IONIS-HTTRx Shows Promising Results in Phase 1/2 Clinical Trial

IONIS-HTTRx Shows Promising Results in Phase 1/2 Clinical Trial

Ionis Pharmaceuticals‘ experimental therapy IONIS-HTTRx significantly reduced levels of the protein responsible for Huntington’s disease (HD) in early stage patients, according to top-line results from a Phase 1/2 clinical trial.

The data, presented at the 13th Annual HD Therapeutics Conference in Palm Springs, California, confirm IONIS-HTTRx as the first therapy in development to lower the disease-causing protein in Huntington’s patients.

Huntington’s is caused by mutations in the huntingtin (HTT) gene that result in the production of an abnormal and toxic protein called mutant huntingtin (mHTT). The mutant protein gradually destroys neurons in the brain, leading to deterioration of mental abilities and physical control.

Among the brain areas most affected by this disorder are the cortex, which has a key role in memory, perception, cognition, thought, language, and consciousness, and the caudate region, which is involved in motor function, language, memory, and learning.

IONIS-HTTRx, also called RG6042, was designed to reduce the production of all forms of the huntingtin protein, including the mutated one. This raises the possibility of treating all Huntington’s patients, regardless of their individual HTT mutation.

Promising results from preclinical studies led to the initiation of the Phase 1/2 study (NCT02519036), which evaluated the safety, tolerability, properties and movement within the body of IONIS-HTTRx in patients with early-stage Huntington’s disease.

The 13-week, randomized, placebo-controlled, dose escalation study enrolled 46 patients aged 25-65. Participants were assigned randomly to receive one of five different doses of IONIS-HTTRx or a placebo, given monthly through the spinal canal, for a total of four doses.

Participants who received either of the two highest doses of the treatment showed an average reduction of 40% in mHTT levels in their cerebral spinal fluid. Some patients experienced an even greater reduction, as high as 60%.

Based on a predictive model developed from preclinical data, researchers believe these reductions correspond to an estimated 55-85% decline of mHTT levels in the brain cortex, and 20-50% in the caudate region. More importantly, the preclinical work suggests these reductions are big enough to yield clinical benefits.

“In this study, we were able to achieve mutant huntingtin protein reductions (…) that were higher than those that produced disease benefit in preclinical models of HD,” C. Frank Bennett, senior vice president of research at Ionis Pharmaceuticals, said in a press release.

With protein levels still declining at the end of the study, Ionis expects to see further reductions, with a maximum decline at six months after the first dose.

Regarding safety of IONIS-HTTRx, no serious adverse events were reported and most adverse events were mild and considered to be unrelated to the therapy.

“With IONIS-HTTRx (RG6042)the HD community has new hope for a therapy that can reduce the cause of HD, and therefore, may slow the progression and potentially prevent the disease in future generations, which is truly groundbreaking,” added Sarah Tabrizi, MD and the study’s lead author.

Since this was a small and short trial, the next step is to conduct larger and longer studies to confirm these results, to investigate whether IONIS-HTTRx slows disease progression, and evaluate long-term safety.

Ionis and Roche are initiating an open-label extension trial (NCT03342053) for the 46 participants who completed the Phase 1/2 trial. The extension study will transition to Roche, which will manage this trial and future studies of IONIS-HTTRx.


  1. Tonia B says:

    This progress is beyond exciting. Thankyou for reporting on this update. I look forward to hearing the outcomes of the next stage of the Roche trial.

  2. Andrew says:

    My niece and her son have HD. Looking forward to treating them. If I had this disease, I would take the treatment immediately.

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