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J01 Effects of IONIS-HTTRX (RG6042) in patients with early huntington’s disease, results of the first htt-lowering drug trial
  1. Sarah J Tabrizi1,
  2. Blair Leavitt2,
  3. Bernhard Landwehrmeyer3,
  4. Edward Wild1,
  5. Carsten Saft4,
  6. Roger Barker5,
  7. David Craufurd6,
  8. Hugh Rickards7,
  9. Anne Rosser8,
  10. Josef Priller9,
  11. Holly Kordasiewicz10,
  12. Christian Czech11,
  13. Eric Swayze10,
  14. Daniel A Norris10,
  15. Tiffany Baumann10,
  16. Irene Gerlach11,
  17. Scott Schobel11,
  18. Anne Smith10,
  19. Roger Lane10,
  20. C Frank Bennett10,
  21. on behalf of the HTT Rx CS1 study teams
  1. 1Huntington’s Disease Centre, UCL Institute of Neurology, London, UK
  2. 2Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada
  3. 3Department of Neurology, Ulm University, Ulm, Germany
  4. 4Department of Neurology, Huntington Centre NRW, Ruhr-University Bochum, St. Josef-Hospital, Bochum, Germany
  5. 5Department of Neurology, University of Cambridge, Addenbrooke’s; Hospital, Cambridge, UK
  6. 6Institute of Human Development, Faculty of Medical and Human; Sciences, University of Manchester and Manchester Academic Health Science Centre, Manchester, UK
  7. 7Birmingham University Imaging Centre and School of Psychology, College of Life and Environmental Sciences, University of Birmingham, Birmingham, UK
  8. 8Schools of Medicine and Biosciences, Cardiff University, Cardiff, UK
  9. 9Department of Neuropsychiatry, Charité- Universitätsmedizin Berlin, Berlin, Germany
  10. 10Ionis Pharmaceuticals, Carlsbad, CA, USA
  11. 11F. Hoffman-La Roche, Ltd, Roche Innovation Center, Basel, Switzerland


Background HD is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the HTT gene resulting in polyglutamine expansion in the mutant huntingtin protein (mHTT) with a toxic gain-of-function disease mechanism. No disease-modifying treatments are currently available. In transgenic rodent models of HD, suppressing HTT production delays disease progression and reverses disease phenotype. A drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT production.

Design/methods In this first-in-human, multi-center, double-blind clinical trial (NCT02519036), 46 patients were randomized (3:1) to receive four doses of IONIS-HTTRx or placebo by monthly bolus intrathecal (IT) injection followed by a 4-month untreated period. Five ascending-dose cohorts were enrolled with independent DSMB review of safety, PK and target engagement prior to dose escalation.

Results IONIS-HTTRx was well-tolerated at all doses tested. Adverse events were mostly mild and unrelated to study drug. There were no adverse trends in laboratory parameters. No patients prematurely discontinued from treatment. ASO was measurable in CSF and plasma. Significant, dose-dependent reductions in CSF mutant HTT (mHTT) were observed.

Conclusions ASO technology has the potential to provide disease-modifying benefits to patients with neurodegenerative diseases. In this Phase 1/2a trial in early stage HD patients, IONIS-HTTRx delivered via IT injection was well tolerated with no study drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTTRx is a promising therapeutic for the treatment of HD.

Study Supported By: Ionis Pharmaceuticals

  • ASO
  • mHTT reductions
  • CSF
  • drug trial

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