Second‐Generation Antisense Nucleotide Targeting Huntingtin Expression Found to Be Safe in Patients With Huntington's Disease

Tabrizi, SJ, Leavitt, BR, Landwehrmeyer, GB, et al. Targeting huntingtin expression in patients with Huntington's disease. N Engl J Med 2019; 380: 2307– 2316. Huntington's disease (HD) is a neurodegenerative autosomal-dominant disorder caused by CAG trinucleotide repeat expansion in the huntingtin gene (HTT). HD is characterized by progressive neuropsychiatric, cognitive, and motor symptoms and is the most common cause of inherited chorea. Even though the HTT gene was identified more than one-quarter of a century ago, there are no disease-modifying therapies that prevent disease onset or slow its progression.1 Recent research efforts have focused on directly targeting the genetic abnormality. Recently, Tabrizi and colleagues have studied the effects of intrathecal administration of a second-generation antisense nucleotide, to inhibit messenger RNA, and therefore reduce huntingtin concentration levels.2 Earlier research demonstrated that decreasing the levels of HTT in transgenic animal models and nonhuman primates with HTT-lowering agents was feasible and safe.3 Forty-six eligible patients between 25 and 65 years of age with early HD, further defined as having ≥36 CAG repeats and a clinical stage 1, were randomized (3:1) into five different dose groups (10, 30, 60, 90, or 120 mg) in an ascending dose design to receive four intrathecal boluses at 4-week intervals of IONIS-HTTRx versus placebo. The primary endpoint was to evaluate safety of the drug. Secondary endpoints included cerebrospinal fluid (CSF) pharmacokinetics as well as plasma pharmacodynamics in addition to identifying its effect on concentration levels of HTT, neurofilament light protein in the CSF, ventricular volume, and the composite cognitive score on the Huntington's Disease Cognitive Assessment Battery. IONIS-HTTRx was found to be safe. Adverse events in both treatment and placebo groups were frequent (reported in 98% of patients), but were mild or moderate and deemed unrelated to direct effects of the drug. The most frequent adverse events were related to the intrathecal administration, including discomfort associated with the lumbar puncture as well as, postdural puncture headache. Serious adverse events were not reported, and no discontinuations or deaths occurred. The concentration of IONIS-HTTRx in the CSF was detectable in patients receiving doses at ≥30 mg and reached a plateau at doses of ≥60 mg with no observed accumulation. Moreover, there was a dose-dependent lowering of mutant HTT levels up to 42% from the baseline. Clinical outcomes remained unchanged, regardless of the dose. Furthermore, no associated adverse events were detected, despite modest increases in ventricular volume, as well as an increase in the neurofilament light protein CSF manifested in some patients who were receiving 90 and 120 mg. The researchers have demonstrated that the drug is safe and well tolerated. There was a dose-dependent reduction in HTT levels in the CSF. Studies currently underway will determine whether this approach results in clinical improvement and alters the disease trajectory. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique. A.M.E.: 1A, 1B, 1C, 3A, 3B V.B.: 1A, 1B, 1C, 3A, 3B J.R.S.: 1A, 1B, 1C, 3A, 3B We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The authors confirm that the approval of an institutional review board was not required for this work based on the submission type. The authors report no sources of funding and no conflicts of interest. The authors declare that there are no disclosures to report.

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