EHDN 2026 Part 2: What’s the latest news for Huntington’s disease clinical trials?

More than 1,300 researchers, clinicians, industry representatives and members of the Huntington’s disease (HD) community gathered in Kraków, Poland, for the 2026 European Huntington’s Disease Network (EHDN) Clinical Research Congress. HDBuzz’s Dr Rachel Harding was there to hear the latest developments firsthand. In Part 1 of our EHDN coverage, we explored the next generation of potential treatments still being developed in the lab. Now we’re turning to medicines already being tested in people with HD. There was plenty to discuss, from encouraging early results and new trials getting underway to disappointing outcomes that remind us why careful clinical testing matters. Here’s a look at some of the major updates.

Turning down huntingtin production

One of the biggest areas of HD drug development involves lowering huntingtin, the protein that causes HD when its genetic instructions contain an expanded CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD. But not all huntingtin-lowering treatments work in the same way. Some aim to selectively lower the expanded, harmful version of huntingtin while preserving the regular protein, which has important jobs in our cells. Others lower both versions. Researchers are also exploring whether treatments should target full-length huntingtin, the complete protein, or HTT1a, a shorter version that may also contribute to HD.

There are differences in how these medicines reach their targets, too. Some are delivered directly into the fluid surrounding the brain and spinal cord through spinal injections, others require surgery to deliver gene therapies into the brain, and some are being developed as pills that can be taken by mouth. Each approach has potential advantages and challenges, and researchers are working to understand which strategies might offer the greatest benefits while minimising unwanted effects.

Brezosiran: RNA interferenceRNA interference A type of gene silencing treatment in which specially designed RNA molecules are used to switch off a gene makes progress

One of the most exciting updates came from Sarah Tabrizi, presenting on behalf of Alnylam, who shared plans to move brezosiran directly into a pivotal Phase 3 trial in 2027 following encouraging early clinical results. Brezosiran, previously known as ALN-HTT02, uses 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 huntingtin production. Importantly, brezosiran targets 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 for both full-length huntingtin and HTT1a, a shorter RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. molecule that may also contribute to the harmful effects of HD.

Brezosiran is delivered into the fluid surrounding the brain and spinal cord through a spinal injection. It uses Alnylam’s C16 technology, which attaches a small fat-like molecule to help the treatment enter and spread through brain cells. Early clinical results showed lowering of expanded huntingtin by up to about 64% when measured in 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.), and the drug has an encouraging safety profile so far. The treatment is designed to have long-lasting effects, potentially allowing injections as infrequently as twice a year.

These findings suggest brezosiran is doing what it’s designed to do: lowering huntingtin. However, we don’t yet know whether this will translate into improvements in symptoms or slower disease progression. The planned Phase 3 trial will be an important next step towards answering these questions.

VO659: Targeting the expanded CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD

Scott Schobel from VICO Therapeuticstherapeutics treatments presented updates on VO659, an antisense oligonucleotideASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene (ASOASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene) designed to target the expanded CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD found in the huntingtin RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins. message molecule. Unlike treatments that lower both regular and expanded huntingtin, VO659 aims to preferentially reduce the harmful CAG expanded version. That’s an appealing possibility because normal huntingtin performs important jobs in cells.

The ongoing trial of VO659 includes people with HD as well as SCA1 and SCA3, other rare brain diseases caused by CAG repeatCAG repeat The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD expansions. Earlier updates showed huntingtin lowering but also some unpleasant spinal inflammationinflammation Activation of the immune system, thought to be involved in the HD disease process when the drug was given monthly. Schobel discussed changes to dosing that could eventually mean treatment just once or twice a year. Earlier safety concerns appeared less prominent in the newer data presented, although careful monitoring remains essential.

Two different pills to lower HTTHTT one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15

Another exciting area of research involves medicines taken by mouth that change how cells process huntingtin RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins.. These are called splice modulators. Rather than directly destroying huntingtin RNARNA the chemical, similar to DNA, that makes up the ‘message’ molecules that cells use as working copies of genes, when manufacturing proteins., splice modulators change how 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 are processed, causing some to be removed or broken down before they can produce protein.

Two distinct medicines in this category featured at EHDN: Skyhawk’s SKY-0515 and Novartis’s votoplam (previously PTC518). Both are oral splice modulators but are being developed through separate clinical programmes.

SKY-0515: Lowering huntingtin and PMS1

Meghan Miller from Skyhawk Therapeuticstherapeutics treatments presented updates on SKY-0515, an oral medicine designed to lower huntingtin proteinhuntingtin protein The protein produced by the HD gene.. Interestingly, SKY-0515 also lowers PMS1, a DNA repair protein implicated in the expansion of CAG repeats over time. This means it could potentially act on two processes involved in HD: huntingtin production and somatic expansionsomatic expansion A process in which the CAG repeat in the Huntingtin gene can change over a person’s lifetime in some cells of the body, particularly in the brain..

Results presented at EHDN included observations over approximately 15 months, with encouraging trends compared with people in the Enroll-HD observationalobservational A study in which measurements are made in human volunteers but no experimental drug or treatment is given study. However, these comparisons involved relatively small numbers of participants. To work out if SKY-0515 slows down the progression of HD, a larger study is needed, one that randomly assigns participants to take the drug or a placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work.. To this end, SKY-0515 is being investigated further through the larger FALCON-HD clinical programme, a Phase 2/3 study designed to assess efficacyefficacy A measure of whether a treatment works or not.

Votoplam: A separate oral huntingtin-lowering approach

Beth Borowsky from Novartis shared updates on votoplam, formerly known as PTC518, another oral splice modulator designed to reduce huntingtin production. Results from the Phase 2 PIVOT-HD study showed reductions of approximately 20% in expanded huntingtin at the doses studied and encouraging 2-year extension data. However, researchers also observed dose-related increases in brain ventricular volume, an imaging finding that requires careful investigation and monitoring. Votoplam is now being evaluated in the Phase 3 INVEST-HD programme, which aims to establish whether the treatment can meaningfully affect HD progression.

Having two different oral splice modulators in development is encouraging, but it’s important not to assume they will have identical effects, benefits or risks. Each medicine needs to demonstrate its own safety and effectiveness.

When lowering huntingtin isn’t enough

Sadly, not every clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings brings the results researchers and families hope for. David Hawellek from Roche presented findings from GENERATION HD2, the Phase 2 trial of tominersen, an ASOASOs A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene that lowers huntingtin production. The treatment reduced expanded huntingtin levels in 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.) by approximately 30%, showing that it was working as designed. Researchers also observed encouraging changes in neurofilament lightNfL biomarker of brain health (NfLNfL biomarker of brain health), a protein released when nerve cells are damaged, with levels improving later in the study.

However, despite these biological signals, the trial did not demonstrate significant improvements in key clinical measures, including Total Functional CapacityTotal Functional Capacity A standardized rating scale for function in HD, used to assess capacity to work, handle finances, perform domestic chores and self-care tasks and the composite Unified Huntington’s Disease Rating Scale. This is disappointing, particularly given the hopes surrounding huntingtin lowering. The improvements in NfLNfL biomarker of brain health are interesting and warrant further investigation, but they also highlight an important distinction: changes in biological markers, even encouraging ones, don’t necessarily mean a treatment is slowing HD or improving people’s lives.

Although Roche will not continue to develop tominersen, the first-ever huntingtin-lowering trial in humans will provide ongoing data and lessons for future therapies and trial design.  Questions remain about how much huntingtin needs to be lowered, where in the brain lowering occurs, when treatment should begin and whether longer follow-up might be needed to reveal benefits of some huntingtin-lowering approaches.

AMT-130: Encouraging signals, important questions

uniQure’s AMT-130 gene therapy was another major topic of discussion. Unlike medicines that need repeated doses, AMT-130 uses a modified virus to deliver genetic instructions intended to lower huntingtin production over the long term. It is administered directly into the brain during surgery.

David Margolin presented exploratory follow-up data from participants receiving the higher dose, using tests of movement symptoms collectively known as the Q-Motor. Some measures showed encouraging trends over three years when compared with external groups of people with HD.

However, the high-dose group included only 17 participants, and the exploratory Q-Motor comparisons discussed at EHDN were not statistically significantstatistically significant Unlikely to have arisen by chance, according to a statistical test. Crucially, these comparisons relied on historical controls rather than a simultaneously enrolled, randomised placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. group. That makes it harder to know whether differences reflect a treatment effect or other factors.

AMT-130 remains an important programme, but determining whether it genuinely slows HD progression requires careful interpretation of the evidence.

Other ways to tackle HD

Not all treatments aim to lower huntingtin. Pridopidine, for example, is being investigated for its potential to support the function and survival of brain cells. Michael Hayden discussed further analyses from the PROOF-HD trial, including findings in participants who weren’t taking certain dopamine-blocking medicines.

These analyses may help researchers understand which factors influence treatment responses, but subgroup findings need particular caution because differences between groups can complicate interpretation. The new Phase 3 PRECISE-HD trial will provide another opportunity to test whether pridopidine offers meaningful clinical benefit.

Meanwhile, researchers are also exploring cell replacement approaches, including the REGEN4HD programme. The idea is to replace or support brain cells damaged by HD, rather than directly targeting the genetic cause. 

These strategies are at different stages of development, but they highlight the importance of looking beyond a single way of treating the disease.

Young people are helping shape the future of HD research

One particularly important update came from Rachael Scahill, who presented the latest findings from HD-YAS, the Huntington’s Disease Young Adult Study. This long-running study follows young adults who carry the HD gene expansion, many of whom are still years away from developing noticeable symptoms. By tracking changes over time, researchers hope to understand the very earliest effects of HD and identify the best ways to measure whether future treatments are working.

But looking more closely revealed a different picture. Brain scans showed shrinkage in the caudate and putamenputamen part of the striatum, a deep brain region important for movement control, that’s affected early in the course of HD., two regions particularly vulnerable to HD, alongside early signs of iron accumulation. Researchers also detected changes in proteins measured in CSFCSF A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord., including increasing levels of NfLNfL biomarker of brain health, a marker of nerve cell damage, and decreasing levels of PENK, a protein linked to the health of certain brain cells. 

These findings suggest that subtle changes associated with HD can be detected long before people experience significant difficulties in their everyday lives. That’s particularly important as researchers consider the timing of future treatments – ideally before substantial brain changes have occurred.

HD-YAS is also a powerful reminder of the vital contribution young people make to HD research. By volunteering for studies that follow them over many years, young adults from HD families are helping scientists understand when the disease begins to affect the brain, how to measure those changes, and when future treatments might have the greatest impact.

How do we know whether a treatment really works?

One of the most valuable discussions at EHDN wasn’t about a particular medicine. It was about how clinical trials are designed and how researchers decide whether a treatment works.

Jeffrey Long highlighted an intriguing challenge: people receiving placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. in HD trials sometimes do better than researchers might predict from observationalobservational A study in which measurements are made in human volunteers but no experimental drug or treatment is given studies such as Enroll-HD. This matters because experimental treatments can sometimes be compared with historical or external control groups when a conventional placeboplacebo A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work. group isn’t practical or ethical.

Such comparisons can be useful, especially for treatments involving complex procedures like brain surgery. But differences in who enters a trial, how they’re assessed and how their symptoms change over time can make the results difficult to interpret. Regulatory dialogue included a presentation from Elena Hernández Martínez de Lapiscina of the European Medicines Agency (EMA, the European equivalent of the FDA). These discussions reinforced why randomised controlled trials remain the gold standard for establishing whether a medicine genuinely benefits patients.

Researchers also shared progress on digital measures of movement, more sensitive clinical assessments and biological markers that could help detect changes earlier. Better measurements could make future trials more informative, particularly if treatments need to begin before substantial damage has occurred.

Progress means learning from every result

The EHDN Congress showed just how varied the HD clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings landscape has become. Researchers are testing RNA-targeting medicines, oral pills, gene therapies, cell-based approaches and treatments designed to support brain cell health. Some programmes are showing encouraging early signs. Others have delivered disappointing results or raised important safety questions. Both are part of making progress.

We still don’t have definitive evidence that any of these experimental treatments can slow HD progression in a large group of people in the long term, and promising biomarkerbiomarker a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable. changes don’t guarantee clinical benefit. But each carefully conducted trial helps answer questions about what works, what doesn’t, and what needs to change. With more approaches being tested, better tools to measure their effects and continued involvement from the HD community, there are reasons for renewed hope as we keep pushing forward.

Summary

• Brezosiran is heading towards a pivotal Phase 3 trial, while VO659, SKY-0515 and votoplam are testing different ways to lower harmful huntingtin.
• Tominersen lowered huntingtin and improved NfLNfL biomarker of brain health levels without showing clear clinical benefit, while encouraging results from AMT-130 still need further investigation.
• Young adults participating in HD-YAS are helping researchers detect subtle brain changes years before symptoms appear, potentially guiding earlier treatment.
• Improved trial designs, more sensitive measurements and smarter data analyses are helping researchers learn more from every clinical trialclinical trial Very carefully planned experiments designed to answer specific questions about how a drug affects human beings, whether results are positive or disappointing.