cohort and switch cohort separately to avoid potential confounding of the results from previous exposure to tetrabenazine for participants in the switch cohort. For the majority of participants in the rollover cohort, the lowest dosage sufficient to show a TMC response was between 24 and 48 mg/d (n = 57 [74.0%]) (Fig. 2). For some participants (n = 6 [7.8%]), this dosage was lower (between 6 and 18 mg/d), whereas others (n = 9 [11.7%]) received higher dosages (between 54 and 72 mg/d) (Fig. 2).

Fig. 2
figure 2

Lowest deutetrabenazine dosage needed for a TMC responsea. a Rollover cohort, b switch cohort. TMC total maximum chorea. aTMC response was considered a ≥ 30% improvement from baseline and was assessed in participants with both baseline and post-baseline TMC scores (rollover cohort, n = 77; switch cohort, n = 35)

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Most (> 50%) participants needed to reach a dosage of ≥ 36 mg/d to achieve at least a 30% improvement in TMC (Fig. 3). At a dosage of ≤ 48 mg/d, more than 80% of participants achieved a TMC response, and at ≤ 72 mg/d, the proportion of TMC responses was more than 90%. No meaningful differences were observed between participants with baseline TMC scores above and below the median value (11.0). Participants were able to achieve TMC responses regardless of their baseline TMC score, and no relationship between the two factors was observed (Fig. 4).

Fig. 3
figure 3

Cumulative proportion of participants with a TMC responsea by deutetrabenazine dosage. a rollover cohort, b switch cohort. TMC total maximum chorea. aTMC response was considered a ≥ 30% improvement from baseline and was assessed in participants with both baseline and post-baseline TMC scores (rollover cohort, n = 77; switch cohort, n = 35). Baseline TMC score median value = 11.0 (rollover cohort) and 12.5 (switch cohort)

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Fig. 4
figure 4

Lowest dosage needed for a TMC responsea by baseline TMC score, a rollover cohort, b switch cohort. TMC total maximum chorea. aTMC response was considered a ≥ 30% improvement from baseline and was assessed in participants with both baseline and post-baseline TMC scores (rollover cohort, n = 77; switch cohort, n = 35). Dot size on the chart is representative of the number of participants at that point

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Although the switch cohort comprised a smaller number of participants, similar results were observed as with the rollover cohort, except for a slight trend where participants with baseline TMC scores above the median of 12.5 received higher dosages (median dosage, 60 mg/d) to achieve TMC response (Figs. 2, 3, 4).

4 Discussion

This post hoc analysis was conducted to evaluate safety and efficacy among participants who received deutetrabenazine treatment with dosages above the maximum approved dosage of 48 mg/d in the ARC-HD study, where titration to dosages up to 72 mg/d was allowed at the investigator’s discretion on the basis of efficacy and tolerability. In the ARC-HD study, participants who received deutetrabenazine dosages > 48 mg/d showed no apparent increases in EAIRs of AEs of interest compared with dosages ≤ 48 mg/d. There were no observed patterns between the timing of AEs and dosage increases of ≥ 12 mg/d. While a minority of participants in this study achieved their therapeutic response goal with a lower dosage, most participants (74.0%) achieved a TMC response (≥ 30% improvement from baseline) when taking deutetrabenazine dosages between 24 and 48 mg/d. Similar minimal efficacious dose ranges were observed for most participants in the pivotal (First-HD) [14] and long-term (ARC-HD) [15] deutetrabenazine studies. However, some participants (11.7%) in the ARC-HD study achieved a TMC response at higher dosages (54–72 mg/d). Overall, these data highlight the importance of adequate titration to an effective and tolerable dosage.

The limited use of the 42-mg/d dosage in this study may be explained by the convenience of the lower number of tablets that need to be taken to arrive at daily dosages of 36 or 48 mg compared with 42 mg, which required the highest number of pills of the dosages evaluated in the study. Convenience, along with safety of the dosing range, may have moved participants to doses lower or higher than 42 mg. Some patients may not experience full efficacy at specific doses, but the flexibility of the deutetrabenazine dose range allows physicians to modify the treatment to a dose that is both tolerable and most efficacious for the patient.

These data do not indicate baseline TMC score as a predictor of deutetrabenazine dose required for response, but rather that stable doses differ between individuals and that patients should be treated on the basis of their individualized response and treatment history, which may be influenced by factors such as concomitant medication and overall HD stage [9].

TMC is a useful tool for measuring overall severity of involuntary movements, however, the location and impact of these movements may vary between patients [18]. To supplement TMC data, future research may consider more granular and/or composite measures that encompass additional aspects of the patient experience, such as patients finding ways to control their involuntary movements and thereby decreasing their impact. Some limitations of the analyses presented here may be that ARC-HD was an open-label study that did not include a control group, and that these analyses are post hoc and not powered for comparison. In addition, study participants may have received dosages > 48 mg/d for a limited period of time.

A slight trend was observed for the switch cohort, where participants with higher baseline TMC scores required higher dosages to achieve TMC responses. This could be explained by the fact that baseline TMC values for these participants were recorded while the participants were being treated with tetrabenazine (in contrast to the rollover cohort, where participants had a 1-week washout period). Participants were able to achieve TMC response regardless of baseline TMC score. These results are similar to those in the Reducing Involuntary Movements in Participants With Tardive Dyskinesia (RIM-TD; ClinicalTrials.gov Identifier: NCT01795859) study, where participants with TD benefited from deutetrabenazine in the same way, regardless of baseline Abnormal Involuntary Movement Scale (AIMS) scores [19].

Because of the complexity and lack of treatment options available for neurodegenerative diseases, there is a clear need for novel strategies for treatment of the symptoms. Individualized treatment to help patients achieve optimal response (accomplished by response-driven dosing) is growing in importance for both clinicians and patients as part of seeking overall improvement in the quality of life of patients [20]. Achieving this improvement is complex, considering that HD and chorea affect patients in different ways. Optimal dosages cannot be generalized across a patient population for which chorea is among a triad of symptoms [21], although, in the context of HD, the presence of chorea itself affects emotional, interpersonal, and professional functioning [22]. This study provides clinicians and patients with information about the safety and efficacy of higher deutetrabenazine dosages. In this study, dosages above the maximal approved therapeutic dosage (48 mg/d) were explored. The data reinforce the safety and tolerability of the different deutetrabenazine dosages, including higher ones. Treating patients with dosages higher than the approved therapeutic dosage may offer greater benefits while retaining the tolerability profile. It may also mitigate early treatment discontinuation and non-adherence because of a lack of efficacy. Additionally, these long-term safety and efficacy results from ARC-HD can enhance physicians’ and patients’ understanding of possible chorea improvement and AEs on higher deutetrabenazine dosages while adhering to the approved dosing regimen.

5 Conclusions

The results of these post hoc analyses of the ARC-HD open-label study show the efficacy and safety profile of participants with chorea in HD who received doses higher than the ones currently approved. Patients who receive higher deutetrabenazine dosages should be closely monitored for safety and tolerability. Response-driven and flexible dosing may increase the number of patients with chorea in HD who achieve therapeutic benefit.