- Among patients with early Huntington’s disease, 4 monthly intrathecal doses of an antisense oligonucleotide that inhibits HTT messenger RNA (HTTRx) reduced the concentration of mutant huntingtin protein in cerebrospinal fluid (CSF) in a dose-dependent manner.
Why this matters
- Current lack of treatments that prevent disease onset, slow progression.
- All patients in HTTRx arm received all 4 doses, completed trial.
- 98% of patients experienced adverse events (all grade 1 or 2).
- Leading events with HTTRx: procedural pain, post-dural-puncture headache; no serious adverse events.
- No clinically relevant adverse changes in laboratory variables.
- Mean percentage change in CSF mutant huntingtin:
- +10% with placebo,
- –20% with HTTRx 10 mg,
- –25% with HTTRx 30 mg,
- –28% with HTTRx 60 mg,
- –42% with HTTRx 90 mg, and
- –38% with HTTRx 120 mg.
- Post hoc analysis: magnitude of mutant huntingtin reduction correlated with improvement in composite Unified Huntington Disease Rating Scale score (ρ, –0.414; 95% CI, –0.629 to –0.141).
- In an editorial, Kenneth H. Fischbeck, MD, and Nancy S. Wexler, PhD, write, “This is a pathbreaking trial that strongly supports further development of HTTRx as a treatment for Huntington’s disease. A confirmatory phase 3 trial is now under way (Clinical-Trials.gov number, NCT03761849), with a plan to follow 660 patients worldwide for up to 2 years.”
- Multinational phase 1/2a randomized controlled trial among 46 patients with early Huntington’s disease.
- Randomization: 3:1 to double-blind HTTRx (ascending doses) vs placebo, bolus intrathecal administration every 4 weeks for 4 doses.
- Main outcome: safety.
- Funding: Ionis Pharmaceuticals; F. Hoffmann–La Roche.
- Lack of power.
- Durability unknown.