Ionis Pharmaceuticals reported numbers from its Phase 1/2a trial of an antisense oligomer (ASO) therapy targeting huntingtin protein at the 13th annual CHDI Huntington’s disease conference March 1. The two highest doses of IONIS-HTTRx, 90 and 120 mg, lowered mutant huntingtin levels in cerebrospinal fluid by 40–60 percent. The current data presentation included no clinical outcomes, so it is not known yet whether cutting CSF huntingtin in half benefits people with manifest HD.

Based on previous data from rodents and nonhuman primates, the CSF findings correspond to a 55–85 percent drop in cortical huntingtin, and 20–50 percent in the caudate region affected in Huntingon’s disease, estimated principal investigator Sarah Tabrizi of University College London. She added that in animal models of HD, researchers saw a clinical benefit at cortical reductions of 30–50 percent. The company had previously announced positive top-line results from the 13-week trial, including favorable safety and tolerability (Dec 2017 news). That data spurred a licensing deal with Roche to develop the therapy, now called RG6042.

The treatment’s pharmacokinetics appeared promising. In most participants, CSF huntingtin continued to fall even a month after dosing stopped. The researchers expect the reduction to bottom out after about six months, Tabrizi said. They will analyze pharmacokinetic data from the trial to see if they can achieve maximal reductions with dosing less frequent than once per month, as well as determine the optimal dose. The findings to date suggest that the 90 mg dose saturates the cortex, Tabrizi said. RG6042 requires infusion into the intrathecal space, although Roche has discussed using its “brain shuttle” technology to deliver the drug in the future (Jan 2014 news; Jan 2018 news). 

The researchers did not present any results from other biomarkers, although Scott Schobel at Roche told reporters in a press call that they have seen encouraging signs of correlation between dwindling CSF huntingtin and favorable changes on other fluid biomarkers. That data will be presented at the American Academy of Neurology annual meeting  in Los Angeles on April 21–27.

All trial participants are now enrolling in a 15-month open-label extension. Researchers will use this study to explore dosing paradigms and to look for links between huntingtin levels and clinical measures. The extension study will use smartphones and watches to collect more frequent, detailed data than traditional clinic-based measures allow, Schobel noted. Trials for other movement disorders have reported that digital technology sensitively captures small clinical changes (May 2017 conference news). 

Meanwhile, Roche is planning a Phase 3 study. Like the Phase 1/2a trial, it will enroll people in the earliest stages of symptomatic disease, who have only mild problems with daily activities and are often still working. Schobel noted that a wealth of observational data have convinced them that this is the optimal stage for drug testing. People at this stage decline significantly over the course of six months, allowing researchers to detect a potential drug benefit even over a short trial, he said. He did not discuss any plans to test the ASO in presymptomatic disease. (See also press release.)—Madolyn Bowman Rogers


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News Citations

  1. Antisense Oligonucleotide Squelches Huntingtin Protein in Phase 1/2a Trial
  2. Brain Shuttle Ferries Antibodies Across the Blood-Brain Barrier
  3. Antibody Shuttle Rouses Anti-Aβ Response in Brain without Waking the Periphery
  4. Do Smartphones Collect Better Clinical Data Than Paper-and-Pencil Tests?

Conference Citations

  1. American Academy of Neurology 2018 Annual Meeting

External Citations

  1. Phase 1/2a
  2. press release

Further Reading