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<p><i>LRRK2</i> (encoding leucine-rich repeat kinase 2) variants are the most common genetic cause of Parkinson’s disease (PD). Lowering LRRK2 levels and/or inhibiting LRRK2 activity may modify PD-associated neuropathology. BIIB094 (ION859), an antisense oligonucleotide, targets <i>LRRK2</i> mRNA for degradation. REASON was a first-in-human randomized phase 1 study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal BIIB094 in patients with PD. In part A, 40 participants received single doses of BIIB094 10–150 mg or placebo. In part B, 42 participants, stratified by <i>LRRK2</i> variant status, received four doses of BIIB094 40–120 mg or placebo every 4 weeks. Adverse events were reported by 64.5% (20/31) of participants in part A and by 84.8% (28/33) of participants in part B. The events were mainly mild to moderate and not dose limiting. No serious adverse events related to BIIB094 were reported in either part A or B. Systemic BIIB094 exposure increased with dose. Cerebrospinal fluid (CSF) LRRK2 and phosphorylated Rab10 levels were lowered by up to 59% and up to 50%, respectively, irrespective of <i>LRRK2</i> variant status. Concomitant reductions in CSF lysosomal protein levels suggested a potential mechanism whereby LRRK2 therapeutics may impact underlying PD pathophysiology. ClinicalTrials.gov identifier, <a href="https://clinicaltrials.gov/study/NCT03976349">NCT03976349</a>; EudraCT number, 2018-002995-42.</p>

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LRRK2-targeting antisense oligonucleotide in Parkinson’s disease: a phase 1 randomized controlled trial

  • 期刊论文

  • 发表日期：

    2026年3月24日

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  • Omar S. Mabrouk,
  • Ben Tichler,
  • H. Moore Arnold,
  • Eva C. Thoma,
  • Sara M. Alexanian,
  • Jingxian Chen,
  • Tzu-Ying Liu,
  • Beth Hirschhorn,
  • Roy Llorens Arenas,
  • John W. Annand,
  • Unnati Kapadnis,
  • Alan A. Shomo,
  • Kelly E. Glajch,
  • Kyle Ferber,
  • Yuka Moroishi,
  • Julie Czerkowicz,
  • Jennifer Inra,
  • Ronald B. Postuma,
  • Tanya Gurevich,
  • Pablo Mir,
  • Huw R. Morris,
  • Jason Aldred,
  • Matthew A. Brodsky,
  • Aaron Ellenbogen,
  • Danielle Larson,
  • Christopher M. Tolleson,
  • Andrew Siderowf,
  • Charalampos Tzoulis,
  • Ernest Balaguer,
  • Maria J. Marti,
  • Hien T. Zhao,
  • Holly B. Kordasiewicz,
  • Roger Lane,
  • Warren D. Hirst,
  • Stephanie Fradette,
  • Danielle L. Graham

摘要

LRRK2 (encoding leucine-rich repeat kinase 2) variants are the most common genetic cause of Parkinson’s disease (PD). Lowering LRRK2 levels and/or inhibiting LRRK2 activity may modify PD-associated neuropathology. BIIB094 (ION859), an antisense oligonucleotide, targets LRRK2 mRNA for degradation. REASON was a first-in-human randomized phase 1 study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intrathecal BIIB094 in patients with PD. In part A, 40 participants received single doses of BIIB094 10–150 mg or placebo. In part B, 42 participants, stratified by LRRK2 variant status, received four doses of BIIB094 40–120 mg or placebo every 4 weeks. Adverse events were reported by 64.5% (20/31) of participants in part A and by 84.8% (28/33) of participants in part B. The events were mainly mild to moderate and not dose limiting. No serious adverse events related to BIIB094 were reported in either part A or B. Systemic BIIB094 exposure increased with dose. Cerebrospinal fluid (CSF) LRRK2 and phosphorylated Rab10 levels were lowered by up to 59% and up to 50%, respectively, irrespective of LRRK2 variant status. Concomitant reductions in CSF lysosomal protein levels suggested a potential mechanism whereby LRRK2 therapeutics may impact underlying PD pathophysiology. ClinicalTrials.gov identifier, NCT03976349; EudraCT number, 2018-002995-42.