Alnylam's brezosiran cuts mutant huntingtin by up to 64%, pivotal study planned for 2027

Alnylam Pharmaceuticals has reported initial Phase 1b results for brezosiran (ALN-HTT02), an RNAi therapeutic for Huntington's disease developed with partner Regeneron. The data were released on 23 October and presented at the EHDN Clinical Research Congress 2026 in Krakow, Poland.

How the drug works

Brezosiran is given intrathecally and is built on Alnylam's C16 conjugate platform, which is designed to carry RNAi drugs into the central nervous system. It targets exon 1 of the huntingtin (HTT) messenger RNA, with the aim of lowering every form of the protein, including the shorter mutant fragment known as HTT1a.

What the trial showed

The randomised, double-blind, placebo-controlled study has enrolled 48 adults with genetically confirmed Huntington's disease across five single-dose cohorts, at sites in Canada, Germany and the UK. A sixth cohort of 12 is still enrolling.

In the highest dose group evaluated so far, mean mutant huntingtin in cerebrospinal fluid fell by 60% to 64% at month three, with the largest individual drop at 83%. Some participants have been followed for up to a year, which Alnylam says points to durable lowering and possibly twice-yearly dosing. The company reported no dose-related rises in CSF inflammatory markers, neurofilament light chain or brain ventricular volume.

"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, M.D., Chief Research and Development Officer, Alnylam

The caveats

This is a biomarker result. The follow-up was too short to measure clinical benefit, and BioSpace points out that Stifel analysts flagged the history here: Roche's tominersen also lowered CSF mutant huntingtin without delivering a clinical benefit, and Roche has since dropped it. Oppenheimer, by contrast, said the data fell within its best-case scenario.

What happens next

Alnylam plans a placebo-controlled pivotal study in 2027, subject to regulatory alignment, to test whether brezosiran slows disease progression. The programme is due to feature at the company's RNAi Roundtable on 26 October.

The bigger picture

According to Alnylam, no approved therapy can yet slow, halt or reverse Huntington's. An RNAi company with six approved medicines taking a CNS asset into a pivotal trial is, in our view, a meaningful signal for neuroscience investment more broadly. If the C16 platform works in the brain, it opens the door to other neurological targets.