Alnylam’s Huntington’s Drug Lowers Disease-Linked Protein in Early Trial

Rare Daily Staff

Alnylam Pharmaceuticals said its experimental Huntington’s disease treatment brezosiran substantially reduced levels of a disease-linked protein in an early clinical trial, supporting plans for a larger study in 2027 to test whether it can slow the disorder’s progression.

The initial phase 1b results showed that a single dose reduced mutant huntingtin protein in cerebrospinal fluid by an average of 60 to 64 percent after three months in the highest-dose group evaluated so far. The largest reduction in an individual participant was 83 percent, the company said.

The findings show that brezosiran is reaching its biological target, but they do not establish whether the treatment can slow Huntington’s disease or help people retain their ability to move, think or manage daily activities. Alnylam presented the results at the European Huntington’s Disease Network Clinical Research Congress in Krakow, Poland.

Huntington’s disease is genetic, progressive brain disorder that causes movement problems, cognitive decline and psychiatric symptoms. The disease results from a genetic change that leads to the production of mutant huntingtin protein. It typically emerges between ages 30 and 50 and progresses over 15 to 20 years. There are no approved treatments that slow, halt or reverse its progression.

Brezosiran, previously known as ALN-HTT02, uses RNA interference, a gene-silencing approach, to reduce production of huntingtin. It acts on messenger RNA, the instructions cells use to make proteins. The treatment, developed with Regeneron Pharmaceuticals, is given by injection into the fluid surrounding the spinal cord. It targets a region of the huntingtin instructions called exon 1 and is designed to lower both full-length huntingtin and a shorter mutant form known as HTT1a. Researchers are investigating the shorter form’s role in disease progression.

The ongoing phase 1b trial is a randomized, double-blind, placebo-controlled study. The reported results cover 48 participants across five single-dose groups. Participants are 25 to 70 years old and have genetically confirmed Huntington’s disease. A sixth group, expected to include 12 participants, is enrolling.

Alnylam said mutant huntingtin reductions increased with dose and were measured using two independent laboratory tests. The company said the persistence of the protein-lowering effect suggests that dosing once every six months may be possible, although that schedule remains under evaluation.

Some participants have been followed for up to 12 months. Alnylam described the safety and tolerability findings as encouraging, reporting no dose-dependent increases in cerebrospinal fluid markers of inflammation, cerebrospinal fluid levels of neurofilament light chain or brain ventricular volume. Neurofilament light chain is a marker used to assess nerve-cell injury.

Eligible participants can enter an open-label extension, in which everyone receives brezosiran once every six months for up to 36 months. That study will examine longer-term safety, sustained protein lowering and exploratory measures of disease progression.

Alnylam plans to begin a placebo-controlled pivotal study in adults with Huntington’s disease in 2027, pending agreement with regulators.

“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,” said Pushkal Garg, Alnylam’s chief research and development officer.