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Targeting Huntingtin expression in patients with Huntington's disease

Tabrizi, Sarah J., Leavitt, Blair R., Landwehrmeyer, G. Bernhard, Wild, Edward J., Saft, Carsten, Barker, Roger A., Blair, Nick F., Craufurd, David, Priller, Josef, Rickards, Hugh, Rosser, Anne ORCID:, Kordasiewicz, Holly B., Czech, Christian, Swayze, Eric E., Norris, Daniel A., Baumann, Tiffany, Gerlach, Irene, Schobel, Scott A., Paz, Erika, Smith, Anne V., Bennett, C. Frank, Lane, Roger M. and Hamandi, Khalid 2019. Targeting Huntingtin expression in patients with Huntington's disease. New England Journal of Medicine 380 (24) , pp. 2307-2316. 10.1056/NEJMoa1900907

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Background 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. Methods 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. Results 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). Conclusions 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.)

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Additional Information: For the Phase 1–2a IONIS-HTTRx Study Site Teams. Khalid Hamandi is a member of the Phase 1–2a IONIS-HTTRx Study Site Teams
Publisher: Massachusetts Medical Society
ISSN: 0028-4793
Date of First Compliant Deposit: 10 July 2019
Date of Acceptance: 20 March 2019
Last Modified: 05 May 2023 13:44

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