HD is a rare, progressive, neurodegenerative disease caused by genetic mutation in the huntingtin gene, resulting in the production of mHTT protein, which gradually destroys neurons in the brain and results in deterioration in mental ability and physical control. Ionis designed IONIS-HTTRx (RG6042), a Generation 2+ antisense drug, to specifically reduce the production of the huntingtin protein, including mHTT.
"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. With the results from the Phase 1/2 study with IONIS-HTTRx, 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," said Dr.
Phase 1/2 Study Results:
- Significant, dose-dependent reductions in mHTT were observed in CSF of treated participants with mHTT reductions of up to approximately 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).
- A 40% to 60% reduction in CSF corresponds to an estimated 55% to 85% reduction in mHTT in the cortex and 20% to 50% in the caudate regions of the brain in humans, based on a predictive model developed from data collected in rodents and non-human primates.
- mHTT levels were continuing to decline at the last measurement time in the study with further decreases in mHTT anticipated; based on modelling and clinical results, maximum reduction predicted at approximately six months after first dose.
- No serious adverse events were reported in treated participants and most adverse events (AEs) were mild and considered unrelated to study drug. No participants discontinued from the study.
Exploratory Clinical Outcome Results:
- In an exploratory post-hoc analysis, the degree of mHTT lowering was correlated with improved scores at three months in several clinical measures commonly used in Huntington's disease clinical studies.
- Total Motor Score (TMS): rho=0.39 (p=0.007)
- Symbol Digit Modalities Test (SDMT): rho=-0.30 (p=0.044)
- Stroop Word Reading Test (SWRT): rho=0.08 (p=0.60)
- Total Functional Capacity (TFC) score: rho=-0.27 (p=0.066)
- In addition, a significant correlation was observed with the degree of mHTT lowering and the Composite Unified Huntington's Disease Rating Scale (cUHDRS) score at Day 85 (rho=-0.41, p=0.004).
"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," added Dr.
About the Phase 1/2 Study
The study was a randomized, placebo-controlled dose escalation study in 46 people with early stage Huntington's disease. Study participants 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 (3:1 active to placebo), administered monthly. The study's primary objective was to evaluate the safety and tolerability of IONIS-HTTRx (RG6042). The study was also designed to measure the effect of IONIS-HTTRx (RG6042) on levels of the mutant huntingtin protein in the cerebral spinal fluid (CSF). Exploratory analyses included several clinical measures commonly used in Huntington's disease studies.
An open-label extension (OLE) study for patients who participated in the Phase 1/2 study is ongoing.
About Huntington's Disease (HD)
Huntington's Disease (HD) is a rare, genetic, progressive, neurodegenerative disease resulting in deterioration in mental abilities and physical control. In the U.S., there are approximately 30,000 individuals (one in 10,000) with symptomatic HD and more than 200,000 people at risk of having inherited HD. HD is referred to as a triplet repeat disorder and is one of a large family of genetic diseases in which certain gene sequences are mistakenly repeated. In HD, the trinucleotide sequence in the gene that encodes for the HTT protein is repeated more than 36 times. The resulting mHTT protein is toxic and gradually damages neurons in the brain. Symptoms of HD usually appear between the ages of 30 to 50 years and continually worsen over a 15- to 20-year period. Ultimately, the weakened individual succumbs to pneumonia, heart failure or other complications. Presently, there is no effective disease-modifying treatment for HD, and current products focus only on managing disease symptoms.
About IONIS-HTTRx (RG6042)
IONIS-HTTRx (RG6042) is an antisense drug designed to reduce the production of all forms of the huntingtin protein (HTT), including its mutated variant, mHTT, which is the driver of HD. IONIS-HTTRx (RG6042) offers a unique approach to treat all patients with HD, irrespective of their individual HTT mutation. IONIS-HTTRx (RG6042) has been granted orphan drug designation by the
About Ionis/Roche Collaboration
Ionis is the leading company in RNA-targeted drug discovery and development focused on developing drugs for patients who have the highest unmet medical needs, such as those patients with severe and rare diseases. Using its proprietary antisense technology, Ionis has created a large pipeline of first-in-class or best-in-class drugs, with over 40 drugs in development. SPINRAZA® (nusinersen) has been approved in global markets for the treatment of spinal muscular atrophy (SMA). Biogen is responsible for commercializing SPINRAZA. Inotersen and volanesorsen are two antisense drugs that Ionis discovered and successfully advanced through Phase 3 studies. Inotersen is under regulatory review for marketing approval in the U.S. and EU for the treatment of patients with hereditary ATTR amyloidosis. Volanesorsen is under regulatory review for marketing approval in the U.S., EU and
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