Antisense Oligonucleotide Squelches Huntingtin Protein in Phase 1/2a Trial

An antisense oligonucleotide knocked down levels of the mutant huntingtin protein in Huntington’s disease patients, who appeared to tolerate treatment well, according to a December 11 announcement by Ionis Pharmaceuticals, Inc., in Carlsbad, California. While formal data have yet to be released, apparent favorable outcomes cemented a deal for Ionis to license IONIS-HTTRx to Roche for $45 million. An ongoing open-label extension and future Phase 3 trials will assess the drug’s efficacy in slowing disease progression.

FDA-Approved Antisense Drugs. [Courtesy of Godfrey et al., 2017, EMBO Molecular Medicine. CC BY 4.0 License.]

Antisense oligonucleotide (ASO) therapies work by targeting complementary RNA sequences for destruction. Researchers have fashioned them to control the expression of proteins involved in various neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, spinal muscular atrophy, and familial amyloid neuropathy. Several AOSs are in various stages of clinical development (see Nov 2015 conference news; Apr 2016 news; Finkel et al., 2017; May 2017 news).

In a breakthrough for this strategy, two Phase 3 trials of nusinersen, an ASO therapy to treat the devastating developmental disease spinomuscular atrophy, aka SMA, were halted after interim analyses revealed that kids taking the drug lived longer and had motor improvement. All children switched to open-label extension so they could all receive the ASO (see Nov 2016 news) and nusinersen was FDA-approved in December 2016.

IONIS-HTTRx targets the huntingtin gene, which causes HD when a CAG repeat sequence is expanded. People with the disease have at least 36 repeats, some have hundreds. The ASO targets both normal and mutant versions of huntingtin RNA for degradation. Preclinically, the strategy slowed disease progression in mouse models (see Jun 2012 news; May 2013 news).

The Phase 1/2a trial enrolled 46 people in the early stages of HD at nine sites in Canada, Germany, and England. They were between the ages of 25 and 65. The study ran for 29 weeks, including an initial 13-week treatment period when participants received spinal cord injections of placebo or the drug once a month. The researchers tested five doses in five successive cohorts of patients. Safety and tolerability were primary outcome measures, CSF pharmacokinetics a secondary measure. Other outcomes included CSF concentration of huntingtin, brain ventricular volume, and performance on the Huntington’s disease cognitive assessment battery composite.

The Ionis statement claimed both favorable safety and tolerability of the drug. Blair Leavitt, a site investigator for the trial at the University of British Columbia in Vancouver, confirmed to Alzforum that there were no adverse events, and all participants completed the trial.

Importantly, the Ionis announcement noted a dose-dependent drop in CSF mHtt, which generally would be regarded as evidence of target engagement. Leavitt helped develop the CSF mHtt detection assay used in the trial, and previously reported that levels of the mutant protein in CSF increase with disease stage (Wild et al., 2015; Southwell et al., 2015).

Leavitt told Alzforum that the trial’s initial goal was to knock down expression of the protein by at least half. While the extent of mHtt reduction in response to IONIS-HTTRx has yet to be revealed, Leavitt said that the study met or far exceeded each of its goals. Ionis did not announce results of any other outcome measures. They plan to present the data at a conference in the first half of 2018.

As part of an ongoing partnership with Ionis, Roche exercised its option to purchase the drug’s license and will assume responsibility of further clinical development. Participants who completed the trial have transferred to an open-label extension, and plans are in the works to start a global Phase 3 trial in 2018. If those trials succeed, Roche aims to apply its “brain shuttle” technology to the drug, which will facilitate its passage across the blood-brain barrier and allow for intravenous, rather than spinal cord, injection (see Jan 2014 news).

While it remains to be seen how much mHtt concentrations actually plummeted in response to treatment, and where in the brain that happened, the fact that they dropped at all is cause for excitement, commented Timothy Miller of Washington University in St. Louis. Miller was not involved in the current trial, but partners with Ionis to develop ASOs that target SOD1 in people with ALS, and tau in people with AD. Miller added that Roche’s move to take over clinical development likely signifies that solid data will ultimately back up the initial announcement.

“These results don’t tell us whether lowering huntingtin protein will have an effect on the disease, but they do suggest that we’re finally in the position to test that hypothesis,” Miller said.


Finkel RS, Mercuri E, Darras BT, Connolly AM, Kuntz NL, Kirschner J, Chiriboga CA, Saito K, Servais L, Tizzano E, Topaloglu H, Tulinius M, Montes J, Glanzman AM, Bishop K, Zhong ZJ, Gheuens S, Bennett CF, Schneider E, Farwell W, De Vivo DC, ENDEAR Study Group. Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy. N Engl J Med. 2017 Nov 2;377(18):1723-1732. PubMed.

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

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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antisense antisense oligonucleotides ASO disease-ad disease-als disease-hd disease-sma familial amyloid polyneuropathy SOD1 SOD1-Rx topic-clinical topic-randd
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