ABSTRACT
Background
Dystonia may respond to VMAT2 inhibition.
Objectives
Providing pilot data on the safety, tolerability, and efficacy of deutetrabenazine in non dopa‐responsive dystonia.
Methods
Deutetrabenazine was titrated by adults with isolated dystonia. Primary study endpoints included the proportion who maintained the individual, maximum tolerated dose for 6 weeks, and how many titrated to 48 mg/day. Secondary endpoints included rates of QTc prolongation/arrhythmias, suicidality, excessive daytime sleepiness, cognitive decline, and drug‐induced parkinsonism. Exploratory endpoints for clinical efficacy were assessed.
Results
Among 15 participants, four (26.7%) withdrew early and six (40%) titrated to 48 mg/day. Common adverse events included fatigue and diarrhea. Secondary safety endpoints did not change significantly, but MDS‐UPDRS III scores worsened by ≥3 points in seven participants (46.7%). PGI‐C and the blinded CGI‐C and GDS improved in three women with blepharospasm.
Conclusions
Most participants tolerated deutetrabenazine for 6 weeks, and those with blepharospasm may have benefitted from its use.
Keywords: isolated dystonia, clinical trial, VMAT2 inhibitor, deutetrabenazine
Deutetrabenazine (a VMAT2 inhibitor currently FDA‐approved for the treatment of Huntington's chorea and tardive dyskinesia in adults), may have a role in dystonia treatment. 1 , 2 , 3 , 4 , 5 We herein report the results of a study to assess its safety, tolerability and potential efficacy in dystonia.
Methods
This 13‐week, single‐center, open‐label, phase I/II trial involved adults (ages 18–80) with isolated, non‐dopa‐responsive dystonia (non‐DRD) in any distribution, as diagnosed by a movement disorders specialist. During titration (ie, between visits 1 and 3), deutetrabenazine (DTBZ) was started at 6 mg twice daily (during Visit 1) and increased weekly by increments of 6 mg/day (ie, 18–24–30–36–42–48 mg/day) until either (1) participants titrated to 48 mg/day, or (2) dose‐limiting side effects emerged. Once the maximal, well‐tolerated individual dose was established, participants were expected to complete six continuous weeks on this dose during the so‐called “maintenance period” (ie, between visits 3 and 4), followed by a 1‐week washout (starting with the last DTBZ dose administered the morning of Visit 4 and ending on Visit 5). For patients titrating to 48 mg/day, the first week on this dose (week 7) counted towards the first week of maintenance. Drug accountability and adverse event (AE) monitoring were performed telephonically during titration. Visits 2 (a week after DTBZ initiation) and 5 were safety visits.
Inclusion Criteria
Eligible participants lacked hypersensitivity or contraindication to DTBZ (or its components), had to score >24 on the Mini‐Mental State Examination (MMSE), read and understand English, provide informed consent, and comply with study procedures, treatment and follow‐up. Stable doses of central nervous system‐acting medications for ≥30 days prior to screening (and for the trial's duration) were allowed. Prohibited medications included dopamine blockers (including antipsychotics and antiemetics), other VMAT2 inhibitors, dopamine agonists, strong anticholinergics and agents potentially interacting with DTBZ. Participants receiving botulinum toxin injections (BoNT) could enroll if >11 weeks had lapsed from the time of their last injections, if they maintained their injection paradigm identical to the previous one, and received injections immediately after Visit 1.
Exclusion Criteria
Participants with possible tardive dystonia, genetically confirmed DRD (or a history of levodopa‐responsive dystonic symptoms), a concurrent diagnosis of parkinsonism, any significant psychiatric, neurologic or cardiac disease, or any unstable medical illness were excluded. Males with a corrected QT (QTc‐Bazett‐) interval of ≥450 (458) milliseconds, and females with ≥460 (472) milliseconds, as documented on a 12‐lead electrocardiogram (ECG) during Visit 1, were also excluded. Pregnancy was exclusionary, and females of child‐bearing age had to agree to using contraception. Finally, participants could not have participated in another study ≤30 days prior to screening.
Endpoints
The primary endpoints were the percentage of participants completing 6 weeks of maintenance therapy, as well as the number able to titrate to 48 mg/day.
Secondary safety endpoints were QTc prolongation/arrhythmias, suicidality, excessive daytime sleepiness, cognitive decline, and drug‐induced parkinsonism. AEs were monitored and reported. Dose reductions, suspensions, and withdrawals due to AEs were recorded.
ECGs, Columbia Suicide Severity Rating Scale (C‐SSRS) and Stanford Sleepiness Scale (SSS) scores were obtained at every visit. The MMSE, MDS‐Unified Parkinson's Disease Rating Scale part III (MDS‐UPDRS III) and dystonia video examinations were captured during visits 1, 4 and the early termination visit. All assessments were done before receiving BoNT injections.
Participant videos followed the Dystonia Study Group (DSG) Videotape examination protocol. 6 Videos were anonymized and raters (W.A., A.L., M.S., T.F.T., P.V.) were blinded to visit number and recording date. Videos from each subject were reviewed by one rater. Video data informed the 7‐point Clinical Global Impression of Change (CGI‐C) and the Global Dystonia Scale (GDS) scores, while participants rated changes in their dystonia through the 7‐point Patient Global Impression of Change (PGI‐C). These scales allowed the identification of “true responders,” defined as participants demonstrating improvements in these three scales.
The study was conducted in accordance with good clinical practice at the University of Pennsylvania's Parkinson Disease and Movement Disorders Center in Philadelphia, PA, USA (ClinicalTrials.gov NCT04173260). Permits were obtained for all licensed scales. Institutional Review Board approval was obtained, and all participants provided written informed consent.
Statistical Analysis
Data from 15 participants who received DTBZ were summarized using medians (and interquartile range [IQR]) for continuous variables and count (%) for categorical variables. Differences in safety outcomes were assessed with Mann–Whitney tests, using the online Mann–Whitney U Test Calculator (https://www.socscistatistics.com/tests/mannwhitney/).
Results
Baseline Demographics and Clinical Characteristics
Seventeen participants consented for participation between April 2021 and December 2023, but two were excluded. Table 1 lists the demographics and clinical characteristics of the participants enrolled.
TABLE 1.
Baseline demographics and clinical characteristics
| Demographic/clinical characteristic | Median (IQR) | N (%) |
|---|---|---|
| Age (years) | 63 (15) | |
| Sex | ||
| Female | 11 (73.3) | |
| Male | 4 (26.7) | |
| Race | ||
| White | 12 (80) | |
| Black or African American | 2 (13.3) | |
| Asian | 1 (6.7) | |
| Disease duration (years) | 15 (26) | |
| Baseline blinded GDS | 8 (10) | |
| Dystonia distribution and management | ||
| Focal | ||
| Cervical dystonia | 5 (33.3) | |
| Blepharospasm | 1 (6.7) | |
| Leg | 1 (6.7) | |
| Multifocal | ||
| Bibrachial | 1 (6.7) | |
| Segmental | ||
| Cranio‐cervical | 3 (20) | |
| Cranio‐laryngo‐brachial | 1 (6.7) | |
| Cranio‐cervico‐laryngeal | 1 (6.7) | |
| Cranio‐cervico‐brachial | 1 (6.7) | |
| Cervico‐laryngeal | 1 (6.7) | |
| Generalized | 0 (0) | |
| BoNT use within previous 3 months | 11 (73.3) | |
| Currently using oral medications for dystonia | 14 (93.3) | |
| Genetic status | ||
| Unknown | 11 (73.3) | |
| No known dystonia‐causing variant found | 2 (13.4) | |
| VPS13D (heterozygous pathogenic variant carrier) | 1 (6.7) | |
| SCN1A (heterozygous variant of unknown significance carrier) | 1 (6.7) | |
| Medications used for the management of dystonia | ||
| Benzodiazepines | 8 (53.3) | |
| Baclofen | 1 (6.7) | |
| Gabapentin | 2 (13.3) | |
| Muscle relaxants | 1 (6.7) | |
| NSAIDs | 11 (73.3) | |
| Acetaminophen | 7 (46.7) | |
| Participants on strong CYP2D6 inhibitors | 0 (0) | |
Primary Endpoints
Eleven (73.3%) participants completed 6 weeks of maintenance. The reasons for early termination included: worsening dystonic symptoms (n = 2, 13.3%), SARS‐CoV‐2 infection (n = 1, 6.7%), and hives (n = 1, 6.7%). Six participants (40%) titrated deutetrabenazine to 48 mg/day. The median DTBZ dose was 36 mg/day (range 18–48 mg) for the entire cohort.
Secondary Safety Endpoints
No statistically significant changes were observed in any of the secondary safety endpoints; no participants developed suicidality. Although the MDS‐UPDRS III scores worsened by ≥3 points in seven participants (46.7%), none reported bothersome parkinsonism. Single cases of 20‐point QTc prolongation and 5‐point SSS worsening were seen. All instances of QTc prolongation resolved by Visit 5, and continued follow up of this cohort demonstrated resolution of all drug‐induced parkinsonism cases.
Adverse Events
All participants encountered ≥1 AE, most commonly fatigue (6 participants), diarrhea (2 participants) and worsening dystonia (2 participants). Rarer AEs attributed to DTBZ use (and not to BoNT injections, when applicable) included hives, somnolence, forgetfulness, headache and dyspepsia. There were no serious AEs (SAEs). Since participants were recruited during the COVID‐19 pandemic, it was unsurprising that three contracted SARS‐CoV‐2.
Exploratory Clinical Efficacy Endpoints
Table 2 summarizes the measured dystonia severity changes among participants. PGI‐C scores improved in 7 (46.7%) while CGI‐C scores in 6 (40%). There was agreement between the PGI‐C and the CGI‐C for six participants (40%), defined as the direction of the change (ie, improvement, no change or worsening), independent of its magnitude. Five participants (33.3%) demonstrated agreement on the PGI‐C, CGI‐C and GDS percentage of change. Blinded video assessments detected improvements in the GDS in four participants (26.7%).
TABLE 2.
Overview of exploratory efficacy endpoints
| Participant | Age/Gender | Dystonia distribution | PGI‐C a | Blinded CGI‐C b | PGI‐C/CGI‐C agreement | Blinded GDS (SC) | Blinded GDS (EM/T) | Blinded GDS % change c | PGI‐C/CGI‐C/GDS agreement |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 71/F | Focal (CD) | 3 (I) | 3 (I) | Yes | 2 | 2 | 0 | No |
| 2 | 69/M | Focal (CD) | 4 (N) | 4 (N) | Yes | 6 | 6 | 0 | Yes |
| 3 | 60/M | Focal (CD) | 4 (N) | 5 (W) | No | 4 | 4 | 0 | No |
| 4 | 29/F | Segmental (cra‐lar‐bra) | 3 (I) | 4 (N) | No | 24 | 25 | +4.2 | No |
| 5 | 68/M | Segmental (cra‐cerv) | 4 (N) | 5 (W) | No | 11 | 12 | +9.1 | No |
| 6 | 45/M | Focal (CD) | 5 (W) | 6 (W) | Yes | 8 | 13 | +62.5 | Yes |
| 7 | 57/F | Segmental (cra‐cerv) | 2 (I) | 3 (I) | Yes | 14 | 13 | −7.1 | Yes |
| 8 | 72/F | Segmental (cra‐cerv) | 2 (I) | 5 (W) | No | 7 | 9 | +28.6 | No |
| 9 | 65/F | Segmental (cra‐cerv‐bra) | 3 (I) | 4 (N) | No | 5 | 5 | 0 | No |
| 10 | 63/F | Focal (Bleph) | 1 (I) | 2 (I) | Yes | 24 | 12 | −50 | Yes |
| 11 | 74/F | Focal (CD) | 4 (N) | 6 (W) | No | 3 | 6 | +100 | No |
| 12 | 54/F | Multifocal (Bi‐bra) | 4 (N) | 3 (I) | No | 8 | 8 | 0 | No |
| 13 | 51/F | Focal (leg) | 4 (N) | 5 (W) | No | 3 | 5 | +66. 7 | No |
| 14 | 68/F | Segmental (cerv‐lar) | 5 (W) | 3 (I) | No | 10 | 8 | −20 | No |
| 15 | 57/F | Segmental (cra‐cerv‐lar) | 2 (I) | 3 (I) | Yes | 22 | 20 | −9.1 | Yes |
Abbreviations: Bleph, Blepharospasm; bra, brachio; cerv, cervico; cra, cranio; CD, Cervical Dystonia; (EM/T), end of maintenance or early termination; (I), improvement; lar, laryngo; (N), no change; (SC), screening, (W), worsening.
PGI‐C scoring interpretation: 1: Dystonia is very much better; 2: Dystonia is much better; 3: Dystonia is a little better; 4: There is no change in dystonia severity; 5: Dystonia is a little worse.
CGI‐C scoring interpretation: 2: Dystonia is much better at the end of maintenance; 3: Dystonia is a little better at the end of maintenance; 4: There is no change in dystonia severity; 5: Dystonia is a little better at screening; 6: Dystonia is much better at screening.
Negative change indicates improvement in blinded dystonia GDS scoring when comparing the end of maintenance (or early termination) video to the screening video, zero indicates no change and positive change indicates worsening in blinded dystonia GDS scoring when comparing the end of maintenance (or early termination) video to the screening video.
“True Responders”
Three female participants (participants 7, 10 and 15 in Table 2, who were on maintenance doses of 48, 36 and 42 mg/day, respectively) were identified as “true responders,” as defined previously. With a median age of 57 (range 57–63), all exhibited upper face involvement, either focally (ie, blepharospasm) or as part of segmental dystonia (cranio‐cervical or cranio‐cervico‐laryngeal). Furthermore, all reported additional symptomatic relief when compared to the prior BoNT injection cycle and expressed interest in continuing DTBZ use after trial completion. Notably, all also demonstrated MDS‐UPDRS III score deterioration during Visit 4 (median 10‐point increase, range 2–13).
Discussion
This study showed that, at the individual maximal dose, >70% of participants with isolated focal, multifocal, or segmental dystonia tolerated 6 weeks of uninterrupted DTBZ treatment. Moreover, 40% titrated up to 48 mg/day. While all participants experienced AEs, most were mild (none were SAEs) and only 20% of them withdrew due to AEs. Fatigue was the most common AE, but it did not lead to study discontinuation, and median SSS scores between visits 1 and 4 did not change significantly (P = 0.77).
Two of the participants who withdrew from the study (participants number 5 and 6 in Table 2) did so due to perceived DTBZ‐related worsening of dystonia. Furthermore, participant 6 exhibited worsening on the PGI‐C, CGI‐C and GDS, suggesting a clinically meaningful change. We suspect this reflects the pathophysiological diversity inherent to dystonia, where only a subset may result from excessive dopaminergic transmission. 7
Most trial participants experienced cervical dystonia (33.3%), mirroring its prevalence in the general population. 8 While efficacy was an exploratory endpoint, we witnessed varied responses to DTBZ, as indicated by the PGI‐C scores: one participant reported mild improvement, three reported no change, and one reported significant worsening. Within the confines of the limited sample size, these findings were unexpected given the resemblance of “phasic” cervical dystonia to chorea. 9 , 10 We suspect torticollis‐related pain 11 may have played a role in our findings, since DTBZ lacks analgesic properties, and modest motor improvements may have been overlooked.
In contrast, blepharospasm is painless, and subtle reductions in eye closure may yield clinically relevant visual improvements. This may explain why all “true responders” exhibited upper face dystonia, and it is plausible that this is a phenotype that responds to VMAT2 inhibition. 12
Our study had several limitations, including a small sample size and an open‐label design. Additionally, genetic testing was not required, and we cannot exclude having recruited DRD patients inadvertently. We also cannot ascertain whether patients without improvements after 12 weeks of DTBZ exposure would improve with longer use.
Whereas participants were allowed to continue their BoNT injections, visits 1 and 4 (during which exploratory efficacy assessments were conducted), coincided with the final days of the injection cycles for most individuals. Moreover, since participants were familiar with the degree of benefit (and side effects) provided by their injections, we doubt this confounder had a significant impact in our findings.
We also cannot exclude a placebo response among participants who reported improvement beyond what objective assessments would indicate. Interestingly, of the four participants with >20% worsening in GDS scores (participants 6, 8, 11, and 13 in Table 2), only one of them (participant 6) rated their dystonia as worse on the PGI‐C, perhaps suggesting comorbidities or non‐motor symptoms could have contributed to their perceptions of dystonia severity. Additionally, blinded evaluators occasionally indicated no change in CGI‐C scores despite discernible variations in GDS scores, and vice versa, which may reflect limitations in our scales' sensitivity and correlation.
Lastly, we cannot exclude that our edited, anonymized videos missed aspects of dystonia that could have been detected during live examinations, despite our strict adherence to the DSG Videotape examination protocol. 6 Videos were necessary to maintain our raters’ blinding.
In summary, deutetrabenazine demonstrated safety and acceptable tolerability among most study participants with isolated non‐DRD. Whereas fatigue, SARS‐CoV‐2 infection and diarrhea were reported, there was no statistically significant worsening in any of our safety outcomes, and no SAEs were recorded. Our data also suggests that individuals with upper facial dystonia may benefit from the use of deutetrabenazine, but randomized controlled trials will be necessary to confirm this potential.
Author Roles
(1) Research project: A. Conception, B. Organization, C. Execution. (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique. (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.
A.D.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B.
W.A.: 1C, 2C, 3B.
C.C.: 1C, 3B.
A.L.: 1C, 3B.
A.O.: 1C, 3B.
M.S.: 1C, 3B.
T.F.T.: 1C, 3B.
P.V.: 1C, 3B.
A.S.: 1A, 1B, 3B.
Disclosures
Ethical Compliance Statement: The Institutional Review Board at the University of Pennsylvania reviewed and approved the study. Written informed consent was obtained from every participant. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflict of Interest: The authors independently designed and conducted the study and prepared the manuscript. The study described in this manuscript was funded as an investigator sponsored study by Teva Branded Pharmaceutical Products, R&D, Inc. who provided a courtesy medical review of the manuscript. AD, MD, MSEd, FAAN, in his role as Associate Professor of Clinical Neurology at the University of Pennsylvania, served as Principal Investigator for this investigator sponsored study. The authors have no other conflicts of interest to disclose.
Financial Disclosures for the Previous 12 Months: AD has received clinical trial funding from Teva Pharmaceuticals, Prevail therapeutics, Cerevel therapeutics, the Dystonia Coalition and Lundbeck Pharmaceuticals. He has participated in advisory boards by Supernus Pharmaceuticals, Abbvie Pharmaceuticals and Amneal Pharmaceuticals. He has received royalties from UpToDate and Elsevier. He has received consulting honoraria from Genus Lifesciences and Manifold Bio. WA has received clinical trial funding from Genentech, Inc./F. Hoffman‐La Roche. She also receives an editorial stipend from Neurology®. CC has nothing to disclose. AL has nothing to disclose. AO has nothing to disclose. MS has received clinical trial funding from USWorldMeds/Supernus, Abbvie Inc, Takeda Pharmaceuticals, Praxis Precision Medicines, Bial, and Scion Neurostim. She has participated in advisory boards for Medtronic and Boston Scientific. She has received royalties from UpToDate. TFT has received grants from the NIH (K23NS114167, P30AG072979) and research support in the form of clinical trial funding (Fox Bio NET 044, Site PI) from The Michael J. Fox Foundation, and the Parkinson Foundation (PDGENEration, Site PI). TT serves as a clinical trial advisory board member for Bial and has received travel expense reimbursement from the Parkinson Study Group and the Parkinson Foundation. PV has received funding for travel from Medtronic. AS has been a consultant to Acadia, Boerhinger‐Ingelheim, GE Healthcare, Wave Life Sciences, Inhibikase, Prevail, Mitzubishi and Alertity Therapeutics. He has served on DSMBs for the Huntington Study Group and The Healey ALS Consortium (Massachusetts General Hospital). He has received grant funding from the Michael J. Fox Foundation, NIA and NINDS.
Acknowledgment
We express our gratitude to all participants for their involvement in this study, especially considering the challenges posed by the COVID‐19 pandemic.
Data Availability Statement
The data that support the findings of this study are available from Teva Pharmaceuticals. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of Teva Pharmaceuticals.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from Teva Pharmaceuticals. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from the author(s) with the permission of Teva Pharmaceuticals.