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

First drug to demonstrate lowering of mutant huntingtin, the disease-causing protein, in people with Huntington’s disease

CARLSBAD, Calif., April 24, 2018/PRNewswire/ — Ionis Pharmaceuticals, Inc. (NASDAQ: IONS), the leader in antisense therapeutics, today presented top-line data from the Phase 1/2 study of IONIS-HTTRx (RG6042) in people with early stage Huntington’s disease (HD) at the 70thAmerican Academy of Neurology (AAN) meeting in Los Angeles, California. Results from exploratory analyses of data from the study demonstrated correlations between reductions in mutant huntingtin (mHTT), the disease-causing protein, and improvements in clinical measures of Huntington’s disease.

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. 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. “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.”

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. C. Frank Bennett, senior vice president of research and franchise leader for the neurological programs at Ionis Pharmaceuticals. “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.”

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.

Ionis’ partner, Roche, exercised its option to license IONIS-HTTRx following the completion of a Phase 1/2 study and is responsible for all development and commercial activities. Planning is already underway for Roche to advance IONIS-HTTRx (RG6042) to a pivotal study to demonstrate the clinical efficacy and safety of IONIS-HTTRx.

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Source: Ionis Pharmaceuticals, Inc.

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