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 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.
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 encodes for 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. mRNA is, therefore, 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 gradually destroys nerve cells. 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, which surrounds the brain and spinal cord.
Tominersen in clinical trials
Ionis completed a Phase 1/2a clinical trial (NCT02519036) of tominersen in late 2017. Researchers conducted the study at nine centers in the U.K., Germany, and Canada. It included 46 patients with Huntington’s disease. Researchers randomly assigned the participants to either receive tominersen in increasing doses or a placebo. The study looked at the pharmacokinetics of the treatment — its movement in the body — and at its pharmacodynamics, or how the body metabolizes it.
The results appeared in The New England Journal of Medicine in June 2019. A key finding was that as researchers increased the dose of tominersen, levels of abnormal huntingtin protein in the participants’ cerebrospinal fluid decreased. Ionis said in a December 2017 press release that tominersen’s safety in the trial, and patients’ ability to tolerate it, supported the therapy’s continued development.
An extension of the Phase 1/2a clinical trial (NCT03342053) for patients who completed the earlier trial has also been completed. However, researchers have not yet published the results. This extension examined the safety, tolerability, pharmacokinetics, and pharmacodynamics of tominersen in patients receiving either a high or low dose of the treatment.
Ongoing clinical trials
A Phase 3 trial (NCT03761849) called GENERATION HD1 has completed patient enrollment. The aim is to evaluate the efficacy, safety, and biomarker effects of tominersen compared to a placebo. Researchers will divide participants into three groups. One group will receive tominersen every eight weeks, while one group will receive tominersen every 16 weeks (receiving a placebo at alternate weeks). Another group will receive placebo only, every eight weeks. The primary outcome measure will be any changes in composite unified Huntington’s disease rating scale from the start of the study to week 101.
Roche is also recruiting participants for a Phase 3 open-label extension study (NCT03842969) in the U.S., Canada, Germany, Spain, and the U.K. The study aims to evaluate the long-term safety and efficacy of tominersen. Patients (1,050 estimated) will randomly receive tominersen by intrathecal injection every eight or every 16 weeks. Adverse events will be recorded, as well as any change from the start of the study in behavior assessed using the Columbia-suicide severity rating scale, or cognition using the Montreal cognitive assessment every six months until the end of the study.
A Phase 1 clinical trial (NCT04000594) to evaluate the long-term safety and effectiveness of tominersen was halted in March 2020 due to infection in two patients. The source of the infection was the device that researchers used to collect cerebrospinal fluid from participants. As of May 2020, 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 6, 2020
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