Selecting dopamine depleters for hyperkinetic movement disorders: how do we choose?

KEYWORDS:

• Deutetrabenazine
• hyperkinetic
• movement disorders
• tetrabenazine
• valbenazine
• VMAT2 inhibitor

1. Introduction

The group of hyperkinetic movement disorders (MD) is characterized by abnormal involuntary movements including dystonia, chorea, athetosis, ballism, tics, tremors, myoclonus and stereotypies [1]. The etiology of these MDs can be classified as acquired (e.g. vascular, inflammatory, tumorous, drug-induced), hereditary (e.g. Huntington’s disease; HD) and idiopathic (e.g. Tourette syndrome) forms. In a few cases of acquired hyperkinetic MDs, the underlying pathology can be treated, whereas in the rest of them only symptomatic therapies are available to reduce the amplitude and frequency of abnormal movements [1].

Symptomatic treatment is aimed at decreasing the hyperdopaminergic state of basal ganglia [1]. This can be achieved by transporter or receptor blockade. The latter approach includes dopamine receptor blocking agents (antipsychotics or neuroleptics) which can improve many hyperkinesia, however these drugs have unfavorable side effects, such as parkinsonism and tardive dyskinesia (TD). On the other hand, vesicular monoamine transporter type 2 (VMAT2) inhibitors aim to deplete dopamine from the neurons without antagonism of dopamine receptors. These dopamine depleters have better side effect profiles with minimal or no risk of developing tardive syndromes.

2. VMAT2 inhibitors

Reserpine, an antihypertensive and antipsychotic agent, was one of the first VMAT inhibitor drugs, however its effect was irreversible and nonselective for VMAT2. Reserpine reduced chorea in Huntington’s disease (HD), but its irreversible and nonselective action resulted in unfavorable side effects, including orthostatic hypotension, gastric dysmotility, depression and extrapyramidal symptoms, therefore it was not a well-tolerated compound [2]. Over the next decades, novel, selective VMAT2 inhibitors were developed, including tetrabenazine, deutetrabenazine and valbenazine. Table 1. contains the most important pharmacological features of these agents, whereas Table 2. summarizes the parameters of the most relevant clinical studies of these drugs.

Table 1. Pharmacological features of VMAT2 inhibitors

Characteristic	Tetrabenazine	Deutetrabenazine	Valbenazine
Approved indication	HD	HD, TD	TD
Date of FDA approval	15 August 2008	3 April 2017 for HD 30 August 2017 for TD	11 April 2017
Starting dose (mg per day)	12.5	6	40
Max total dose (mg per day)	100	48	80
Dosing	TID	BID	Once daily
Peak plasma concentration (Cmax)	1–1.5 h	3–4 h	4–10 h
Half life	5.5 h	8.6 h	20 h
Metabolism	CYP2D6	CYP2D6	CYP2D6

(BID: Bidaily, CYP2D6: Cytochrome P450 2D6, FDA: Food and Drug Administration, HD: Huntington’s Disease, TID: Thrice daily, TD: Tardive Dyskinesia)

Table 2. Characteristics of most relevant clinical trials of VMAT2 inhibitors

Drug	Disease	Study	Phase	Number of included patients	Purpose of study	Dose	Comparator	Duration	Relevant results	Most common side effects (% of patients, only those reaching 2% or higher are indicated)	References
TBZ	HD	TETRA-HD	III	84	Efficacy, dosing, tolerability and safety of TBZ in HD	25–100 mg/day (mean: 74.7 mg)	PLC	12 weeks	Significant reduction in total maximal chorea of UHDRS in comparison to PLC (−5 vs. −1.5) and TBZ was superior to PLC in CGIC Global Improvement Scale (3.0 vs. 3.7)	Drowsiness 31.5, Insomnia 25.9, Fatigue 22.2, Fall 16.7, Depression 14.8, Agitation 14.8, Anxiety 14.8, Nausea 13, Purpura 11.1, Upper respiratory tract infection 11.1, Ataxia 9.3, Hyperkinesia 9.3, Nervousness 9.3, Coughing 7.4, Diarrhea 7.4, Vomiting 5.6, Dose-limiting symptoms: Sedation 27, Akathisia 8, Parkinsonism 4, Depression 4	[5]
TBZ	TS	Kenney et al.	Retrospective	77	Safety and efficacy of TBZ in TS patients	6.3–125.0 mg/day (mean: 50.4 ± 27.0)	–	23.7 ± 41.1 months	TBZ was safe and well tolerated. Most side effects were dose-related and controlled with dose reducetion. The efficacy was measured in 5 point scale (1 means the best, 5 means the worst), in the last visit 83.1% of the patients have 1 or 2 points	Drowsiness 36.4, Nausea 10.4, Depression 9.1, Insomnia 7.8, Parkinsonism 6.5, Nervousness/Anxiety 5.2, Akathisia 3.9, Tremor 2.6, ‘Trance-like/Zombie’ 2.6, Rash 2.6, Drooling 2.6, Speech difficulties 2.6	[4]
TBZ	Hyperkinetic MDs (TD, dystonia, chorea, tics, myoclonus)	Kenney et al.	Retrospective	448	Long-term efficacy and tolerability of TBZ in hyperkinetic MDs	12.5–300 mg/day (mean: 60.4 ± 35.7)	–	Mean time on treatment: 2.3 ± 3.4 y (up to 21.6 years)	TBZ was safe and well tolerated. All adverse events were dose-related and abated when dosage was reduced. TBZ was effective, efficacy was measured in 5 point scale (1 means the best, 5 means the worst), in the last visit most of the patients have 1 or 2 points (TD: 85.7%, chorea: 81.4%, tics: 76.7%, myoclonus 71.4%, dystonia: 69.5%)	Drowsiness 25, Parkinsonism 15.4, Depression 7.6, Akathisia 7.6, Nausea/Vomiting 5.6, Nervousness/Anxiety 5.1, Insomnia 4.9, Salivation 2.7, Dizziness 2.5	[6]
DTBZ	HD	FIRST-HD	III	90	Efficacy and safety of DTBZ in HD	12–48 mg/day (mean: 39.7 mg)	PLC	12 weeks	Significant reduction in total maximal chorea of UHDRS in comparison to PLC (−4.4 vs. −1.9) and DTBZ showed favorable effect compared to PLC in CGIC (51 vs. 20%), PGIC (42 vs. 13%) and improvement in SF-36 (0.7 vs. −3.6)	Somnolence 11.1, Dry mouth 8.9, Diarrhea 8.9, Irritability 6.7, Insomnia 6.7, Fatigue 6.7, Fall 4.4, Dizziness 4.4, Depression or agitated depression 4.4	[8]
DTBZ	TD	ARM-TD	II/III	117	Efficacy and safety of DTBZ in TD	18–48 mg/day (mean: 38.3 mg)	PLC	12 weeks	Significant reduction in AIMS scores in comparison to PLC (−3.0 vs. −1.6)	Somnolence 13.8, Fatigue 6.9, Insomnia 6.9, Headache 5.2, Diarrhea 5.2, Akathisia 5.2, Anxiety 3.4, Dizziness 3.4, Dry mouth 3.4, Upper respiratory tract infection 3.4	[10]
DTBZ	TD	AIM-TD	III	298	Efficacy, safety and tolerability of DTBZ in TD	3 groups: 12 mg/day, 24 mg/day and 36 mg/day	PLC	12 weeks	Significant reduction in AIMS scores in 24 mg/day and 36 mg/day group compared to PLC (−3.2 [24 mg/day], −3.3 [36 mg/day] vs. −1.4 [PLC]) and 24 mg/day DTBZ group showed significantly higher proportion of ‘very much improved’ or ‘much improved’ on CGIC compared to PLC (49 vs. 26%)	Headache 5, Anxiety 4, Diarrhea 4, Nasopharyngitis 4, Fatigue 3, Somnolence 2, Depression 2, Dry mouth 2	[11]
DTBZ	TD	Fernandez et al.	Open-label	343	Long-term safety and efficacy of DTBZ in TD	12–48 mg/day (mean: 39 mg)	–	106 weeks	DTBZ was safe and effective. Significant reduction in AIMS score (−6.3 at Week 80) and CGIC was improved or very much improved in 70% of the patients at Week 80. Most AEs were mild or moderate in severity.	Somnolence 9, Depression 9, Anxiety 9, Headache 7, Diarrhea 6, Nasopharyngitis 6, Urinary tract infection 6	[12]
DTBZ	TS	Jankovic et al.	Open-label	23	Efficacy, safety and tolerability of DTBZ in TS	18–36 mg/day (mean: 32.1 mg)	–	8 weeks	DTBZ was safe and effective. Significant reduction in YGTSS score (11.6 points, 37.6%) and improvement in TS-CGI score (1.2 points) and TS-PGIC showed that 76.2% if patients were much improved or very much improved compared with baseline. All AEs were mild to moderate in severity.	Fatigue 17, Headache 17, Irritability 13, Somnolence 8, Hyperhidrosis 8, Diarrhea 8, Nasopharyngitis 8	[13]
VBZ	TD	KINECT 2	II	102	Efficacy, safety and tolerability of VBZ in TD	25–75 mg/day	PLC	6 weeks	Significant reduction in AIMS score compared to PLC (−3.6 vs. −1.1) and VBZ was superior to PLC in CGI-TD (2.3 vs. 3.1) and PGIC scores (2.2 vs. 2.9)	Fatigue 9.8, Headache 9.8, Decreased appetite 7.8, Nausea 5.9, Somnolence 5.9, Dry mouth 5.9, Vomiting 5.9, Constipation 3.9, Urinary tract infection 3.9, Sedation 3.9, Back pain 3.9	[14]
VBZ	TD	KINECT 3	III	234	Efficacy, safety and tolerability of VBZ in TD	2 groups: 40 mg/day, 80 mg/day	PLC	6 weeks	Significant reduction in AIMS score compared to PLC (−3.2 [80 mg/day], −1.9 [40 mg/day], vs. −0.1 [PLC])	Somnolence 5.3, Akathisia 3.3, Dry mouth 3.3, Suicidal ideation 2.6, Arthralgia 2.6, Headache 2.6, Vomiting 2, Dyskinesia 2, Anxiety 2, Insomnia 2, Fatigue 2, Urinary tract infection 2, Weight increase 2	[15]
VBZ	TD	KINECT 3 Extension	III	198	Long-term efficacy, safety and tolerability of VBZ in TD	2 groups: 40 mg/day, 80 mg/day	–	42 weeks	Significant reduction in AIMS score (−4.8 [80 mg/day], −3.0 [40 mg/day] compared to baseline. VBZ was safe and well-tolerated	Headache 7.1, Urinary tract infection 6.6, Diarrhea 5.6, Dizziness 5.6, Suicidal ideation 5.1, Depression 4	[16]

AE: adverse event, AIMS: Abnormal Involuntary Movement Scale, CGIC: Clinical Global Improvement of Change, CGI-TD: Clinical Global Improvement of Change TD Scale, DTBZ: Deutetrabenazine, HD: Huntington’s Disease, MD: Movement Disorder, PGIC: Patient Global Impression of Change, PLC: Placebo, SF-36: 36-Item Short Form Healthy Survey, TBZ: Tetrabenazine, TD: Tardive Dyskinesia, TS: Tourette syndrome TS-CGI: TS Clinical Global Impression, TS-PGIC: TS Patient Global Impression of Change, UHDRS: Unified Huntington’s Disease Rating Scale, VBZ: Valbenazine, YGTTS: Yale Global Tic Severity Scale.

2.1. Tetrabenazine

Tetrabenazine (TBZ) was the first selective VMAT2 inhibitor, synthesized in 1950 for the treatment of psychosis [3]. However, phenothiazines were more effective antipsychotics, thus TBZ was not significantly used in this indication. In addition, TBZ has the potential to ameliorate hyperkinetic MDs, including chorea, TD, dystonia, tics and Tourette syndrome (TS). On the other hand, in most of these MDs only non-randomized or retrospective studies and, in a few cases, randomized, double-blind, placebo-controlled trials with small numbers of patients, were performed [3,4]. The only exception is the TETRA-HD study, which was conducted in 2006 by the Huntington Study Group. This randomized, double-blind, placebo-controlled, multicentre study demonstrated that TBZ can effectively reduce chorea in HD and was well-tolerated by all the participants. Drowsiness, insomnia and fatigue were the most common side effects, while the most prevalent dose-limiting symptoms were sedation, akathisia, parkinsonism and depression [5]. This side effect profile was reinforced by a relevant open-label, retrospective, long-term tolerability study on a variety of hyperkinetic MDs (TD, dystonia, chorea, tics and myoclonus) treated with TBZ. Fortunately, all side effects were dose-related and remitted when the dosage was reduced [6]. Based on the convincing results of the TETRA-HD study, TBZ was approved by the US Food and Drug Administration (FDA) for the treatment of chorea in August 2008.

2.2. Deutetrabenazine

Deutetrabenazine (DTBZ) is the deuterated form of TBZ, which incorporates six deuterium isotopes, also known as heavy hydrogen, because its atomic nucleus contains one neutron plus one proton, in contrast to the most common hydrogen isotope, protium, which does not have a neutron [1]. This molecular modification creates an 8-times stronger hydrogen (deuterium) carbon bond, making the agent more resistant to its metabolizing enzyme, CYP2D6. Therefore, DTBZ has longer plasma half-life than TBZ, and it enables less frequent daily dosing with the advantage of more constant plasma concentrations with lower peaks and fluctuations [7]. A randomized, short-term, multicentre, double-blind, placebo-controlled trial (FIRST-HD) delineated that DTBZ can effectively reduce chorea in HD, while the adverse event rate was lower than side effect frequencies of TBZ in the TETRA-HD study [8,9]. Besides HD, DTBZ was also examined in class I, short-term studies for the treatment of TD (ARM-TD and AIM-TD). These two trials showed the efficacy, safety and tolerability of DTBZ in TD, which was reinforced by a long-term, open-label trial [10–12]. On this basis, DTBZ was approved by the US FDA for the treatment of HD in April 2017 and for the treatment of TD in August 2017, and it was the first deuterated drug to receive FDA approval. Moreover, an open-label study of 23 patients with TS found DTBZ to be effective and safe in adolescent patients with tics related to TS [1,13]. A currently ongoing larger, randomized, double-blind, placebo-controlled trial is attempting to confirm the hopeful results of the pilot study (https://clinicaltrials.gov/ct2/show/NCT03452943).

2.3. Valbenazine

Valbenazine (VBZ) is the purified prodrug of α-dihydrotetrabenazine (α-HTBZ), which is the most active metabolite of TBZ [1]. α-HTBZ is a highly selective VMAT2 inhibitor and its half-life of approximately 20 hours permits once daily dosing [7]. Two randomized, double-blind, placebo-controlled, short-term studies (KINECT 2 and 3) of VBZ in TD revealed that VBZ has the potential to significantly reduce abnormal involuntary movements in TD [14,15]. In addition to efficacy, VBZ showed a favorable side effect profile and it was well tolerated by patients. A long-term study (KINECT 3 Extension) reinforced these outstanding results about efficacy, safety and tolerability [16]. The most common adverse events were headache, urinary tract infection, diarrhea, dizziness, suicidal ideation and depression [16]. Moreover, a further analysis of these studies confirmed the statistically significant improvements in TD severity both overall and in separate body regions [17]. Based on these trials, VBZ became the first FDA-approved treatment for TD in April 2017. Besides TD, VBZ is under investigation as a treatment for TS, however the results of this trial are not yet available (https://clinicaltrials.gov/ct2/show/NCT03325010?term=valbenazine&rank=8).

3. Expert opinion

Currently, VMAT2 inhibitors are the best medications for treating hyperkinetic MDs. However, as we mentioned above, results from multicentre, randomized, double-blind, placebo-controlled studies are limited to HD and TD so far, therefore use of these agents in the treatment of other hyperkinetic movements are off-label.

Regarding HD, only TBZ and DTBZ have FDA approval for the treatment of choreiform movements. In the lack of direct head-to-head studies, the selection between these drugs may depend on indirect comparisons and good clinical practice. An indirect comparison of TBZ and DTBZ in HD according to the TETRA-HD and FIRST-HD studies published by Claassen et al. demonstrated that DTBZ has a more favorable tolerability profile than TBZ for the treatment of HD chorea [18]. They found that DTBZ presented a significantly lower risk for the most prevalent neuropsychiatric side effects compared to TBZ, including drowsiness, insomnia, depression, akathisia, parkinsonism and agitation. However, Rodrigues et al. performed the same comparison using a different statistical method and they demonstrated that there was no difference between the efficacy and safety profiles of the two drugs [19]. In light of these controversial results, and the availability and price of these two agents, it is suggested to start the treatment with TBZ, and in the case of remarkable intolerance, a shift to DTBZ may be recommended. Furthermore, in a case of severe concomitant neuropsychiatric symptoms with the possibility of considerable aggravation by TBZ, DTBZ may come into account as a first choice. Regarding TD, a real-world study published in 2019 and a review article focused on TD highlighted that all three VMAT2 inhibitors are effective and safe for treatment of these abnormal involuntary movements [20,21], but only DTBZ and VBZ have FDA approval. There is only one indirect comparison of these two agents available which delineated VBZ as statistically more effective than DTBZ in AIMS score improvements, whereas there was no relevant difference in safety parameters [22]. Although the application of TBZ in TD is off-label, due to its widespread availability and relatively low price compared to the other two VMAT2 inhibitors, it may also be applied in selected cases.

VMAT2 inhibitors do not have FDA approval for other hyperkinetic MDs, and therefore they can only be applied off-label in these conditions. Regarding TBZ observational cohort studies, retrospective investigations and case reports may support its use in TS, dystonia, myoclonus, dyskinesia and other hyperkinetic MDs. Some prospective studies are ongoing without available results. The experience with DTBZ and VBZ in these disorders is considerably limited.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee declares that they have served as a consultant for Teva Pharmaceuticals for studies related to deutetrabenazine in tardive dyskinesia. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by the Hungarian Brain Research Program [Grant No. 2017-1.2.1-NKP-2017-00002 NAP VI/4], project GINOP 2.3.2-15-2016-00034 and by the Ministry of Human Capacities, Hungary grant [20391-3/2018/FEKUSTRAT]. Dénes Zádori was also supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences.