Antisense Therapy Cuts Huntingtin Protein in CSF by Half

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.

IONIS-HTTRx. [Courtesy of Lu and Yang, 2012, Neuron.]

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 (see 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 (see Jan 2014 news; Weber et al., 2018).

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 study. Researchers will use this study to explore dosing paradigms and to look for links between huntingtin levels and clinical measures (see Wild et al., 2015; Southwell et al., 2015). 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.

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.)


Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JR, Zetterberg H, Leavitt BR, Kuhn R, Tabrizi SJ, Macdonald D, Weiss A. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J Clin Invest. 2015 May;125(5):1979-86. Epub 2015 Apr 6 PubMed.

Southwell AL, Smith SE, Davis TR, Caron NS, Villanueva EB, Xie Y, Collins JA, Ye ML, Sturrock A, Leavitt BR, Schrum AG, Hayden MR. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci Rep. 2015 Jul 15;5:12166. PubMed.

Further Reading

Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. 2017 Oct;16(10):837-847. PubMed.

Lu XH, Yang XW. “Huntingtin holiday”: progress toward an antisense therapy for Huntington’s disease. Neuron. 2012 Jun 21;74(6):964-6. PubMed.

Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, Andres PL, Mahoney K, Allred P, Alexander K, Ostrow LW, Schoenfeld D, Macklin EA, Norris DA, Manousakis G, Crisp M, Smith R, Bennett CF, Bishop KM, Cudkowicz ME. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 2013 May;12(5):435-42. PubMed.

Winer L, Srinivasan D, Chun S, Lacomis D, Jaffa M, Fagan A, Holtzman DM, Wancewicz E, Bennett CF, Bowser R, Cudkowicz M, Miller TM. SOD1 in cerebral spinal fluid as a pharmacodynamic marker for antisense oligonucleotide therapy. JAMA Neurol. 2013 Feb;70(2):201-7. PubMed.

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