Rare Daily Staff

Ionis Pharmaceuticals said that top-line data from a completed phase 1/2 study of its experimental antisense therapy for people with early stage Huntington’s disease demonstrate that is the first drug in development to lower the disease-causing protein in people with the neurodegenerative disease.

Huntington’s is a rare, progressive, neurodegenerative disease caused by genetic mutation in the huntingtin gene, which results in the production of a toxic protein, the mutant huntingtin (mHTT). The mutant protein gradually destroys neurons in the brain resulting in deterioration in mental abilities and physical control.

Ionis designed IONIS-HTTRx (RG6042), a Generation 2+ antisense drug, to specifically reduce the production of all forms of the huntingtin protein, including mHTT. Ionis is developing the drug through a collaboration with Roche announced at the end of last year.

“For nearly twenty years, I have seen many families devastated from losses to this progressive neurodegenerative disease,” said Sarah Tabrizi, professor of clinical neurology, director of the University College London’s Huntington’s Disease Centre and the global lead investigator on the study. “With IONIS-HTTRx (RG6042), the HD community has new hope for a therapy that can reduce the cause of HD, and therefore, may slow the progression and potentially prevent the disease in future generations, which is truly groundbreaking,”

In the study presented at the 13th Annual CHDI HD conference, 46 people with early-stage Huntington’s disease were treated for 13 weeks with four intrathecal injections of 10 mg, 30 mg, 60 mg, 90 mg or 120 mg of IONIS-HTTRx (RG6042) or placebo, administered monthly.

Significant, dose-dependent reductions in mHTT were observed in CSF of treated participants with mHTT reductions of up to approximately 60 percent and mean reductions of approximately 40 percent in CSF observed at the two highest doses, 90 mg and 120 mg.

Based on a predictive model developed from data collected in rodents and non-human primates, a 40 percent to 60 percent reduction in CSF corresponds to an estimated 55 percent to 85 percent reduction in mHTT in the cortex and 20 percent to 50 percent in the caudate regions of the brain in humans, the company said.

Levels of mHTT were continuing to decline at the last measurement with further decreases in mHTT anticipated; maximum reduction expected by approximately six months after first dose.

No serious adverse events were reported in treated participants and most adverse events were mild and considered to be unrelated to study drug. No participants discontinued from the study.

An open-label extension study for patients who participated in the Phase 1/2 study is ongoing.

“In this study, we were able to achieve mutant huntingtin protein reductions in study participants that were higher than those that produced disease benefit in preclinical models of HD,” said Frank Bennett, senior vice president of research and franchise leader for the neurological programs at Ionis Pharmaceuticals. “We were pleased that this antisense approach, which targets all forms of the huntingtin protein, proved to be safe and well tolerated in this study.”

March 2, 2018
Photo: Frank Bennett, senior vice president of research and franchise leader for the neurological programs at Ionis Pharmaceuticals