Valbenazine granted breakthrough drug status for treating tardive dyskinesia

Abstract

The chronic use and high dosing of typical neuroleptics or centrally acting dopamine receptor blocking antiemetics predispose patients to the onset of tardive syndromes. One particular subtype, tardive dyskinesia, is characterized by rapid, repetitive, stereotypic, involuntary movements of the face, limbs or trunk. The inhibition of the vesicular monoamine transporter system, using tetrabenazine therapy, improves the severity of tardive dyskinesia. But there are also drawbacks to tetrabenazine treatment, such as a fluctuating response and the need for frequent intake due to its rapid metabolism. Clinical research on the potentially more efficacious and easier to use tetrabenazine analogs is already under way. One of them is valbenazine, the purified parent drug of the (+)-α-isomer of tetrabenazine. The FDA lowered approval hurdles for valbenazine due to a successful Phase II trial, which showed a distinctive improvement in tardive dyskinesia symptoms during valbenazine administration. This resurgence in the clinical research of tardive syndrome therapy is most welcome. This author notes that the putative long-term side effects of valbenazine should carefully be investigated in the future via naturalistic observational trials. Furthermore, valbenazine may also support the onset of symptoms, such as Parkinsonism and depression, with chronic administration, as it, to a certain extent, shares the mode of action of tetrabenazine.

Keywords:

• dyskinesia
• tardive dyskinesia
• tetrabenazine
• Tic
• Tourette syndrome
• valbenazine

1. Introduction: the phenomenology of involuntary movements in humans

Abnormal movement control occurs in various human diseases. Symptoms are slowed movement execution, termed as bradykinesia; increased muscle tone, designated as rigidity; and tremor and involuntary movements, predominantly characterized as dyskinesia as the most common form. They affect limbs, face and trunk in an individually pronounced and variable fashion. Dyskinesia may also appear as mild and barely noticeable. Generally, hyperkinetic movements interfere with daily activities of affected patients. Any kind of emotions may increase severity of hyperkinetic movement behavior [1]. They often disturb caregivers more than affected patients themselves [2]. Rapid and dance-like uncontrollable movements are commonly described as chorea or choreiform movements. Slower, painful and twisting movements are termed dystonia. This syndrome may even enforce unnatural postures. One may confound dyskinesia with tics. These sudden, repetitive and non-rhythmic motion sequences emerge with or without vocalization, eye blinking or throat clearing, such as in the case of the Tourette syndrome. Tics often involve small muscle groups only. They may be invisible in the case of abdominal tensing or toe crunching. Onset of hyperkinetic movements may be a disease symptom, for instance Huntington’s disease, or a result of drug treatment, for instance chronic and high l-DOPA dosing in patients with Parkinson’s disease [2]. Blocking of dopamine receptors in the brain with typical neuroleptics or the antiemetic metoclopramide may induce onset of acute dystonia [3,4]. It responds to intravenous or oral application of anticholinergics. It is not proven that an elevated sensitivity for this drug-induced dystonia predisposes for the delayed occurrence of hyperkinetic movements, the so-called tardive syndrome [1,5-7]. This term was first used in the early 1960s. At that time, tardive syndromes were more and more observed due to the increasing use of so-called typical neuroleptics, such as phenothiazine-derived drugs or butyrophenones. Up to 30% of patients, exposed to typical neuroleptics, suffer from a tardive syndrome sooner or later. There are several phenomenological distinct types of a tardive syndrome [5,7]. Tardive dyskinesia is characterized by a rapid, repetitive, stereotypic movement mostly involving the oral, buccal and lingual areas. Tardive dystonia appear in focal, segmental or generalized form. Often, they affect the face and neck and to a lesser extent arms and trunk. Tardive akathisia is characterized by a feeling of inner restlessness and jitteriness combined with an inability to sit or stand still. Other tardive syndromes include tardive tics, myoclonus, tremor and withdrawal-emergent syndrome [5,7].

Due to the increased incidence of tardive syndromes, the so-called atypical antipsychotic drugs were developed and introduced in the 1970s. Atypical neuroleptics, such as the dibenzazepines clozapine, olanzapine or quetiapine, show a reduced risk for onset of a tardive syndrome [1,6]. However, the atypical antipsychotic benzisoxazole derivatives, such as risperidone, have an elevated risk for onset of acute dystonia and tardive syndromes. The reason may be the structural similarities between the benzisoxazole-related neuroleptics and butyrophenones. The etiology of tardive syndromes is not known [1,3].

1.1 Risk factors for tardive syndromes

Old age, a certain predisposition of women, mental retardation, history of substance abuse and traumatic head injury are looked as predisposing factors for the onset of tardive syndromes [8].

2. Objectives

This narrative review aims to discuss valbenazine application for the therapy of tardive dyskinesia against the background of the available tetrabenazine. Valbenazine received a granted breakthrough drug status by the FDA in the US.

3. Current treatment options

Prevention is the pragmatic therapeutic approach for a tardive syndrome. One strategy is application of only low dosages of compounds known to facilitate the onset of this serious condition. Another practice is the switch to different drugs, for instance, use of atypical neuroleptics. Benzodiazepines, such as clonazepam; amantadine; levetiracetam; piracetam; propranolol; vitamin B6; ginkgo biloba; reserpine; anticholinergics and, in particular, tetrabenazine, may provide some symptomatic relief from tardive syndromes [1,6,9-11].

3.1 Tetrabenazine as symptomatic approach for tardive dyskinesia

Vesicular monoamine transporter 2 function (VMAT2) is responsible for the monoamine transport from cellular cytosol into the synaptic vesicles [3,12]. Compounds, like tetrabenazine, dihydrotetrabenazine, amphetamine and methamphetamine, bind at distinct VMAT2 sites of this membrane protein and inhibit its activity [12-14]. As a result, monoamine concentrations reduce in the synaptic cleft and therefore, tardive syndromes improve. Tetrabenazine has orphan drug status in the US and is approved in certain European countries. Its use is also allowed for therapy of chorea in patients with Huntington’s disease. However, tetrabenazine may also induce tardive dyskinesia according to a case report [9,15]. Tetrabenazine is rapidly metabolized and must frequently be administered evenly throughout the day [3,9].

3.2 Metabolites of tetrabenazine degradation

The turnover of tetrabenazine is quite complex. The drug itself is a one-to-one mixture of enantiomers. These are referred to as the α and β enantiomers [14,16-19]. The carbonyl group (=O) of tetrabenazine is rapidly degraded to a hydroxyl group (−OH) of dihydrotetrabenazine via carbonyl reductase. Each enantiomer of tetrabenazine gives rise to two isomers of this dihydrotetrabenazine metabolite, so there are a total of four isomers at this stage. Of these, those derived from α-tetrabenazine are active VMAT2 inhibitors [14,16-19]. They contribute to the therapeutic effects of the drug. The two dihydrotetrabenazine derivatives of β-tetrabenazine are antagonists at the dopamine D₂ receptor [16-19]. They may particularly induce sedation and parkinsonism, both of which is often observed during chronic tetrabenazine intake. All four dihydrotetrabenazine isomers are metabolized to inactive O-demethylated compounds by the action of CYP enzymes in the liver. The α isomers can be converted to inactive O-demethylated metabolites by either of two cytochrome enzymes, CYP2D6 or CYP3A4. The β-isomers are transformed to inactive O-demethylated solely by CYP2D6 [9,14,19]. Generally, the activity of the CYP enzyme system varies between individuals and is sensitive to drug interactions, because many psychoactive compounds are degraded via this genetically determined pathway. Therefore, efficacy and side effects of any given tetrabenazine dose differ individually. VMAT2 inhibition with slower metabolized compounds would be a promising therapeutic alternative. Currently, clinical research on safer and better tolerated tetrabenazine analogs is under way; one of them is valbenazine [1,20].

3.3 Valbenazine

Valbenazine is the purified prodrug of the (+)-α isomer of tetrabenazine (Figure 1). Valbenazine is a l-valine (2R,3R,11bR)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-yl ester. This agent has a slowed cleavage, low VMAT2 interaction and an attenuated maximum concentration. Dosing of this inert parent molecule, which must first be transformed to the selective and potent active metabolite, reduces the pharmacokinetic variability. Valbenazine allows an only once-daily administration [1,20]. Similar to deutetrabenazine, which is not in the focus of this review, valbenazine is tested in clinical trials for the treatment of patients with tardive dyskinesia [1,11,20].

Figure 1. Metabolism of valbenazine to its active derivative (+)-dihydrotetrabenazine (DHTBZ).

3.4 Efficacy of valbenazine in patients with tardive dyskinesia

A Phase IIb trial, the so-called KINECT 1 Study, investigated valbenazine within a randomized, parallel, double-blind, placebo-controlled, clinical design in patients with moderate-to-severe tardive dyskinesia and an underlying schizophrenia or schizoaffective disorder. Data of this trial are only available via various press releases of the company Neurocrine Biosciences, Inc. to the best of knowledge. One hundred and nine participants received two doses of valbenazine o.i.d. over a 6-week interval in comparison with a period of placebo therapy. One cohort took 50 mg valbenazine for 6 weeks and the other group received 100 mg valbenazine in the first 2 weeks. Then, the patients were down titrated to 50 mg valbenazine for the final 4 weeks of this study. After the placebo interval, all participants were eligible to enter a 6-week open-label safety extension. They received 50 mg of valbenazine o.i.d. and were further scored with the abnormal involuntary movement scale (AIMS). The primary study end point was a comparison of placebo versus valbenazine effects on the AIMS scores at the end of week 6: 50 mg valbenazine did not significantly improve AIMS scores at week 6; 100 mg valbenazine reduced symptoms, when again scored via a blinded central video AIMS assessment at the end of the 100 mg dosing interval. Valbenazine was safe and well tolerated in the KINECT 1 study. The frequency of treatment-related adverse events was 37% during the placebo period and 26% during the valbenazine intake. No drug-related serious adverse events were found. The most common treatment-associated adverse events were mild and transient somnolence during placebo application.

Patients with moderate respectively severe tardive dyskinesia and a history of underlying mood disorders, schizophrenia and schizoaffective disease, or gastrointestinal disorders were included the KINECT 2 Study. One hundred and two patients were randomized into an initial 6-week placebo-controlled dosing period. Half of the study participants were put on placebo therapy and half of them were treated with 25-mg valbenazine. The treating physician was then allowed to escalate the dose at 2-week interval up to a maximum dose of 75 mg o.i.d at the end of week 2 or week 4. This uptitration was done by the treating physician based on the on-site AIMS rating results and the safety and tolerability evaluations at the end of weeks 2 and 4. The primary study end point was the comparison of placebo with valbenazine AIMS score changes at the end of week 6. AIMS ratings were additionally done by scrambled blinded central video assessments conducted by two movement disorder specialists. At week 6, these AIMS scores improved by 2.6 points in the valbenazine intention-to-treat (ITT) population (n = 45) in comparison with a decrease of 0.2 points in the placebo arm (n = 44) (p < 0.001). The responder rate (≥ 50% improvement from baseline) was 49% in the valbenazine ITT cohort in comparison with 18% in the placebo group (p = 0.002). In the per-protocol group (n = 78), AIMS scores declined by 3.3 points in the valbenazine-treated patients (p < 0.001), with a corresponding responder rate of 59% (p < 0.001). This improvement of the AIMS score at week 6 was confirmed by the on-site treating physicians with the Clinical Global Impression–Tardive Dyskinesia scale outcomes. Sixty-seven percent of the valbenazine-treated patients ‘much improved’ or ‘very much improved’ at week 6 in comparison with 16% of the placebo-treated patients (p < 0.001) [20].

3.5 Conclusion

The KINECT 1 trial was more or less a failure, probably due to low valbenazine dosing. The blinded dyskinesia assessment revealed promising effects of valbenazine. KINECT 2 showed positive outcomes [20]. Study participants well tolerated valbenazine in both studies. One component of this trial design, employing movement disorder specialists for blinded central AIMS rating, proved to be an appropriate rating procedure of tardive dyskinesia [21,22].

4. Expert opinion

4.1 Consequences of inhibition of VMAT2 function

VMAT2 inhibition results in diminished monoamine neurotransmitter levels in the synaptic cleft. Therefore, the likelihood increases for the development of a syndrome characterized by parkinsonism with balance problems and depression-related symptoms, such as irritability, anxiety, somnolence, sedation and fatigue [9,23-25]. This not-yet-defined symptom compilation resembles clinical features observed after chronic monoamine reuptake inhibition, for instance, following chronic cocaine abuse. Here, a decrease of monoamine concentration also occurs in the synaptic cleft as a result of an exhaustion of monoamine synthesis and vesicle storage [25]. Various chronic neurologic and/or psychiatric disorders share the clinical symptoms resulting from chronic VMAT2 inhibition. Neuroleptics are often at least temporarily applied in these disease entities and generate an increased risk for onset of a tardive syndrome. Its therapy with chronic VMAT2 inhibition may aggravate symptoms or even support resurgence of the underlying disorder. From this point of view, real-world observations lasting several months or years with a focus on this aforementioned topic will be needed after valbenazine approval. To date, clinical trials within the artificial study world only focused on the improvement of tardive dyskinesia by valbenazine in well-selected patients. Valbenazine was administered over few weeks only. It is likely that valbenazine will also ameliorate tardive dyskinesia in the ongoing Phase III program similar to findings with tetrabenazine. No head-to-head trials between valbenazine and tetrabenazine are under way yet. Therefore, one may perform a meta-analysis. However, the available data for valbenazine are not enough. Therefore, a comment on the superiority of valbenazine over tetrabenazine in terms of improvement of tardive dyskinesia is not appropriate and fair from the scientific point of view at the current stage. However, one should also stress that it is not enough to claim that long-term effects of VMAT2 inhibition will probably not be so severe due to the pharmacological profile of valbenazine. Both, tetrabenazine and valbenazine, have one same metabolite, the VMAT2 inhibitor (+)-α-dihydrotetrabenazine. Accordingly, both drugs share the side-effect profile to a certain extent. It is well known that tetrabenazine use has drawbacks due to its short half-life, the need for frequent daily intakes, and side effects, such as parkinsonism, severe depression, fatigue, anxiety, irritability and suicide risk. One may hypothesize that suicidal behavior may rise in patients with tardive dyskinesia as a consequence of both long-term VMAT2 inhibition and the underlying disease [3,9,26]. More recent naturalistic trials investigated this topic in patients with Huntington’s disease [27-29]. These trials provided some evidence that concomitant antidepressant therapy during tetrabenazine exposure may avoid depression and suicidal behavior to a certain extent [27-29]. However, one should not underestimate other factors, such as care giving, concomitant drug therapy and social environment on these results.

4.2 Antidyskinetic therapies are needed

It is positive that clinical researches and the pharmaceutical industry investigate new therapeutic approaches which aim to improve dyskinetic movements in various disease entities. There have been failed trials of antidyskinetic compounds in the past. As an example, sarizotan or the metabotropic glutamate receptor 5 (mGluR5) antagonist, mavoglurant, failed in patients with Parkinson’s disease suffering from l-DOPA-related dyskinesia. These trials mostly focused only on motor behavior and dyskinesia [30,31]. The employed rating instruments were subjective and partially not very specific. Their use was also suggested by the drug-approving authorities. However, these rating scales do not reflect all the consequences of hyperkinetic movement behavior on the quality of life of patients and their caregivers. Generally, placebo effects were high in these trials. Placebo releases dopamine, which plays an eminent role in the control of expectation, emotion and reward, all of which are primarily modulated by the mesolimbic system. There are close associations between the mesolimbic and the nigrostriatal system with its dopamine-dependent impact on movement behavior [32]. These relationships may be responsible for the observation that hyperkinetic movements emerge and become more intense in investigational and thus also emotional situations. Therefore, it is difficult to score the antidyskinetic efficacy of a drug during conventional study visits with standardized rating scales only. A better scenario would probably be an assessment of hyperkinetic movements in combination with more objective movement recording instruments and/or with video analysis monitoring over longer intervals. These observations should be performed in the familiar surroundings with the help of telemedicine and caregivers [22]. In this regard, it was an initial step forward, as the KINECT 1 and 2 trials demonstrated the value of blinded central video assessment of tardive dyskinesia by experienced movement disorder specialists. This procedure was also accepted by the advising US FDA. Generally, performance of trials in hyperkinetic movement disorders is risky, challenging and expensive. Therefore, it would be more appropriate to undertake only small trials with a straightforward number of participants in very experienced study centers. Moreover, it would be advisable to lower the approval hurdles for future antidyskinetic compounds. In this respect, the granted breakthrough status for the treatment of tardive dyskinesia with valbenazine by the FDA was a step forward in the right direction. To date, real effective, safe, well tolerated and approved treatment possibilities are rare for patients with tardive dyskinesia. The quality of life of these patients is severely impaired. Therapy mainly is a long, sometimes desperate interplay of risk/benefit calculations of possible side effects for the patients and a try and error paradigm for treating physicians [1].

4.3 The future of antidyskinetic drugs

From the pharmacological point of view, valbenazine may be more specific and efficacious against tardive dyskinesia in comparison with tetrabenazine. There are some aforementioned pharmacological arguments that claim a better side-effect profile of valbenazine [1,20]. Symptoms of parkinsonism or depression insidiously emerge. The available clinical valbenazine study outcomes result from relative short treatment intervals. Therefore, these trials do not allow the conclusion yet that the side-effect profile of valbenazine is superior to that of tetrabenazine. Valbenazine requires once a day application and thus eases compliance. More frequent intakes are necessary during treatment with tetrabenazine. Patients with underlying schizophrenia, depression or schizoaffective disorders tend to have adherence problems. Therefore, future valbenazine use will be advantageous in comparison with tetrabenazine. Generally, the weakness of VMAT2 inhibition is that it only provides some symptomatic relief but no cure from tardive dyskinesia. Even sophisticated techniques, such as deep brain stimulation, do not provide a convincing likelihood to achieve recovery from tardive syndromes or hyperkinetic movement disorders generally [1].

4.4 Outlook

The FDA lowered the approval hurdles for valbenazine. This procedure shows that the importance of tardive syndromes is well recognized as a long-term side effect of certain drugs. Future research should aim to develop further therapeutic options for hyperkinetic movement disorders in general. Research should also focus on disorders like the Tourette syndrome, idiopathic dystonia, Huntington’s disease or l-DOPA-related dyskinesia in Parkinson’s disease. Due to the insufficient drug treatment possibilities in all these disease entities, one can expect that the efficacy of valbenazine in the treatment of these hyperkinetic movement disorders will be investigated in investigator initiated trials, once valbenazine is approved and available.

Declaration of interest

The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.