Alnylam Reports Mutant Protein Reduction in Highest-Dose Trial Group

Alnylam Pharmaceuticals announced Friday, Oct. 23, that its investigational Huntington’s disease drug brezosiran lowered mutant huntingtin in spinal fluid in the highest-dose group, an early sign of target engagement that does not show whether treatment slows the disease.

That group had a mean reduction of 60% to 64% from baseline three months after one intrathecal dose. The largest individual reduction was 83%. These biomarker results do not establish a clinical benefit or slower disease progression.

The interim results covered 48 participants across five single-dose cohorts. A sixth cohort of 12 people was still enrolling and had not been evaluated. The trial includes adults ages 25 to 70 with genetically confirmed disease at HD-ISS Stage 2 or early Stage 3, and uses a randomized, double-blind, placebo-controlled design.

In Dose 5, nine participants had results for each of two assays. Mean maximum observed reductions were 64.8% on SMCxPRO and 59.2% on NULISA; the largest individual reductions were 77.2% and 83%, respectively. These maximum-observed figures are distinct from the month-three mean reduction.

The trial’s primary goal is to assess safety and tolerability. Mutant huntingtin levels are a pharmacodynamic measure of the drug’s biological effect, while clinical and imaging measures of disease progression are exploratory. Among participants followed for up to 12 months, no dose-related increases were observed in cerebrospinal fluid inflammatory markers, neurofilament light chain or brain ventricular volume.

As of Sept. 10, four of 12 participants in the pooled Dose 4-or-placebo group had at least one serious adverse event. None was judged related to the study drug. The group combined blinded active-treatment and placebo participants, so it was not possible to identify who received brezosiran.

Neurologist Blair R. Leavitt, director of research at the Centre for Huntington Disease at the University of British Columbia Hospital and a Phase 1b principal investigator, called the findings “a very promising advance for this program at a time when there are still no approved disease-modifying therapies.”

Eligible participants may enter an open-label extension with doses every six months for up to 36 months. Alnylam plans a placebo-controlled study in 2027, pending regulatory alignment, to test whether brezosiran slows disease progression.