IONIS-HTTRx, also called RG6042, is a potential treatment for Huntington’s disease developed by Ionis Pharmaceuticals.

Ionis licensed IONIS-HTTRx to Roche in late 2017, making Roche responsible for the further development and commercialization of the therapy. Roche is developing IONIS-HTTRx as RG6042.

How IONIS-HTTRx works

Huntington’s disease, an inherited disorder that affects nerve cells in the brain, is caused by a mutation in the HTT gene, which encodes for the huntingtin protein. In order to make a protein, a temporary copy of DNA is made. This is called a messenger RNA (mRNA). This mRNA is used as the template for the production of a protein. mRNA is a vital intermediary between a gene and protein that can be targeted therapeutically.

The abnormal form of the protein seen in Huntington’s disease is degraded by the body, but the digested pieces of protein build up and aggregate or clump, which gradually destroys nerve cells. People with Huntington’s have problems thinking and controlling their movements, symptoms that worsen over time.

IONIS-HTTRx is an antisense therapy, which is designed to stick to a faulty HTT messenger RNA, targeting the mRNA for degradation. This reduces the amount of abnormal huntingtin protein that is produced by the cell.

IONIS-HTTRx in clinical trials

Ionis completed a Phase 1/2a clinical trial (NCT02519036) of IONIS-HTTRx in late 2017. The study included 46 Huntington’s patients at nine centers in Britain, Germany, and Canada. The participants were randomly assigned to either receive IONIS-HTTRx in increasing doses or a placebo. The treatment was administered to each participant’s spinal canal.

The study looked at IONIS-HTTRx’s pharmacokinetics, or how it was distributed and metabolized in the body, as well as its pharmacodynamics, or movement in the body.

Ionis said in a December 2017 news release that IONIS-HTTRx’s safety in the trial, and patients’ ability to tolerate it, supported the continued development of the therapy. A key finding was that as the dose of IONIS-HTTRx was increased, levels of abnormal huntingtin protein in the participants’ spinal fluid decreased.

Ionis and Roche have started an extension trial (NCT03342053) for patients who completed the Phase 1/2a trial. Expected to run through September, the trial will further examine the treatment’s safety, patients’ ability to tolerate it, and its pharmacokinetics and pharmacodynamics. Participants will be assigned to one of two groups. One will receive a low dose and the other a high dose of IONIS-HTTRx. Investigators will continue measuring levels of abnormal huntingtin protein and assess the participants’ thinking ability. 

A Phase 3 clinical trial (NCT03761849) is currently recruiting 660 patients with Huntington’s disease to evaluate the efficacy, safety, and biomarker effects of IONIS-HTTRx compared to placebo. Patients will be divided into three groups. One group will receive IONIS-HTTRx every four weeks, one group will receive IONIS-HTTRx every eight weeks (receiving placebo at alternate weeks), and one group will receive placebo only every four weeks. The treatment will be delivered intrathecally (an injection into the cerebrospinal fluid). The primary outcome measure will be changes in composite unified Huntington’s disease rating scale (cUHDRS) from the start of the study to week 101. The study is recruiting patients at 26 locations across the U.S. and Canada.

An open-label extension of the previous clinical trial is also planned (NCT03842969). The study, based across several locations in the U.K. and Canada, will evaluate the long-term safety and efficacy of IONIS-HTTRx. Patients (900 expected) will be randomly assigned to receive IONIS-HTTRx by intrathecal injection every four weeks or every eight weeks. Adverse events will be recorded, as well as any change from the start of the study in behavior (assessed using the Columbia-suicide severity rating scale) or cognition (using the Montreal cognitive assessment) every six months until the end of the study in five years.

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