Scientists searching for new ways to stop Huntington’s disease (HD) have focused in on the repeating C-A-G letters of genetic code that cause the disease. That’s because the exact way these C-A-G letters repeat may have a big impact on when and whether someone develops HD. A group in Boston led by Dr. Jong-Min Lee recently applied a cutting-edge technology to try to change the letters of the C-A-G repeat in cells grown in a dish and mice that model HD. Were they successful? And what could this mean for future therapeutic approaches?
Three repeating letters – and an interruption to the repeat
The genetic code of every living organism is made up of 4 letters – C, A, G, and T. They’re combined in different ways to make every gene in our body, like letters on each page of a book. That’s a lot of diversity for just 4 letters!
HD is caused by a stretch of repeating C-A-G letters in the huntingtin gene – like three letters repeated on one specific page of the book. People who develop HD are born with 36 or more CAG repeats, one after the other at least 36 times, like this on the page: …CAG CAG CAG CAG CAG…
In most people, however, these repeating CAG letters actually have a slight imperfection near the end, which looks like this: …CAG CAG CAG CAA CAG. Notice those three CAA letters? Scientists call this the “CAG repeat interruption”, because it “interrupts” the repeating CAG letters. The CAG repeat interruption is found in the DNA of almost everyone, including people who have the gene that causes HD.
Two words, one meaning
Letters in the genetic code are grouped by threes to create “words” that code for building blocks to create proteins. C-A-G codes for a protein building block called “glutamine”. This is why you may have heard of the CAG repeats referred to as a “polyglutamine” stretch – there’s lots of glutamines in a row.
But C-A-G isn’t the only word that codes for glutamine. C-A-A does as well! This means when the CAG repeat is interrupted by CAA, it doesn’t change the protein word that’s spelled. It still codes for glutamine.
It’s noteworthy that if you get a genetic test for HD and you’re told that you have a certain number of repeats, like 42 for example, that number is the pure CAG repeats. They’re not including any CAG repeat interruptions you may have in your genetic code. There may be more glutamines present, but the CAG repeat stretch, uninterrupted, is 42.
More interruptions please
Not long ago, HD researchers discovered that some people with HD have no CAG repeat interruption – and some even have an extra interruption in the CAG repeat!
What is especially interesting about people without the CAG repeat interruption is that they develop HD much earlier than expected – about 12 years earlier. And people with an extra interruption appear to develop HD later – perhaps 5 year later. So there may be something special about those CAA letters that interrupt the repeated CAG letters. Losing the interruption in the middle of CAG letters might make HD symptoms appear earlier – and an extra interruption in the middle of CAG letters might make HD symptoms appear later.
Could adding extra CAG repeat interruptions into the DNA of people with HD help delay or slow symptoms? Changing the DNA of a person is no easy task, but a group of scientists led by Dr. Lee decided to try a cutting-edge approach to introduce more CAG repeat interruptions into cells grown in a dish and mice, as a proof-of-concept to seeing if it would be possible in people.
Changing bases
Dr. Lee’s group teamed up with Dr. Ben Kleinstiver, an expert in “base editing”, to try out their idea of adding more CAG repeat interruptions. What’s base editing? It’s basically a new technology that allows you to change a specific letter on a specific page of the book. It’s targeted to a specific letter like a homing missile. The technology is based on CRISPR discoveries that have been used to create medicines that recently received regulatory agency approval. Base editing is basically based on CRISPR. Ok, I’ll stop with the bad puns.
Base editing is hot-off-the-press technology, so scientists are still working out the kinks. They don’t really know which ingredients of base editing work best to change specific letters in DNA sequences. So Dr. Lee’s group tried a bunch of different combinations of ingredients to see what happened in cells in a dish that have a CAG repeat resembling the repeat in people who have the gene for HD.
In a few combinations of base editing ingredients, up to 50% of cells in a dish had CAA interruptions added to the CAG repeat sequence. That’s pretty amazing! Scientists can’t yet control exactly where these interruptions are added in the CAG repeat, but a few of the letter changes even looked like the extra interruption we see in people with delayed onset of HD symptoms.
Not quite ready for prime time
Getting all the ingredients to make base editing work into people is a big task, similar to the hurdles facing CRISPR therapeutics for HD. This is really hard if you’re trying to get all those ingredients into the brain, where people who have the gene for HD need them.
But scientists are a tenacious bunch of people and Dr. Lee’s group was not about to let the challenge stop them from trying. His group tried the best combinations of base editing ingredients in mice that have the CAG repeat from people that have the gene for HD, with some early indicators that the approach may be working to add interruptions.
We will no doubt hear more about this work in the future, and learn more about whether adding interruptions to the CAG repeat would be a new promising approach to slow HD. Stay tuned!
Since its inception in 2010, HDBuzz has existed with the financial support of non-profit organizations within the Huntington’s disease (HD) space. In our 14 years of service, we have never directly asked the HD community for donations. However, recently during a tenuous time in the existence of HDBuzz, we lost the support of one of our largest and longest standing backers. This seriously jeopardized the existence of HDBuzz. We want to ensure that this never happens again. So that HDBuzz will continue to exist and report science in plain language for the global HD community, we’re asking for your help.
Where does HDBuzz get funding?
To date, HDBuzz has been funded by a consortium of HD community organizations. Our founding partners are the Huntington’s Disease Association of England and Wales, the Huntington Society of Canada, and the Huntington’s Disease Society of America. The Griffin Foundation, a non-profit educational foundation, is a major funding partner. More recently, we’ve received vital financial and stewardship support from the Michael Berman Family Foundation and the Hereditary Disease Foundation (HDF). Currently, we are housed as a project within the HDF until we can get our footing.
These organizations have funded and supported HDBuzz as a service to the entire HD community, but have never received special access to its content, which is freely available to all. They have never had any editorial control over our content, nor have they ever asked for it.
Critically, HDBuzz has never accepted funding or support from drug companies. HDBuzz loves drug companies – we’re hoping they help us cure HD! But taking money from any organization dedicated to a particular therapy could give the impression of bias in our reporting, which we diligently aim to avoid.
Why is HDBuzz’s funding model changing?
In 2024, HDBuzz operations transferred from the UK to the US. This made sense considering the leadership of HDBuzz was no longer located in the UK, but rather in North America.
While this transition was happening, we lost financial sponsorship, stewardship, and support from one of our largest and longest standing donors within the HD nonprofit space. It became clear that solely relying on donations from other HD nonprofits was a finicky model with the potential to jeopardize the existence of HDBuzz.
We realized that we need to explore other models that are more sustainable and are a better reflection of the value that we bring to the HD community. This will allow us to maintain HDBuzz long into the future.
However, our mission remains the same – to report science in an unbiased, easy-to-understand way so that the HD community can better understand HD, research, and clinical trials. Particularly as we advance toward disease modifying drugs, we hope that our services will enable HD families to make educated decisions about their lives, treatment, and care.
Our ask
To build a long-lasting, sustainable model, we are now directly asking our readers to consider contributing to the mission of HDBuzz. With enough generosity, this will allow us to be completely independent from other organizations in the HD space.
Please consider making a donation if you value the services that HDBuzz provides. We want HDBuzz to be sustainable so that we can continue to report unbiased science to the HD community. With your support, we can ensure the continuity of our services. Nothing is expected, but everything is appreciated and sustains what we do at HDBuzz. Please consider giving what you’re able.
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In this article, we’re bringing you advice from the 2024 Lancet Commission on dementia prevention, intervention, and care – a group of experts who have combed through massive amounts of previous research collected over decades to highlight 14 risk factors associated with dementia. The good news? Those 14 factors are things that can be modified. So making lifestyle changes around the factors identified here can help improve brain health, and potentially keep people that have the gene for Huntington’s disease (HD) healthy for longer.
Dementia vs HD
While HD and dementia may have different root causes, underlying factors that are beneficial for one will be beneficial for the other. Dementia is a general term for a reduced cognitive ability – the ability to think, remember, and reason.
A reduction in cognition is only one component of HD, which is caused by an inherited expansion of the genetic code in the huntingtin (HTT) gene. HD also affects a person’s mood and has a movement component similar to Parkinson’s disease, called chorea.
While there are currently no disease-modifying treatments for HD, there are several very promising ongoing clinical trials, such as those by uniQure, Wave Life Sciences, PTC Therapeutics, and Skyhawk Therapeutics. These companies are directly targeting the cause of HD, aiming to lower the HTT message. There are also companies with ongoing trials for drugs that would treat the cognitive aspect of HD, like Sage Therapeutics.
But we want to make sure that folks with the gene for HD stay as healthy as possible until we do have a disease-modifying treatment for HD in hand. So what active changes can people make to ensure that happens?
14 factors that affect brain health
1. Less education
People who have more childhood education and those who go on to attain higher education have a reduced risk of developing dementia. This could be because these groups are more likely to obtain more cognitively stimulating jobs, challenging their brain more frequently. Less education is considered a risk factor from early life that if rectified, would reduce the cases of dementia by 5%.
2. Hearing loss
It seems like a strange correlation, but the Commission found an association between dementia and hearing loss. While this is a factor typically associated with older people, age wasn’t the variable contributing to the risk of dementia here since they accounted for age. The authors think there could be social factors at play, such as isolation due to the inability to hear in social situations, leading to low mood and motivation. They also floated the idea of biological factors, such as vascular disease that could affect both the cochlea of the ear and the brain. However, none of those theories relating hearing loss to dementia have been proven. Hearing loss is considered a midlife risk factor, and eliminating it, for example with hearing aids, would reduce the number of dementia cases by 7%.
3. High blood pressure
People with untreated high blood pressure, aka hypertension, have an increased risk of dementia. However, this risk is lost when hypertension is treated with medication. The study specifically notes that risk of dementia increases when systolic pressure (the top number) is over 130. So getting blood pressure in check by age 40 so that it’s closer to 120/80 is good for your brain. Hypertension is a midlife risk factor that accounts for a 2% increase in dementia cases.
4. Physical inactivity
Exercise is tricky to measure since it varies so much across a person’s life, between cultures and socioeconomic status, and occurs at different intensity levels. However, the study shows that physical activity, particularly sustained physical activity across a person’s life, is associated with better cognition by the age of 69. The thought behind why exercise is so good for us is that it improves blood flow and reduces blood pressure, which could improve brain plasticity and reduce brain swelling – certainly things that could be beneficial for HD! Eliminating this midlife risk factor by living more active lifestyles could reduce the number of dementia cases by 2%.
5. Diabetes
While there’s a correlation between diabetes and increased risk for dementia, this appears to only be the case for diabetes acquired in midlife, not later than age 70. No one is sure why there is a correlation between diabetes and dementia, but they think it may be because of the effect that diabetes has on blood vessels, which run throughout the brain. It could also be because the brain requires insulin for metabolism and insulin resistance can lead to brain swelling. Improving health to eliminate type 2 diabetes in midlife could reduce dementia cases by 2%.
6. Social isolation
Infrequent social contact shows an increased risk for dementia. Criteria that counted toward social isolation were living alone, visits with friends and family less than once per month, and lack of participation in weekly group activities. Studies have found that socialization can improve the brain’s resilience to damage, promote healthy behavior, lower stress, and reduce inflammation. Eliminating social isolation in later life could reduce the number of dementia cases by 5%.
7. Excessive alcohol consumption
The report finds that heavy drinking comes with an increased risk for developing dementia compared to light drinking. Interestingly, not drinking at all had a higher risk for dementia than light drinking. A reason to imbibe?! Probably not. The jury is still out on how sound those findings are since various factors could be at play here, like not drinking because of alcoholism or other non-related health issues. Reducing alcohol consumption by midlife could reduce dementia cases by 1%.
8. Air pollution
Air quality is determined by the amount and size of particles in the air. Fine particles equal to or smaller than 2.5 μm are notoriously dangerous. The report found that sustained breathing of particles that are equal to or smaller than 10 μm increases the risk of developing dementia. Since there is a strong link between air quality and socioeconomic circumstance, developing policies and regulations around clean air will be important for reducing this risk for people from various social and geographical backgrounds. Having access to healthy air to breath later in life accounts for a 3% reduction in dementia cases.
9. Smoking
We now have an overwhelming amount of data to show that smoking is unequivocally bad for your health, and that includes your brain. Smoking increases the risk of dementia, with a higher risk for those who start smoking earlier. The good news is that this risk is only associated with current smokers; there was no increased risk of dementia between ex-smokers and people who had never smoked. Quitting smoking habits by midlife can reduce the cases of dementia by 2%.
10. Obesity
While obesity is associated with increased risk for dementia, this is a tricky factor to measure. Obesity is associated with other factors on this list, such as physical inactivity, diabetes, and high blood pressure. So it’s hard to tease out which is the factor really associated with dementia risk. However, most studies adjust for these other factors and obesity is still associated with higher dementia risk. Even a modest weight loss of 5 pounds improved cognition, suggesting that keeping an eye on your weight is good for your brain. Maintaining a healthy weight by midlife would reduce dementia cases by 1%.
11. Traumatic brain injury
Perhaps unsurprisingly, a bad knock on your noodle is bad for your brain! The study found that people who got a traumatic brain injury at younger ages were more likely to develop dementia. Avoiding traumatic brain injuries by midlife could reduce the number of dementia cases by 3%.
12. Depression
The report noted that the correlation between depression and dementia was bidirectional – that depression could be both a cause and consequence of cognitive changes. Theories about how depression could affect cognition relate to less self care and social contact, as well as biological factors like increased levels of the stress hormone cortisol that could affect the brain. Encouragingly, seeking treatment, like therapy, for depression by midlife could reduce dementia cases by 3%.
13. Vision loss
Vision loss was a new factor added since the 2020 Commission report. Specifically, they found an increased risk for dementia related to untreated vision loss. For conditions like cataracts where people sought treatment, there was no increased risk. But for people who had cataracts or diabetic retinopathy and didn’t seek treatment, there was an increased chance they would develop dementia. The report specifically noted the correlation wasn’t seen for other eye conditions, like glaucoma or age-related macular degeneration. Getting a handle on preventable vision loss by late life could reduce dementia cases by 2%.
14. High cholesterol
High LDL cholesterol is also a new addition since the 2020 report. Since then, studies have been done to show that high cholesterol is indeed associated with an increased risk for dementia. Taking a lipid-lowering drug, like statins that are widely prescribed to lower cholesterol, was not associated with an increased dementia risk. So the correlation seems to be with untreated high cholesterol. High LDL cholesterol is a midlife risk factor that if eliminated could reduce dementia cases by 7%.
However, there doesn’t yet seem to be a conclusive link between sleep disturbances and an increased risk for dementia. So far, studies haven’t been able to tease out how the risk for developing dementia might be associated with various facets of sleep, like duration compared to quality of sleep.
Diet was also not included as a risk factor in the report. While diet heavily plays into several factors on the list, like obesity and diabetes, there isn’t yet enough evidence for specific diets like the Mediterranean diet. However there’s lots of evidence that reducing consumption of ultra processed foods is good for overall health, so opting for an apple over chips will always be a good decision!
Surprisingly, even genetics can be overcome
The more surprising findings from the report are that developing dementia can be modified even for people who are at an increased genetic risk. The paper states that, “for the first time, it is clear that risk can be modified even in people with increased genetic risk of dementia.” It’s likely that these findings can be applied to HD as well – even if someone has the gene for HD, modifiable lifestyle choices could delay onset, increase healthy years, and reduce disease burden.
Since the previous report in 2020, the field has seen a massive expansion in the use and utility of biomarkers – biological changes that track with a disease and can be used to measure progression. Shockingly, there are many older people who have biomarkers of dementia, like amyloid plaques within their brains, who never go on to develop dementia. These findings strongly suggest that brain changes associated with dementia don’t mean that the disease is inevitable, supporting the 14 modifiable factors highlighted here.
Unsurprisingly, being healthy is good for you
This report from the Lancet Commission on dementia can not only be used by individuals to improve their own brain health, but it’s also used to guide policy changes at the national and international governmental levels. This could take the form of prioritizing early education across socioeconomic backgrounds, destigmatizing and encouraging seeking help for mental health, and enacting helmet laws for contact sports and bicycles.
Overall, the report shows what people certainly already know – living a healthy lifestyle and being kind to yourself will give you more healthy years. Things that are good for your brain, like education and preventing brain injury, will keep your brain healthy. And things that are good for your heart, like exercise, not smoking, and less alcohol, are also good for your brain.
You may have also noticed that each of these factors is relatively small by comparison – a few percentage points here or there, with the highest being 7%. So even if someone can’t check off every factor on the list, their chances of developing dementia are still low. It’s when health issues compound that the risk for developing dementia really increases. The take home message here is take care of – and be kind to – yourself.
Today, on International Ataxia Awareness Day, we’re bringing awareness to a group of brain disorders known as Ataxia, which can take many forms. Like Huntington’s disease (HD), Ataxia is degenerative; it damages brain cells, causes changes in movement, and involves complex symptoms that worsen over time. HD and some forms of Ataxia have a shared genetic origin, and we’ll talk about medical and research overlap.
What is Ataxia?
Like HD, Ataxia is a rare form of neurological disease. It can lead to a variety of symptoms including lack of coordination, slurred speech, and difficulty walking – this can appear similar to the effects of alcohol. Ataxia is usually caused by damage to a part of the brain that coordinates movement, known as the cerebellum, which is located at the back of the head right above the neck.
The symptoms of ataxia can vary a lot by the person, and they can also vary by the type of Ataxia. Some forms are passed down from one parent, as with HD – just one copy of the faulty gene causes disease. This is known as autosomal dominant inheritance. Other forms of Ataxia are passed down only when a person inherits two copies of a faulty gene – the parents don’t have ataxia, but they are each a “carrier” of the gene. Ataxia can also be caused by a brain injury or infection (acquired), or have unknown causes (idiopathic/sporadic).
Why should the HD community be aware of Ataxia?
Ataxia can refer to a group of disorders, but it can also simply refer to uncoordinated movements. If you’ve ever had too much to drink, you’ve likely experienced alcoholic ataxia. And many people with HD experience ataxia at some point over the course of their disease. Ask many healthcare workers with HD expertise, and they’ll tell you that when you’ve seen one person with Huntington’s disease, you’ve seen one person with Huntington’s disease. We all know that HD is complex and that symptoms can vary from day to day, let alone between individuals. Symptoms of ataxia can affect people with HD, especially in later stages.
HD affects the part of the brain that is important for voluntary movements, and it is more likely to cause chorea, which can appear jerky and dance-like. Ataxia affects the part of the brain that coordinates movement, and it is more likely to cause movements that appear unstable or slow. Both diseases worsen over time and cause people to have difficulties with speech, walking, and day-to-day tasks. There are even case reports where a person with HD was misdiagnosed with ataxia because their early symptoms involved difficulties with balance and coordination.
The genetics of HD and Ataxia
The greatest area of overlap in HD and Ataxia research is within a group of Ataxias that is caused by the same genetic error. We know that HD is inherited dominantly (from one parent), and that it is always caused by the expansion of CAG repeats within a gene called huntingtin. Some ataxias are also inherited dominantly, including a group of disorders known as spinocerebellar ataxia (SCA), and several of these are also caused by the expansion of CAG repeats.
In HD, the extra CAGs are found within the huntingtin gene, whereas SCA is caused by CAG repeats within other genes. Some examples are ataxin-1, ataxin-3, and ataxin-7, but there are a whole family of genes with CAG repeat expansions that are known to cause rare Ataxias (among other diseases). We recently heard about research into SCA from Dr. Harry Orr at the Hereditary Disease Foundation conference, which we covered.
New genetic causes of Ataxia have been discovered very recently, including ones caused by triplet repeats. In fact, in 2024 a new 5-letter DNA repeat was revealed as the cause of many hereditary Ataxia cases. Like the discovery of the gene that causes HD in 1993, this is a huge step forward for folks who have this type of Ataxia! Bill Nye the Science Guy, a well-known science communicator (and source of inspiration to us at HDBuzz) has family members who have this form of Ataxia, known as SCA27B. He has partnered with the National Ataxia Foundation in the USA to create several videos about this condition.
Historical research overlap
Historically, genetic research in HD and Ataxia has followed a similar path. There were initial efforts in the 1980s and 1990s to narrow down the “neighborhood” followed by the exact location of the genes that led to disease. There followed the creation of animal models in the 1990s and 2000s allowing scientists to study the development, progression, and treatment of HD and hereditary Ataxias. These paths involved similar laboratory techniques that built upon one another across fields.
Importantly, research developments in the HD and Ataxia fields involved similar collaborative efforts between researchers and family members who agreed to donate their time, samples, and brain tissue for the benefit of future generations.
Research today
The shared nature of the CAG repeat in HD and several hereditary Ataxias means that researchers can continue to learn from one another, working together and in parallel, and employing a shared set of tools and ideas. Bi-annual international conferences continue to gather global scientists studying CAG repeat disorders, and many labs work on HD in addition to hereditary Ataxias like SCA. The phenomenon of CAG repeats getting longer in some cells (somatic expansion) holds true for these Ataxias in addition to HD, knowledge that can be leveraged towards treatments.
What’s more, we’re already reaping the benefits of shared insights in drug research. The development of ASOs for huntingtin-lowering has led to similar efforts in the Ataxia field, which also involves an extra-long, clumpy protein. Similarities between diseases in how CAGs repeat themselves has even led to the development of a drug by VICO Therapeutics that may be used to treat people with Huntington’s disease, SCA1, or SCA3. Stay tuned for a deeper dive into the recent positive momentum of that human trial, which involves participants with all three disorders.
The takeaway
Ataxia and HD share many similarities. It’s productive for researchers to gain insights from one another across disease fields, especially those with common genetic features. And it’s gratifying to know that other families challenged with an inherited disease have built their own supportive networks whose parallel efforts drive clinical research and advocacy.
HDBuzz is proud to acknowledge the Ataxia community on Ataxia Awareness Day. We’d also like to give a shout-out to Dr. Celeste Suart at the National Ataxia Foundation (NAF) for her input. The NAF hosts SCAsource, a site similar to HDBuzz which provides plain-language research news written by scientists. If you’re interested in learning more, SCAsource is a great place to start.
Disclaimer: I have written this piece from a position of privilege – as an HD family member that has been fortunate to receive an education that allows me to deeply understand the nuances of Huntington’s disease. I know what it means not only at the biological level, but also at the family level. I am profoundly aware of the desire for a disease-modifying drug. But my hopes are tempered through the privileged lens of understanding complex scientific data and interpretation. Here, I report facts and my opinion of those facts with no vested interest in any specific therapeutic approach. If Prilenia feels errors have been made, they are invited to reach out and any factual corrections will gladly be made.
Recently, there have been a few press releases from Prilenia Therapeutics about their advancement of the drug pridopidine toward regulatory approval for the treatment of Huntington’s disease (HD). There’s also been mixed messaging about findings from pridopidine clinical trials and statements made by the company. Let’s break down what the research really says and what the recent press releases mean in the bigger picture.
MermaiHD Trial
We’ve written about the long and storied path of pridopidine before. It’s been tested in a number of different clinical trials, by a few different companies. Over the years, the use of pridopidine has shifted. Once thought to have utility for helping to regulate movements associated with HD, it’s now being tested for potentially slowing the disease course.
In 2008, pridopidine (previously called Huntexil) was tested in a European Phase 2 trial called MermaiHD. Back then, the company running the trial, NeuroSearch, thought the drug could be used to help with changes in movement control caused by HD.
Specifically, they thought the drug could help people control their voluntary movements that get more stiff and rigid as HD progresses. While people on pridopidine had slight improvements in movement control, the effect wasn’t large enough to determine that it was caused by pridopidine, and the trial failed to meet its endpoints.
HART Trial
Around the same time, NeuroSearch also carried out the HART study in America. Again in this study, there wasn’t a conclusive improvement in voluntary movements associated with stiffness and rigidity.
After the HART study, they pooled that data with the MermaidHD study to find that with this combined dataset, there did seem to be an improvement on voluntary movements. However, both the US FDA and European EMA determined that a larger trial was needed to conclude what effect pridopidine was truly having on HD-associated movement changes.
PRIDE-HD Trial
After this, the rights and ownership for the drug changed hands. The new owners, Teva Pharmaceuticals, wanted to test if a higher dose of pridopidine was needed to see a positive effect on HD movements. Enter the 2013 trial called PRIDE-HD.
In PRIDE-HD, a key goal was to see if pridopidine could improve total motor score – a robust collection of tests that assign a numerical value to movement symptoms associated with HD. Unfortunately, again, pridopidine failed to meet its primary endpoint and did not show an improvement in total motor score.
Now, the idea was that pridopidine might not just control HD-associated movements, but might modify disease course. This would mean pridopidine isn’t just treating the symptoms of HD, but is treating the disease itself – a huge difference.
New goal for PRIDE-HD
With this new theory, the drug developers added a few new goals mid-way through the PRIDE-HD study. The primary endpoint of testing movement was the same, and wasn’t met, but they also added a second test – total functional capacity, or TFC.
TFC is measured through a collection of tests that determine how well someone functions day-to-day. Things like the ability to hold a job, manage finances, and perform domestic chores. These abilities decline as HD progresses.
So did pridopidine improve TFC in the PRIDE-HD study? Kind of. Out of the 4 doses tested, only the lowest dose showed improvement on the TFC scale. These results were inconsistent, TFC wasn’t a primary endpoint of the trial, and there wasn’t enough data to draw a firm conclusion – so for the drug to have a chance of getting licensed, yet another trial would be needed.
Big conclusions were drawn – too big
Despite these inconsistent findings, Teva interpreted the results from PRIDE-HD to mean that the drug was slowing the progression of HD. This was a big message for the data that was generated. Quite frankly, too big of a message. This conclusion cannot be substantiated with the results from this trial.
Why not? It’s important to understand that improving or stabilizing TFC does not necessarily mean that something has slowed HD progression. For example, successful treatment of depression in a person with HD could enable them to resume work, improving that person’s TFC by 1 or 2 points – but not because the underlying progression of the disease has been slowed.
To be clear, a drug that improves the ability of people with HD to function would be fantastic. And a drug that slows the progression of HD would be super fantastic! But there is a clear distinction between those two.
Improvements in function cannot directly be interpreted as slowing HD progression – that requires much more solid evidence, from direct measures like MRI scans or biomarkers that can tell us whether something has rescued brain cells, or from much longer-term improvements in symptoms.
PROOF-HD Trial
Following the results from PRIDE-HD, pridopidine changed hands again, this time to Prilenia Therapeutics. Another trial was begun to test the ability of pridopidine to modify disease course of HD. This new Phase 3 trial began in 2020 under the name PROOF-HD.
This time, the primary endpoint was TFC, which it did not meet. People who took pridopidine in the PROOF-HD trial did not show any improvement in day-to-day functioning as measured by TFC. Again, this was a negative pridopidine trial. The trial also failed to meet its secondary endpoint, an overall assessment of HD severity called the composite Unified Huntington’s Disease Rating Scale (cUHDRS).
Previous results had suggested an interaction between pridopidine and drugs that reduce dopamine activity in the brain. Dopamine is a chemical that helps control movement, memory, and mood. The interaction between pridopidine and these dopamine-altering drugs is perhaps unsurprising, given that pridopidine was originally designed to alter dopamine activity to help with HD movements.
Drugs that reduce dopamine activity in HD include commonly-used medications like tetrabenazine for chorea, or ‘neuroleptic’ drugs like olanzapine and risperidone, which are used to help control some of the most difficult symptoms of HD like aggression, impulsivity, paranoia, delusions, or suicidality. Physicians don’t take prescribing these medications lightly, and often do so to reduce the risk that a person with HD will harm themselves or others.
Prilenia decided, in advance, to do a ‘subgroup analysis’ of the PROOF-HD trial results in people who were not taking any of these dopamine-altering drugs. This group had only 79 people with HD compared with the full trial population of 499 people with HD. They reported that this subgroup had benefited from treatment on cUHDRS and one measure of cognition, but not the TFC.
A troubling narrative
Of the drug, Prilenia CEO Dr. Michael Hayden is quoted as saying, “Pridopidine has delivered consistent efficacy benefits across multiple key measures of HD”. We at HDBuzz do not agree that the data collected to date support this interpretation.
Pridopidine has been tested in more trials than any other drug in the HD landscape, and has consistently failed to deliver the benefits anticipated by the companies running the trials. Apparent improvements seen in one aspect of HD have not been replicated when tested in subsequent trials.
What if it’s true that pridopidine works in people not taking neuroleptics? That would be good news! But to make this claim and have the regulatory agencies believe it, another clinical trial would generally be needed, focusing exclusively on this group and enrolling enough people to test this robustly. This is a valid scientific hypothesis, and it’s reasonable to test it with such a trial.
However, that’s not what Prilenia are planning.
We were troubled by an announcement from a recent, non-peer-reviewed poster summary supported by Prilenia where the authors claimed to show links between neuroleptic treatment and the progression of HD. This is a very difficult thing to prove with existing data and statistics, since neuroleptics are generally given to people whose HD symptoms are worse, or whose HD is progressing more rapidly.
It is certainly important to study how different medications might impact HD progression. But when a company whose unapproved drug may rely on people not taking neuroleptics, starts supporting research into whether neuroleptics may be bad for people with HD, we worry about what conclusions HD families might draw, and we worry especially about people stopping medicines that are protecting themselves and others from harm.
Hope vs. hype
At HDBuzz, we’re less worried about the science around pridopidine – in every trial, the results are what you get, and continuing to test theories based on those results is reasonable, if the sponsor thinks there is a real effect to be found in a particular group of people. This process is what needs to be done until we get better drugs for HD.
What troubles us is the message being put out about pridopidine, downplaying the big things it has failed to do, and emphasizing less compelling findings in subgroups or individual endpoints. We worry that people from HD families – families like mine – could end up with a much more favorable impression than is warranted of pridopidine being the first disease-slowing drug for HD. Unfortunately, all the evidence so far does not support that hope.
Hope that a drug will work is useful – but only when that hope is grounded in truth.
We want people from HD families to participate in trials for drugs with a good chance of working. Drugs that have strong scientific reasoning and solid evidence to support asking people and families to make the sacrifice of time, effort, and risk.
We have the right to expect that trial results will be presented plainly and understandably. Trials that fail to meet their outcomes should not be presented as positive, and companies with vested interests should be extremely careful about commenting on how HD clinicians and their patients choose from currently available treatment options.
What the press release actually says is that Prilenia has put together the paperwork to ask the EMA to consider the results from pridopidine to date, and the EMA has accepted the submission of their application.
Getting applications accepted for consideration is a process that every approved drug goes through. But it’s also a process that every refused drug goes through. Applying to get into a university is very different from being accepted. We’re reliably informed by an expert familiar with EMA procedures that this step is not that big of a deal.
Most of the time, we don’t hear about when companies go through these minor steps. Press releases generally aren’t issued for these commonplace steps throughout the regulatory process. While it’s broadly good that Prilenia are ensuring the HD community gets regular updates on where they are in the regulatory chain, we want to make sure that the news isn’t causing undue hype. We’re more keen on seeing the full, peer-reviewed results of the PROOF-HD trial in a scientific journal.
What we know
Pridopidine has been tested in various clinical trials with various primary endpoints, all of which have sadly failed to be met. Regardless of the messaging being put out from Prilenia, thus far pridopidine has produced negative results from every major endpoint in every trial. Period.
We’re not even remotely happy about this: we love drugs that work, and we love trials that prove it. We even love negative trials – when the results are presented clearly, without spin, and give a scientifically-grounded path ahead, whether that’s planning another trial or calling it quits.
The goalpost for the intended use of pridopidine continues to shift: to control movements, to modify disease course, to modify disease course for those not on neuroleptics. It’s fantastic that Prilenia continue to study pridopidine in the lab! It’s in everyone’s best interest that researchers understand medicines from as many angles as possible. However, we need to make sure the intended use of a drug is shown through positive clinical trial results.
An application has been submitted to the EMA for consideration. So far, this doesn’t mean much. An application was submitted. It will be reviewed.
Seeking truth
Scientists are truth seekers. At HDBuzz, we believe researchers have a duty to accurately relay scientific findings to the patient communities seeking answers for a cure. For truth.
If hope that a drug will work becomes so blind that it turns to hype, something has gone wrong. Results from clinical trials, by design, are not subjective. Reporting results should also not be subjective. Messaging matters. Headlines matter. Ensuring that the patient community receives and understands the full, balanced truth matters.
The team at HDBuzz honestly does hope that pridopidine delivers on everything Prilenia says it does, and more! We all want a drug that makes a positive difference to people with HD, but right now there is only data from 79 people to support moving this drug forward. In our opinion, that isn’t sufficient for regulatory approval – time will tell whether the regulators have the same view or are persuaded otherwise.
Until we get there, HDBuzz will be here to report the truth and tease out the hope from the hype. We’re sorry if our take is disappointing, but we make no apology for keeping openness, frankness, and science at the heart of our reporting.
