Tominersen (Previously IONIS-HTTRx and RG6042)

Tominersen (previously IONIS-HTTRx and RG6042), is a potential treatment for Huntington’s disease that Roche is developing. The therapy, designed by Ionis Pharmaceuticals, was the first treatment in clinical development that sought to target the underlying cause of Huntington’s disease. Ionis licensed the treatment to Roche in late 2017, making Roche responsible for its further development and commercialization. 

Roche stopped dosing in most clinical trials evaluating tominersen in 2021, after interim data from the Phase 3 GENERATION HD1 clinical trial indicated the therapy was not benefiting participants. Roche has stated that it is continuing to collect and analyze data on tominersen to look for possible paths forward.

How does tominersen work?

Huntington’s disease is an inherited disorder that affects nerve cells in the brain. A mutation in the HTT gene causes the disease. This gene provides instructions for making the huntingtin protein. To make a protein, cells first make a temporary copy of the gene, called a messenger RNA (mRNA). They then use the mRNA as a template to produce the protein, making mRNA a vital intermediary between a gene and a protein that researchers can target therapeutically.

The body degrades the abnormal form of the protein in Huntington’s disease. However, the digested pieces of protein build up and aggregate, or clump together. This destroys nerve cells gradually. People with Huntington’s disease have problems thinking and controlling their movements. These symptoms usually worsen over time.

Tominersen is an antisense therapy. Researchers designed it to bind to the faulty HTT mRNA, targeting it for degradation. This should reduce the amount of abnormal huntingtin protein produced by cells. 

The treatment is administered into the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord.

Tominersen in clinical trials

Ionis completed a Phase 1/2a clinical trial (NCT02519036) of tominersen in late 2017. In the trial, 46 Huntington’s patients were assigned randomly to either receive tominersen in increasing doses, or a placebo. Results of the study, published in 2019, indicated the treatment decreased levels of abnormal huntingtin protein in the participants’ CSF.

An extension of the Phase 1/2a clinical trial (NCT03342053) for patients who completed the earlier trial also has been completed. This extension examined the safety, tolerability, pharmacokinetics (the drug’s effects on the body), and pharmacodynamics (the drug’s movement in, through, and out of the body) of tominersen in patients receiving either a high or low dose of the treatment.

A Phase 3 trial (NCT03761849) called GENERATION HD1 enrolled 791 adults with Huntington’s, who were divided evenly into three groups. One group received tominersen every eight weeks, while one group was given tominersen every 16 weeks (receiving a placebo at alternate weeks). Another group was given placebo only every eight weeks.

Roche announced in March 2021 that dosing of tominersen would stop in GENERATION HD1. The decision was made after an assessment of data from an independent panel of experts demonstrated the therapy was not conferring any benefit to patients. Specifically, participants given tominersen every 16 weeks had similar scores on measures of functional ability, motor function, and cognition, at time points up to 69 weeks (about 1.5 years) of treatment. Participants given tominersen every eight weeks consistently had worse scores than the other two groups. The more-frequent dosing also was associated with more severe adverse reactions.

Dosing in GEN-EXTEND (NCT03842969), an open-label extension study with people who participated in other tominersen trials, also was paused following the interim analysis from GENERATION HD1.

Roche is continuing to collect data from GENERATION HD1 and other trials to determine its next steps.

Dosing is continuing in the open-label Phase 1 trial GEN-PEAK (NCT04000594). This small trial is designed to test tominersen’s pharmacokinetics and pharmacodynamics in 20 participants. The trial was halted in March 2020 due to infections in two patients, later determined to be due to the device researchers used to collect participants’ CSF samples. As of April 2021, the U.S. National Library of Medicine’s Clinical Trials website lists the trial as recruiting participants in the Netherlands and the U.K. 

Last updated: May 07, 2021


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