Alnylam Pharmaceuticals (NASDAQ:ALNY) outlined early clinical data for brezosiran, an investigational RNA interference therapy for Huntington’s disease, reporting dose-dependent reductions in cerebrospinal fluid mutant huntingtin after a single intrathecal dose and plans to begin a placebo-controlled pivotal study in 2027, pending regulatory alignment.
Huntington’s disease is a progressive, fatal inherited neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. The disease can affect movement, cognition and mood, and Alnylam estimates that more than 100,000 symptomatic patients live globally. There are currently no approved disease-modifying treatments.
Exon 1 Strategy Targets Multiple Huntingtin Forms
Brezosiran, previously called ALN-HTT02, is designed to target a sequence in Exon 1 of the huntingtin gene. Alnylam said this approach is intended to reduce both full-length mutant huntingtin and a shorter form known as huntingtin 1a, as well as wild-type huntingtin.
Kevin Sloan, Alnylam’s vice president of development programs and program lead for brezosiran, said prior huntingtin-lowering programs have often targeted sequences downstream of Exon 1, meaning they may lower full-length huntingtin without directly addressing huntingtin 1a.
“We ultimately selected” an inclusive Exon 1-targeting approach “designed to lower all relevant huntingtin species in the CNS,” Sloan said.
Gill Bates, professor of molecular neuroscience and co-director of the Huntington’s Disease Centre at University College London, discussed research suggesting huntingtin 1a may contribute meaningfully to disease biology. She said somatic expansion of the CAG repeat in vulnerable neurons is believed to be an early event in Huntington’s disease pathogenesis.
Bates described three mouse-model studies published this year that examined the effects of reducing huntingtin 1a. In one study, preventing production of huntingtin 1a delayed aggregation and normalized certain cerebrospinal fluid biomarkers while full-length mutant huntingtin remained present. Other studies found that approaches lowering huntingtin 1a alongside full-length mutant huntingtin had larger effects on aggregation and transcriptional dysregulation than approaches aimed only at full-length huntingtin.
However, Bates said it remains difficult to measure huntingtin 1a in living patients because it may be produced in relatively small populations of cells with highly expanded repeats and may remain trapped in cellular aggregates. She said reductions in full-length huntingtin could potentially serve as an indirect indicator of huntingtin 1a lowering for therapies directed at Exon 1.
Initial Phase Ib Data Showed Up to 83% Individual Reductions
Toby Ferguson, Alnylam’s senior vice president and head of neuroscience, presented initial results from an ongoing randomized, double-blind, placebo-controlled phase Ib study in patients with stage 2 or early stage 3 Huntington’s disease. The trial enrolled patients between ages 25 and 70 with more than 39 CAG repeats in Canada, Germany and the United Kingdom.
The data cut included five dose cohorts with up to three months of follow-up after one intrathecal administration of brezosiran. The study’s primary endpoint is safety and tolerability, while secondary measures include cerebrospinal fluid and plasma pharmacokinetics and changes in cerebrospinal fluid mutant huntingtin.
Using two assays, including a newer mutant huntingtin NULISA assay, Alnylam reported dose-dependent reductions in cerebrospinal fluid mutant huntingtin. At the highest evaluated dose, the company reported mean reductions of 60% to 64% at month three, with maximum individual reductions of up to 83%.
Ferguson said the NULISA assay avoided lower-limit-of-quantification issues observed with a traditional assay, particularly after deeper huntingtin lowering.
Safety Findings and Development Plans
Alnylam said adverse events occurred in most participants, as is common in neurodegenerative-disease studies, but reported no dose-related increase in serious or severe adverse events across the five cohorts. There were no deaths or treatment discontinuations due to adverse events.
The company reported two severe and serious events in one dose group: a radius fracture and likely bacterial meningitis. It also reported an acute myocardial infarction that resolved with sequelae and a resolved post-lumbar puncture syndrome in that same dose group. A severe, non-serious headache in another group had resolved.
Ferguson said cerebrospinal fluid white blood cell counts and protein levels were similar between treated and placebo participants, with no evidence to date of dose-related central nervous system inflammation. The company also reported no dose-dependent increases in cerebrospinal fluid neurofilament light chain, a biomarker associated with neuronal injury, and no dose-dependent changes in ventricular volume on MRI.
“Our findings to date do not establish clinical efficacy,” Ferguson said, adding that longer and larger studies will be required.
Participants may enter an open-label extension in which they can receive brezosiran every six months. Alnylam said the extension will help characterize longer-term safety and explore potential efficacy trends, though Ferguson said it may take 24 to 36 months to meaningfully assess clinical effects in Huntington’s disease.
The company plans to pursue a placebo-controlled pivotal study beginning in 2027, subject to regulatory discussions. Alnylam said the trial is intended to determine whether brezosiran can slow disease progression and would, to its knowledge, be the first placebo-controlled test of the huntingtin 1a-lowering hypothesis.
About Alnylam Pharmaceuticals (NASDAQ:ALNY)
Alnylam Pharmaceuticals, Inc is a biopharmaceutical company focused on developing and commercializing medicines based on RNA interference (RNAi). The company’s therapies are designed to silence specific genes involved in disease, with the goal of addressing the underlying causes of genetic and other serious conditions.
Alnylam’s marketed products include ONPATTRO (patisiran) and AMVUTTRA (vutrisiran) for hereditary transthyretin-mediated amyloidosis, GIVLAARI (givosiran) for acute hepatic porphyria, and OXLUMO (lumasiran) for primary hyperoxaluria type 1.
