Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College

Dr. Henchcliffe reports she is a consultant for Amneal Pharmaceuticals, Prevail Therapeutics, and US WorldMeds, and receives grant/research support from Biogen.

SYNOPSIS: In this Phase I/IIa clinical trial, investigators administered antisense huntingtin oligonucleotides intrathecally to patients with early Huntington’s disease (HD), and demonstrated safety, tolerability, and dose-dependent reduction in CSF mutant huntingtin. This approach now is being tested for clinical efficacy in HD in a Phase III clinical trial.

SOURCE: 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.

In this Phase I/IIa clinical trial in individuals with early Huntington’s disease (HD), antisense huntingtin (HTT) oligonucleotides (termed HTTRx, also known as RG6042) were used to specifically target mutant HTT mRNA (mHTT) in the study participants. These patients, recruited between 2015 and 2017, were randomized to receive intrathecal administration of HTTRx (n = 34) or placebo (n = 12). The study drug was administered four times, once every four weeks in ascending doses: placebo (n = 12); 10 mg (n = 3); 30 mg (n = 6); 60 mg (n = 6); 90 mg (n = 9); or 120 mg (n = 10), followed by a four-month observation period. The mean age in the treated group was 46 ± 10 years vs. 49 ± 10 years in the placebo group, with 14/34 (41%) women in the treated group vs. 4/12 (33%) in the placebo group. CAG repeat numbers were similar between the groups, and disease-burden, independence, and motor scores were well matched. The primary endpoint of safety was successfully achieved, with no deaths, no serious adverse events related to HTTRx, and no dose-limiting adverse events. Milder adverse events occurred in almost all of participants (98%), most commonly postprocedural pain and headache after intrathecal HTTRx and after lumbar punctures for cerebrospinal fluid (CSF) collection. Just one study participant had an increased leukocyte count at eight weeks’ post-procedure (60 mg HTT group) but without any clinical symptoms. HTTRx concentration in CSF was measurable in all but two patients who received the 30 mg and higher doses (although not the 10 mg dose), with trough levels at a plateau from the 60 mg and higher doses. Most importantly for this study, there were dose-dependent reductions in mHTT levels in CSF at 28 days’ post-dose (from -20% in the 10 mg group to -42% in the 90 mg group and -38% in the 120 mg group). In contrast, those in the placebo group experienced an increase by 10% from baseline over the course of the study. Unexpected findings included increased ventricular volume in the two highest dose groups revealed by MRI, and elevated CSF neurofilament light protein concentration in some of these individuals. However, no clinical sequelae were linked to these biomarker abnormalities. Clinical measures addressing cognitive, psychiatric, neurological, and functional aspects of HD did not differ significantly between HTTRx and placebo arms, but in a post hoc analysis relationships emerged between the degree of CSF mHTT reduction by HTTRx and components of the composite Unified Huntington’s Disease Rating Scale (cUHDRS).

COMMENTARY

HD is a severe neurodegenerative disease arising from a triplet repeat CAG expansion in the huntingtin HTT gene. HD is inherited in an autosomal dominant pattern, and the mutation gives rise to a protein with expanded polyglutamine repeats that abnormally aggregates, resulting in degeneration affecting the caudate and multiple other brain regions. Individuals with HD suffer from progressive chorea, cognitive decline, and dementia, and multiple psychiatric symptoms including depression and psychosis. Treatment is symptomatic and despite robust efforts in the research community; as yet, there is no intervention that will prevent HD in mutation carriers or halt or slow progression once it is clinically manifest.

Tabrizi et al undertook this study using antisense oligonucleotides based on the rationale that suppressing mHTT expression will improve HD symptoms, as demonstrated in transgenic mouse models of HD. Therefore, this first-in-human Phase I/IIa clinical trial is encouraging in at least two respects. First, it demonstrated dose-dependent reduction in mHTT in CSF following HTTRx, presumed to reflect a corresponding reduction in the brain. Second, no serious adverse events were encountered, and there were no dose-limiting effects. There were some unexpected findings in exploratory biomarker outcomes. Whether the apparent reduction in brain volume (based on increased ventricular volume) demonstrated on MRI in the higher dose groups is caused by a reduction in inflammation, as the authors suggest, remains to be answered. And why neurofilament light, a marker of neurodegeneration, was increased in some of these individuals was unclear. The main question remaining though, is whether this intervention will show clinical efficacy and improve the lives of those with HD. A Phase III randomized, double-blind, placebo-controlled clinical trial is now underway to evaluate efficacy with a target 660 patients in 101 international sites, including the United States, providing some hope for the HD community.