Gene silencer reduces mutant huntingtin protein in early-stage Huntington’s patients

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mHTT is a promising Huntington’s target, but caveats abound

The press release from Ionis Pharmaceuticals sounds very promising. There is reason to believe that lowering mHTT protein might prevent or delay Huntington’s disease, and this antisense molecule appears to be safe and to lower mHTT in cerebrospinal fluid. However, there are several caveats.

First, it is unclear whether lowering mHTT protein might help those who already have clinical Huntington’s disease.

Dr. Michael S. Wolfe, the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence

Dr. Michael S. Wolfe

Second, it is unclear whether lowering mHTT in the cerebrospinal fluid reflects what is happening in the region of the brain – the basal ganglia – that is involved in controlling voluntary movement.

Third, no information is given in the press release about the degree of reduction of mHTT observed and whether there is evidence that this lowering might be sufficient for a therapeutic effect.

Fourth, neurotoxicity may not only result from the mHTT protein but also directly from the mRNA itself. The contribution of mutant mRNA to pathogenesis is a key open question in the study of Huntington’s disease and other related “repeat disorders.”

Michael Wolfe, PhD , is the Mathias P. Mertes Professor of Medicinal Chemistry at the University of Kansas, Lawrence. He has no relevant disclosures.


An investigational gene-silencing molecule safely and dose-dependently reduced production of the mutant huntingtin protein in people with early-stage Huntington’s disease in a small, early-phase study, according to an announcement from the drug’s developer, Ionis Pharmaceuticals.

The antisense oligonucleotide IONIS-HTTRx – the first potentially disease-modifying drug for Huntington’s – will now go forward in a larger study to determine whether lowering mutant huntingtin protein (mHTT) confers any clinical benefits upon patients with the fatal neurodegenerative disease.

IONIS-HTTRx reduced mHTT by fractions that “exceeded expectations” set for the 46-person trial, C. Frank Bennett, PhD, senior vice president of research at Ionis, said in a press statement.

Although the phase 1/2a study didn’t assess clinical outcomes, the intrathecally administered molecule is a potential blockbuster for the Huntington’s field, according to Sarah Tabrizi, PhD, principal investigator for the trial.

“The results of this trial are of groundbreaking importance for Huntington’s disease patients and families,” said Dr. Tabrizi, director of the Huntington’s Disease Centre at University College London. “For the first time a drug has lowered the level of the toxic disease-causing protein in the nervous system, and the drug was safe and well tolerated. The key now is to move quickly to a larger trial to test whether the drug slows disease progression.”

Upon receiving the positive data, Roche Pharma exercised its $45 million option to license the molecule. Roche now takes all regulatory and clinical development responsibility for IONIS-HTTRx.

There are few publicly available data on the IONIS-HTTRx study. It enrolled 46 patients with early-stage Huntington’s who were recruited from nine sites in the United Kingdom, Germany, and Canada. They were randomized to placebo or to four ascending doses of IONIS-HTTRx. The primary outcomes were mHTT levels in spinal fluid, safety, and tolerability. It produced significant, dose-dependent reductions of mHTT without concerning or dose-limiting safety signals, the press statement noted.

Dr. Michael S. Wolfe

Patients in the placebo-controlled study now have the option to enroll in a 74-week, open-label extension trial.

A larger study with clinical endpoints is next up, according to a statement Ionis and Roche jointly issued to the Huntington’s Disease Society of America.

“The next step for this program will be to conduct a safety and efficacy study to investigate if decreasing mutant huntingtin protein with IONIS-HTTRx can benefit people with Huntington’s disease,” the statement noted. “Future studies for the program will be conducted globally, including in the U.S. Roche will announce details about future studies, including eligibility criteria and planned start dates, as this information becomes available. All relevant information on upcoming studies will also be posted on HDTrialFinder.org and ClinicalTrials.gov.”

Huntington’s disease is caused by an expansion of at least 36 repeats of the CAG trinucleotide sequence in the huntingtin gene. The resulting mHTT is toxic and gradually damages neurons. IONIS-HTTRx interrupts the messenger RNA that fuels this toxic protein buildup, and it is the only drug that has ever attacked the disease at this level. This development is “a historic moment in the fight against Huntington’s, as it represents the successful completion of the first trial to treat the underlying cause of Huntington’s disease, the genetic mutation itself,” according to a statement by Louise Vetter, president of the Huntington’s Disease Society of America.

“The fact that levels of mutant huntingtin were reduced in correlation to the dose of IONIS-HTTRx that was given is significant, and the fact that participants in this first Phase 1/2a study are able to continue on the drug through an open-label extension gives us optimism regarding its safety,” Ms. Vetter said.

In January 2016, the Food and Drug Administration granted orphan drug status to IONIS-HTTRX; the European Medicines Agency had previously granted it similar status.

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