Huntington’s Disease Clinical Research Congress 2025 – Day 2

We’re back for Day 2 of Huntington’s Disease (HD) Clinical Research Congress in Nashville, Tennessee! Daniel Claassen from HSG and Cristina Sampaio from CHDI kick off the meeting with an overview of what we’ll hear about in HD clinical research and discovery. 

They are highlighting the search for biomarkers, the buzz over recent results from uniQure, as well as the collaboration between HSG and CHDI that launched this new Congress. 

Keynote: Progress in Clinical Developments

First up was a keynote from Dr. Merit Cudkowicz from Harvard/MGH addressing her work running “platform trials” in ALS, which compare multiple treatments to a common control group. Her talk focussed on what the HD field can learn from ALS researchers, and vice versa. 

The ALS community has many parallels to HD – research has progressed to a better understanding of the disease, with ongoing trials, an engaged community, and global trial networks. However, the ALS field has multiple disease modifying treatments, and 300+ companies in the space. ALS researchers are particularly committed to open collaboration, and Dr. Cudkowicz heads up NEALS (Northeast ALS Consortium), which holds trainings for clinical researchers and promotes big data projects. Many companies in the ALS space share their control data in a common database that can benefit future trials. 

She described another consortium, ALLALS, a multi-institutional effort to organize the ALS clinical research landscape, which advocates with regulatory agencies and organizes studies to understand the earliest stages of disease, track progression, and identify new biomarkers. Dr. Cudkowicz talked about the evolution of ALS research and the major clinical trials leading to successful drugs that can extend people’s lives. The accelerated approval of tofersen was based on changes in NfL levels, the same biomarker that is tracked in many HD trials. 

Many current efforts (at least 6 experimental medications) target a gene called SOD1, which produces a toxic protein that damages nerves in ALS. There are additional genetic approaches underway, targeting other genes known to play a role in ALS. Unlike Huntington’s disease, the majority of ALS cases don’t have a known genetic cause. A variety of companies are taking other approaches to ALS biology to try and target pathways affected over the course of the disease. 

NEALS collaborators came together to design a “platform trial” called HEALEY. This is an ongoing way to evaluate drugs for safety and efficacy, using a common control group, so that fewer participants in clinical trials are given a placebo. Dr. Cudkowcz noted that this required tremendous partnership among ALS community members, donors, pharmaceutical companies, researchers, and the FDA. The platform has already supported testing of 7 drugs, and 3 more trials will begin soon. 

The trial’s structure allows for a 3:1 ratio of drug to placebo, where study participants are randomly assigned to a specific drug, and all of the placebo data is combined across trials. After the study period, participants can enter an open label extension portion of the study, where everyone receives drug. These platform trials have many benefits – they can be completed faster, at a lower cost, and with fewer participants assigned to placebo. It’s also a unique way to understand aspects of ALS that are tested across all drug arms, from behaviors to biomarkers. 

Companies have to apply to enter their drug into this platform trial. The consortium chooses promising therapeutics with diverse mechanisms of action. Around 1400 ALS patients have participated so far. Importantly, the researchers frequently step back and evaluate how well this structure is working, so that they can learn from their efforts and adapt the protocol to strengthen the statistics, streamline operations, and center the participant experience. The placebo data is pooled into a big database, along with biosamples that are made available to academic researchers studying biomarkers and progression of ALS. 

The HEALEY trial has been ongoing for 5 years; the team has spoken to 114 companies about it, and about half have applied to participate. They also have weekly open Zoom calls, and many types of opportunities for academics and companies to get involved. 

A recent paper examines the financial landscape in ALS and a common Catch-22: it’s hard to get funding for a clinical trial without demonstrating robust human data. The platform trial model is just one way to tackle the problem of helping companies gain momentum with good data. The HEALEY platform is also helping to match individual participants to early phase trials based on the biology of the person and the mechanism of the drug. They’re also accelerating the screening process by partnering with a “rapid response” team called an ACE (accelerated center of enrollment). 

Dr. Cudkowcz wrapped up with big thanks to all of the stakeholders that make this collaboration possible, from the philanthropists, to the researchers, regulators, and trial participants. Working toward successful clinical trials takes a village. 

HD Clinical Trial Updates

The next session was all about HD clinical trial updates from different companies working in this space. We’ll be hearing from uniQure, Novartis, and Skyhawk – 3 companies with exciting updates over the past year. All of the updates come from companies who are developing huntingtin lowering therapies – different types of drugs which aim to reduce levels of the harmful huntingtin protein. 

uniQure

First up we heard from Dr. Victor Sung (UAB) who will cover the big news from uniQure about AMT-130, the gene therapy delivered by brain surgery that they are developing for HD. uniQure recently announced positive top-line results from its Phase I/II trial of AMT-130 which suggests this drug is able to slow down the progression of HD – you can read a detailed overview here. 

Victor started by reviewing the details of the trial – delivery in six locations via brain surgery, how a harmless virus helps AMT-130 enter brain cells, and the design of the trial, which involved a group that received “sham” surgeries and did not get the drug. Those who received the sham surgery made up the control group, and were only part of the trial for 1 year because some groups felt it was unethical to intentionally give placebo to some people knowing they would progressively have worsening HD symptoms.  

There are groups that received low and high doses of AMT-130. Instead of a traditional placebo group, the team used data from the Enroll-HD study from people observed in early stage HD. Enroll-HD is the largest observational study for people with HD, currently tracking over 22,000 people in 23 countries across 157 sites across the globe. It follows people with HD as they live and age so that researchers can learn more about the natural progression of the disease. These external comparisons use specialized statistical methods to remove bias and match people in and out of the clinical trial. It’s also important to note that all of uniQure’s analyses were pre-specified – decided upon before the drug was ever given. 

When trial results are presented the first thing that is always shown are the traits of the participants – things like their CAG lengths, health measures, and symptoms at the beginning of the study. On average the groups should “match” pretty well in these characteristics. Victor reiterated the main results of the trial – people who received a high dose of AMT-130 progressed slower on measures of function (Total Functional Capacity, or TFC) as well as individual and combined scores on tests of thinking and movement (cUHDRS). This was less robust for the low dose. 

NfL is a biomarker that tends to increase as HD progresses; those participants who got AMT-130 had lower levels of NfL three years after receiving the surgery – one indication that brain health might be moving in a healthier direction. Dr. Sung acknowledged the participants in this trial, who are continuing over the course of *years* to undergo lumbar punctures on a monthly basis to study safety and biomarkers of HD. There haven’t been any major safety issues reported since December of 2022. 

Although there are caveats, like a small number of participants in the high dose group, these are positive data. This is the first time any drug in more than 100 trials seems to have changed the course of HD. 

Novartis

Up next was Dr. Beth Borowsky from Novartis, sharing an update on their plan to move votoplam (formerly PTC-518) forward. This drug was originally developed by PTC Therapeutics. After successful clinical trial results, Novartis licensed the drug to advance it to a Phase 3 trial and, hopefully, regulatory approval, which Novartis will be responsible for. 

Beth shared updates from the Phase 2 PIVOT-HD clinical trial of votoplam, an oral huntingtin-lowering drug taken as a pill. This trial tested low and high doses of the drug, compared to a placebo group. The overall results showed that votoplam lowered huntingtin, and decreased NfL levels, suggesting the drug could be helping signs and symptoms of HD. 

The side effects, or “treatment emergent adverse events” (TEAEs), were pretty balanced across groups, but nothing notable came up – though, as expected, folks starting the study later in the course of HD seemed to have more falls during the course of the study. 

This study was not designed to look at votoplam’s effect on symptoms, but nevertheless there were positive trends in the cUHDRS (a score that takes many movement and thinking tests into account). Like uniQure, Novartis/PTC looked at Enroll-HD data as an external control, and saw similar trends. 

One observation they made when looking at MRI data is that there were changes in the volume of the brain’s ventricles (fluid-filled spaces) and tissue in the striatum, the area most affected by HD. This is hard to interpret but Novartis suggests that this could be because of a change in how CSF flows throughout the nervous system. 

Just a reminder that this data is not new, and that moving forward Novartis is planning a Phase 3 trial that will test votoplam in a larger group of people with early HD. If positive results hold, they hope the drug could help people across a range of HD stages. 

Roche

Now we heard from Peter McColgan from Roche about their HD drug candidate called tominersen. Tominersen is another type of huntingtin lowering drug, but this time given by spinal injection. We heard earlier this year about Roche’s plans with tominersen in the clinic, specifically their choice to only continue with the higher dose of the drug.

Dr. McColgan reviewed the history of tominersen’s development at Roche, from the GENERATION-HD1 study that came to an end, to the ongoing GENERATION HD2 study being conducted in people with early HD. GENERATION-HD2 recruited 301 people with early HD, who received either a low dose of tominersen, a high dose, or a placebo. In April 2025, an independent data monitoring committee (IDMC) recommended that the study move forward with just the high dose. 

Dr. McColgan then talked about other huntingtin-lowering approaches in development at Roche, RG6662, a gene therapy originally developed by Spark Therapeutics that is delivered via brain surgery, and an ASO that lowers only expanded huntingtin, delivered via spinal injection. 

Selective lowering of mutant huntingtin requires detection of a tiny genetic difference between the healthy and expanded copies of the gene, known as a SNP (“snip”). SNPs are single genetic letter changes within genes that help make us all unique, but can also be targeted for these types of approaches. Roche’s new ASO targets a particular SNP, and they are trying to understand how common it is in the general population. 

Dr. McColgan is also reviewing Roche’s larger efforts in data sharing and digital data collection, done in partnership with families, other companies, nonprofits, and government entities. 

Skyhawk 

Next was Dr. Meghan Miller from Skyhawk Therapeutics, who are developing a molecule called SKY-0515, an oral huntingtin lowering drug. In addition to huntingtin, SKY-0515 may also reduce levels of PMS-1, a genetic modifier of HD that plays a role in the expansion of CAG repeats (somatic instability). While this would be an amazing “two for one” type of approach, we’ve not seen this data thus far. The drug works by sticking an extra piece of genetic material into the genetic message that makes the huntingtin protein – the insertion makes the resulting letter code look like nonsense, so the cell won’t turn it into protein. 

The first clinical study of SKY-0515 explored three doses of the drug in healthy volunteers, people who did not have HD. This allowed Skyhawk to look at the safety of the drug and the biology of its interaction with the human body. They saw no serious side effects, and the drug circulated through the body and was found at higher levels when higher doses were given. This “pharmacokinetic” or PK data is important for showing how the drug works in people. SKY-0515 also lowered levels of (healthy) huntingtin, and lowering was stronger with more drug. This is known as pharmacodynamic or PD data, showing that the drug is hitting the right target and having the expected action. 

In a third, “Part C” of the Phase 1 study, SKY-0515 is being tested in HD patients, first for 3 months at 2 doses, then participants have the opportunity to enter an open label extension for a year where everyone gets the drug. They are looking at safety, PD/PK, and some tests of symptoms. Similar to healthy individuals, people with HD had higher concentrations of the drug in their blood and spinal fluid at higher doses, and lower levels of huntingtin when treated with SKY-0515, also depending on dose. 

Dr. Miller is showing a decrease in levels of PMS1 as well, especially in the high dose group. This is our first look at this data! While the high dose reduces HTT by 62%, it also reduces PMS-1 by 26%. However we still don’t know if this is significant enough to change somatic expansion. There also does not seem to be an increase in the level of NfL after treatment, like we’ve seen with some other HTT lowering drugs. This is a good sign for safety and brain health. 

Skyhawk began a larger, Phase2/3 study called FALCON-HD, at 10 sites across Australia and New Zealand, and they hope to recruit about 120 participants to continue testing SKY-0515 at different doses for up to 1 year. Plans are underway to expand into other countries.  

Progress in Biomarker Research

The next session focussed on biomarkers for HD. Measureable shifts in huntingtin levels, NfL, and imaging, among other measurements, allow us to track disease and see how well therapies might be working. Emilia Gatto from INEBA kicked us off with an introduction to the progress being made in this field and reminding us how biomarkers are reshaping HD research. 

The first talk in this session was from Hilary Wilkinson at CHDI who is diving into a new biomarker lots of researchers are trying to establish – how might we measure somatic instability, the changes in CAG number over time, and the challenges of tracking this possible driver of HD. Hilary began by sharing the historical timeline of biomarker development for a completely different area of health research – heart disease – and how measurement of cholesterol as a biomarker became a main indicator of heart health. 

Similarly, Hilary proposed that measurement of CAG repeat instability could be a good biomarker because it is central to how HD begins and progresses, and is linked to other measures of health in people with HD. CAG repeat instability is a complex target, because the number of CAGs may change in individual brain cells, but this is much more subtle in blood. CHDI is working on measuring CAG repeat length using different technologies that produce different types of data. 

There are several technological and biological considerations when trying to measure CAG repeat instability, such as the precision and integrity of the assay, the location of the cells, and the amount of tissue used, among many other factors. The ability to quantitatively measure somatic instability will be essential as more researchers begin to develop therapeutics to stop the expansion of CAG repeats. Hilary notes that the nature of the drugs and the instability rates in different tissues will ultimately drive the development of these technologies. 

Next up is David Hawellek from Roche who discussed the use of huntingtin and NfL as biomarkers to influence decision-making in clinical trials. The audience loved his visual to explain how he used to think about academia as a magical world, versus his stark idea of industry, and how that thinking has evolved to one of partnership through innovation and exploration….

He details the journey of how the HD field was able to develop ways to detect huntingtin protein in the spinal fluid, a convergence of many ideas and resources between academic and industry researchers over the course of a decade, to where we now have accurate tests to measure expanded huntingtin protein.  

Assays to detect mHTT are complex and a lot of factors can influence how much huntingtin is detected in spinal fluid, including the size of the protein piece and how much the protein sticks to itself. Dr. Hawellek talked about different quantitative ways to measure mHTT, like through RNA tests, as well as sequencing assays that help determine whether a person has a particular genetic letter difference (a SNP) that might make them eligible to try an experimental therapy. 

In 2026-2027, Roche will be rolling out an assay called Elecsys for the measurement of NfL, a collaboration with CHDI. The HARMONISE: HD-NfL study led by Dr. Lauren Byrne will look at data from many studies of NfL to create a robust dataset that will help shape NfL as a biomarker. He cautioned that NfL levels are heavily influenced by a variety of health factors which should be taken into account during clinical trials, and acknowledges all of the industry, academic, and family members of the HD community who contribute to research on biomarkers. 

Our penultimate speaker in this session was Killian Hett from Vanderbilt. Killian’s research explores brain imaging as well as biomarkers in the spinal fluid and what they might reveal about HD progression. Dr. Hett uses MRI data to create beautiful visual maps of CSF flow. The way that fluid moves around the nervous system can have a profound influence on drug delivery. It is influenced by both the cardiac (heart) and respiratory (breathing) systems. Dr. Hett completed a large study of 145 participants who had scans in a specialized 3 Tesla MRI machine. They are studying the role of the choroid plexus, which regulates the contents and the circulation of CSF. 

His team uses mathematical modeling methods to detect the choroid plexus and other brain areas in MRI images, reconstruct it visually, and then draw conclusions about how it changes during aging and disease. They are also able to measure how quickly the CSF flows around the brain and spine, its maximum speed and volume, and again how this changes with aging and disease. In HD, there is a decrease in the volume of fluid, but increased speed. These findings will be important to consider for any research team that is aiming to deliver a treatment for HD into the spinal fluid. 

To wrap up this session, we heard from Jamie Adams from the University of Rochester and her research into digital measures in HD, highlighting how these tools can support better trial design, monitoring, and care. 

Dr. Adams started with some art and some history, showing an early stethoscope, simply a rolled tube of paper used to amplify the sounds of the heart through the chest, and a painting of an early knee surgery, in which the doctors notably have poor lighting and no protective or sanitary equipment. She used this as an example of how we have evolved to incorporate new tools and technologies into medicine throughout history. Digital health measures are now allowing us to monitor people with HD continuously and with less bias, in their day to day life. 

Digital health technology (DHTs) is any system that uses computing platforms, connectivity, and software to record and transmit large amounts of data about a person’s health. Wearable DHTs like smartwatches have been used in HD to understand how much movement people with HD have at home, what stage of disease they are at, and other aspects of their movement and behavior outside of a doctor’s office. 

In the Parkinson’s field, and also in HD studies of drugs to treat chorea, DHTs have been used to show that a medication effectively treats a person’s movement symptoms. They’ve even revealed insights about sleep and people’s patterns of movements around their own homes. 

There are different approaches to gathering this type of digital data. Some of it can be supervised, with a person coming to clinic. Semi-supervised approaches use tasks on tablets or smartphones for frequent collection at home, and passive data collects information continuously, like a smartwatch worn by a participant. 

Jamie Adams and Lori Quinn (Columbia) are co-leading the MEND-HD study, which will validate at-home measurements of gait and chorea, daily physical activity, and sleep quality using wrist and back sensors worn by participants at home. It’s fully remote – no clinic visits are necessary at all! 

Dr. Adams is also working with a company called Biosensics to test a remote monitoring solution called HDWear+ to monitor other aspects of gait and chorea in HD. They are also working on measuring HD speech using audio devices. 

Through these studies they hope to provide a roadmap for how to use these types of devices as meaningful endpoints in future clinical trials, and how to reduce burden for participants with HD. 

Clinical Research Insights

The final session of today was clinical research insights which will dive into the challenges and opportunities in trial design, clinical measures, and the HD-ISS staging system. 

First up is Jeff Long from the University of Iowa. He has been investigating the relationship between antidopaminergic drug (ADMs) use and outcomes in HD. ADMs are a cornerstone of treating HD symptoms including unwanted movements, depression, and psychosis. They are critical for many people with HD who may be in danger of harming themselves or others. 

Jeff is a statistician and is digging into big datasets to understand whether ADMs cause faster change in clinical signs and symptoms of HD. For this question, he used the Enroll-HD database, looking at movement, thinking, and functioning metrics over 2 years. While this isn’t a drug trial, he can carefully select the data from people on and off ADMs, before and after they began taking these medications, to try to “simulate” a trial from human data after it has been collected. Then they use mathematical methods and AI to approach the statistics. 

After geeking out over the statistical methods he used, Jeff shared data suggesting that various thinking measurements worsen slightly when people take ADMs, but this doesn’t seem to be the case with movement-related symptoms. When he looked only at people taking antipsychotic medications, he saw similar results – people taking these drugs seemed to have worse cognitive symptoms, but overall movement symptoms don’t seem to be affected. Jeff also looked at different doses of these medications. Only people taking a high dose of ADMs had worsening of cognitive symptoms. 

He then showed data from a similar analysis he did using some of the data from Prilenia’s PROOF-HD trial, suggesting ADMs were associated with faster clinical change. This work was supported in part by Prilenia. There’s evidence that Prilenia’s drug pridopidine may have greater benefit in people who are not taking ADMs. It’s important to remember that ADMs remain a critical medication in our tool kit against HD, which Jeff himself notes.

Jeff makes a note of saying that he “can’t infer causation here” and we would really need a controlled clinical trial to understand if ADMs accelerate HD progression. So while there seems to be an association between ADM use and worsening of some HD symptoms, the results aren’t conclusive.  

During the Q&A, there was a comment around Jeff’s data suggesting ADMs increase disease severity – people who take these medications do so because they have cognitive issues, so it can be misleading to say that the medication could be causing cognitive issues. 

With a very tuned-in patient population, like we have in the HD community, the message that ADMs could make people worse can be particularly harmful.   

Our final talk for today is from Stan Lazic who is based at Prioris.ai. He has been investigating how some of the psychological symptoms of HD might contribute to HD-ISS staging, and what this means for research and care. HD-ISS stands for the Huntington’s disease integrated staging system – a unified way to track people in their journey with HD. 
To answer this question, Stan used data from the SHIELD-HD trial, originally started by Triplet Therapeutics and taken over by CHDI. While participation in these observational trials can be tedious for HD families, the data gets put to very good use by many researchers! 

Stan is also a statistician and went into detail about some of the specific patterns he pulled out from the data around the disease stages participants were in. He thinks these unique patterns may be related to symptoms of depression and anxiety. He also asked this same question for people who participated in the TRACK-HD and Enroll-HD studies, which increased the number of people he was able to analyze. 

Essentially participants in Enroll and other observational studies with a disorder related to anxiety and depression, and some other factors like arthritis and addiction, were more likely to “skip” an ISS stage of HD – in short, their disease course is less predictable. This information is important as existing scales evolve and improve, so that researchers can take into account many facets of HD to better define its progression. 

More updates to come

That concludes the talks for Day 2! Tonight we’ll be attending a poster session showcasing HD research from all over the globe. Join us tomorrow for Day 3, featuring translational science, hot topics, and issues relevant to HD youth.