KINECT-HD
Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial
Clinical Question
Is valbenazine effective and safe for treating chorea associated with Huntington's disease?
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 45 of 55 valbenazine participants treated at week 12 (82%) were taking the 80 mg target dose. This establishes valbenazine as the third VMAT2 inhibitor studied for HD chorea, offering once-daily dosing convenience.
Major Points
- Valbenazine (up to 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 (LS mean difference 1.4, 95% CI -1.5 to 4.3; P=0.3304); Neuro-QoL Lower Extremity Function was not formally tested per the fixed-sequence procedure
- Of the 55 valbenazine participants treated at week 12, 45 (82%) were taking the 80 mg target dose (7 [13%] on 60 mg, 2 [4%] on 40 mg, 1 [2%] on 20 mg)
- 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
- Titration schedule: 40 mg/day for 2 weeks, with 20-mg increments allowed at the ends of weeks 2, 4, and 6 to a target of 80 mg/day; dose-adjustment period baseline to week 8; maintenance weeks 9-12
- Post-hoc sensitivity analyses using different baseline definitions (screening only, baseline only, average) all confirmed robustness of primary result
Design
Study Type: Phase 3, randomised, double-blind, placebo-controlled, parallel-group trial
Randomization: 1
Blinding: Double-blind (participants, investigators, site staff, sponsor)
Enrollment Period: November 13, 2019 to October 26, 2021 (with COVID-19 pause March 15 to July 1, 2020)
Follow-up Duration: 12 weeks double-blind + 2-week washout/follow-up
Centers: 46
Countries: United States, Canada
Sample Size: 128
Analysis: Mixed-effects model for repeated measures (MMRM); full-analysis set (all randomized who received ≥1 dose and had ≥1 evaluable post-baseline TMC assessment)
Inclusion Criteria
- Age 18-75 years
- Genetically confirmed Huntington's disease (CAG repeat ≥37)
- UHDRS Total Maximal Chorea (TMC) score ≥8 at both the screening and baseline assessments
- UHDRS Total Functional Capacity (TFC) score ≥5 at screening; a reliable caregiver was required if TFC was 5-10
- Stable doses of concomitant HD medications (benzodiazepines/opiates ≥2 weeks, antidepressants ≥8 weeks before baseline)
- Capacity to provide informed consent (UCSD Brief Assessment of Capacity to Consent)
Exclusion Criteria
- Any previous or current treatment with a VMAT2 inhibitor (tetrabenazine, deutetrabenazine, or valbenazine)
- Use of antipsychotics/other dopamine receptor blockers, CYP3A4 inducers, dopamine agonists and precursors, or monoamine oxidase inhibitors within 30 days before baseline
- Serious, unstable, untreated, or undertreated medical or psychiatric illness
- HADS depression subscale score ≥11
- Recent (past 3 months) active suicidal ideation with intent or behaviour, or evidence on C-SSRS
- History or evidence of long QT syndrome, or QTcF >450 ms (male) or >470 ms (female), or any other important cardiac condition or abnormality
- Clinically manifest dysphagia (Swallowing Disturbance Questionnaire score ≥11), unless CRSPSP dysphagia item ≤2
- Clinically important laboratory or haematological abnormalities
Arms
| Field | Valbenazine | Control |
|---|---|---|
| Intervention | Valbenazine initiated at 40 mg/day for 2 weeks, with 20-mg dose increments allowed at the ends of weeks 2, 4, and 6 to a target of 80 mg/day (dose-adjustment period baseline to week 8); maintenance weeks 9-12; oral once daily | Matching placebo capsules, oral once daily |
| Duration |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change in UHDRS Total Maximal Chorea (TMC) score from screening/baseline average to maintenance period (average of weeks 10 and 12) | Primary | -1.4 | -4.6 | -3.2 | <0.0001 |
| CGI-C response (much/very much improved) at week 12 | Secondary | 13% | 43% | 0.0007 | |
| PGI-C response (much/very much improved) at week 12 | Secondary | 26% | 53% | 0.0062 | |
| Neuro-QoL Upper Extremity Function T-score change (LS mean, difference 1.4, 95% CI -1.5 to 4.3) | Secondary | -3.0 | -1.6 | 0.3304 | |
| Neuro-QoL Lower Extremity Function T-score change (LS mean, difference -0.9, 95% CI -3.2 to 1.4; not formally tested per fixed-sequence procedure) | Secondary | 0.6 | -0.3 | NA | |
| Any TEAE | Adverse | 64% | 77% | ||
| Serious TEAE | Adverse | 3% | 2% | ||
| TEAE leading to dose reduction | Adverse | 5% | 14% | ||
| TEAE leading to discontinuation | Adverse | 6% | 8% | ||
| Somnolence | Adverse | 3% | 16% | ||
| Fatigue | Adverse | 10% | 14% | ||
| Falls | Adverse | 13% | 13% | ||
| Urticaria | Adverse | 0% | 9% | ||
| Rash | Adverse | 0% | 8% | ||
| Akathisia | Adverse | 5% | 6% | ||
| Diarrhea | Adverse | 2% | 5% | ||
| Headache | Adverse | 5% | 3% |
Subgroup Analysis
Prespecified subgroup analyses on the basis of age, sex, race, baseline CGI-S categories, and baseline PGI-S categories. Effect on the primary endpoint observed regardless of whether baseline was defined as screening, day 1, or average of both (three prespecified sensitivity analyses).
Criticisms
- Short 12-week duration may underestimate long-term efficacy, safety, and functional benefits (Neuro-QoL UEF was non-significant; LEF was not formally tested per fixed-sequence procedure)
- Predominantly White population (94-98%) limits generalizability
- Titration design means most efficacy data reflect exposure to 80 mg; efficacy of 40 mg alone less clear
- COVID-19 pandemic caused a study pause and may have introduced bias (7 participants withdrawn due to site closures)
- Sponsor (Neurocrine Biosciences) was involved in study design and data analysis; Neurocrine-affiliated authors contributed to interpretation
- Prohibition of concomitant antipsychotics may not reflect real-world treatment patterns (to be examined in KINECT-HD2)
- No active comparator (tetrabenazine or deutetrabenazine) for head-to-head comparison
Funding
Neurocrine Biosciences
Based on: KINECT-HD (Lancet Neurology, 2023)
Authors: Furr Stimming E, Claassen DO, Kayson E, ..., Haubenberger D; Huntington Study Group KINECT-HD Collaborators
Citation: Lancet Neurol 2023; 22: 494-504
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