Alnylam Pharmaceuticals reported initial Phase 1b results on October 23 for brezosiran (ALN-HTT02), an RNA interference therapeutic given by intrathecal injection for Huntington’s disease. Across the first five single-dose cohorts, covering 48 participants, reductions in mutant huntingtin protein in cerebrospinal fluid were dose-dependent. In the highest dose group evaluated so far, the mean reduction from baseline at month 3 was 60 to 64 percent, measured with two independent assays, with a maximum individual reduction of 83 percent. A sixth cohort of 12 participants is still enrolling. The data were presented at the European Huntington’s Disease Network Clinical Research Congress in Krakow, Poland.
Brezosiran is designed to lower all forms of huntingtin, including full-length mutant huntingtin and the shorter mutant HTT1a fragment that a growing body of evidence links to disease progression, a broader target than allele-selective approaches. With follow-up of up to 12 months, Alnylam reported no dose-dependent increases in cerebrospinal fluid inflammatory markers, neurofilament light chain, or brain ventricular volume, the three safety measures that have troubled earlier huntingtin-lowering programs. The durability of the lowering points to dosing once every six months, and participants can move into an open-label extension receiving brezosiran every six months for up to 36 months.
Alnylam plans a placebo-controlled pivotal study in 2027, pending regulatory alignment, to test whether brezosiran slows disease progression. That distinction is the whole story at this stage: lowering the protein is target engagement, not clinical benefit, and the field carries the scar of a previous huntingtin-lowering drug whose late-stage program was halted. The Phase 1b safety pattern is what makes this readout different in kind, and it is still only 48 patients.