Pharmacology

Understanding the pharmacology of valbenazine and deutetrabenazine requires some knowledge of tetrabenazine pharmacology and metabolism (Figure 1). Tetrabenazine is a racemic mixture of 2 enantiomers that are reduced to form 4 isomeric dihydrotetrabenazine (HTBZ) metabolites: [+]-α-HTBZ, [+]-β-HTBZ, [−]-α-HTBZ, and [−]-β-HTBZ. Of these 4 metabolites, [+]-α-HTBZ has the highest affinity for VMAT2, followed by [+]-β-HTBZ.Reference Yao, Wei and Wu^28–Reference Brar, Vijan and Scott³⁰ The [−]-α-HTBZ and [−]-β-HTBZ isomers have negligible affinity for VMAT2, but they (and to a lesser extent [+]-β-HTBZ) demonstrate appreciable affinity for various dopamine, serotonin, and adrenergic receptor subtypes. The use of tetrabenazine is limited by its short half-life and that of its active metabolites, as well as its side effect profile.

Figure 1.

Pharmacology of VMAT2 inhibitors. (A) The structural relationships between tetrabenazine, valbenazine, and deutetrabenazine are presented. Valbenazine is the valine ester of [+]‑α-HTBZ, the tetrabenazine metabolite with the highest affinity for VMAT2. Valbenazine undergoes hydrolysis to form only one HTBZ metabolite ([+]‑α-HTBZ). Deutetrabenazine is the deuterated form of tetrabenazine. Both tetrabenazine and deutetrabenazine are racemic mixtures and each are reduced to four HTBZ metabolites. (B) Concentrations and affinities of HTBZ metabolites are presented for the three VMAT2 inhibitors. For valbenazine, the only circulating metabolite is [+]‑α-HTBZ (purple bar), which has very strong affinity for VMAT2, as indicated by the low inhibitory constant (K_i=1.4 nM). Tetrabenazine and deutetrabenazine have similar profiles, with >60% of circulating metabolizes composed of [-]-α-HTBZ/deuHTBZ and [-]-β‑HTBZ/deuHTBZ (light gray bars), which have negligible affinity for VMAT2. For both drugs, the most abundant metabolite with affinity for VMAT2 is [+]-β-HTBZ/deuHTBZ.

Abbreviations: deuHTBZ, deuterated form of HTBZ metabolite; HTBZ, dihydrotetrabenazine; TD, tardive dyskinesia; VMAT2, vesicular monoamine transporter 2.

References: [1] Brar et al., Clin Pharmacol Drug Dev 2023(4);12:447–56. [2] Skor et al., Drugs R D 2017;17(3):449–59. [3] Yao et al., Eur J Chem 2011;46(5):1841–8.

Once [+]-α-HTBZ was identified as having the highest affinity and selectivity for VMAT2, valbenazine was created to be a potent, selective, and longer lasting VMAT2 inhibitor by adding a valine ester to [+]-α-HTBZ.Reference Harriott, Williams and Smith³ This increased the half-life of the active moiety and facilitated once-daily dosing. After oral ingestion of valbenazine, [+]-α-HTBZ metabolite is formed via hydrolysis of the valine ester and is then further metabolized by CYP2D6; no other HTBZ metabolite is formed. Valbenazine also undergoes oxidative metabolism, primarily via CYP3A4/5 enzymes, to form minor metabolites.Reference Grigoriadis, Smith, Hoare, Madan and Bozigian²⁹ Valbenazine and its major metabolite have affinity for VMAT2, with [+]-α-HTBZ having the strongest affinity.

Deutetrabenazine, a deuterated form of tetrabenazine, is the first deuterated drug to receive regulatory approval in the United States.Reference Cummings, Proctor and Stahl^31, Reference Schneider, Bradbury and Baillie³² Like tetrabenazine, deutetrabenazine is a racemic mixture that forms 4 deuterated HTBZ (deuHTBZ) isomers that are further metabolized by CYP2D6, with contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites. The most prevalent metabolite is [−]-α-deuHTBZ, which has negligible affinity for VMAT2 and varying affinity for off-target receptors.Reference Brar, Vijan and Scott³⁰ The major active metabolites at VMAT2 for tetrabenazine and deutetrabenazine are [+]-β-HTBZ and [+]-β-deuHTBZ, respectively; both have affinity for VMAT2, but less than [+]-α-HTBZ and [+]-α-deuHTBZ, which account for only approximately 2% of their circulating metabolites.

Pharmacokinetics and dosing

Valbenazine and deutetrabenazine were designed to allow less frequent dosing than is required for tetrabenazine (as indicated for HD chorea).²⁵ However, their pharmacokinetic profiles are different, which affects their dosing.

Valbenazine is rapidly absorbed after oral administration, reaching a maximum plasma concentration within 1 hour (Supplementary Table S1).¹ Its primary active metabolite, [+]-α-HTBZ, reaches maximum concentration in 4–8 hours. The half-lives of valbenazine and [+]-α-HTBZ (15–22 hours¹) allow once-daily dosing without any sustained release modification.

The valbenazine label includes 3 clinically effective once-daily doses (40, 60, and 80 mg) that can be taken with or without food (Figure 2). Two doses were initially approved (40 and 80 mg), but it became apparent that a third dose (60 mg) could potentially fill a clinical need. Efficacy for valbenazine 60 mg was established using the FDA’s model-informed drug development approach (Supplementary Table S2),Reference Nguyen, Kuan and Crass³³ and this dose was approved by the FDA in April 2021. A stepwise increase from 40 to 60 to 80 mg is not required but can be used for patients with TD. After taking valbenazine 40 mg for 1 week, patients can continue with 40 mg or switch to either of the higher doses (60 or 80 mg) as warranted by patient clinical status, though the treatment effect size when comparing the randomized groups was greater in magnitude for the 80 mg dose.Reference Citrome³⁴

Figure 2.

Dosing and administration for valbenazine and deutetrabenazine. Information in this figure reflects prescribing recommendations for TD, as stated in the package inserts for valbenazine (INGREZZA® and INGREZZA® SPRINKLE) and deutetrabenazine (AUSTEDO® and AUSTEDO® XR), along with results from an in vitro study of crushed valbenazine capsule contents (Sajatovic 2023).

Abbreviations: BID, twice-daily; QD, once-daily; TD, tardive dyskinesia; XR, extended-release.

References: [1] Prescribing information for INGREZZA® and INGREZZA® SPRINKLE; February 2025. [2] Prescribing information for AUSTEDO® and AUTEDO® XR; February 2025. [3] Sajatovic et al., Clin Ther 2023;45(12):1222–7.

The maximum plasma concentrations of deutetrabenazine and its metabolites are reached at approximately 3–4 hours after oral administration (Supplementary Table S1).² Its deuterated HTBZ metabolites are primarily metabolized by CYP2D6, with minor contributions from CYP1A2 and CYP3A4/5. The metabolite half-lives range from 9 to 12 hours, allowing for twice-daily dosing with the original tablet formulation, which is also required to be taken with food.

Extended release tablets using passive osmotic diffusion were developed to enable once-daily dosing with deutetrabenazine.² In contrast to the twice-daily tablets, the extended release tablets can be taken with or without food. As noted in the phase 1 study that demonstrated acceptable bioequivalence with the original twice-daily tablet (Supplementary Table S2), extended release deutetrabenazine can reduce pill burden and potentially improve medication adherence.Reference Sunzel, Rabinovich-Guilatt and Iyengar³⁵ The dose titration schedule, however, remains unchanged (Figure 2). Most patients need 4 weeks to reach an effective dose (36 mg), as evidenced in a flexible dose study,Reference Anderson, Stamler and Davis¹⁴ though 24 mg, observed to be therapeutic in a fixed dose study,Reference Fernandez, Factor and Hauser¹³ is reached by Day 15. Regardless of formulation or target dose, retitration is needed when stopping deutetrabenazine for ≥1 week.

Alternative routes of administration

Valbenazine sprinkle capsules were developed to address the needs of patients with TD and HD who have difficulties swallowing or do not want to take whole capsules due to motor symptoms, advanced age, or other conditions. The capsules can be opened manually, allowing the granule contents to be sprinkled onto soft foods.¹ An in vitro study established that these granules are compatible with a wide range of soft foods (eg, mashed fruit, mashed potatoes, yogurt, pudding), and a phase 1 study established bioequivalence with the original valbenazine capsule (Supplementary Table S2).Reference Jimenez, Hebert and Rees³⁶ Moreover, the compacted powder content of the original capsule has been studied in vitro and met acceptable criteria when crushed and mixed with soft foods or liquids, or dispersed in water for delivery via a gastrostomy tube.Reference Sajatovic, Patel and Hebert³⁷ Thus, both valbenazine capsules offer options for patients who have difficulty swallowing, fear of choking, or other forms of pill aversion. For these patients, deutetrabenazine might not be an option since the prescribing information advises that tablets are to be swallowed whole, and not chewed, crushed, or split.²

Somnolence and sedation

Both medications carry a warning about somnolence and sedation, which can affect a patient’s ability to drive or operate hazardous or complex machinery.^{1, 2}

As reported in the prescribing information for valbenazine, the incidence of somnolence (defined as somnolence, fatigue, sedation) was 10.9% versus 4.2% for placebo.¹ In the 6-week KINECT 3 study, the incidences for each of these adverse effects separately were as follows: somnolence (5.3% vs. 3.9% for placebo); fatigue (2.0% vs. 1.3%); sedation (0.7% vs. 0%).Reference Hauser, Factor and Marder¹¹

Incidence of somnolence in TD (either alone or pooled with fatigue and/or sedation) is not reported in the product label for deutetrabenazine as the rate did not meet the reporting threshold of at least 2% of patients and greater than placebo.² Reported incidences in the 12-week TD trials were as follows: ARM-TD (somnolence, 13.8% vs. 10.2% for placebo; fatigue, 6.9% vs. 8.5%); AIM-TD (somnolence 2% vs. 4% for placebo; fatigue, 3% vs. 1%; sedation, <1% vs. 0%).Reference Fernandez, Factor and Hauser^13, Reference Anderson, Stamler and Davis¹⁴

Parkinsonism and other abnormal movements

Valbenazine and deutetrabenazine both carry a warning about parkinsonism, with deutetrabenazine also carrying a warning for akathisia, agitation, and restlessness.^{1, 2} For both medications, postmarketing cases of parkinsonism were reported in patients with TD, mostly within the first 2 weeks of starting treatment or increasing the dose. The reported incidence of akathisia/restlessness/agitation was 2–3% for both medications. All patients taking these medications should be monitored for any signs of parkinsonism, akathisia, or other non-TD movements.

Hyperprolactinemia

A dose-related increase in prolactin was observed in the DBPC trials of valbenazine, and the potential for cholestasis is noted.¹ Prolactin was not evaluated in the deutetrabenazine studies, but hyperprolactinemia is included as a warning for deutetrabenazine use based on studies with tetrabenazine. In healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold after administration of tetrabenazine 25 mg.²

With concomitant medications

The effects of comedications on valbenazine pharmacokinetics were evaluated in phase 1 studies.Reference Loewen, Luo and Smith^38, Reference Smith, Loewen and Luo³⁹ Coadministration of valbenazine with strong CYP3A4 inducers is not recommended, as these drugs may reduce the exposure (and therefore effectiveness) of valbenazine and [+]-α-HTBZ (Supplementary Table S4).¹ There are no prohibitions for taking valbenazine with a strong CYP3A4 inhibitor or strong CYP2D6 inhibitor, and the 40-mg dose is recommended as these drugs may increase the exposure of valbenazine and [+]-α-HTBZ.

Regarding deutetrabenazine, a phase 1 study in healthy individuals was conducted with paroxetine, a strong CYP2D6 inhibitor (Supplementary Table S4). The exposure of α-deuHTBZ and β-deuHTBZ metabolites was found to increase by 1.9- and 6.5-fold, respectively.² Therefore, the maximum recommended daily dosage of deutetrabenazine is 36 mg in patients who are taking a strong CYP2D6 inhibitor. In vitro studies showed that at clinically relevant concentrations, deutetrabenazine and its active metabolites did not inhibit or induce CYP3A4 enzymes.²

The effects of CYP3A4 inhibitors or inducers on deutetrabenazine pharmacokinetics have not been reported. No dose modification of deutetrabenazine is required in the presence of CYP3A4 inducers or inhibitors.

In specific populations

For both valbenazine and deutetrabenazine, there are limited or no available data for the following: use in pregnant women or breastfeeding infants; effects on milk production or presence in human breast milk; use in pediatric patients (Supplementary Table S5).^{1, 2}

The effects of hepatic impairment, renal impairment, and poor CYP2D6 metabolism on valbenazine pharmacokinetics were evaluated in phase 1 studies. Based on these study results, dosing recommendations for valbenazine are as follows: dose reduction in patients with moderate or severe hepatic impairment (Child-Pugh score 7–15); no dose adjustment for patients with mild, moderate, or severe renal impairment; dose reduction in CYP2D6 poor metabolizers.¹ Finally, based on available data from TD and HD clinical trials, no dose adjustment is needed in elderly patients.

The effects of hepatic and renal impairment on deutetrabenazine pharmacokinetics have not been clinically evaluated. However, based on findings with tetrabenazine, deutetrabenazine is contraindicated in patients with hepatic impairment. No dosing recommendations are available for patients with renal impairment (Supplementary Table S5). Based on the increased exposure of deutetrabenazine metabolites when coadministered with paroxetine, a strong CYP2D6 inhibitor, a maximum daily dose of 36 mg is recommended for patients who are CYP2D6 poor metabolizers. The TD and HD clinical trials of deutetrabenazine did not include a sufficient number of elderly patients to determine specific dosing recommendations; however, the product label suggests starting with a low dose and increasing doses with caution.

Valbenazine

Both DPBC trials of valbenazine met their primary endpoint (Supplementary Tables S6 and S7). At Week 6 in KINECT 2, the least squares mean difference (LSMD or “placebo-corrected” difference) for the AIMS total score change from baseline was −2.4 (p = 0.0005), indicating a significantly greater improvement with valbenazine (25–75 mg once-daily) versus placebo.Reference O’Brien, Jimenez and Hauser¹⁰

KINECT 3 (phase 3 study) implemented a fixed sequence testing procedure, with the first step (primary endpoint) defined as statistical significance for valbenazine 80 mg versus placebo for AIMS total score change.Reference Hauser, Factor and Marder¹¹ This step was met, with LSMDs at Week 6 of −3.1 (p < 0.001) and −1.8 (nominal p = 0.002) for valbenazine 80 and 40 mg, respectively (Figure 3). Both valbenazine dose groups showed a statistically significant improvement in AIMS total score by Week 2: 40 mg (LSMD −1.4, nominal p = 0.031); 80 mg (LSMD −1.6, nominal p = 0.001) (data on file).

Figure 3.

AIMS outcomes in DBPC trials and long-term studies. **p<0.01; ***p<0.001 versus placebo.

The AIMS is a 12-item scale used to evaluate the severity of abnormal movements, and the total score is calculated by summing the item scores from each body region (items 1-7). In phase 3 clinical trials (KINECT 3 and AIM-TD), the AIMS was scored by central video raters who were blinded to treatment assignment and study visit. In open-label studies (KINECT 4 and RIM-TD), AIMS was scored by study investigators. (A) At Week 6 in KINECT 3, placebo-corrected LS mean changes from baseline (i.e., LSMD) were significant for both valbenazine doses (40 and 80 mg, once daily) [data on file]. At Week 48 in KINECT 4, AIMS total score decreased by -10.2 points, and ~90% of participants achieved ≥50% improvement from baseline. (B) At Week 12 in AIM-TD, placebo-corrected LS mean changes from baseline (i.e., LSMD) were significant for two deutetrabenazine doses (18 and 24 mg, twice-daily). At Week 145 in RIM-TD, AIMS total score decreased by 6.6 points, and 67% achieved ≥50% improvement from baseline.

Abbreviations: AIMS, Abnormal Involuntary Movement Scale; BID, twice-daily; LS, least squares; LSMD, least squares mean difference; OL, open-label; TD, tardive dyskinesia.

References: [1] Hauser et al., Am J Psychiatry 2017;174(5):476–84. [2] Marder et al., J Clin Psychopharmacol 2019;39(6):620–7. [3] Anderson et al., Lancet Psychiatry 2017;4(8):595–604. [4] Hauser et al., Front Neurol 2022;13:773999.

Results from J-KINECT (Japanese phase 3 study)Reference Horiguchi, Watanabe and Kondo¹² were consistent with those from KINECT 3, and its findings supported the approval of valbenazine for TD in Asia. For AIMS total score change from baseline to Week 6, LSMDs indicated statistical significance for valbenazine 40 mg (−2.2, p < 0.001) and 80 mg (−3.6, p < 0.001) versus placebo.

Deutetrabenazine

Both DBPC trials of deutetrabenazine met their primary endpoints (Supplementary Tables S6 and S7). At Week 12 in ARM-TD, a significantly greater decrease in AIMS total score was found with deutetrabenazine (6–24 mg BID) versus placebo, with an LSMD of −1.4 (p = 0.019).Reference Fernandez, Factor and Hauser¹³

In AIM-TD (phase 3 study), significant improvements in AIMS total score were found with two deutetrabenazine doses, 12 mg BID (24 mg/day) (LSMD −1.8, p = 0.003) and 18 mg BID (36 mg/day) (LSMD −1.9, p = 0.001) (Figure 3).Reference Anderson, Stamler and Davis¹⁴ Statistically significant improvements on AIMS total score were detected by Week 2 with both doses: 12 mg BID (LSMD −1.4, nominal p = 0.006); 18 mg BID (LSMD −1.1, nominal p = 0.032).

AIMS effect size

Cohen’s d, which is calculated from the standardized mean difference between 2 groups (eg, active drug and placebo), is typically interpreted using benchmarks of ~0.2 (small effect), ~0.5 (medium effect), and ~0.8 (large effect).Reference Cohen⁴⁰

Cohen’s d effect sizes have been reported based on AIMS total score changes from baseline (Table 2). In KINECT 3, effect sizes at Week 6 for valbenazine 40 mg and 80 mg were 0.5 and 0.9, respectively.Reference Correll, Cutler and Kane⁴¹ In AIM-TD, an effect size of 0.6 was detected at Week 12 for both deutetrabenazine doses (12 and 18 mg BID) that demonstrated statistical significance for AIMS total score improvement.Reference Citrome⁴²

Table 2.

Clinical relevance of AIMS clinical trial results

Abbreviations: AIMS, Abnormal Involuntary Movement Scale; CFB, change from baseline; LSM, least squares mean; NNT, number needed to treat; PBO, placebo.

* p < 0.05 versus placebo.

^a AIMS item score ratings: 0 = none, 1 = minimal, 2 = mild, 3 = moderate, 4 = severe.

^b Negative NNT indicates better outcome with placebo. NNTs were not estimable if the same result was found for valbenazine and placebo.

Number needed to treat

NNT describes how many patients need to receive one intervention versus another (eg, active drug vs. placebo) to expect one additional desired outcome, with a lower NNT indicating a stronger treatment effect versus placebo.Reference Citrome and Ketter⁴³ In the phase 3 trials of valbenazine and deutetrabenazine, the percentage of participants who reached a response threshold of ≥50% improvement in AIMS total score at the end of DBPC treatment was significantly greater with active drug than with placebo (Table 2). Calculated NNTs versus placebo using these response data for valbenazine were 7 (40 mg) and 4 (80 mg) at Week 6.Reference Citrome³⁴ For deutetrabenazine, a NNT versus placebo of 5 was found for both statistically significant doses (12 and 18 mg BID) at Week 12.Reference Citrome⁴²

NNTs versus placebo for valbenazine have also been presented for AIMS item shift analyses, defined as shifting from an AIMS item score ≥3 (moderate or severe) at baseline to a score ≤2 (mild to none) at Week 6.Reference Correll, Cutler and Kane⁴¹ For valbenazine 80 mg, NNTs of 6 or lower were found in all 7 body regions (Table 2).

AIMS MCID or MCIC

AIMS data were pooled from DBPC trials to estimate the MCID for valbenazine and MCIC for deutetrabenazine.Reference Stacy, Sajatovic and Kane^44, Reference Hauser, Barkay and Wilhelm⁴⁵ The AIMS MCID for valbenazine was based on the mean change from baseline in AIMS total score in all study participants from KINECT, KINECT 2, and KINECT 3, regardless of treatment (valbenazine or placebo), who had global ratings of “minimally improved” or better (score ≤3) per CGI-TD (clinician impression) or PGIC (patient self-report). The AIMS MCIC for deutetrabenazine was based on the mean change from baseline in AIMS total score in participants from ARM-TD and AIM-TD who were treated with deutetrabenazine and had a global rating of “minimally improved” (score = 3) per clinician impression (CGIC) or patient self-report (PGIC).

For both VMAT2 inhibitors, a 2-point decrease in AIMS total score was found to represent a clinically meaningful improvement in TD severity, with 3–4 points considered a more robust improvement threshold.Reference Stacy, Sajatovic and Kane^44, Reference Hauser, Barkay and Wilhelm⁴⁵ Mean improvements in AIMS dyskinesia total scores were clinically meaningful for both medications.

Subgroup analyses

Post hoc analyses have shown that both valbenazine and deutetrabenazine are effective in various subgroups of clinical interest. Valbenazine was evaluated in older patients (age ≥55 years),Reference Sajatovic, Alexopoulos, Burke, Farahmand and Siegert⁴⁶ elderly patients (age ≥65 years),Reference Watanabe, Susuta, Nagano, Masui and Kanahara^47, Reference Sajatovic, Alexopoulos and Jen⁴⁸ and patients with schizophrenia/schizoaffective disorder or a mood disorder.Reference McIntyre, Calabrese and Nierenberg^49, Reference Nagano, Susuta, Masui, Watanabe and Watanabe⁵⁰ Deutetrabenazine was evaluated in older patients (≥55 years),Reference Sajatovic, Finkbeiner and Wilhelm⁵¹ patients with schizophrenia/schizoaffective disorder or a mood disorder,Reference Hauser, Barkay and Fernandez⁵² and regardless of concomitant antipsychotic use.Reference Hauser, Barkay and Fernandez⁵²

Valbenazine

The long-term studies for valbenazine included KINECT Extension (open label),⁹ KINECT 3 Extension (with double-blind dosing, but no placebo),Reference Factor, Remington and Comella¹⁵ J-KINECT Extension (Japanese study with double-blind dosing, but no placebo),Reference Horiguchi, Watanabe and Kondo¹² KINECT 4 (open label),Reference Marder, Singer and Lindenmayer¹⁶ and Study 1506 (open-label roll-over).Reference Lindenmayer, Verghese and Marder¹⁷ Results from these studies indicated ongoing TD improvements in patients who received up to 48 weeks of valbenazine treatment (Supplementary Table S8).

KINECT 4 was designed to be more reflective of real-world use. The primary objective of this study was to evaluate the long-term safety of valbenazine. Participants who had a CGI-TD score ≤2 (“much improved” or “very much improved”) at the end of Week 4 continued on 40 mg daily, whereas those who did not had their daily dose increased to 80 mg. The most common treatment-emergent adverse events (TEAEs) from Week 4 (end of initial treatment with 40 mg) to Week 48 (end of treatment with 40 or 80 mg) were urinary tract infection (8.5%) and headache (5.2%). Evaluations based on Columbia-Suicide Severity Rating Scale (C-SSRS) scores indicated that 5 participants had nonactive suicidal ideation at baseline (score 1–3), none of whom experienced worsening of suicidal ideation during valbenazine treatment; no suicidal behaviors (C-SSRS score 6–10) were reported. Psychiatric status remained stable, and no notable changes in vital signs, electrocardiograms (ECGs), or clinical laboratory tests were observed.

As part of the open-label design, AIMS scoring was based on assessments of movement severity by study investigators, rather than by blinded central video raters (as used in the DBPC trials). At Week 48, mean changes from baseline in AIMS total score were −10.2 and −11.0 with valbenazine 40 mg and 80 mg, respectively (Figure 3). These mean score changes were supported by the percentage of participants who met the following response thresholds at Week 48 (40 mg, 80 mg): AIMS ≥50% improvement (90.0%, 89.2%); CGI-TD score ≤2, defined as rating of “much improved” or “very much improved” (90.0%; 95.9%); and PGIC score ≤2 (90.0%, 89.2%) (Figures 3 and 4).

Figure 4.

Global improvement outcomes in long-term studies. Global improvements in TD, as assessed by study investigators (CGI-TD, CGIC) and self-reported by study participants (PGIC), are presented. (A) In the 48-week open-label KINECT 4 study, approximately 90-95% of participants met the threshold for CGI-TD and PGIC response, which were both defined as a score of 1 (“very much improved”) or 2 (“much improved”). (B) The same response thresholds were used in the long-term open-label study with deutetrabenazine. At Week 145 in this study, 73% of participants had a CGIC score ≤2 and 63% had a PGIC score ≤2.

Abbreviations: CGIC, Clinical Global Impression of Change; CGI-TD, Clinical Global Impression of Change-Tardive Dyskinesia; PGIC, Patient Global Impression of Change.

References: [1] Marder et al., J Clin Psychopharmacol 2019;39(6):620–7. [2] Hauser et al., Front Neurol 2022;13:773999.

All individuals who completed a DBPC or long-term clinical trial were eligible to enroll in Study 1506, which was designed to provide additional long-term safety data in patients who wanted to continue taking valbenazine until it became available commercially.Reference Lindenmayer, Verghese and Marder¹⁷ Including participants’ treatment in prior studies and in Study 1506, the mean total duration of valbenazine exposure was 19.7 months (range, 9.9–26.9 months). All participants were required to undergo a valbenazine washout before starting open-label treatment in this study, which included a 4-week initiation period with valbenazine 40 mg. After Week 4, the most common TEAEs were back pain (4.5%) and urinary tract infection (4.5%), as reported in 157 participants who had up to 60 weeks of valbenazine treatment in this study. The individuals who enrolled in this study presumably did so because of a positive experience with valbenazine in a previous study, which should be considered when interpreting study results. Notably, however, approximately 98% of participants expressed satisfaction with valbenazine before starting this study and by the end of the study, which was stopped when valbenazine became commercially available.

Deutetrabenazine

Participants who completed the ARM-TD and AIM-TD trials were eligible to continue in the long-term extension study (RIM-TD), with reported results at Week 106Reference Fernandez, Stamler and Davis¹⁸ and Week 145Reference Hauser, Barkay and Fernandez¹⁹ (Supplementary Table S8). Evaluation of long-term safety and tolerability was the primary objective of this study, and adverse events (AEs) were presented as exposure-adjusted incidence rates (EAIRs) with no breakdown by dose. At Week 145, the mean daily dose of deutetrabenazine was 39.4 mg. Among participants in the Week 145 analysis (N = 337), the most common AEs were anxiety (EAIR = 0.07, n = 42 [12.5%]), somnolence (EAIR = 0.05, n = 34 [10.1%]), and depression (EAIR = 0.005, n = 33 [8.9%]).Reference Hauser, Barkay and Fernandez¹⁹ No notable changes were observed in safety scales that measured akathisia, anxiety, depression, sleepiness, and cognitive impairment.

In participants who reached the Week 145 visit, the mean change from baseline in AIMS total score was −6.6 (Figure 3).Reference Hauser, Barkay and Fernandez¹⁹ This outcome was supported by the percentage of participants who met the following response thresholds at Week 145: AIMS ≥50% improvement (67%); CGIC score ≤2 (73%); PGIC score ≤2 (63%) (Figures 3 and 4).