Research news

The Huntington’s disease (HD) community received the news on November 20, 2024 that Sage Therapeutics would be halting the development of their drug dalzanemdor (previously SAGE-718) for HD. Sage had hoped that dalzenemdor would work to improve thinking problems experienced by people with HD and had recent setbacks with the same drug for other diseases. There’s no other way to say it: this is disappointing news and many people will feel disheartened today. Let’s break down what we learned from Sage in their recent press release and what this means for the HD community.

Thinking and memory in Huntington’s

HD is classically thought of as a movement disorder and onset is still often clinically defined as when these motor symptoms begin. However, HD causes many other effects, such as changes in cognition (thinking, learning, and memory).

Newer types of tests can measure cognitive changes in people with HD. The Huntington’s disease cognitive assessment battery (HD-CAB) was developed about a decade ago specifically to look at changes in thinking, learning, and memory in people with HD. This is a set of tests that measures things like problem solving, matching, language, and other aspects of thought and executive function.

These new tests show that the cognitive changes that happen over time as HD progresses can be measured. With that, it has allowed drug developers to target thinking, learning, and memory, with the hopes of developing drugs to improve these cognitive symptoms. Medications targeted at cognitive changes could have a massive benefit for people with HD, such as helping them to maintain work performance and keep their jobs longer, which could expand working years for some people to defray the financial burden of HD.

Turning up the volume on thinking

Sage Therapeutics has focused on developing drugs to help treat cognition. Not just for HD, but for other diseases, like Parkinson’s and Alzheimer’s, where cognitive changes also occur.

Their drug dalzanemdor works by amplifying molecular messages in the brain. These molecular messages help brain cells communicate and work to try and improve cognitive function. In diseases like HD, these molecular messages are lower. The hope is that by turning up the volume on these molecular messages, thinking, learning, and memory will improve

Dalzanemdor trials

Sage began running several trials to test the ability of dalzanemdor to improve cognitive impairment for various diseases, including Parkison’s, Alzheimer’s, and HD.

Unfortunately, they announced in April of 2024 that, while dalzanemdor was generally safe and well tolerated, the trial did not meet the clinical endpoints for Parkinson’s disease. The trial showed that people taking dalzanemdor did not have meaningful differences in thinking tests compared to those on a sugar pill. Then in October of 2024 there was a similar announcement for their trial testing dalzanemdor for Alzheimer’s disease.

The Phase 2 DIMENSION study in HD was the last major trial to see if dalzanemdor could improve problems with thinking, learning, and memory for people who had a disease that causes cognitive problems. Unfortunately, we learned today, that the outcome for dalzanemdor for HD was similar to the previous trials

DIMENSION

The DIMENSION study was a 12-week clinical trial testing the effects of dalzanemdor on cognitive function in people with HD. There were 189 people that were randomly assigned to either take the drug or a sugar pill. Overall, dalzanemdor was generally safe and well tolerated.

In the study, cognitive function was measured with various tests, like the Symbol Digit Modality Test (SDMT). In this test, people are essentially asked to break a code - numbers are assigned to abstract symbols and people are asked to read out the numerical code associated with a string of symbols. This test measures various components of cognition, such as attention, visual processing, working memory, and thinking speed.

Unfortunately, those taking dalzanemdor didn’t show any cognitive improvements when compared to the group taking the sugar pill. Overall, DIMENSION failed to meet the clinical endpoints of the trial. Because of this, Sage has decided to halt the trial and future development of dalzanemdor. This includes halting the PURVIEW Study, which was an open label extension of their previous SURVEYOR Study, a small 28-day trial testing dalzanemdor in HD.

No trial is a failure

Trials may fail to meet their clinical endpoints, but no trial is a failure. There’s always something to be learned. From dalzanemdor, there are three main takeaways:

Firstly, the HD community is eager to have drugs that could improve cognitive changes. A recent meeting with the US Food and Drug Administration (FDA) hosted by the Huntington’s Disease Society of America (HDSA) made that clear. This all-day event gave HD families a platform to share the effects and daily impacts of HD with the US regulatory agency responsible for approving HD drugs. What was clear from this meeting is that HD families want drugs to help with cognitive symptoms caused by HD.

Secondly, trials like DIMENSION collect a huge amount of data from a large number of people. These rich datasets and the findings of the trial can help researchers better understand different aspects of HD. Specifically, this kind of data can help to better pinpoint how HD changes cognition over time, and give insights into how drugs might be better designed in the future.

Thirdly, we now know that running clinical trials that test the ability of drugs to change cognitive symptoms is possible. The advent of tests like the HD-CAB and SDMT, along with their use in clinical trials like DIMENSION, show that we can objectively measure these changes in people with HD. Now it’s up to the drug developers to use this information and continue to advance drugs for cognitive changes in HD.

Dusting ourselves off

Sometimes bad news is just that, bad. There’s no doubt that this news will come as a massive disappointment to many people in the trial that felt they were gaining something from dalzanemdor. It’s ok to be upset about this, but try to not let yourself get stuck there.

There’s a lot of good that’s going on right now in HD research. There are over 60 companies working in the HD space right now. There are 13 clinical studies currently recruiting for HD and many more are being planned. We heard very positive clinical trial updates from four companies just this year for potential disease-modifying drugs.

We are living in the age of clinical trials for HD! It would be fantastic if every single one of these companies knocked it out of the park every time. Unfortunately, that wouldn’t be realistic. It’s of course disappointing when a trial is halted, but the fact that there are dozens of other companies looking to start new trials should be encouraging.

It’s not about how many times you get knocked down, it’s about how many times you stand back up. So while today may have knocked us down, tomorrow we’ll dust ourselves off, and stand back up.

A recent study published in Nature Medicine, looked at how common certain genetic diseases are within the population. The diseases they looked at are referred to as repeat expansion diseases and include Huntington’s disease (HD). The researchers found that the genetic traits which underlie these diseases are more common than previously calculated. In this article, we will get into what the scientists found, and what this will mean for the HD community and beyond.

What are REDs?

HD is caused by an expansion of a repeating stretch of -C-A-G- DNA letters in the huntingtin gene. Everyone has these repeating CAGs but if you have too many, then you will develop HD if you live long enough.

HD is not the only kind of disease caused by this type of genetic change. In fact, there is a whole family of genetic disorders referred to as Repeat Expansion Disorders, or REDs. These include diseases like spinocerebellar ataxias, some forms of ALS/Lou Gerhig’s disease, Fragile X disease, Friedreich's ataxia, Myotonic Dystrophy, spinal bulbar muscular atrophy, and others.

Calculating how many people are affected by REDs

A long-standing issue in human genetics and the study of diseases like HD, is that most of our human data is limited to DNA samples from White populations in the west. This can lead to an inaccurate idea of how many people are affected by HD and can have real-world implications for how non-White people with HD can access healthcare and other resources.

We also only tend to genetically test folks who are symptomatic already or who we know to be at risk. This means if someone doesn’t have a textbook series of symptoms, they might not have a genetic test and it’s possible that their doctor might misdiagnose them.

These incidence numbers are also important when HD advocates and patient organisations appeal to governments worldwide to provide support for research and care for HD. Collectively, REDs tend to be referred to as rare, but with the limited data we have had to date, do we know this to be true?

Big data to answer big questions

A large group of researchers, anchored in University College London (UCL) in the UK, with Dr. Arianna Tucci, looked at a massive dataset of the entire genetic makeup of people to see how common REDs really are. This study used DNA from over 82,000 people randomly sampled from diverse populations worldwide. In these samples, a person's entire DNA was sequenced, not just one or two genes.

Armed with this huge set of genetic data, they asked a series of simple questions: looking across many regions and ethnicities without any bias for any disease, do we continue to see these REDs are mostly in White populations? Are these diseases that mostly affect Europeans and people of European ancestry?

The answers from this study were profound in two aspects. First, REDs were seen in similar incidence across Europeans, Africans, Americans, East and South Asians. This challenges the status quo that REDs are primarily found in European populations, an assertion based on more limited historical datasets. In fact, they are represented in all broad populations.

The second surprise from this data was that the incidence of REDs was much higher than predicted in the past! The data show new incidence numbers of 1 in 283 for all REDs combined. From a different perspective, this means over 1.2 million people's DNA contain the genetic traits corresponding to REDs just in the USA. For HD alone, the incidence was seen at 1 in 4100, but with a variance from 1 in 2700 to 1 in 6300. Older statistics had this number around 1 in 10,000.

This finding tallies with some of the research talks we covered from the CHDI therapeutics meeting earlier this year. Sahar Gelfman from the Regeneron Genetics Center presented data from a study where they had looked at the HD gene from nearly a million peoples DNA. Although their samples did not include many people from outside Europe and North America, they did see that the genetic trait for HD was found in ~1 in 2000 people.

Comparing genetic data to what is happening in the clinic

But does this mean that 1 in 283 people have these genetic diseases? Maybe not. The frequency of these genetic expansions does not match up with the number of people diagnosed by doctors to have REDs.

There could be two reasons for this. Firstly, many people may not yet have been properly diagnosed with a RED, or may be misdiagnosed with a different disease. Given how rare some of these diseases are thought to be, some non-specialist clinicians may have a hard time pin-pointing a diagnosis, especially if the presentation of symptoms is a little bit unusual or does not follow the textbook definition.

A second and more hopeful reason is that despite having a repeat expansion mutation in a known disease gene, some people will have very mild, limited, or no symptoms of these diseases. This is referred to in human genetics as reduced penetrance. This could be because of lifestyle factors or other genetic differences between people which can cause the disease onset to be delayed or progression of symptoms to be slowed down.

This has been an intense area of focus in HD research with Genome Wide Association Studies (GWAS). The hope is that we could design drugs to mimic the genetic traits which might cause someone to have disease later in life or a slower progression of symptoms. Now that we know even more people might have the HD gene but might not get sick as quickly, or at all, scientists could expand GWAS to include these folks, and maybe find new ideas for developing medicines.

Take home messages

From this study, the message to doctors worldwide is that REDs are a lot more common than they were taught in their training in the past. This will hopefully empower them to test for these disorders with specific genetic tests when symptoms overlap with more common diseases.

Often, diagnosing someone with a neurological disorder can be like solving a mystery, as symptoms can look and change differently in different people, symptoms between common and less common diseases can overlap, and family history is often not known. This may lead a doctor to test for certain common diseases, but not recognize a less common disease because they don't experience it often in their careers.

The study also gives us an idea of what the HD mutations look like in different ethnicities – this is important information to potentially tune therapeutics designed to specifically lower the expanded copy of huntingtin so that they’re more effective in a broader range of people worldwide.

For example, the huntingtin lowering drug WVE003 from Wave Life Sciences currently in clinical trials, targets a genetic signature in the HD gene so that only the expanded toxic form of the HD protein is lowered. Current data suggests that the genetic signature they are targeting is found more commonly in people of European ancestry. Greater knowledge of the type of signatures found in different populations would help companies like Wave design drugs which might treat a more diverse pool of patients.

Importantly, this work will also be a message to governments and health agencies to rethink the term "rare" when it comes to these genetic diseases. Greater awareness of these diseases by policy makers and other stakeholders could help give communities, like ours, more resources and support to help affected families, provide appropriate healthcare, and develop new medicines.

We’re back for the 3rd and final day of the Huntington Study Group (HSG) Conference. You can also read updates from day1 and day 2. They saved the best for last - family day! Follow along for our last day of HSG!

Demystifying research

Family Day is opening with a talk from Dr. Martha Nance, a neurologist from the University of Minnesota. This “Demystifying Research” session will walk through the basics of research studies, participation, and how science leads to treatments. She reminds us of the benefits and challenges of working on HD research. For example, it’s caused by a single gene and has a wonderful, engaged participant community, but it’s rare, complex, and affects the brain.

Now Martha is revisiting the basics of genetics, how our genes are composed of a letter code that we represent with the letters A, C, T, and G. HD is caused by a change to a single gene called huntingtin, abbreviated HTT.

Within the huntingtin gene, everyone has repeats of the letters CAG - most people have between 10 and 26. Those with 40 or more will go on to develop HD. 36-39 repeats may or may not lead to HD symptoms in someone’s lifetime. CAGs of 27-35 can sometimes lead to longer repeats in the next generation - so the parent might not have HD, but their children could inherit more repeats and develop symptoms. It’s important to note that none of these ranges are absolutes; other genes and environmental factors can affect HD and its onset.

Martha reminds us that genes (DNA) can be made into genetic copies (RNA) which are used to make the cell’s building blocks (proteins). She also lists the different types of research approaches that can be productive for learning more about a disease and developing treatments.

Observational studies and surveys help researchers understand how genetics, biology, and symptoms connect, or how symptoms affect people’s lives. Examples are MyHDStory, JOIN-HD, CHANGE-HD, and ENROLL-HD.

Other studies focus on the biology of HD to study the “downstream effects” - what happens to brain cells because of a genetic change, like inflammation, damage, and dysfunction, and how to help clean up any cellular “trash”, like unused protein fragments or toxic proteins.

Martha talks about some of the approaches to treating HD, like targeting the underlying CAG repeats, addressing dysfunction in cells, lowering huntingtin, and focusing on symptoms to improve quality of life.

She discusses some of the nuances of huntingtin lowering and the many approaches being explored. Designing drugs to “stick” to the RNA message, focusing on one or both copies of huntingtin, how to deliver these potential treatments - there are many ways to address these challenges with novel science.

She also lists the different drugs already available for helping with HD symptoms, and mentions new ideas that have gone from basic research to drug development, like trying to slow down the gradual expansion of CAG repeats that can happen in brain cells over time (somatic instability).

Martha is now talking about how we measure the progression of HD and determine eligibility for trials. One example is a CAP score, a formula that takes into account CAG repeat size and age to determine an “expected” age of onset. This of course varies by individual.

She also touches on historical and current ways to separate HD into “stages.” For research purposes, today’s scientific and clinical community uses the HD-ISS.

Bridging research to treatment

The next session is a panel discussion and Q&A on clinical research participation, involving patients, researchers, doctors, and other community members who are here to speak about their experiences and answer questions about the path from research to treatment.

Topics that came up included perseverance despite setbacks, learning from clinical trials that didn’t end as expected, frustration with eligibility criteria, and contributing to research through participation in observational studies.

All of the panelists encouraged the audience to get involved with research and with their local communities in any way that they can, whether that’s a study of a medication, an observational trial, or simply connecting with others in the community to spread awareness and receive support.

HD biology and basics

The afternoon session begins with Dr. Victor Sung, a neurologist (and community advocate) at the University of Alabama who focuses on HD. He’s speaking about HSG’s work in the HD space from research basics to the clinic.

He’s got a great analogy for thinking about DNA repair and lengthening of CAG repeats - the two strands of DNA act like a stuck zipper that gets off track, mismatching with the opposite side. The attempt to fix the lopsided zipper adds even more CAGs by accident.

We’ve heard a lot about the biomarker NfL, which is released from damaged brain cells and goes up over the course of HD. Victor likens the release of NfL to a tornado, where things get flung around - the more damage, the bigger the tornado.

He also revisits the HD-ISS staging system and how it is helping to design trials to slow down the progression of HD. Having a way to better define the pre-symptomatic and very early stages of HD will be an asset when deciding when to treat.

He notes that the field has evolved from vitamins (and even blueberries!) as experimental treatments, to a wide variety of genetic and biology-based approaches in just a decade. The field welcomes researchers to “throw their hats in the ring” and attack the challenge of HD from all angles.

Victor also reminds us that 2024 is the first time we’ve had four positive press releases so close together about milestones in huntingtin-lowering drug development (from Wave, uniQure, PTC Therapeutics, and Skyhawk).

Launching hope from the lab to the clinic

Our next speaker is HDBuzz’s own Dr. Sarah Hernandez! Her talk is about hope in research, from the clinic, to experiments, to ideas. She’s first sharing her own family’s HD story and how far we’ve come from before the discovery of the HD gene to today.

Sarah’s family background and discovering the story of Nancy Wexler’s Gene Hunters led her to pursue a PhD and to study HD. She now heads up “all things science-y” at the Hereditary Disease Foundation, an HD research-focused nonprofit started by Nancy Wexler.

She revisits the rapid-fire good news from the summer of 2024, which HDBuzz covered following press releases from Wave, uniQure, PTC Therapeutics, and Skyhawk. Sarah encourages a bird’s-eye view of this positive news, which together is starting to show that HTT-lowering could become a successful treatment approach. She reminds us that there are even more HTT lowering strategies in the works, from companies like Latus Bio, Incisive Genetics, Atalanta Therapeutics, and Alnylum Pharmaceuticals.

She also mentions approaches to stopping the expansion of CAG repeats, from companies like Rgenta and LoQus23, or stem cell replacement therapies, in development by Neuexcell, Sana Biotechnology, and universities like UC Irvine and UC San Diego. Sarah also finds hope in basic research, like new tools to zoom in on single brain cells, and efforts to improve delivery of drugs to the brain through the nose, or using ultrasound!

Sarah shouts out the many HD organizations dedicated to care, support, research, and education in the US, like HDF, HDSA, HDBuzz, HDYO, HSG, HD-Reach, Help4HD, and more. She also reminds us that there is ongoing research into improving quality of life for people with HD, through studies on sleep, lifestyle choices, and equity in research and care. A hopeful talk indeed!

Igniting hope for HD

The next session is a panel discussion on hope, from HD community members on their personal stories about what inspires them to keep pushing for treatments and cures for HD.

Erin Patterson, author of Huntington’s Disease Heroes, shared her personal history with the disease, being gene positive as a caregiver for her father. She finds hope in the grace with which her father faces HD. She says even if there isn’t a treatment in time for her, she knows that she’ll be ok because of the way her dad approaches life.

Charles Sabine, OBE, founder of the HiddenNoMore Foundation, relays the hope that he helped foster when he orchestrated a meeting between Pope Francis and HD families. He made a movie about this encounter, called Dancing at the Vatican. Charles recently shared his story in a TED talk.

Dr. Karen Anderson shared that she gets hope from the HD families that come to community events like HSG. This wasn’t the case when she first got into the HD field! She’s worked with HSG on MyHDStory, which is an online research platform to connect people affected by HD, to better understand the needs of those living with HD, and break down barriers for clinical trial participation.

That’s all from us for HSG 2024! HDBuzz had a great time sending live updates to the community and we hope you enjoyed the coverage!