IONIS-HTT Data Shows Link Between Reduction in Huntingtin Protein and Clinical Improvement

APRIL 25, 2018
Mathew Shanley
Yesterday, top-line data from the Phase 1/2 study of RG6042 (IONIS-HTTRx) was presented at the 70th Annual American Academy of Neurology (AAN) meeting in Los Angeles, and results demonstrated correlations between reductions in the mutant huntingtin protein (mHTT) and improvements in clinical measures of Huntington’s disease (HD).

The mHTT protein, which is produced as the result of a mutation in the huntingtin gene, gradually destroys neurons in the brain and results in deterioration in mental ability and physical control. RG6042 was developed to reduce the production of the huntingtin protein, including the mutant protein.

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, emphasized the importance of drug development and clinical trials for HD. "Since the discovery of the gene that causes Huntington's disease 25 years ago, we've been working to discover a drug that targets the cause of the disease—the mutant huntingtin protein.”1

The study was a randomized, placebo-controlled dose escalation study in 46 people with early stage HD. Those enrolled were treated for 13 weeks with 4 intrathecal injections of 10 mg, 30 mg, 60 mg, 90 mg or 120 mg of RG6042 or placebo (3:1 active to placebo), administered monthly. Safety and tolerability served as the primary objective, however, the study was specifically designed also so that it could measure the effect of the drug on levels of the mutant huntingtin protein in the cerebral spinal fluid (CSF).

“With the results from the Phase 1/2 study with IONIS-HTTRx,” added Tabrizi, “we have cleared the first major hurdle in developing such a drug. The substantial lowering of the mutant huntingtin protein, combined with additional data from exploratory clinical measures presented today and the good safety profile we observed in the study, give us hope that this new drug may have the potential to slow, or perhaps halt, the progression of this devastating disease. The next step is to advance the drug into a larger study designed to demonstrate the potential clinical benefit of reducing the toxic mutant huntingtin protein in people with Huntington's disease."

Significant, dose-dependent reductions in mHTT were observed in CSF of treated participants with mHTT reductions of up to an estimated 60% and mean reductions of an estimated 40% in CSF observed at the 2 highest doses, 90 mg (p<0.01) and 120 mg (p<0.01). Based on a predictive model developed from data collected in rodents and non-human primates, a 40% to 60% reduction in CSF corresponds to an approximately 55% to 85% reduction in mHTT in the cortex and 20% to 50% in the caudate regions of the brain in humans.

Dr C. Frank Bennett, senior vice president of research and franchise leader for the neurological programs at Ionis Pharmaceuticals, highlighted the prominence of the study’s results. "These important clinical results further demonstrate that targeting the reduction of the toxic mutant huntingtin protein with IONIS-HTTRx has the potential to be disease-modifying. Following SPINRAZA for the treatment of patients with spinal muscular atrophy, this is our second antisense drug to show good target engagement in the CNS. These drugs, along with the two others we have in clinical studies and the five we have in preclinical development further validate the broad potential of our antisense technology to treat patients with neurological diseases."

mHTT levels continued to decline at the last measurement time in the study with additional reductions in mHTT expected; based on modelling and clinical results, maximum reduction predicted will occur at approximately 6 months after first dose.

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

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

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  1. New Data from IONIS-HTT Rx Phase 1/2 Study Demonstrates Correlation Between Reduction of Disease-causing Protein and Improvement in Clinical Measures of Huntington's Disease. Accessed April 25, 2018.

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