Turning down huntingtin: Alnylam’s brezosiran shows promising early result

On October 23, 2026, Alnylam Pharmaceuticals announced promising early results for brezosiran (previously known as ALN-HTT02), an experimental treatment designed to lower the huntingtin proteinhuntingtin protein The protein produced by the HD gene. that drives HD. The results, presented at the European Huntington’s Disease Network (EHDN) meeting in Poland, show huntingtin lowering after a single dose, with encouraging safety data so far. 

Alnylam plans to move directly to a pivotal clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings in 2027, meaning the next study will try to establish whether this treatment can actually slow HD progression and provide the evidence needed for approval. Let’s dive into what this encouraging news means for the community.

A big drop from a single dose

Brezosiran works by RNA interferenceRNA interference A type of gene silencing treatment in which specially designed RNA molecules are used to switch off a gene, or RNAiRNA interference A type of gene silencing treatment in which specially designed RNA molecules are used to switch off a gene, to lower levels of the huntingtin proteinhuntingtin protein The protein produced by the HD gene.. It works by targeting the messenger RNAmessenger RNA A message molecule, based on DNA, used by cells as the final set of instructions for making a protein., the instructions that cells use to make huntingtin, with the goal of turning down the volume on huntingtin proteinhuntingtin protein The protein produced by the HD gene. levels. The treatment is delivered by spinal tap into the cerebrospinal fluidCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. (CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord.), the fluid which bathes the brain. 

Brezosiran uses Alnylam’s C16 technology, which attaches a small fat-like molecule to the RNA-targeting drug. This helps the treatment better enter and spread through cells in the brain and spinal cord. RNA-based medicines can struggle to reach their targets in the nervous system, so improving delivery is an important part of developing effective treatments. 

The ongoing Phase 1b trial included people with HD-ISS Stage 2 or early Stage 3: those with measurable changes in movement or thinking, whose ability to work or manage everyday activities is still largely preserved (Stage 2) or beginning to decline (Stage 3). 48 participants  were divided into five groups, each receiving a different dose of brezosiran. Then these participants were monitored for 12 months using blood and spinal fluid tests and MRImagnetic resonance A technique using powerful magnetic fields to produce detailed images of the brain in living humans and animals scans to look for potential safety concerns, like inflammationinflammation Activation of the immune system, thought to be involved in the HD disease process, or signs of damage to the brain. 

At the highest dose, levels of the expanded form of huntingtin in CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord. fell by about 60% on average after three months. Importantly, these reductions followed just a single injection! Data from  suggests that huntingtin lowering with brezosiran could last long enough for treatment to be given only twice a year, although longer-term data are needed to confirm this.

Encouraging safety findings

Lowering huntingtin is only part of the challenge. Brezosiran hits the expanded and regular forms of huntingtin. Huntingtin is an important protein with lots of key jobs in the cell, so researchers need to understand whether reducing its levels with this therapy can be done so safely.

The early findings are encouraging. Among participants followed for up to 12 months, there were no impacts on markers of inflammationinflammation Activation of the immune system, thought to be involved in the HD disease process, neurofilament lightNfL biomarker of brain health chain (NfLNfL biomarker of brain health, a marker of nerve cell health), or the size of the brain’s fluid-filled spaces, called ventriclesventricle Normal fluid-filled spaces within the brain..

Four serious adverse events were reported, but none were considered related to brezosiran itself. Two were associated with the lumbar puncture procedure used to administer the treatment.

Overall, these findings suggest that brezosiran appears safe so far. However, this is still a relatively small, early-stage study, and longer-term monitoring will be essential in future trials to confirm this finding.

Two forms of huntingtin: why does HTT1a matter?

One particularly interesting feature of brezosiran is that it targets both full-length huntingtin and a shorter form called HTT1a which is thought to be a driver of toxicity in people with HD. 

To understand why this matters, let’s recap how huntingtin is made. The HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene contains instructions for producing huntingtin, a large protein that has many important jobs in our cells. In people with HD, one copy of the HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene contains an expanded stretch of CAG repeats, producing an abnormally long huntingtin proteinhuntingtin protein The protein produced by the HD gene..

Usually, cells read the complete genetic instructions to produce full-length huntingtin. But some evidence from HD mouse studies suggests that the expanded HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15 gene can also produce a much shorter RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. message, called HTT1a, which contains only the beginning of the instructions. This produces a much smaller protein containing the disease-causing expansion.

Because this short protein contains the expanded region without the rest of the full-length protein, it is particularly prone to clumping together. Some laboratory studies suggest that HTT1a could be an important contributor to the damage seen in HD.

Brezosiran lowers both full-length huntingtin and HTT1a. It targets a section of the RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. instructions called exonExons The small fraction of our DNA that is directly used to instruct cells how to make proteins 1, which is shared by both messages. However, brezosiran is not selective for expanded huntingtin. It is designed to reduce huntingtin produced from both the expanded HD gene and the healthy copy. This makes monitoring safety especially important.

Could reducing HTT1a alongside full-length huntingtin be a better strategy for treating HD? It’s an intriguing possibility, but we don’t yet know. The results reported so far measure expanded huntingtin in CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord., not HTT1a directly, and we have no insight on whether the drug slows HD yet so this remains an open question.

Moving towards the trial that matters

Perhaps the biggest news is what comes next. Rather than proceeding through a separate, conventional Phase 2 trial, Alnylam plans to launch a placebo-controlled pivotal study in 2027, pending agreement and alignment with regulators. A pivotal trial is a large study intended to establish whether a treatment works and potentially provide evidence to support approval by regulators. 

This is an important step forward. Moving directly to a pivotal study could shorten the time needed to find out whether brezosiran can meaningfully slow HD progression. However, the trial design, size and timeline have not yet been announced, and moving faster does not guarantee success.

Meanwhile, participants in the current study can enter an extension trial, receiving brezosiran every six months for up to 3 years while researchers continue monitoring safety, huntingtin lowering and possible changes in disease progression.

Another shot on goal

The HD community has seen both encouraging results and disappointing setbacks from huntingtin-lowering therapies. These experiences have taught us an important lesson: lowering huntingtin proteinhuntingtin protein The protein produced by the HD gene. is not the same as demonstrating that a treatment slows HD.

Brezosiran has not yet been shown to improve symptoms or slow disease progression. But these early findings provide several reasons for cautious optimism. Sustained huntingtin lowering after a single dose, reassuring safety data, potential for a convenient dosing schedule, and an approach designed to target both full-length huntingtin and HTT1a is certainly encouraging!

Importantly, brezosiran adds another shot on goal in the search for effective huntingtin-lowering treatments. Different approaches may ultimately offer unique advantages, and each carefully designed trial brings us closer to understanding what might work. For now, the results are promising, and we look forward to learning more about the planned pivotal study!

Summary: 

• Alnylam’s experimental treatment brezosiran reduced mutant huntingtin levels in spinal fluid by around 60% after a single dose.
• The treatment has shown a reassuring safety profile so far, with no major drug-related safety concerns emerging, although longer-term monitoring is needed.
• Brezosiran lowers both full-length huntingtin and the shorter HTT1a protein, but it is not selective for expanded huntingtin. Whether targeting HTT1a offers additional benefits remains unknown.
• Alnylam plans to begin a pivotal trial in 2027, bringing us closer to finding out whether brezosiran can actually slow HD progression.