Huntington Study Group (HSG) Conference 2024 – Day 1

The Huntington Study Group (HSG) is a clinical research network focused on accelerating treatments for Huntington’s disease (HD). This year, the annual conference is being held in Cincinnati, where clinicians, clinical coordinators, social workers, researchers, and pharmaceutical companies are all gathered to share research updates and exchange ideas. HDBuzz is attending the meeting, live tweeting scientific updates as they happen. For those who couldn’t catch our live updates, we’ve compiled our tweets into a summary. Read on to learn what happened on Day 1 of #HSG2024!

Welcome to HSG 2024!

HSG leadership is kicking things off with a series of intros and brief updates about the meeting agenda and the future of the organization. Stay tuned today as well as Friday and Saturday as we share updates on clinical trials and content from sessions on genetic therapy and innovative drug development.

MyHDStory

The next session involved a few brief updates on clinical trials which are being run by HSG. First, Dr. Karen Andersen from Georgetown and Dr. Alex Dalrymple from the University of Virginia spoke about two research projects under the MyHDStory platform.

MyHDStory is an at-home online study that anyone from an HD family in the USA can participate in. The speakers explained that the study allows people to share their experiences with HD and to participate in upcoming online studies to help improve HD research and care.

KINECT-HD

Next, Drs. Erin Furr-Stimming of the University of Texas at Houston and Dr. Olga Klepitskaya of Neurocrine Biosciences talked about the KINECT-HD study of valbenazine, which was approved earlier in 2024 by the FDA in the USA to treat HD chorea.

KINECT-HD successfully showed that valbenazine can help control unwanted movements. Newer data analysis shows that the biggest side effects, like episodes of sleepiness, happen in the first few weeks of taking the drug, then taper off.

A pro and con debate on huntingtin lowering

For huntingtin lowering

The next session is a keynote involving a bit of debate about the pros and cons of huntingtin-lowering therapies. First, Dr. Blair Leavitt, a clinical HD researcher at the University of British Columbia, will talk about the pros of this approach.

As a refresher, the extra CAGs in the huntingtin gene lead to an extra-long protein. Dr. Leavitt is first presenting evidence from studies of the human gene and protein to show that this expanded form of huntingtin can be harmful. He points to evidence that people with HD who naturally produce less expanded huntingtin protein have delayed onset of HD symptoms.

He also shares data from studies in different animal and cell models showing that it’s safe to lower huntingtin, and often beneficial. The amount of lowering to aim for remains a major question that many laboratory and clinical researchers continue to explore.

Blair also emphasizes that the huntingtin lowering clinical trials of tominersen (Roche), branaplam (Novartis), and Wave drugs were not failures, as researchers continue to learn from them, redesigning drug chemistry, reimagining how therapies are trialed, and incorporating community feedback.

Against huntingtin lowering

Next Dr. Alberto Espay of the University of Cincinnati is speaking to the challenges of huntingtin lowering and the evidence against this approach. He reminds us that huntingtin is found in many, many species, and has multiple functions in different cells and organs, so we need to be careful about removing too much of it.

He states that we are certain that the huntingtin protein can function when it is a typical length, but we are not completely sure it can’t function when it’s extra-long. He is urging everyone to consider a gray area where an “abnormal” protein can do both good and harmful things.

Clumps of huntingtin appear in brain cells over the course of HD, but this is not always directly connected to the loss of brain cells. Plus, huntingtin has hundreds of “dance partners” and not all scientists are convinced that it’s a good idea to cut in and break up the dance!

Overall, his argument is that defining extra-long huntingtin as “toxic” might be jumping to conclusions, and we should be careful when deciding when and how much huntingtin-lowering to attempt.

He also suggests that we could consider approaches to increase the amount of “normal” or “wild-type” huntingtin as an alternative to lowering the extra-long or “mutant” kind. The only problem with this suggestion is that this has been tried in mice that model HD and the effects weren’t notable, so it wasn’t worth advancing toward trials.

Data will advance therapies

This lively session is staged in “debate” format! Dr. Leavitt concedes that huntingtin is very important, but counters Dr. Espay’s point that we could try increasing wild-type huntingtin with the point that lots of evidence points to the expanded copy being toxic. Just adding more wild-type protein won’t get rid of the toxicity of the expanded copy. However, there is probably a therapeutic window for each huntingtin-lowering drug where the right timing and level of lowering will be essential to figure out.

Dr. Espay urges all the companies and researchers in the room to think about the huntingtin protein and its important role in cells as they continue to innovate in the huntingtin-lowering therapy space.

HD advocate and journalist Charles Sabine, OBE has taken the podium to remind everyone that there remains hope in huntingtin lowering, but that a diversity of research approaches will lead us to a better future for people with HD. A strong conclusion of this interesting debate from Dr. Blair Leavitt: “We will advance therapies based on data!”

Drug delivery

The next session will feature speakers talking about drug discovery. Dr. Mali Jiang from Johns Hopkins is designing novel delivery systems for huntingtin-lowering and other approaches to genetic therapy. Her work in Dr. Lishan Lin’s laboratory focuses on a way to re-program liver cells to produce little “bubbles” known as exosomes that can help deliver genetic drugs throughout the bloodstream.

The lab is working on a drug called ER2001 which has already been tested in a very small human trial in China. Dr. Jiang showed data on levels of the drug in the body after it was given through IV injections over the course of a few months.

The ultimate goal is to use this new approach to lower huntingtin. The Lin lab and the company behind this work (ExoRNA Bioscience) are hoping to move forward with larger studies (~30 participants) in China and the US if they are able to find financial support.

PTC-518 has a new name! Votoplam!

Next, Brian Beers from PTC therapeutics is speaking about the PIVOT-HD study of PTC-518, now named votoplam. We wrote earlier this year about the early positive results of this study.

Brian is re-capping the results from people who were on votoplam for up to 12 months. These folks had lower levels of huntingtin in their blood and spinal fluid compared to those who got a placebo (pill with no drug).

This study has enrolled participants across a broad spectrum of early-stage HD symptoms. The side effects reported, like headaches, have been mild, and one update at this conference is that there were no immune system reactions. As we shared in June, PTC is also seeing some early trends in improved function.

Controlling CAG repeats

Up next is a research session on gene editing (altering DNA) and combatting somatic instability (stopping CAG repeat expansion). First Dr. Vanessa Wheeler from Mass General Hospital and Harvard Medical School detailed recent work looking at CAG expansions at the single cell level. This technique has really taken off in the past 10 years and gives researchers TONS of data. Compare looking at the stars with your eyes, or using a powerful telescope. A huge difference!

Vanessa also discussed GWAS data – genetic data that analyzes every single gene in a person. Using these large datasets from lots of people with the gene for HD, scientists can start to determine what genetic information affects age of symptom onset.

This identifies genetic markers (called modifiers) that track with earlier or later age at symptom onset. Getting a better understanding of these genes that modify the course of HD helps identify potential targets for drugs to delay HD symptom onset.

Vanessa and her team are currently looking at modifiers of somatic instability – the perpetual expansion of the CAG repeat in vulnerable brain cells. They’re hoping to identify genes that control somatic instability that they can target therapeutically.

Right now they’re testing these target genes in mice that model HD. When they use CRISPR to alter levels of these targets they find that they’re able to control the amount of somatic instability. So far they’ve tested 60 different targets. That’s a lot of work!

Every modifier gene that controls somatic instability in cells or mice has the potential to become a therapeutic target. They’re also testing combinations of targets, which, as you can imagine, gets quite complicated with 60 targets!

Vanessa and her team are also considering how single or combined targets could have different effects in different types of cells. So one modifier that slows or stops somatic instability in support cells in the brain (glia) may have a different effect in neurons.

She also shared details about a specific modifier that they’re examining, called LIG1, that seems to reduce somatic expansion in the brains of mice that model HD. We’ll be eagerly waiting for more data on this modifier!

Ultimately, Vanessa’s goal is to identify genetic modifiers of somatic expansion that will control instability, keep brain cells healthy for longer, slow symptom onset, and give people affected by HD more healthy and happy years.

CRISPR for gene editing

Up next is Dr. Ricardo Mouro Pinto, also from Mass General Hospital and Harvard Medical School. He’ll be talking to us about gene editing – the approach of changing the DNA blueprint to investigate and ultimately to treat HD. Exciting!

Ricardo started with a primer on CRISPR – a powerful genetic editing tool that you can think of like molecular scissors. Researchers can identify DNA targets that they want to edit, deploy CRISPR against that DNA letter code, and swap it out with a new sequence.
We wrote about the advancements made in medicine for Sickle Cell Disease using CRISPR.

Ricardo’s getting into the nitty gritty of how different DNA letters can be swapped out using different techniques. There is so much innovation in this area since the advent of CRISPR technology just 10 short years ago.

Ricardo touches on two major challenges for CRISPR in clinical HD research: delivery and safety. How do we get the drug to the brain, and how do we make sure that the drug is only making the DNA changes we want it to?

He notes that the NIH (science/medicine funding agency in the USA) has created a new funding initiative to support the advancement of gene editing therapies. Two of the 5 currently funded projects are focused on HD!

One of these projects focuses on trying to chop out extra CAG repeats from within the huntingtin gene, and the other tries to prevent CAG repeats from growing longer, combating somatic instability.

Some people with HD have “interruptions” in their CAG repeats, with a CAA thrown in instead. These folks tend to have later onset of symptoms. One group of NIH-funded collaborators (including Ricardo) is working on techniques to change CAGs to CAAs.

Ricardo refers back to some of those “modifiers” of somatic instability that Vanessa brought up. He is focusing on one called MLH3, exploring complex CRISPR editing techniques to tamp down its levels. In cells, this can slow or stop the growth of CAG repeats. The next step is to test these techniques in mice and in human cells that more closely mimic HD.

We’re likely quite far from human trials of these approaches, but it’s exciting nonetheless to see that this work is gaining traction and funding. The great potential advantage of a gene editing therapy is that it could be administered once with permanent effects.

Current strategies for HD therapeutics

In the next session, companies developing innovative therapies for HD will each give short talks on their most recent updates. HDBuzz’s own Dr. Sarah Hernandez is beginning with a brief overview covering the basics of different approaches and companies in the space.

Sarah is getting into the alphabet soup of huntingtin lowering techniques and delivery methods, like ASOs, RNAi, AAVs, and splice modulators. Several companies will have a chance to talk about their drug development efforts in more detail. She also mentions other therapeutic approaches to HD, like targeting somatic expansion, replacing lost brain cells, and enhancing cell-to-cell communication.

Sarah concludes with an exciting slide showing the many dozens of companies working in the HD space. We’re truly living in the age of clinical trials for HD research!

Alnylam Pharmaceuticals

First up in the innovator’s forum is Dr. Kevin Sloan from Alnylam Pharmaceuticals. They’re using a strategy called RNAi – RNA interference – that adds a bit of genetic code targeting the huntingtin message to lower the protein.

Kevin first covered the details of how RNAi works. One of the major challenges for RNAi-based drugs is delivery. They want to make sure the drug gets to where it needs to go – for HD, that’s all over the brain. Alnylam is also working on other diseases, and Kevin is sharing data from an RNAi drug they have for Alzheimer’s disease that’s moving into a Phase 2 trial.

Now they want to do the same thing for HD. They have an RNAi drug designed for huntingtin called ALN-HTT02. It targets all forms of huntingtin, including short bits prone to clumping. These are called huntingtin exon 1 fragments and they are thought to be toxic to brain cells.

We’ve written about these huntingtin exon 1 fragments, also called HTT1a. This tiny little fragment of the huntingtin message seems to code for a protein only made in people with the expanded huntingtin gene.

Alnylam is now testing ALN-HTT02 in monkeys, the step before moving drugs to human clinical trials. Just this week Alnylam announced that they’re starting a Phase 1 trial for this drug! This early trial will be initiated in the UK and Canada with recruitment in additional countries planned to follow.

The primary goal will be safety and tolerability, but they’ll also look at how well it targets huntingtin and how levels change in the CSF, the fluid that bathes the brain. They’ll use clinical tests to measure symptoms, but would need a larger trial to understand if ALN-HTT02 works to change clinical features of HD. It’s always exciting to have new trials announced and we’ll be eagerly waiting for new updates from Alnylam!

Rgenta

Up next is Dr. Travis Wager from Rgenta Therapeutics. They are developing small molecules that could be taken as a pill to target somatic instability, the perpetual expansion of the CAG repeat in vulnerable brain cells.

Rgenta are trying to target a gene called PMS1 – not the PMS related to mood swings… Levels of PMS1 are higher in people who show symptoms of HD earlier. Rgenta are trying to decrease its levels in the hopes of delaying the onset of signs and symptoms of HD.

Travis tells us how it’s super important to choose the right place on PSM1 to target. So they’ve spent a lot of time developing small molecules that target PMS1 in the right spot. The best candidates also check other boxes, like getting into the brain when taken as a pill.

Rgenta has been testing their drug in lots of different animal models. They’ve shown that it’s very robust. Lowering PMS1 by 50% stalls instability by 70% – the rate of CAG expansion slows down a whole lot. Exciting!

Travis gave a big shout out to all the researchers in the HD community for being so collaborative and sharing their resources. He said Rgenta wouldn’t be where they are today without HD scientists being so collaborative and willing to share.

LifeEdit

Our next speaker is Dr. Logan Brown from LifeEdit Therapeutics, who are advancing gene therapies for HD using CRISPR technology. LifeEdit is working on a CRISPR-based therapy called LETI-101 that selectively lowers expanded huntingtin. They can do this by targeting a genetic signature that differs between a person’s two copies of huntingtin.

Not everyone shows this small genetic difference between their two copies of huntingtin. For this reason, LifeEdit estimates that if LETI-101 were to become a drug, it would work for 30% of people with the gene for HD.

The good news about this approach is that because it uses CRISPR for gene editing, it would be a one-and-done approach, so people would only need this treatment once, in theory, to lower huntingtin for the rest of their lives.

So far, they’ve tested LETI-101 in cells grown in a dish and mice that model HD, and now they’re testing it in monkeys. But they’re also working to develop a strategy for moving into people, which will require brain surgery.

Sana Biotechnology

Next up is Dr. Joana Osorio from Sana Biotechnology, who are working on cell replacement therapies using stem cells. Sana’s technology grew out of experiments showing that support cells in the brain, called glia, contribute to HD disease features in neurons.

With this knowledge, Sana then asked if transplanting non-HD glia cells could improve disease features in mice that model HD. When they did this, they saw improvement in movements and other features of the disease, including increased the lifespan of the mice.

Scientists at Sana found that when they transplanted non-HD glia into the brains of mice, they “out-competed” the HD glia – they essentially replaced the sick HD glia in the brain! HDBuzz previously covered this work when it was published.

Sana is now working to move these findings into clinical trials, and while they’re not quite there yet, they have a plan for getting there. So stay tuned!

Spark Therapeutics

Dr. Juha Savola from Spark Therapeutics is our next speaker in this session, sharing work Spark is doing to advance gene therapies. Spark is best known for their development of a gene therapy for a hereditary form of vision loss (back in 2017). Now they’re focusing on HD.

Spark is developing a gene therapy called SPK-10001, which is designed to slow down or halt progression of HD by lowering huntingtin. Right now they’re testing SPK-10001 in monkeys and they’re seeing that for up to 12 months, HTT levels remain lower.

In the monkeys, they’re testing different doses of SPK-10001 and tracking HTT lowering in different brain areas. This will help them to choose doses to test in people when they move into clinical trials. Juha is sharing details for inclusion and exclusion criteria for the upcoming Phase I/II trial that Spark is planning in people with HD, which will test 2 doses, a low dose and a high dose.

The primary objective of this trial will be safety, but they’ll also look at a few clinical metrics to try and get some hints about whether SPK-10001 will work to treat HD symptoms. We’ll be eagerly awaiting the recruitment announcement for this trial!

Atalanta Therapeutics

Our last speaker of this session is Dr. Serena Hung from Atalanta Therapeutics, who are working on RNAi-based therapeutics for HD. As Sarah explained earlier in her overview, this is one among several approaches to lower huntingtin.

The advantage of Atalanta’s approach is potency. They use a novel technology that helps the drug spread easily to deep regions of the brain. With delivery using a spinal injection, they see that their drug, called ATL-101, is still active out to 6 months in animal models.

Atalanta has shown that in monkeys, they can lower HTT by 75-90% and levels of NfL remain stable. NfL is a marker of brain health that increases as brain cells are damaged and increases as HD progresses. So lots of people keep their eyes on NfL in trials because keeping it level (or even lower!) would be a good thing.

Atalanta is planning to initiate clinical trials for ATL-101 in 2025. We’ll keep you posted when we learn any updates about the advancements of this exciting research!

Tune back in tomorrow!

We are off to explore more than 80 research posters presented by HD scientists and clinicians from all over the world. Brief talks will shine a spotlight on brain imaging biomarkers and aspects of the Enroll-HD platform. See you tomorrow for sessions on clinical challenges in HD, biomarkers, trial design, and more.

2024 HDBuzz Prize: Social Skills – The Hidden Gem in Improving Quality of Life for People with Huntington’s disease?

People with Huntington’s disease (HD) may develop a number of symptoms which can be identified by other people. These symptoms include uncontrollable muscle movements, difficulty with swallowing, and struggling to move around. These symptoms are often the focus for many research projects because they are easier to recognise for other people, as problems that people with HD can face. However, what about social struggles people with HD may have, which are not as obvious to other people? Scientists are now beginning to investigate these less obvious effects of HD because there is an increasing awareness of how much these can impact an individual and their quality of life.

The missing link – a connection between quality of life and social skills?

Quality of life simply means how satisfied a person is with their life, overall. Quality of life may be considered from multiple approaches. Some of these approaches include, physical well-being (how healthy someone feels), emotional well-being (mood and mental health), and social well-being (strength of relationships and how supported they feel). Physical, emotional, and social well-being are believed to be the three building blocks to determine a person’s quality of life.

People with HD may struggle with social skills, causing greater difficulty with social situations. For example, understanding and explaining how other people might feel in particular social situations. In addition, people with HD may experience an increased difficulty in understanding emotions from facial expressions and body language in other people.

Previous scientific research has uncovered two interesting findings about people with HD. Firstly, they have shown that quality of life is reduced in people with HD (particularly at later stages of the condition), compared to the general population. Secondly, some people with HD have greater difficulty with social situations. However, scientists had not yet researched if there was a link between these two ideas until recently, in work led by Professor Hugh Rickards from the University of Birmingham in the United Kingdom.

So, how do we tap into our life satisfaction radar?

Hugh and his team are studying what could link these two ideas, on quality of life and difficulties with social situations in people with HD. To understand quality of life, a questionnaire was given to people with HD that measures physical, emotional, and social well-being.

Scientists also asked people with HD questions about feelings they were experiencing. Some questions explored how frustrated people with HD could become, or how overwhelmed they felt. These questions helped scientists to understand the many different emotions people with HD can experience.

Scientists were particularly interested if people with HD were having trouble expressing their usual feelings. For example, your friend has a real sweet-tooth and presenting them with their favourite bar of chocolate usually makes them feel very happy. However, one day you give your friend their favourite chocolate bar and strangely, they do not seem to express any feelings of happiness. This represents a situation where a person may not be expressing their usual feelings.

What’s your social IQ?: measuring interpersonal skills in people with HD

To understand difficulties with social situations, people with HD were invited to complete different tasks. One example is the ‘Animations Task’. In the Animations Task, people with HD watched cartoons of two triangles. These triangles moved in ways that looked like real-life social situations. For example, two triangles dancing together, or one triangle trying to ‘persuade’ the other triangle to come out of the box. After watching the cartoon, people with HD had to explain what they thought the triangles were doing.

How well people can think and plan activities may also affect how they respond to social situations. Imagine a chef preparing a complicated meal. The chef would have to plan what ingredients they need to gather, organise the pots and pans needed, and control their impulses to eat the entire lasagne in one go! This is the perfect example of the many important skills required when thinking and planning activities.

One question you might be wondering is, how were these thinking and planning skills measured in people with HD? These skills were measured using a ‘Trail Making Test’. In part one of this test, people with HD had to draw lines between circles which each contained a number in the centre (from numbers 1-25). These lines had to connect the circles from the lowest number to the highest number.

Part two of this test was more complicated. This time, there were circles containing letters (A-L) and circles containing numbers (1-12). People with HD had to switch between drawing lines from circles with numbers, to circles with letters. They joined the circles up from the lowest number to the highest number and in alphabetical order. For example, a line would be drawn from circle 1 to circle A and then from circle A to circle 2, and so on. This task helped to give the scientists a measure of how well people with HD can think and plan.

Does being the Sherlock Holmes of social skills mean a happier life?

This study found that a reduced quality of life (specifically, a decrease in social and emotional well-being) in people with HD could be predicted by several social skills and behaviours. One social skill that predicted a reduced quality of life in people with HD is the ability ‘to put yourself in someone else’s shoes’ to figure out their thoughts and feelings.

This was shown in the study when people with HD, who had a poorer overall social well-being, were less likely to be able to explain what the cartoon triangles looked like they were doing (in the Animations Task). For example, one triangle appears to be trying to persuade or encourage the other triangle to come out of a box. When people with HD (who had a lower social and emotional well-being) were asked to explain what the triangles were doing in this video, they simply described that the triangles appear to be ‘moving’ around each other.

Additionally, the results concluded that a reduced quality of life in people with HD could also be linked to having trouble expressing their usual feelings (think back to the chocolate bar example).

Take a deep breath and make a plan

Another interesting finding from this study suggested that a reduced quality of life (in terms of a person’s ability to carry out daily tasks at work and/or home), in people with HD, can be linked to how overwhelmed or frustrated they feel. This decreased ability to carry out daily activities could also be due to having trouble when trying to plan activities (remember all those important planning and organisational skills a chef needs to make the perfect lasagne!).

Together, these results may hint that by improving these particular social skills in people with HD, it could improve their quality of life.

In a nutshell: key insights and the road ahead

The key message from these findings is that when people with HD struggle to understand social situations, it can really affect their quality of life. In the future, scientists should consider exploring solutions to help people with HD improve their social skills.

Some specific social skills to address include, improving people’s ability to express their feelings, addressing their difficulties with planning and organisation, or tackling their feelings of frustration. This is because these are the social skills that have been highlighted as important in determining quality of life, in people with HD.

So no need to break out your cherrywood pipe or wool plaid hat to search for hidden jewels – working on these social skills could be the gem itself in improving quality of life and increased feelings of happiness for people with HD.

2024 HDBuzz Prize: Thinking beyond therapies – it’s time to consider racial disparity in HD care and research

Huntington’s disease (HD) is a progressive brain disease that typically starts to show symptoms between the ages of 30 to 50, when people are in the prime of life. It’s also heritable, meaning anyone who has a parent with HD has a 50% chance of getting it. HD has historically been thought of as more common among those of White ancestry, but new data challenges this, suggesting comparable rates in Black individuals. Racial and ethnic health inequalities are well documented in North America, with Black and Latino individuals found to be less likely to receive neurological care, even when socioeconomic and insurance payer factors are controlled for. How, then, does this affect HD gene carriers?

Delayed diagnosis for Black people living with HD in North America

Until now, questions around racial health disparities in HD have received little attention, but a new study from Adys Mendizabal and colleagues from UCLA has begun to address this.

Adys and her team explored racial disparities in HD care by looking at data from over 4,000 North American HD gene carriers in the ENROLL-HD database.

ENROLL-HD is the world’s largest observational study for HD families, where people living with HD from all over the world are asked questions by their neurologist during clinic visits with the option to donate blood samples. No treatments are tested – ENROLL-HD purely aims to give researchers a better understanding of HD. It’s a collaboration between HD families, clinicians, and researchers.

Adys and her team used the ENROLL-HD database to see how much time there was between when a gene carrier’s family first noted symptoms, to when a diagnosis of HD was made. They found that, on average, the time to receiving a diagnosis was one year longer for Black compared to White individuals in North America. This fits with findings from other studies, showing that Black individuals are typically at a more advanced stage of HD when they enter ENROLL-HD compared to White individuals.

A likely underestimate

What’s more, the realities are likely worse. In the study, almost 90% of participants were White, while 3.4% were Latino, and 2.3% were Black. These proportions don’t marry up with what clinicians typically report seeing in their clinics, suggesting racial and ethnic minority groups are less frequently recruited to ENROLL-HD.

This highlights a second issue facing HD gene carriers in North America: that of under-representation in research studies. Indeed, the fact that differences weren’t seen for other racial and ethnic groups in the study is likely because there were too few such participants in the study at all.

It’s also important to consider that ENROLL-HD participants as a whole are a somewhat skewed reflection of the HD community. This means the figures from the UCLA study are likely an underestimate, and the real-world racial and ethnic disparities in HD care are probably even greater. This is because ENROLL-HD only takes place at HD Centers of Excellence, in urban and academic-affiliated settings.

HD Centers of Excellence provide multidisciplinary care for HD families, with neurologists, psychiatrists, social workers, therapists, counselors, and other professionals who have experience working with HD families. Centers of Excellence are, in part, supported by the Huntington’s Disease Society of America.

Factors at play

It’s important to note that Mendizabal and colleagues’ study wasn’t designed to drill down on exactly what is driving this delay in diagnosis, so currently this is speculative.

The researchers couldn’t tell, for example, if it was because Black HD gene carriers delay going to doctors, or have greater delays in accessing specialist care. However, they point out evidence from other disease groups, where Black individuals have been found to be more frequently misdiagnosed, and less frequently referred for genetic testing.

Likewise, they highlight the possibility of the interaction with other sociodemographic factors, for example employment status, but had too few participants in their study to be able to explore this meaningfully. They also cite studies raising concerns of racial disparities in the stigmatization of genetic conditions.

From an ENROLL-HD recruitment perspective, they raise the possibility of unequal access to HD Centers of Excellence, a potential lack of culturally similar research staff, and data from other diseases suggesting that racial and ethnic minority groups are less likely to be invited to take part in research.

Importantly, they also point to decades of unethical experimentation in Black, Latino, and Native American communities in the United States, which has promoted community mistrust of research.

Pointers for the research community

One of the key takeaways from this study is that we need more research to really uncover the drivers behind these differences, so we can figure out how best to address them.

This is particularly important since advanced imaging scans are now being brought into HD diagnosis and stage classification – which has the potential to widen the gap for underserved populations.

In the meantime though, modifications to ENROLL-HD could help address this area by:

  1. Expanding racial and ethnic grouping options, to more accurately capture diversity among participants. For example, multiracial or multiethnic individuals currently have no categorisation option besides ‘Other’.
  2. Adopting a standardized recruitment approach that promotes more balanced racial and ethnic representation within the study.
  3. Increasing the numbers of ENROLL-HD sites in under-represented areas, such as Latin America, Australasia, Asia, and Africa.

A silver lining

While the results of this study raise concern, we can also see them as a positive. In the absence of a treatment breakthrough, findings like these remind us to think outside the box and remember that there are other ways that we can seek to improve the lives of those living with HD in the here-and-now.

This study also shows the value of the time, energy, and effort that HD families put into participating in ENROLL-HD. This study is just one example of the many that use the data collected from ENROLL-HD to advance our understanding of HD, and hopefully get us to a treatment sooner.

To date, ENROLL-HD has 21,669 participants from 155 clinical sites across 23 countries. This is fantastic participation from the patient community! But this study reminds us that it’s vital that everyone from the HD community is represented, including historically marginalized communities. If you would like to learn more about ENROLL-HD or join the study, you can do so here.

Announcing the 2024 HDBuzz Prize for Young Science Writers!

We’re excited to announce that the 2024 HDBuzz Prize opened this summer, seeking to find effective communicators to help us break down the latest and greatest Huntington’s disease research! This fall (or autumn, if you’re feeling fancy, or just British to be honest) we’ll be bringing you articles written by the selected prize winners, who bring a fresh voice to HDBuzz. Read on to learn about the who, why, what, when, where, and how of the 2024 competition.

Who and why

The HDBuzz Prize sought to diversify the voices that bring you content on HDBuzz. Huntington’s disease (HD) researchers come from many different scientific backgrounds with varied training, and they don’t all interpret data in exactly the same way. Having multiple viewpoints represented across our writers ensures that HD families are getting content that spans what the HD field is thinking.

The HDBuzz prize was open to anyone with an active involvement in any aspect of HD-related research. Our goal was to find young scientists with a gift for communicating research news clearly and imaginatively.

We’re particularly keen on the fresh take that your trainees, such as PhD students and postdoctoral fellows, provide and are actively seeking researchers with clinical experience. So if that’s you, hit us up!

What

The HDBuzz Prize is an opportunity for early-career HD researchers to get involved in communicating HD science to the global community, see their work published here, and win $200 US dollars!

Public engagement is important for every scientist’s training, so apart from the cash, this would enhance the CV of any eager young HD researcher.

When and where

The 2024 HDBuzz prize was first announced at the Hereditary Disease Foundation (HDF) conference in August, where HDBuzz live-tweeted from the front row. If you missed our live summaries, you can still catch the amazing science that was shared at the meeting by reading our tweet compilations.

While at the HDF conference, we took advantage of having the ears of almost 300 of the world leaders in HD research. We announced the 2024 HDBuzz Prize, calling on young HD researchers to put their writing talents to good use and make a difference for HD family members by showcasing science in the field.

How

Applicants submitted summaries of prospective articles, detailing what they wanted to write about and why they thought it was important for HD families to know about. Then we excitedly watched the applications roll in. Those who passed the first round were invited to submit full articles and we’re excited to share those with you over the next few months!

Even though the 2024 competition is over, we’re always looking for talented writers. Whether you’re a Principal Investigator (that’s ‘head honcho’ in laboratory-speak) or an HD family member, chances are you know a young scientist with a neat turn of phrase and a gift for communication. If so, please put them in touch with us or send them to this article.

So, to all our fellow science nerds – get in touch and get cracking!

Bringing HD Treatments to Market: The Role of Regulatory Oversight

There has been a lot of buzz in the Huntington’s disease (HD) space recently with multiple updates from companies testing many different drugs in the clinic. As these drugs move closer to seeking approval from the regulators, this has raised some questions. Why are some trials held in certain countries and not others? What does it matter if a company applies to the European or US regulators? How does a drug really move from being tested in a lab to being approved for sale on pharmacy shelves? We spoke with Cristina Sampaio, MD, Chief Medical Officer at the CHDI Foundation and former longtime member of CHMP, a committee that evaluates applications to the European Medicines Agency (EMA) for new drugs to be approved to be sold in the European Union (EU). Here, we get into the nitty gritty of drug regulation and find some answers to these important questions.

Getting a drug to market

After a company has been busy in the lab and has worked with different animal models to test their drug, the next step is to begin testing their drug in people in clinical trials. Clinical trials are typically divided into Phases 1, 2, and 3. As a drug progresses through these phases, more participants are dosed for longer periods of time.
Each phase seeks to answer different questions about the drug being tested: Phase 1 is about what dose of the drug is safe for people; Phase 2 aims to work out if the drug is working and doing what it is designed to do while continuing to monitor safety; and Phase 3 seeks to confirm the effect of the drug, generally in a larger more diverse group of people, usually over a longer period of time, and looking out for possible side effects.

If a drug successfully moves through all phases of the clinical trial process, the company behind the drug will then apply to the regulators for approval which would allow them to market and sell their drug. This is the ideal outcome for companies, patients, and other stakeholders as it means we have a bigger arsenal of drugs to treat different diseases and conditions. In the case of HD, we’re hoping to soon have the first agency-approved, disease-modifying drug – what a thought!

Regulators – laying down the law on clinical trials and drug approvals

Testing new drugs in clinical trials is however a very risky business. Scientists do their utmost to make sure that new drugs they help develop are safe, effective, and could halt, slow, or alleviate symptoms of disease in humans, based on experiments they do in cell and animal models in the lab. However, there is always a risk that things might not go as well as everyone hoped when the drug is first given to people, with potentially very bad or disappointing outcomes, a scenario with which the HD community is unfortunately very familiar.

To work in the best interests of patient groups, it is important that all aspects of this process are carefully vetted and overseen by an independent panel of experts, from the very first people to be dosed with a drug, all the way to the final approval so that the drug can be made available. This is one of the roles the regulators play, helping to get drugs from the lab bench to the people who need them the most, the patient communities.

Most countries have drug regulatory agencies, although the scope, structure, and responsibilities of these agencies varies a lot. Regulators are responsible for ensuring the safety, efficacy, and quality of drugs, medical devices, and in some cases, other health-related products. All of these regulatory agencies serve different populations with different interests and needs, operating within different healthcare systems.

Regulators in Europe and the US

You are probably familiar with some of these regulators already – the European Medicines Agency (EMA) in the EU which is the central agency for approving and monitoring medicines across all 27 EU member states; and the Food and Drug Administration (FDA), which is responsible for regulating drugs, medical devices, and food safety, but is a federal agency representing the citizens of a single country, albeit a big one, the US.

As the FDA and EMA are currently the two big players in advancing HD drugs to market, they will be the focus of this article. The FDA and EMA are also two of the most important regulatory agencies in the world because of their global influence, scientific expertise, and high standards for drug evaluation and approval. This makes them key players in ensuring the safety, efficacy, and quality of pharmaceuticals and medical products in the global landscape of drug development.

However, it is important to note that there are many more regulators beyond those governing the US and the EU. This includes Health Canada (no points for guessing where they operate!), the National Medical Products Administration (NMPA) in China, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, and the Central Drugs Standard Control Organization (CDSCO) in India.

The FDA is an end-to-end authority on drug testing and regulation in the US

The FDA is a self-contained entity, with full control over drug approvals in the US in a very standardized process. The companies developing the drug will first file an investigational new drug (IND) application when they want to begin clinical trials. The FDA then reviews this huge dossier of information that comprises that application, detailing all of the pre-clinical data (experiments in cells and animal models) the company has worked to put together, and they then either approve it so the company to start clinical trials and begin testing their drug in people, or they don’t and things will pause.

The company might continue to have interactions with the FDA as needed and seek advice as drug development progresses through Phase 1 and Phase 2 trials. Then at the end of Phase 2 trials, all companies have to meet with the FDA and discuss plans for their Phase 3 trial. Together, this means that the FDA has a very prescriptive series of interactions with each company as they progress through the drug development pipeline. Because the FDA has been in the loop the whole way through this process, they should have the complete back story on each drug.

After the Phase 3 trial concludes, they will often privately advise companies on their potential chances of success if they were to file a new drug application (NDA), the final approval needed to bring their drug to market. This does not mean if a company files an NDA it will definitely be approved but more the opposite; that if the FDA suggests that a company NOT file for approval because the data for their drug are too weak, they will generally follow this advice.

The EU regulatory system works to serve all of its member states

In contrast to the US system, the EU system has multiple layers of organization, a reflection of the fact that it works to represent so many different countries.The EMA itself is not the regulator of clinical trials in the EU; this is controlled by each of the member states. This means that it is perfectly possible, although generally inadvisable, that the first time a drug company will interact with the EMA is when it starts the process to seek approval for its drug.

However, the EMA does offer scientific advice to companies, to support the development of new drugs. Scientific advice could be used to check with an independent body about the company’s choice of endpoints (what they plan to measure and benchmark against in the trial) or the population they plan to test in, and whether this all makes sense. This service helps companies do a better job designing and running their preclinical and clinical studies. This can help ensure that they meet regulatory criteria before submitting their drug for approval, reduce the risk of failure, and streamline the drug development process.

Once clinical trials are complete, in the EU system the companies will prepare a dossier with all kinds of information about the drug they have been testing to submit to the regulators. This is a huge administrative task and a lot of work for the companies to do and can take a very long time – up to 12 or 14 months! In fact, big pharmaceutical companies like Pfizer and Novartis will have dedicated teams whose sole job is to put applications like this together. We asked Cristina about the significance of this step in the drug approval process and what this might indicate about the likelihood that a drug would be approved. She clarified that submitting this package had little to do with the merit of the application, and it is a largely administrative milestone in the drug approval timeline.

EMA approval is directed by a committee of experts

The EMA also differs from the FDA as it does not itself hold the decision-making power about whether a drug is approved. The approval instead comes from another body called the European Commission (EC). Linking the EMA and EC is the committee for medicinal products for human use (CHMP) comprised of a representative from each member state, and experts in the fields of science relevant for the application. CHMP reviews all of the materials provided in the dossier submissions to the EMA by drug companies and gives an opinion on whether the drug should be approved to the EC. But it is the EC who makes a final decision on whether a license will be granted for a particular drug.

This is a complex process, not made any easier to understand by all the acronyms! Cristina sat on the CHMP for 13 years and is an expert on drug approval in the EU. She tells us that whereas just one faction is ultimately in charge of approvals at the FDA, there is a large and complex network of people in the EU system, making sure that the collective interests of all EU citizens are considered and represented in the process.

Despite this diversity of perspective, the CHMP works to ensure consensus of opinion in their recommendation, and does their best to avoid a split vote, which could open the door to applicant companies exploiting possible wedge issues. In practice, this can mean that CHMP could make a recommendation for approval, but with caveats, to ensure that consensus is reached. These caveats might be about permitted dosing strategies or who can receive the drug. For example, a breast cancer drug might be approved but only for patients with a certain genetic mutation instead of all breast cancer patients.

Do all drugs follow this same approval process?

Often, this is not the end of the process and there is considered to be a Phase 4 of clinical trials, as drugs are monitored for their effect after approval. This is to make sure that in much larger populations over longer periods of time, side effects or other occurrences which were not spotted in the course of the normal clinical trial time frame can be identified and assessed.

Sometimes, if the needs of patient groups are extreme and there are no drugs available yet, drugs might be approved even before a Phase 3 trial. This was the case for a PTC Therapeutics drug for Duchenne muscular dystrophy (DMD), Translarna (ataluren), which was conditionally approved by the EU regulators in 2014. Although the Phase 2 trial did not meet its primary endpoint, when the company sliced and diced the data, there did seem to be a somewhat promising effect in a subgroup of trial participants.

Translarna was approved by the EMA under the condition that additional data from a Phase 3 trial confirmed that the drug truly worked in the subgroup PTC had identified. Sadly, this Phase 3 trial did not reach its primary endpoint either. The application to the FDA for approval was denied and the EMA recommended the drug be withdrawn from the market. The EMA concluded that Translarna did not improve walking ability in patients sufficiently, resulting in the non-renewal of its marketing authorization in the EU. This decision was upheld despite appeals from PTC as well as from patient advocacy groups. PTC continues to seek FDA approval, but the inconsistency in clinical trial results remains a challenge for its approval.

This example demonstrates that even after agency approval, this is not the end of the road in drug regulation. However, companies with robust clinical trial data are unlikely to encounter such a turbulent back-and-forth with the regulators for approval of their drug as in this instance, especially if they’re backed by positive data from a Phase 3 trial showing endpoints were met.

Why might the EMA and FDA make different decisions?

In general, the EMA tends to be more restricted in their approvals, compared with the FDA. In fact, there is a growing divide in drugs approved and available in the US that are not approved in the EU. But not all of these differences in approvals are to the benefit of people in the US.

For example, the Alzheimer’s drug, Aducanumab was initially approved by the FDA in 2021 under the accelerated approval pathway. However, its approval sparked significant controversy in regards to its efficacy, as clinical trials did not provide clear evidence of a clinical benefit​. This led to the company withdrawing the drug in 2022 as it was no longer commercially viable – the drug had a huge price tag and very few doctors were prescribing it. Following the withdrawal, Aducanumab became a notable example of the complexities and challenges involved in drug approvals, particularly for conditions like Alzheimer’s where treatment options are severely limited​.

These setbacks are indescribably disappointing for patient families. The rollercoaster of hope for those battling diseases like DMD, Alzheimer’s, and certainly HD is sufficiently fraying without regulatory approvals and withdrawals of medications that these families hope will modify the course of their disease. The hope, energy, and risk associated with advancing these ineffective medications could have been better spent with additional clinical testing to ensure endpoints are met, preventing such agency withdrawals.

Why are trials held in some countries and not others?

People from HD families have undoubtedly searched for clinical trials they may be eligible for only to be met with the disappointment that those trials aren’t taking place in their country. While certainly disheartening at the time, the decision to restrict trials to certain countries could actually help move drugs along more quickly, hopefully for the benefit of people with HD across the globe.

We recently heard positive Phase 1 trial news from Skyhawk Therapeutics, who is conducting their trial in Australia. Their decision to do this is likely a matter of cost. Healthcare costs in Australia are dwarfed in comparison to those in the US. So companies testing drugs there pay fewer fees to physicians and hospitals, making the trials a fraction of the cost. Although some drug companies are extremely wealthy organizations, smaller companies and start ups are often very cash-strapped. Spending less money to run a trial can improve their chances of survival, hopefully helping them advance their drug more quickly to convince more investors to pitch in and keep the program running.

In Europe, certain countries have faster or slower regulatory application review. Some countries, like Poland, Germany, or Hungary, have notoriously fast review processes. This allows them to attract different companies to their country for clinical trials. Other countries, like France, can be challenging to conduct clinical trials in for companies based in foreign countries, making it more common to see trials conducted there by French companies.

A company will consider trial costs and speed of regulatory approval when deciding where to conduct their trial. Ultimately though, these decisions should help a drug either fail more quickly or reach approval sooner. While we certainly don’t want drugs being tested for HD to fail, if they’re going to fail, we want that to happen as soon as possible. The sooner we know a drug won’t work, the sooner we can move on to something that will. And once we get to drugs that will work, we want those to move toward regulatory approval as quickly as possible.

On our way to triumphs

We would like to extend our heartfelt thanks to Cristina for sharing her expertise with us and talking through all of these complicated processes and considerations for drug approval so we could put this piece together. We are grateful to have experts like Cristina who dedicate their time and energy to helping the HD community.
Overall, the process of developing drugs isn’t easy. Rightfully so! It’s a risky business and we want to make sure drugs are effective, doing what is intended with little to no side effects, before they’re dolled out to the masses.

Right now is an exciting time in HD research – there are countless companies working on drugs for HD, many companies are testing their HD drugs in clinical trials, and some are at the stage of applying for regulatory approval. As more drugs reach this stage, we at HDBuzz want to make sure HD families understand that process, what each of the phases and stages of approval mean, and where we could see setbacks and, hopefully soon, triumphs.

The future undoubtedly holds regulatory approval for HD-modifying drugs. While we take that journey, HDBuzz will be here to help you understand the steps along the way in getting those drugs from the lab bench to the pharmacy shelves.