Brezosiran Demonstrates Mutant Huntingtin Reduction in Phase 1b Huntington Disease Study

Brezosiran (ALN-HTT02), an investigational RNA interference (RNAi) therapeutic in development for Huntington disease (HD), demonstrated dose-dependent reductions in cerebrospinal fluid (CSF) mutant huntingtin (mHTT) levels in an ongoing Phase 1b clinical trial (NCT06585449), according to new data announced by developer Alnylam Pharmaceuticals. Among participants receiving the highest dose evaluated to date, mean CSF mHTT reductions ranged from 60% to 64% at month 3, with an individual reduction of up to 83%.¹

The initial findings, presented at the 2026 European Huntington’s Disease Network (EHDN) Clinical Research Congress in Krakow, Poland, also showed evidence of sustained target engagement, with some participants followed for up to 12 months after dosing. According to the company, the observed durability of mHTT lowering suggests the potential for a twice-yearly dosing approach in future development.¹

“Brezosiran is designed to lower all forms of HTT, including full-length mutant HTT and the shorter mutant HTT1a, which a growing body of evidence suggests may play a key role in the progression of Huntington disease,” Blair R. Leavitt, MDCM, FRCPC, neurologist and director of research at the Centre for Huntington Disease at the University of British Columbia Hospital and a principal investigator in the study, said in a statement.¹ “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.”

The randomized, double-blind, placebo-controlled Phase 1b trial is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intrathecal doses of brezosiran. The study enrolled 48 adults aged 25 to 70 years with genetically confirmed HD in HD Integrated Staging System (HD-ISS) stage 2 or early stage 3 across the first 5 dose cohorts. An additional sixth cohort, enrolling 12 participants, is ongoing and has not yet been evaluated.

Investigators reported positive safety and tolerability profiles across the initial five dose cohorts, with no dose-dependent increases observed in CSF inflammatory markers, CSF neurofilament light chain (NfL), or brain ventricular volume. Target engagement was demonstrated using 2 independent assays.¹

Eligible participants in the trial may transition into an open-label extension study, in which they receive brezosiran every 6 months for up to 36 months. The extension will further evaluate long-term safety, sustained target engagement, and exploratory measures of disease progression.

Read more: SKY-0515 Shows Sustained Benefit at 15 Months in Huntington Disease

For context, brezosiran uses Alnylam's proprietary C16 conjugate platform for delivery to the central nervous system and targets exon 1 of the huntingtin (HTT) messenger RNA transcript. This approach is designed to reduce production of both full-length mutant HTT and the shorter mutant HTT1a protein. The therapeutic is being developed in collaboration with Regeneron Pharmaceuticals.

Alnylam plans to initiate a placebo-controlled pivotal study in adults with HD in 2027, pending regulatory alignment. The planned study will evaluate whether brezosiran can slow disease progression.

Currently, no disease-modifying therapies are approved to slow, halt, or reverse HD progression. The autosomal dominant neurodegenerative disorder is caused by an expanded CAG repeat in exon 1 of the HTT gene and is characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms.

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REFERENCES
1. Alnylam Announces Positive Initial Phase 1b Data for Brezosiran (ALN-HTT02) Demonstrating Deep and Durable Huntingtin Lowering in Huntington’s Disease. Alnylam Pharmaceuticals. News Release. October 23, 2026. Accessed November 2, 2026. https://investors.alnylam.com/press-release?id=0ea5d557-9f90-444e-9c30-3edf5dbdfe68