The therapy, designed by Ionis Pharmaceuticals, was the first treatment in clinical development to target the underlying cause of Huntington’s. Ionis licensed IONIS-HTTRx to Roche in late 2017, making Roche responsible for its further development and commercialization. Roche is developing IONIS-HTTRx as RG6042.
How IONIS-HTTRx works
Huntington’s disease is an inherited disorder that affects nerve cells in the brain. It 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 the gene is made, called a messenger RNA (mRNA). The mRNA is used as the template for the production of a protein. mRNA is a vital intermediary between a gene and a 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 together, which gradually destroys nerve cells. People with Huntington’s have problems thinking and controlling their movements. These symptoms usually worsen over time.
IONIS-HTTRx is an antisense therapy, which is designed to bind to a faulty HTT mRNA, targeting it 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 was conducted at nine centers in the U.K., Germany, and Canada, and included 46 patients with Huntington’s disease. The participants were randomly assigned to either receive IONIS-HTTRx in increasing doses or a placebo. The treatment was administered to each participant’s cerebrospinal fluid (the fluid surrounding the brain and spinal cord) by intrathecal injection.
The study looked at the pharmacokinetics of the treatment — its movement in the body — and at its pharmacodynamics, or how it was distributed and metabolized in the body.
The results of the trial were published in The New England Journal of Medicine. 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 said in a December 2017 news release that IONIS-HTTRx’s safety in the trial, and patients’ ability to tolerate it, supported its continued development.
An extension of the Phase 1/2a clinical trial (NCT03342053), for patients who completed the earlier trial, is ongoing. That extension will examine the safety, tolerability, pharmacokinetics, and pharmacodynamics of IONIS-HTTRx in patients receiving either a high or low dose of treatment.
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. Participants will be divided into three groups. One group will receive IONIS-HTTRx every four weeks, while one group will receive IONIS-HTTRx every eight weeks (receiving placebo at alternate weeks). Another group will receive placebo only, every four weeks. The treatment will be delivered by intrathecal injection. The primary outcome measure will be any 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 this clinical trial (NCT03842969) also is planned. That 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.
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