KINECT-HD
(2023)Objective
To evaluate the efficacy, safety, and tolerability of valbenazine for the treatment of chorea associated with Huntington's disease
Study Summary
• CGI-C response (much/very much improved): 43% valbenazine vs 13% placebo (P=0.0007)
• PGI-C response: 53% vs 26% (P=0.0062)
• Neuro-QoL Upper Extremity Function T-score change not significant (P=0.33)
• Most common AE was somnolence (16% vs 3%); no worsening of depression, suicidality, parkinsonism, or akathisia
• 82% of valbenazine patients achieved and maintained target dose of 80 mg/day
• Third VMAT2 inhibitor studied for HD chorea, with advantage of once-daily dosing
Intervention
Valbenazine (up to 80 mg/day, once daily) vs placebo
Inclusion Criteria
Adults 18-75 with genetically confirmed HD (CAG ≥37), UHDRS TMC ≥8, UHDRS Total Functional Capacity 5-10, reliable caregiver
Study Design
Arms: Valbenazine (n=64) vs Placebo (n=64)
Patients per Arm: Valbenazine: 64, Placebo: 64 (128 randomized, 125 in full-analysis set)
Outcome
Bottom Line
Valbenazine (up to 80 mg/day) significantly reduced Huntington's disease chorea compared to placebo, with a 3.2-point greater reduction in UHDRS Total Maximal Chorea score (P<0.0001). The drug was well tolerated with no worsening of depression, suicidality, parkinsonism, or akathisia, and 82% of patients achieved the target 80 mg dose. This establishes valbenazine as the third VMAT2 inhibitor studied for HD chorea, offering once-daily dosing convenience.
Major Points
- Valbenazine 80 mg/day met the primary endpoint with UHDRS TMC reduction of -4.6 vs -1.4 for placebo (LS mean difference -3.2, 95% CI -4.4 to -2.0, P<0.0001)
- CGI-C response rate (much or very much improved) was significantly higher with valbenazine: 43% vs 13% (P=0.0007)
- PGI-C response rate was also significantly higher: 53% vs 26% (P=0.0062)
- Neuro-QoL Upper Extremity Function did not reach significance (P=0.33), possibly due to 12-week duration being insufficient to capture functional gains
- 82% of valbenazine patients achieved and maintained the target dose of 80 mg/day by week 12
- Somnolence was the most common differentiating adverse event (16% vs 3%), followed by urticaria (9% vs 0%) and rash (8% vs 0%)
- No clinically meaningful worsening of depression, suicidality, parkinsonism, or akathisia observed
- Third VMAT2 inhibitor studied for HD chorea after tetrabenazine and deutetrabenazine, with advantage of once-daily dosing and no CYP2D6 metabolizer-based dose adjustment
- Study used a titration-to-effect design (40 mg for 4 weeks, then up to 80 mg) followed by 8-week maintenance, totaling 12 weeks
- Post-hoc sensitivity analyses using different baseline definitions (screening only, baseline only, average) all confirmed robustness of primary result
Study Design
- Study Type
- Phase 3, randomised, double-blind, placebo-controlled, parallel-group trial
- Randomization
- Yes
- Blinding
- Double-blind (participants, investigators, site staff, sponsor)
- Sample Size
- 128
- Follow-up
- 12 weeks double-blind + 2-week washout/follow-up
- Centers
- 46
- Countries
- United States, Canada
Primary Outcome
Definition: Change in UHDRS Total Maximal Chorea (TMC) score from screening/baseline average to maintenance period (weeks 10-12)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -1.4 | -4.6 | - (-4.4 to -2.0) | <0.0001 |
Limitations & Criticisms
- Short 12-week duration may underestimate functional benefits (Neuro-QoL was non-significant)
- Predominantly White population (94-98%) limits generalizability
- Titration design means most efficacy data reflect 80 mg dose; 40 mg efficacy less clear
- COVID-19 pandemic affected enrollment and may have introduced bias
- Sponsor-funded with sponsor involvement in study design and data analysis
- CYP2D6 poor metabolizers were excluded, limiting safety data in this population
- No active comparator (tetrabenazine or deutetrabenazine) for head-to-head comparison
Citation
Lancet Neurol 2023; 22: 494-504