Antisense Therapy Tominersen Holds Promise in Huntington Disease

NeurologyLiveApril 2020
Volume 3
Issue 2

The drug successfully demonstrated an ability to reduce mutant huntingtin protein, but the clinical benefits of that effect are yet to be determined.

Scott Schobel, MD, MSc

Scott Schobel, MD, MSc

Tominerson (Roche), formerly known as IONIS-HTTRx and RG6042, made history in May 2019 when results from a phase 1/2a trial published in the New England Journal of Medicine demonstrated that the investigational antisense oligonucleotide was the first therapeutic to successfully target and reduce levels of mutant huntingtin protein in patients with Huntington disease (HD).1

That trial, which enrolled 46 patients with early HD, showed dose-dependent reductions of mutant huntingtin protein in the cerebrospinal fluid, with the greatest reductions recorded in the 2 highest-dose groups (90 mg, 42% reduction; 120 mg, 38% reduction). Although nearly all patients experienced mild to moderate adverse events (AEs), investigators reported no serious AEs in patients who received the study drug.1

“[Tominersen] is the first therapy in development designed to target the underlying cause of the disease by limiting production and lowering the levels of the specific toxic protein that breaks down the nerve cells in the brain, which may affect a person’s everyday functions, such as mobility and thinking,” Scott Schobel, MD, MSc, associate group medical director and clinical science leader for the IONIS/Roche HTT Rx program at Roche/Genentech in Switzerland, told NeurologyLive®.

Results from the early-phase trial increased confidence as Roche moved to launch the phase 3 GENERATION HD1 trial (NCT03761849), a pivotal study in which investigators hope to demonstrate the drug’s ability to slow or stop HD progression (FIGURE).

120 mg every 2 months, tominersen 120 mg every 4 months (with placebo during alternating procedures), or placebo every 2 months over a 101-week treatment period. Although the original trial design called for once-monthly dosing, investigators made adjustments after a review of 9-month data from the 15-month open-label exten-sion of the phase 1/2a study (NCT03342053), which suggested that more frequent dosing was not associated with a clinical benefit.2

“While it is not yet appropriate to draw conclusions about clinical efficacy or longer-term safety, we are pleased that there are now data to support these study design changes and the explora-tion of less frequent dosing. We believe this will make study partic-ipation less demanding for patients, families, and health care providers,” Schobel said.

The global trial will include more than 900 participants aged 25 to 65 years with manifest HD, defined as a diagnostic confidence level score of 4 as well as an Independence Scale score >70. Patients excluded from the trial include those with any serious medical condition or vital sign abnormality, those who are currently pregnant or breastfeeding, and those who plan to become pregnant during the study.

Primary outcome measures of the study include a change from baseline to week 101 in the Composite Unified Huntington’s Disease Rating Scale, as well as the change from baseline to week 101 in Total Functional Capacity Score. Other secondary outcome measures include a change from baseline in Total Motor Score, Symbol Digit Modalities Test, Stroop Word Reading Test, Clinical Global Impression, Severity Scale.

Although GENERATION HD1 is expected to conclude in the third quarter of 2022, an ongoing open-label extension trial (NCT03842969) will help further tease out the therapy’s long-term impact. Patients eligible to enroll in the open-label study will receive tominersen 120 mg once every 8 weeks or once every 16 weeks via intrathecal injection. The study will assess primary outcomes such as percentage of participants with AEs and change from baseline in behavioral findings, as assessed by the Columbia-Suicide Severity Rating Scale. Additionally, investigators will use the Montreal Cognitive Assessment to assess changes from baseline in cognition.

Launched in April 2019, the extension study has an estimated completion date of August 2023.

“While early clinical trial findings are encouraging, we still have a lot to learn about the benefits and risks of [tominersen], which can only formally be shown in a longer, controlled clinical study,” Schobel concluded.


1. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, et al;  Phase 1—2a IONIS-HTTRx Study Site Teams. Targeting huntingtin expression in patients with Huntington’s disease [erratum in N Engl J Med. 2019;381(14):1398. doi: 10.1056/NEJMx190024]. N Engl J Med. 2019;380(24):2307-2316. doi: 10.1056/NEJMoa1900907

2. Nguyen M-L. Update on the phase III GENERATION HD1 study. Huntington’s Disease Society of America website. Published October 14, 2019. Accessed February 25, 2020.

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