Experimental therapy lowers mutant Huntington’s protein
Brezosiran reduces levels of mutant huntingtin, early trial data show
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The experimental therapy brezosiran can reduce levels of the mutant huntingtin protein in people with Huntington’s disease, according to interim data from a small clinical trial.
The results were shared in oral and poster presentations at the European Huntington’s Disease Network Clinical Research Congress 2026, held Oct. 22-24 in Krakow, Poland.
“The deep and durable mutant huntingtin lowering observed after a single dose, together with the encouraging safety profile seen to date, give us confidence to advance brezosiran into a pivotal study,” Pushkal Garg, MD, the chief research and development officer at Alnylam Pharmaceuticals, the therapy’s co-developer along with Regeneron Pharmaceuticals, said in a company press release. “We plan to evaluate our differentiated huntingtin-lowering approach in a rigorous placebo-controlled study to determine whether it can alter the course of Huntington’s disease.”
That pivotal study, intended to provide robust data to support an approval submission, is expected to begin next year, pending alignment with regulatory authorities.
Huntington’s is caused by mutations in the gene that provides instructions to make the huntingtin (HTT) protein. The full-length mutant version (mHTT), as well as a shorter mutant version called HTT1a, are thought to drive the progressive brain damage that underlies Huntington’s symptoms.
Slowing disease progression
Brezosiran, previously known as ALN-HTT02, is an RNA-based therapy designed to shut down the production of all forms of the HTT protein, including the healthy version, mHTT, and HTT1a.
Data from mouse models of Huntington’s showed that HTT-lowering approaches that also target HTT1a are more effective at preventing disease-related molecular processes than those targeting only mHTT.
By reducing levels of these two forms of mutant HTT, the therapy, administered by injection into the spinal canal, aims to slow Huntington’s progression.
Launched in late 2024, the Phase 1b trial (NCT06585449) is testing increasing doses of brezosiran against a placebo in adults ages 25-70 who have stage 2 or early stage 3 Huntington’s. The study is still recruiting patients at sites in Canada, Germany, and the U.K.
Participants are randomly assigned to receive a single injection of either brezosiran or a placebo and are followed for at least one year. The main goal is to evaluate safety, while secondary goals include changes in mHTT levels in the cerebrospinal fluid (CSF), or the liquid that surrounds the brain and spinal cord.
The new data cover 48 participants who received brezosiran at one of five doses or the placebo. Safety findings have so far been positive; no serious safety concerns related to the experimental treatment have been documented.
Brezosiran is also reducing mHTT levels as intended, with greater reductions among patients given higher doses of the experimental therapy. Specifically, CSF mHTT levels decreased by a mean of 60%-64% three months after a single brezosiran injection, with some individuals achieving reductions of as much as 83%.
According to Alnylam, the long-lasting effect of brezosiran on mHTT levels supports the potential for brezosiran to be administered twice yearly in future trials. CSF analyses also showed that markers of nerve damage and brain inflammation have been stable over the course of follow-up, the company reported.
“The evidence suggesting that brezosiran has the potential to achieve robust and durable HTT-lowering, while maintaining an encouraging safety profile, is a very promising advance for this program at a time when there are still no approved disease-modifying therapies for Huntington disease,” said Blair R. Leavitt, a principal investigator on the trial and a neurologist at the University of British Columbia Hospital.
Participants who complete the trial’s placebo-controlled portion will have the option to transition to its open-label extension, in which all will receive brezosiran once every six months for up to three years, with the aim of tracking long-term safety and potential efficacy trends.
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