Huntington’s disease: novel targeted therapy advances to phase 3 trial

  • Tabrizi SJ & al.
  • N Engl J Med
  • 6 May 2019

  • International Clinical Digest
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  • 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.

Key results

  • 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).

Expert comment

  • 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 ( number, NCT03761849), with a plan to follow 660 patients worldwide for up to 2 years.”

Study design

  • 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.