RG6042 Top-Line Data Shows Significant Reductions of Mutant Huntingtin Protein

Late yesterday, Ionis Pharmaceuticals, Inc. reported positive top-line data from a completed Phase 1/2 study of RG6042 (Ionis HTT_Rx) in people with early stage Huntington’s disease (HD).

The results were presented at the 13^th Annual CHDI HD conference in Palm Springs, California, and demonstrate that the drug is the first in development with the ability to lower the disease-causing protein in people with HD.

HD is a life-threatening neurological disease caused by a genetic mutation in the huntingtin gene, which leads to the production of the toxic huntingtin (mHTT) protein. The mutant mHTT protein progressively destroys neurons in the brain, resulting in the depreciation of both cognitive abilities and physical control.

The generation 2+ antisense therapy was granted orphan drug designation by both the U.S. Food and Drug Administration (FDA) and European Medicines Association (EMA) in January 2016, and enrollment for the randomized, placebo-controlled, dose escalation study was completed in June. It has been designed explicitly to lessen the production of all forms of the huntingtin protein, including mHTT.

"With IONIS-HTT_Rx, 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," said Dr 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 in a press release.

For 13 weeks throughout the study, 46 people with early stage HD were treated with four intrathecal injections of 10 mg, 30 mg, 60 mg, 90 mg, or 120 mg of RG6042 or placebo, administered monthly. Significant, dose-dependent reductions of mHTT were observed in cerebrospinal fluid (CSF) of treated participants with mHTT reductions of up to an estimated 60% and mean reductions of approximately 40% in CSF observed at the two highest doses, 90 mg (p<0.01) and 120 mg (p<0.01).

"These important clinical results demonstrate that our approach of targeting the toxic mutant huntingtin protein can significantly reduce the underlying cause of this terrible disease. 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 Dr. C. 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. We look forward to working with Roche to quickly advance IONIS-HTTRx (RG6042) into a pivotal study, which we hope will lead to marketing approval for this new drug for people with HD."

Data collected in rodents and non-human primates served as a predictive model for the study, and a 40% to 60% reduction in CSF parallels an estimated 55% to 85% reduction in mHTT in the cortex and 20% to 50% in the caudate regions of the brain in humans. mHTT levels continued to decline at the most recent measurement with further decreases in mHTT still anticipated.

Maximum reduction of mHTT is expected by approximately 6 months after the first dose.

No serious adverse events (AEs) were reported in the study’s participants and most AEs were mild and considered to be unrelated to RG6042. No enrolled patients discontinued from the study, and an open-label extension study for participants is ongoing.

"I look forward to a longer-term, larger study that can establish the benefit of reducing the toxic mutant huntingtin protein in people with HD,” said Dr Tabrizi.

Roche, who has been working closely with Ionis on this program since 2013, is now leading the development of RG6042 and is currently planning a pivotal trial to evaluate the clinical efficacy and safety of the drug.

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