The effect of deuterium substitution on clinical outcomes with deutetrabenazine in the First-HD and ARM-TD studies

Background: Deutetrabenazine (DTB) is a novel, highly selective vesicular monoamine transporter type 2 (VMAT2) inhibitor that contains deuterium, a naturally occurring, nontoxic form of hydrogen. Deuterium forms a stronger bond with carbon than does hydrogen, requiring more energy for cleavage. Deuterium attenuates metabolism and results in a unique pharmacokinetic profile that leads to more uniform systemic exposure without altering the target pharmacology of the original molecule. The resultant pharmacokinetic profile may enable less‐frequent, lower daily doses, achieving adequate systemic exposure with lower peak concentration. Collectively, deuterium technology has the potential to improve the risk‐benefit profile of medications.

OBJECTIVE:

To assess whether DTB provides a clinical benefit for patients with chorea associated with Huntington disease (HD) in the First‐HD study and tardive dyskinesia (TD) in the ARM‐TD study.

METHODS:

Patients with HD or TD were randomized 1:1 to DTB or placebo in the respective 12‐week, double‐blind trials, First‐HD (N=90) and ARM‐TD (N=117), which evaluated efficacy, safety, and tolerability. The primary efficacy endpoint of First‐HD was the change from baseline to maintenance in the UnifiedHuntington'sDiseaseRating Scale (UHDRS) total maximal chorea (TMC) score. The primary efficacy endpoint of ARM‐TD was the change in Abnormal Involuntary Movement Scale (AIMS) score from baseline to Week 12. Adverse events (AEs) and specific safety scales were monitored throughout both studies.

RESULTS:

In First‐HD, DTB significantly decreased the UHDRS TMC score compared with placebo (‐4.4 vs‐1.9; P?0.0001). In ARM‐TD, DTB significantly reduced mean AIMS scores compared with placebo (‐3.0 vs‐1.6; P=0.0188). DTB was generally well tolerated in both studies. In First‐HD, AEs were mostly mild to moderate, and AE rates were similar for DTB and placebo; both groups also had the same low rates of dose reductions (6.7% each), suspensions (2.2% each), and withdrawals (2.2% each) due to AEs. Likewise, the incidence of AEs in ARM‐TD was also similar between DTB and placebo. These were also mostly mild to moderate in nature. For the DTB and placebo groups in ARM‐TD, respectively, there were low rates of dose reductions (10.3% vs 5.1%), suspensions (5.2% vs 8.5%), and study withdrawals (1.7% vs 3.4%) due to AEs.

CONCLUSIONS:

The favorable efficacy and safety profile of DTB observed in the HD and TD populations in First‐HD and ARM‐TD may be attributed to the unique pharmacokinetic profile of DTB achieved by deuterium substitution.