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N Engl J Med. 2019 Jun 13;380(24):2307-2316. doi: 10.1056/NEJMoa1900907. Epub 2019 May 6.

Targeting Huntingtin Expression in Patients with Huntington's Disease.

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From University College London (UCL) Huntington's Disease Centre, Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, and the U.K. Dementia Research Institute at UCL, London (S.J.T., E.J.W.), the Department of Clinical Neuroscience, Addenbrooke's Hospital, University of Cambridge, Cambridge (R.A.B., N.F.B.), Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust, and the Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine, and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester (D.C.), the University of Edinburgh and the U.K. Dementia Research Institute, Edinburgh (J.P.), the Institute of Clinical Sciences, College of Medical and Dental Sciences, University Hospital Birmingham, Birmingham (H.R.), and the Cardiff University Brain Repair Group, Brain Repair and Intracranial Neurotherapeutics Unit, Neuroscience and Mental Health Research Institute and School of Biosciences, Cardiff (A.R.) - all in the United Kingdom; the Centre for Huntington's Disease, Department of Medical Genetics, and the Division of Neurology, Department of Medicine, University of British Columbia, and the Centre for Molecular Medicine and Therapeutics, B.C. Children's Hospital, Vancouver, Canada (B.R.L.); the Department of Neurology, Ulm University, Huntington's Disease Centre, Ulm (G.B.L.), the Department of Neurology, Huntington Center North Rhine-Westphalia, Ruhr University Bochum, St. Josef-Hospital, Bochum (C.S.), and the Department of Neuropsychiatry, Charité-Universitätsmedizin Berlin, Deutsches Zentrum für Neurodegenerative Erkrankungen, Berlin (J.P.) - all in Germany; Ionis Pharmaceuticals, Carlsbad, CA (H.B.K., E.E.S., D.A.N., T.B., E.P., A.V.S., C.F.B., R.M.L.); and F. Hoffmann-La Roche, Basel, Switzerland (C.C., I.G., S.A.S.).



Huntington's disease is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mutant huntingtin protein. IONIS-HTTRx (hereafter, HTTRx) is an antisense oligonucleotide designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin.


We conducted a randomized, double-blind, multiple-ascending-dose, phase 1-2a trial involving adults with early Huntington's disease. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intrathecal administration every 4 weeks for four doses. Dose selection was guided by a preclinical model in mice and nonhuman primates that related dose level to reduction in the concentration of huntingtin. The primary end point was safety. The secondary end point was HTTRx pharmacokinetics in cerebrospinal fluid (CSF). Prespecified exploratory end points included the concentration of mutant huntingtin in CSF.


Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all four doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98% of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Predose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively).


Intrathecal administration of HTTRx to patients with early Huntington's disease was not accompanied by serious adverse events. We observed dose-dependent reductions in concentrations of mutant huntingtin. (Funded by Ionis Pharmaceuticals and F. Hoffmann-La Roche; number, NCT02519036.).

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