GENERATION HD1
(2023)Objective
To evaluate the efficacy and safety of intrathecal tominersen (antisense oligonucleotide) in slowing progression of Huntington's disease by lowering huntingtin protein levels
Study Summary
• Every-8-week tominersen group showed significantly worse cUHDRS scores compared to placebo (-0.54 points, P=0.001) at week 69
• Every-16-week tominersen group showed no significant differences from placebo in clinical outcomes
• Tominersen achieved dose-dependent reduction in CSF mutant HTT levels but was associated with increased ventricular volume, transient CSF NfL elevation, and more adverse events
Intervention
Intrathecal tominersen 120 mg every 8 weeks or every 16 weeks vs placebo
Inclusion Criteria
Adults with manifest Huntington's disease
Study Design
Arms: 3 arms: Tominersen 120 mg every 8 weeks, Tominersen 120 mg every 16 weeks, Placebo
Patients per Arm: Approximately 264 per arm (791 total participants randomized 1:1:1)
Outcome
• Secondary: Dose-dependent reduction in CSF mutant HTT (approximately 40% reduction in every-8-week group); increased ventricular volume; transient increase in CSF NfL at week 21 in every-8-week group; no whole-brain volume loss despite ventricular expansion
Bottom Line
The GENERATION HD1 trial of intrathecal tominersen in manifest Huntington's disease was stopped early due to unfavorable benefit-risk assessment. The every-8-week dosing regimen showed worse clinical outcomes compared to placebo, while the every-16-week regimen showed no significant clinical benefit. Despite dose-dependent reductions in CSF mutant HTT, increases in ventricular volume without whole-brain atrophy and transient elevation in CSF NfL suggest possible inflammatory or toxic effects.
Major Points
- Phase 3 randomized, double-blind, placebo-controlled trial with 791 participants with manifest Huntington's disease randomized 1:1:1 to tominersen 120 mg every 8 weeks, every 16 weeks, or placebo
- Trial was stopped early in March 2021 based on independent data monitoring committee benefit-risk assessment
- Ad hoc analysis at week 69 showed significantly worse cUHDRS scores in the every-8-week group compared to placebo (-0.54 points, P=0.001) but no significant difference in TFC scores
- The every-16-week group showed no significant differences from placebo in either cUHDRS or TFC outcomes
- Tominersen achieved dose-dependent reduction in CSF mutant HTT levels (approximately 40% reduction in every-8-week group, 20% in every-16-week group)
- Unexpected increases in ventricular volume occurred in both tominersen groups without corresponding whole-brain volume loss
- Transient increase in CSF neurofilament light (NfL) levels at week 21 in every-8-week group
- Post hoc analyses suggest younger participants with less disease burden may potentially benefit, leading to GENERATION HD2 phase 2 dose-finding trial
Study Design
- Study Type
- Phase 3 randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 791
- Follow-up
- Planned 101 weeks; trial stopped early with ad hoc analysis at week 69
Primary Outcome
Definition: Change from baseline in composite Unified Huntington's Disease Rating Scale (cUHDRS) score at week 101 (analyzed at week 69 due to early termination). Scores range from -8 to 25, with higher scores indicating improvement.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Baseline to week 69 change: approximately -1.0 points | Every-8-week: -1.54 points; Every-16-week: -1.16 points | - | Every-8-week vs placebo: P=0.001; Every-16-week vs placebo: P=0.84 |
Limitations & Criticisms
- Trial was stopped early, and analysis was ad hoc rather than at the pre-specified primary endpoint (week 101)
- The mechanism of harm cannot be distinguished between antisense oligonucleotide-related toxic effects versus effects of total HTT lowering
- Ventricular expansion without whole-brain volume loss is inconsistent with the natural history of Huntington's disease
- No linear relationship between CSF NfL levels and clinical outcomes was demonstrated
- Baseline characteristics were not provided in detail in this correspondence letter
Citation
N Engl J Med 2023;389:2203-2206