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Scientists have developed a new model that maps out the different stages of Huntington’s disease (HD) in detail. Using artificial intelligence approaches, the researchers were able to sift out information from large datasets gathered during observational trials contributed by Huntington’s disease patients. A team of researchers from IBM and the CHDI Foundation have published a new model of HD progression in the journal Movement Disorders that they hope will improve how HD clinical trials are designed in the future.

Predicting the progression of HD symptoms is complicated

HD is caused by an expansion in the huntingtin gene which leads to the production of an expanded form of the huntingtin protein. Studies of lab models of HD as well as people carrying the HD gene, show that having the expanded gene and making the expanded form of the protein causes a cascade of problems. Starting with small molecular changes, people with HD will eventually end up experiencing a range of different symptoms related to thinking, movement and mood that get worse over time.

Symptoms of HD typically start to show between the ages of 30 and 50, but a number of factors influence when this happens. We have known for a long time that people with bigger expansions in their huntingtin gene tend to get symptoms earlier, healthy lifestyle choices like a balanced diet and regular exercise can delay symptom onset, and other so-called genetic “modifiers” can also influence how early the disease might affect a gene carrier.

However, there’s still a lot we don’t understand about how Huntington’s disease progresses over time and how the symptoms get worse. To try and tackle this problem, scientists from around the world have run numerous observational trials and natural history studies where patients’ symptoms, biomarkers, and other measurements are monitored over time. These include PREDICT-HD, REGISTRY, TRACK-HD, and Enroll-HD. Together these studies have generated very large datasets which comprise more than 2000 different measurements recorded from 25,000 participants. This is tons of really helpful data, all made possible by the dedication of HD families to participating in these trials.

Machine learning helps us learn more about HD progression

Scrutinising all these datasets at once can help scientists spot new patterns and make novel conclusions but doing this type of analysis manually is extremely laborious and challenging. This is where the clever computer scientists come in! Scientists are able to use cool new methods to get the computers to look at all the data at the same time using special types of programs often referred to as artificial intelligence or AI.

One commonly used AI approach is called machine learning. This type of AI software becomes better at making predictions of certain outcomes by building models from training data sets which it uses to “learn” without being explicitly programmed to do so. Machine learning is a field in its own right in biomedical research but also has lots of different applications for things like email filtering and speech recognition.

IBM and CHDI researchers used machine learning approaches to build and test a new model to understand how HD progresses and to categorise different disease stages. The model was then tested against a number of different measurements commonly collected and compiled in HD research that track disease progression, including the Unified Huntington’s Disease Rating Scale (UHDRS), total functional capacity (TFC), and the CAG-age product, also called the CAP score.

The new model defines 9 states of HD, all specified by different measurements that assess movement, thinking, and day-to-day function. These states span from the early stages of the disease before motor symptoms begin, all the way through to the late-disease stages that have the most severe symptoms. The model was able to predict how likely participants in the studies were to transition between states as well as how long participants spend in the different phases of HD. While other studies have determined that the entire disease course occurs over a period of about 40 years, this is the first time researchers have predicted the expected amount of time HD patients will spend in each of the 9 states that were described in the new model.

New models of HD progression will hopefully inform clinical trial design

Having this handy new 9-state model of HD progression can help scientists and clinicians learn more about the different stages of HD and the timeframes it takes people with HD to move from one state to the next. With this information in hand, the researchers at IBM and CHDI believe this could help select the best-suited participants for particular HD clinical trials, identify robust biomarkers for monitoring how the disease progresses, and also help design better clinical trials.

This is an exciting step forward for HD research and we look forward to learning more about other AI applications in HD research as novel approaches are designed and this exciting field of science matures further.

For those who were following the live tweets from HDBuzz about the CHDI HD Therapeutics Conference or tuned in to the HDSA Convention, we may have caught your attention with the new HD staging system. And if you missed it, you’re in luck! The publication detailing this new classification system, how it’s used, and its benefits is hot off the press. Let’s see what they have to say.

Tracking disease progression – time for an update

Until now, people with Huntington’s disease have been categorized primarily based on their clinical symptoms. Physicians watch a patient walk, perform hand movements, or ask them to think of different words. A mix of tests related to thinking, movement, and mood helps medical doctors gauge where individuals are in the course of their disease.

Diagnosing patients and categorizing their disease stage with clinical symptoms has been going on since the 1800s, long before scientists identified the gene that causes Huntington’s! However, this type of categorization of people with HD is quite dated, and it doesn’t always capture the full picture.

Currently, “pre-symptomatic”, “prodromal”, or “premanifest” patients all fall into a single category. These are individuals who are gene positive for Huntington’s but have no clinical signs of the disease – or at least no movement symptoms, which are the most common way HD is diagnosed. This category can include individuals from birth until about the age of 40. This is a huge pool of patients over a long period of time!

As research around Huntington’s disease advances, we’re learning a lot about very subtle changes that occur even decades before any clinical symptoms are apparent. This has prompted a team of researchers, known as the Huntington’s Disease Regulatory Science Consortium (HD-RSC), to develop a more sophisticated scoring system.

How the new system was developed

The Huntington’s disease Integrated Staging System – HD-ISS – combines information from brain scans, clinical tests, and day-to-day abilities to determine where HD patients are in their disease. This new scoring system takes into account the entire life of the individual, classifying every age, from birth to death.

To develop this new scoring system, the HD-RSC team used data from the Enroll-HD, TRACK-HD, IMAGE-HD, and PREDICT-HD trials, all observational studies which follow people in HD families over time. A big thank you to everyone who has or is sacrificing their time to participate in these trials – you’ve made the creation of this new scoring system possible! They also consulted a variety of different groups, including patient advocacy groups.

HD-ISS stages

In a recent talk to the HD community at the HDSA Convention, Dr. Sarah Tabrizi, who is leading the charge on the HD-ISS, likened the new system to what is used in cancer. Cancer is classified into stages based on the size and spread of the tumor. The HD-ISS will work in a similar way, categorizing patients into 4 stages – stage 0 through 3 from no impairment (birth) through severe impairment (end-of-life). Each stage is sequential, meaning a patient will experience components of the previous stage to be classified into the following stage. The staging system is also progressive, meaning patients will always begin at stage 0 and progress through to stage 3.

Stage 0: HD gene present, no other changes

An individual who has been genetically diagnosed with HD (40 or more CAG repeats), but has no detectable changes associated with Huntington’s disease. This stage begins at birth and tracks an individual until they have some sort of detectable change.

Stage 1: HD gene present, biomarker changes only

Individuals move into this stage when there are detectable changes in biomarkers known to occur with Huntington’s disease. Based on data from thousands of participants in clinical studies, the biomarkers they chose were the volume of 6 specific areas of the brain using MRI. Changes in these areas are known to decrease in people with HD as cells in the brain are lost.

Stage 2: HD gene present, biomarker changes, and clinical signs

This stage begins when a patient shows clinical signs of Huntington’s disease. The new scale focuses on motor and cognitive changes, as measured with movement tests and a thinking task that asks people to pair numbers with symbols.

Stage 3: HD gene present, biomarker changes, clinical signs, and difficulties with daily function

The last stage begins when a patient experiences functional decline, such as difficulty carrying out day-to-day tasks. Additionally, stage 3 is broken up into mild, moderate, and severe functional decline. Mild stage 3 includes individuals that may take a long time to do routine tasks, but don’t require assistance. Moderate stage 3 includes those who require assistance with some routine tasks. Severe stage 3 includes those who require assistance with all routine tasks.
The amount of time spent in each disease stage will differ from person-to-person. How quickly an individual progresses through each stage is variable, but strongly depends on age and CAG repeat length.

Why we need the HD-ISS

The HD-ISS will help standardize clinical research by categorizing patients in a more predictable way. This will allow clinicians conducting clinical trials to more quickly select research participants for studies who are likely to have a similar disease course or respond similarly to a treatment. Standardizing the categorization of different stages of Huntington’s disease, particularly between birth and the onset of clinical symptoms, is necessary to help the field move toward testing drugs earlier, before clinical symptoms are apparent. Many people think the most effective time to treat HD will be before a person even gets sick, so having a system in place before these trials are designed is critical.

Also, these clear delineations of patient populations will make it easier for researchers to compare data across studies – something that has been a bit muddy in the past because of loose definitions of disease stage. Comparing data across studies will allow researchers to gain as much information as possible from each trial, which will decrease the amount of time it takes to get to our end goal – a treatment for HD.

How will the HD-ISS affect research and care?

It’s important to note that the HD-ISS is focused on research – it aims to streamline the design and recruitment of clinical trials. This newly published system doesn’t mean that doctors who treat HD will suddenly be categorizing their patients. In fact, that’s not necessary to develop an individualized treatment plan based on a person’s current symptoms. But once therapies to slow disease progression become available, the system could help guide treatment decisions.

Another key message is that a more rigorous system for trial selection doesn’t mean the therapies being tested couldn’t benefit others in a different stage of HD. This is first and foremost a way to make trials smoother and data easier to interpret, which has the potential to speed the drug pipeline by leaps and bounds.

Implementation of the new HD-ISS scoring system should be straightforward for the Huntington’s community. In fact, the upcoming PTC Therapeutics trial for PTC-518 will be the first to use the HD-ISS. Most of the measurements collected for this staging system, like CAG repeat length, brain imaging, and functional capacity scores, are standard in Huntington’s disease research. Standardizing the way various stages of Huntington’s disease are classified is a clinical advancement that will help organize trial selection and data interpretation as we advance toward treatments for HD.

A research group in Spain is planning a clinical trial to explore if biotin and thiamine supplementation may help treat motor symptoms of Huntington’s Disease. This strategy emerged from their observations that some protein changes in both mice and people with the HD gene mutation resembled those seen in another rare brain disorder, biotin-thiamine responsive basal ganglia disease (BTBGD). Like HD, BTBGD affects a part of the brain called the striatum and causes movement problems. Daily biotin and thiamine vitamin supplementation is an approved treatment for BTBGD, and has been used with success for individuals with this condition. A recent publication provides some evidence that this treatment could be worth a try in HD, too, but a rigorous clinical trial in people with HD would be needed first.

Approaching Huntington’s disease treatment from a new angle

Individuals with Huntington’s Disease (HD) have a mutation in a gene called huntingtin, which creates an expanded, longer-than-normal huntingtin protein. The protein builds up in the brain and is thought to be toxic to brain cells, leading to the symptoms of HD. Research on HD treatment has largely focused on targeting the huntingtin gene and protein itself. Many of these treatments and therapies aim to lower huntingtin protein levels through various methods, and several current clinical trials, both past and present, have been developed with this goal in mind.

However, the field of HD research is diverse, and scientists are exploring other treatment targets from different angles. Recently a group of HD researchers in Spain has investigated the role of a family of proteins called CPEBs in neurodegenerative diseases. The research group’s work was published in Science Translational Medicine in September of 2021 and presented by Dr. Jose Lucas on Day 1 of the CHDI HD Therapeutics conference in March 2022.

The basic job of CPEB proteins in cells is to modify the genetic RNA message molecule in a way that affects the size and the amount of the proteins the RNA message produces. CPEBs affect protein creation by lengthening or shortening a part of the RNA message called the poly-A tail. This tail can be placed in slightly different locations, allowing one gene to make different “recipes” to produce proteins of multiple lengths. When a poly-A tail is very short, this signals that the RNA recipe should be destroyed. Therefore, the actions and amounts of CPEBs can significantly affect the lengths and levels of important protein molecules in cells.

From CPEBs to vitamin deficiency

CPEB proteins are known to play a role in brain development and in adult nerve cells. Changes in the actions and levels of CPEB proteins have been seen while studying autism and epilepsy, but CPEB proteins had not yet been looked at closely in neurodegenerative diseases like HD. In this recent study, Lucas’s team observed changes in CPEB levels in the brains of humans and mice with the HD gene. This led them to look more closely at how that affected the levels of other RNA messages and proteins related to HD and other brain diseases.

One of the genes affected by changes in CPEB levels was a gene identified in biotin-thiamine-responsive basal ganglia disease (BTBGD). This is a very rare genetic disorder (one in a million) that usually strikes in early childhood and hinders the brain’s ability to use dietary thiamine (also known as vitamin B1). Like HD, BTBGD causes damage to a part of the brain called the striatum, which leads to problems with movement, mood, and thinking. But unlike HD, there is a treatment that can do more than manage symptoms. With daily oral administration of biotin and thiamine, complete clinical recovery from BTBGD is typically reported if treatment is started soon after noticing symptoms, and if lifelong treatment is maintained. The clinical similarities between BTBGD and HD and their genetic findings prompted Lucas’s group to explore whether thiamine deficiency could also be occurring in HD, and if vitamin supplementation could be a way to treat it.

Indeed, the researchers found that mice with HD showed BTBGD-like bloodwork, including thiamine deficiency, and human HD brain tissue also showed signs of thiamine deficiency. This led them to move forward with testing a combination of high-dose biotin and thiamine in two types of mice with HD. The treatment prevented deficiency in brain thiamine, improved brain health, and decreased the rate of loss of nerve cells, in comparison to untreated mice. Based on these observations, the researchers think it’s possible that individuals with HD might also benefit from thiamine and biotin vitamin supplementation.

Moving findings in mice into people?

These promising results in mice don’t mean that individuals HD should start taking large quantities of biotin and thiamine from the grocery store. The research done in mouse models was limited to the motor symptoms of HD and did not evaluate the cognitive and psychiatric symptoms of HD. As we’ve learned many times over, animals and cells in a dish can provide valuable insight into HD and a starting point for testing therapies, but the only way to test safety and effectiveness of new treatments is to conduct clinical trials. To date, promising vitamin-based therapies (CoQ10, for example) have not panned out in human trials.

Despite these limitations, a randomized trial based in Spain to use biotin and thiamine to treat people with HD is being designed, with the hope that the combined oral therapy might be able to modify the progression of HD in people with HD in the early-to-middle stages. Clinical testing may be a logical next step, though some researchers and clinicians have questioned why the design of the trial does not include a placebo group for comparison. Nevertheless, vitamin supplementation is easily implementable, and high dose combination treatment of biotin and thiamine has already been proven safe. Furthermore, both vitamins are approved by various regulatory agencies and are available at a low cost. We are encouraged by the knowledge that this type of therapy is evidence to be well-tolerated, safe, and effective for patients with BTBGD and look forward to hearing more news about the upcoming trial in people with HD.

Scientists at Novartis and The Children’s Hospital of Philadelphia have recently published a paper detailing how the drug branaplam, originally developed for the neurological disease spinal muscular atrophy (SMA), could be repurposed to treat Huntington’s disease. Branaplam can lower levels of the huntingtin protein and is now being tested in the clinic in a phase IIb study, VIBRANT-HD.

Huntingtin-lowering therapies are being pursued by lots of companies

Despite setbacks with some recent clinical trials, many experts in the field agree that huntingtin-lowering remains an attractive strategy for treating HD. Every person with HD has an expansion in their huntingtin gene which means they will make an expanded form of the huntingtin protein. This expanded form of the protein seems to be toxic and is thought to cause to the signs and symptoms of HD. If we can reduce the amount of this toxic form of the protein, researchers hope we might slow or stop the progression of HD.

Lots of companies are testing huntingtin-lowering drugs in the clinic, including Roche, Wave Life Sciences, and uniQure, all of whom are using slightly different approaches to target the genetic message which is made into the huntingtin protein. The drugs they have developed cannot easily spread through the body, so they are given to patients through spinal tap or direct injection into the brain. While this means the drug can get to the parts of the body most badly affected by HD, these procedures are demanding for patients and very expensive. These are also not treatment options which could be trivially rolled out to the global community of people with HD due to healthcare access issues and prohibitive costs.

Repurposing an SMA drug to try to treat HD

What scientists call “small molecule therapies” are an attractive option to treat diseases affecting the brain. This type of drug can often be formulated so it can be taken orally as a pill or syrup, which is much easier for patients, and these drugs have a better likelihood of crossing from the bloodstream into the brain so patients can avoid onerous procedures. For a long time, it was a pipedream for many folks in the HD community that a small molecule huntingtin-lowering therapy could ever be made and then, two independent companies did just that! Very similar drugs developed by both Novartis and PTC Therapeutics can lower huntingtin – we recently wrote about a paper which describes the PTC drug on HDBuzz. Now we have more details about the Novartis drug, called branaplam.

Branaplam targets machinery in our cells which processes genetic messages, called splicing machinery. Each genetic message can be thought of like a story book, and when the story is over, the final part of the message reads the genetic equivalent of “the End” to tell the cell that the sequence for that message is complete. Drugs like branaplam rejig the pages of the story book so “The End” is read before it makes sense. When this happens, the cell will destroys the message and won’t make the associated protein, similar to how you might get rid of a book that had a premature ending which made no sense.

Branaplam was originally developed for a fatal childhood disorder called SMA because it also changes the levels of a protein called SMN2, which underlies that disease. Scientists at Novartis discovered that branaplam also changed the levels of the huntingtin protein so switched gears to test if branaplam would be a good treatment for people with HD and have now published their findings which we’ll digest for you here.

Working out how branaplam lowers levels of the huntingtin protein

First, the research team treated cells in a dish with branaplam and looked at how the genetic messages in the cells were affected. They found that a signature in the huntingtin genetic message, which is normally chopped out by the splicing machinery, called a pseudoexon, was kept in the message molecule in branaplam treated cells. The scientists went on to show that this reduced the amount of the huntingtin genetic message because keeping in the pseudoexon genetic code, targets the huntingtin message to the trash bin of the cell. When the branaplam treated cells were no longer treated with the drug, this effect was reversed, and the levels of the huntingtin message bounced back to normal.

Whilst changes to the huntingtin message are a good sign, what we are really interested in is the levels of the huntingtin protein. The team measured huntingtin protein levels when different amounts of branaplam was dosed in cells in a dish and showed that the more drug was given, the more the level of huntingtin protein was lowered. The team next tested if this finding held true for cells in a dish derived from people with HD i.e. folks who have the Huntington’s disease mutation. They showed that the levels of huntingtin message and protein were also reduced by branaplam in these cells too.

Insights from branaplam in HD animal models and SMA patients

Next, the scientists went on to see how branaplam performed in a mouse model of HD. Mice were given different oral doses of branaplam and then the levels of the huntingtin message were measured in different areas of the brain. In four different brain regions, they showed that the level of the huntingtin message including the pseudoexon was increased the more drug that was administered. This was matched by a decrease in the levels of the huntingtin protein. The scientists found that if mice were no longer treated with branaplam, the effect was reversed and huntingtin levels bounced back.

Lowering the levels of huntingtin is all well and good, but what the research team really wanted to know is if this improved symptoms in the HD mouse model. Next, they tested the motor skills of the HD mice who had been treated with branaplam and compared them to HD mice which hadn’t be treated as well as regular lab mice. The scientists suggest that the branaplam treated mice are more like the regular mice but the presented data is fairly limited.

The team finally looked at the levels of the huntingtin message in blood from branaplam treated SMA infant patients. Patients in the open-label extension of the SMA branaplam trial received weekly doses of branaplam for over 2 years. After over 900 days, a sustained decrease in the levels of the huntingtin message in these blood samples could still be seen, showing ~40% decrease at this timepoint in the study. The Novartis team believes this indicates that the drug was having the desired effect over a long period of time in people.

What’s next for branaplam?

We recently heard from scientists at Novartis at the recent CHDI therapeutics meeting who gave us updates on their branaplam program. Dr Beth Borowsky gave us details of a now completed phase I study, where the drug was tested for the first time in adults to figure out a safe amount and frequency of dosing. As branaplam was originally developed to treat SMA in infants, figuring out a safe dose for adult patients is an important first step.

The next step for branaplam is a phase IIb study called VIBRANT-HD. This will be the first time branaplam is tested in adults with HD and this study will work out what dose of the drug needs to be administered to lower huntingtin. Branaplam will be given as an oral liquid, like cough medicine, that people in the trial will drink once a week. Different patients will be given different doses of branaplam so Novartis can work out what dose will work best for a second phase of the trial. Lots of different clinical measurements will be collected from participants in the trial, including levels of various biomarkers, like huntingtin and neurofilament. Recruitment for this trial is underway and hopefully we’ll hear updates on how the trial is proceeding soon.

Good morning! Today is the 3rd and final day of the #CHDI HD Therapeutics Conference in Palm Springs. Follow our feed today to get live updates!

Biomarkers and clinical tools

The fourth session of research talks will cover biomarkers and clinical tools for diagnosing, tracking, and treating HD. It is being introduced by Dr. Edith Monteagudo of CHDI and Dr. Niels Skotte, of University of Copenhagen.

Biomarkers Task Force!

The first talk is by Dr. Cristina Sampaio & Dr. Robert E Pacifici, both from CHDI. They’ll be discussing CHDI’s Biomarker Task Force, focused on developing a strategy for moving biomarkers for HD forward.

Biomarkers are critical for drug development. They allow researchers to track how patients are progressing as their disease advances. They’ll also be critical as the field moves forward with treatments, because they’ll allow researchers to determine if patients are getting better. CHDI and other organizations are committed to making biomarker data (and many other types of data) available in a way that can benefit the entire HD research and family community, not just an individual company. CHDI is focused on advancing biomarkers related to imaging (such as MRI scans), blood, and spinal fluid.

One molecule that didn’t turn out to be a great biomarker in blood is expanded huntingtin. Even though it’s directly involved in causing HD, it turns out it doesn’t track well with disease progression. It seems like imaging is a strong bet in the biomarker field. Identifying biomarkers that can be assessed using imaging would give researchers a non-invasive way to continually track HD patients over time. Another key component of defining biomarkers is to find those that change with very early HD progression. This will allow researchers to start monitoring disease at the very earliest stages, before symptoms appear – a time when some think treatment needs to begin.

The lengthening of CAG repeats in some cells over time, known as somatic repeat expansion, is not only gaining interest because of the effects it has on age of disease onset, but it may also be useful as a biomarker. There are also ways to take advantage of “wearables” – digital devices, like watches, that people with HD can wear to gather lots of data in real time. These devices could track movement, sleep habits, and other metrics. CHDI has a 2-year goal for defining some of these important biomarkers and is eager to collaborate with the entire HD research community for this important project.

Biomarker discovery – the future is bright!

The next speaker is Dr. Jim Rosinski from CHDI. He’ll be sharing his work using large datasets that will help profile people with HD for biomarker discovery. He feels “the future is bright!”

We are in a new age of data where scientists are able to measure thousands of changes in genetic messages and protein over time in many individuals. Using powerful analysis techniques, sorting through this data can be very valuable for drug development. Doing this requires a strong “pipeline,” from being able to collect blood and spinal fluid samples from many people with HD, to developing the skills and software to understand the data. This is where observational studies like Enroll-HD and HDClarity come into play.

Samples donated by HD families who participate in these studies are essential for the many different types of analyses that can be made, by looking at how genes turn on and off, and examining changes in levels of different forms of RNA and protein. Looking at changes in protein levels across a brain area, organism, or group of people with a disease is known as proteomics. Using spinal fluid samples donated through the HDClarity study, researchers can link clinical data from Enroll HD with protein changes.
Dr. Rosinski shared some exciting preliminary data tracking many proteins in a large group of HDClarity participants. Looking at each individual protein alongside clinical data will help define biomarkers for disease progression and identify routes for drug design.

One biomarker that’s been defined in HD is neurofilament light – NfL. It turns out, it’s a really great biomarker! Dr. Rosinski found that just looking at this one protein can predict HD status! Wow! They also identified a few other proteins that are predictive of where a person might be in their HD symptoms. Ultimately, combining these findings could power more individualized care and treatment in HD.

The future is bright! Instead of scientists talking about IF we’ll have a treatment for HD, they’re focused on WHEN we get a treatment, we need biomarkers that will help us track how patients are doing. We’ve come a long way!

Next up is Dr. Aline Delva from KU Leuven. Dr. Delva will be describing her work using a type of imaging called PET. We recently wrote about it here: https://en.hdbuzz.net/319

PET ligands allow scientists and clinicians to visualize things inside the body or brain. This particular ligand is designed to stick to huntingtin and make it light up in a brain scanner, so levels can be tracked over time, and eventually during treatment.
Dr. Delva is sharing new data from a human study where the PET ligand sticks to synapses, connection points between brain cells, to track their health over time, especially in areas of the brain that are most vulnerable to HD.

It appears that these PET ligands can detect changes even in premanifest HD patients! This is great news because it gives researchers a tool to determine if a treatment is making a patient better before there are even noticeable HD-related changes.
Next, Dr. Delva described her work looking at PET ligands that examined the huntingtin protein itself. The goal of this study was to determine if huntingtin could be used to track disease progression using PET technology. After testing the PET ligands in mouse and primate models, they did a small study in humans, and were able to figure out the best one to use, and find a safe and effective dose.

The results from the study showed that the PET ligand is useful for lighting up the cortex and striatum – brain regions that are particularly vulnerable in HD. While this is expected, it’s exciting because it shows that this tool could work well for studying HD! A major advantage of these PET ligands is that they are examined using noninvasive, painless imaging techniques – similar to an MRI. So they can be done relatively easily and frequently on HD patients to track disease progression. All great qualities for a biomarker!

Next steps will be to expand these studies by testing the PET ligands in a larger group of people with HD. Such tools are now widely used and accepted in the Alzheimer’s disease field, which sets a good precedent for their development in HD.
We’re taking a break, but will be back shortly after refueling with some coffee! Stay tuned!

Digital Monitoring of HD

Up next is an exciting update from Drs. Peter McColgan and Jonas Dorn from Roche are here to provide an update from the GENERATION-HD1 trial of Tominersen. Appropriately, Dr. McColgan begins with an acknowledgement of the disappointment of HD families and thanks them for their incredible contributions to these studies.

The specific update for this talk is a discussion of some results from the digital monitoring platform – digital tools used to track HD progression in participants in Roche’s various studies with tominersen. The trial participants had a smartphone to track measurements of HD-relevant symptoms, such as movement and cognitive changes. These are do-it-at-home versions of the kinds of tasks that physicians use to track HD in clinics.

Data was collected from 784 patients, with more than 350,000 days of tests recorded. That’s a lot of information to process! Each participant spent 30-60 minutes per day, on average, conducting tasks on their phones. Many of the tasks reveal clear changes between HD patients and controls, including a speeded tapping task. This requires participants to quickly and repetitively tap a button, which becomes more difficult as HD progresses.

Because at-home testing is new, the team compared results for tests done at home, then repeated in a formal clinical setting. This resulted in excellent consistency – so collecting data at home seems feasible. Surprisingly simple tasks – including the speeded tapping – show very clear worsening during the course of the trial. This suggests these measures could be useful for future trials, and potentially save participants and families having to do so much in a clinic.

Dr. Dorn explains that there are some complexities in the digital data. For example, people who were doing worse on some tasks were more likely to stop completing the tasks early. Perhaps because those are the people with more severe symptom progression? For some of the tasks, including a “draw a shape” task, trial participants were clearly learning how to do the task faster. This is called a “practice effect,” and it makes it tricky to generate useful data over a long time for those tasks.

A lot of work remains to digest these huge sets of data from the participants in Roche’s tominersen trials. Expect to hear more from Roche as they continue to dive into the data.

In the next talk, Dr. Sarah Tabrizi (UCL) and Dr. Jeff Long (University of Iowa) will talk about the development of a staging system to help better define where a person is in their HD journey. This will be important for planning trials in people who haven’t yet shown symptoms.

Staging systems are very important for grouping people with similar disease characteristics so they can be properly treated based on their current symptoms. This has been very helpful in fields like cancer treatment. HD needs this kind of staging system because it is still mainly diagnosed based on chorea, which can occur much later than other thinking and mood changes. By analyzing tens of thousands of data sets from people with HD, a large consortium of researchers has been able to create a system with stages 0 through 3. This demonstrates the power of participating in studies like Enroll-HD.

At the scale’s most basic level, 0 means the person has the gene but nothing else has changed, 1 is when biomarker changes can be detected (like in blood or brain images), 2 is changes measured in clinical tests, and 3 is when HD begins to affect day to day function.

Creating a scale for use by the entire clinical and research community is important for ensuring that care and research are consistent and we can learn as much as possible from every trial. The research community is now building powerful new tools around this existing scale. One example is a program to help determine whether an individual is a good fit for a clinical trial by taking into account their CAG repeat number, their age, and the results of many tests and brain images.

Combining and analyzing many measurements – brain images, tests of movement and thinking, shifts in abilities at home and work, potential changes in blood and spinal fluid – is a very powerful way to track progression and determine response to a drug.
As with many aspects of HD, there can be a lot of variability within the four stages, and researchers are tackling ways to further define them based on things like age, genetics, and findings from exams in the clinic.

This is an even more refined way to help recruit the right people for trials than current methods, which use clinical scores (you may have heard of CAP or PIN). This conference is a great venue for presenting novel tools like this because so many players in HD research are present.

It’s lunch time for us here in sunny CA. We’ll be back after the break to share exciting updates from various HD clinical trials. Tune back in soon!

Clinical and Human data

We’re back for the last session of the conference! We’ll be sharing exciting talks focused on recent clinical trials.

Up first are Dr. Jamie Hamilton and Dr. Mark Guttman from University of Toronto who will be introducing this clinical session. Dr. Guttman is acknowledging the resilience of the HD community over the past few years and the continued hope to be found in clinical trials.

Tominersen in the spotlight

The first talk this afternoon is from Dr Peter McColgan and Dr Lauren Boak from Roche. They will be giving us an update on tominersen, the huntingtin-lowering drug under investigation in the Phase III GENERATION HD1 study. Lauren is kicking things off – she has shared the slides of the Roche presentation through this link if you want to follow along or look at these later: https://bit.ly/3sH1faG

Roche has several approaches for lowering huntingtin. They’re not just using tominersen to lower total huntingtin, but they also have programs to specifically reduce levels of the expanded huntingtin copy and other tools they’re exploring. It’s encouraging to hear that Roche is committed to HD. But today Lauren will just be focusing on what they learned in GENERATION-HD1 with their tominersen program. The final analysis of the data from this trial is ongoing.

There are in fact 3 different trials Roche is conducting where data analysis is not yet complete – the Natural history study, GEN-PEAK study and GENERATION HD1 but today the focus will be on the halted phase 3 GENERATION HD1 study. Lauren is now recapping the data from animal models which informed the trial. These were used to determine the dose of tominersen in the GENERATION HD1 study – 120 mg every 8 or 16 weeks which Roche predicted would lower huntingtin by 25-45%.

Now Peter will tell us about the analysis they’ve done so far of the data from GENERATION-HD1. Levels of expanded huntingtin were reduced in both the 8 and 16 week groups as predicted. This suggests tominersen was engaging the target. However, when they looked at certain scores that measured overall how participants were doing, people who were treated with tominersen did worse than people who were treated with placebo, particularly when treated every 8 weeks.

Peter shares that more adverse events (side effects) were seen for folks who got the drug more frequently, fitting with the trend we see with the overall scores for patients in the different drug groups. Our previous session taught us a lot about biomarkers for HD. One biomarker we learned about was NfL. Unexpectedly, Roche found that NfL levels went up after tominersen dosing. They’re still not sure why this is.

Tominersen lowered huntingtin levels but the trial did not reach its endpoints and did not improve symptoms in patients. Scientists are now working hard to understand why.

Roche have been looking at the data collected from patients in the trial after they stopped taking tominersen. 84% of patients stayed in the trial even after dosing was halted which is very helpful for Roche scientists to try and figure out what happened.
The number of patients that stayed in the trial following the dosing halt is a true testament to HD patients. From this it’s evident that the HD community is passionate about participating in research and contributing to finding a treatment.

Changes in brain structure were reported for patients in the trial with bigger changes seen for patients who took the drug more frequently. Peter suggested there may be some recovery of the brain structure after dosing was stopped, but analysis of this data is ongoing. Roche scientists used a common clinical measurement called UHDRS which looks at lots of different signs and symptoms of HD. Looking at this score after dosing was halted, no significant difference was seen between people who did or did not receive the drug in the trial.

A similar pattern is seen in another clinical measurement called total functional capacity, which measures daily function in activities at home and work. There was no statistically significant difference between patients after dosing was stopped. Roche wanted to divide people in the trial into groups to see whether severity of symptoms might have played a role in how they responded to the drug. This was done after the trial was designed, known as a post-hoc analysis – so all results must be taken with a pinch of salt.

As we previously wrote, Roche thinks that younger participants who had less advanced symptoms of HD might have done somewhat better in the trial than older more advanced ones. https://en.hdbuzz.net/316

BUT! This is not a statistically significant finding and is the subject of heated debate by scientists in the field. Roche have sliced and diced the data in lots of different ways to work out if the drug was beneficial for a subgroup of patients. Another factor is how much drug the patients were exposed to which they work out by measuring the drug in spinal fluid.

Peter is now sharing data which suggests people in the trial exposed to less of the drug might have fared slightly better, but, again, there are not enough people to power these statistical analyses. A lot of folks working on making medicines for HD will learn from this trial to help inform the design of future clinical trials, including which types of drugs, dosing, and delivery might work best. The data seem to indicate that younger less advanced HD patients might be better candidates for huntingtin lowering, and that lower drug doses may be more beneficial. This doesn’t mean it couldn’t help a wider population, but it’s useful for designing the next trial.

In a new phase II study, Roche plans to enroll younger people with HD, with less advanced symptoms, and to use 2 new doses. These were not disclosed in the talk, but they would be lower than the doses used in the GENERATION-HD1 study. Peter is now talking us through how this younger cohort fits into the new HD-ISS staging which was described in the talk by Prof. Tabrizi earlier in the day. This new system will be important to help define exactly which people might benefit from huntingtin-lowering drugs like tominersen.

The Q&A is lively and technical! No details have been shared yet about the potential Phase II trial, but it will once again rely on the strength and enthusiasm of future participants and their families.

Gene therapy for early stage HD

Next up is neurosurgeon Dr David Cooper from uniQure who will give us an update on the gene therapy trials, HD-GeneTRX-1 and HD-GeneTRX-2, for their one shot drug called AMT-130 which they are testing to treat early-stage HD. Dr. Cooper describes the structure of the drug – a harmless virus particle filled with instructions to make a set of RNA that leads to the lowering in of the Huntigntin gene into regions it is injected into. In this case, deep brain structures.

UniQure did a lot of studies of their drug in a range of different HD models including cells in a dish as well as monkeys and pigs. These studies informed their studies now underway in people with HD. The deep parts of the brain impacted most in HD – the “striatum” – are tricky to reach, and hard to infuse with uniQure’s viral particles. Decades of work have led to procedures for infusing brain structures to maximize how much is treated with drug.

AMT-130 lowers total huntingtin – the normal and the expanded forms of the protein. uniQure’s goal isn’t 100% reduction of huntingtin, but to significantly lower levels, for life, after a single injection. There are two studies – one in Europe and one in the US, with 15 and 26 patients respectively. There will be patients with low dose, higher doses, or placebo.

The primary objective of both studies is to establish whether the treatment is safe and tolerated. Additional objectives include trying to understand if – as predicted by the mouse work done – the therapy is persistent for years after a single injection
As with many trials, there are limitations in who can participate in the study. For example, participants must be able to handle anesthesia. Given the ongoing pandemic, this means that people must be 8-12 weeks past any COVID infection so omicron has made things more tricky.

The current goals are to include people with at relatively early stages of HD, and people whose deep brain regions are preserved enough to safely inject them with the drug. This is the first gene therapy for HD, and the first time anyone has done as many brain injections as uniQure is planning to do – 6! This gives them the best chance to cover the whole striatum with a single surgical procedure. Each surgery is reviewed by a team of neurosurgeons, who must all agree that the planned surgeries are likely to be safe.

No two brains are exactly the same, so each patient’s brain scans have to be carefully analyzed before surgery.
A harmless contrast agent is injected along with the AMT-130 which helps the surgeons see exactly where the injected material spreads to. This allows the surgeons to confirm successful delivery of the drug across the entire targeted region. In the first 4 patients treated, all left the hospital the next day without any serious complications. Similarly, no bad changes were observed in brain imagery during this first year after the patients were treated with AMT-130.

Despite the challenges posed by the pandemic, the US cohort is nearly completely treated, and the first few patients in Europe have been treated. UniQure are now fine-tuning the surgical procedures which are needed to inject the AMT-130 into the brain, to make sure that the drug is going to the right regions every single surgery and that the surgery is not taking too long to do.
What they’ve learned about the surgical procedure will help inform a planned third trial group (cohort) in the US in the near future.

We’re taking a quick break before we head into the final talks of the conference, covering updates from some of the other clinical trials underway right now.

Innovations that led to SELECT-HD

First up after the break is Dr. Michael A Panzara from Wave Life Sciences. Dr Panzara will be telling us about the phase 1b/2a clinical trial called SELECT-HD, which is testing an expanded huntingtin-specific lowering therapy. Wave makes anti-sense oligonucleotides or ASOs which target the huntingtin “message” molecule in the cell, to lower levels of huntingtin protein. This is similar to the approach Roche took with Tominersen except their drug only targets expanded huntingtin.

PRECISION-HD1 and PRECISION-HD2 were trials testing two ASOs against expanded huntingtin. Although the drugs were safe, they did NOT lower huntingtin as expected. Both trials used drugs which were specific to expanded huntingtin as they target genetic signatures called SNPs (“snips”) – parts of genetic code that differ between gene copies – only found on the expanded huntingtin gene.

Wave have since developed another ASO drug called WVE-003 that targets a different SNP and has updated chemistry. This drug can be tested in some of the HD animal models as they also have the SNP targeted by WVE-003 and the results so far are promising. Wave is hopeful that this new approach will allow for more effective lowering of harmful huntingtin at lower doses of ASO, while leaving the healthy form of huntingtin intact. It is being tested now in a new trial called SELECT-HD.

When Wave tested their new and (hopefully) improved drug in HD mouse models, the drug lowered levels of expanded huntingtin by at least 50% and this effect was sustained for about 3 months. The scientists at Wave also checked if unexpanded huntingtin was affected by this new drug. HD mouse models treated with the drug did not have any significant change in their unexpanded huntingtin levels – good news! Wave also tested their drug in monkeys to see how it dispersed in the brain. They wanted to ensure that all of the important regions would get a sufficient dose of the drug – these data were also very encouraging.

In order for people with HD to be enrolled in the SELECT-HD clinical trial, they must have the SNP which the drug targets, so Wave have developed a diagnostic test to check thiss. Wave are designing the trial to be “adaptive” – this means that based on the data, they might change the dose or frequency of dosing of the drug while the trial is ongoing. But these changes won’t affect results since they’re being planned for in the beginning.

Deep brain stimulation in HD

Next up is Dr. Jan Vesper, from Heinrich Heine University in Düsseldorf to discuss HD-DBS. This is a proposed pilot trial for deep brain stimulation in people with HD. Deep brain stimulation is a procedure that uses electrical signals to stimulate the brain. A pilot trial was conducted nearly 10 years ago now which showed that some HD movement symptoms were reduced when people with HD were treated with deep brain stimulation.

A much larger trial called HD-DBS was then run across multiple sites around the world, which looked to measure lots of different clinical signs and symptoms of HD in participants who received the treatment or the placebo. To ensure participant safety, the inclusion and exclusion criteria were extensive, so it took a pretty long time to recruit people for the trial, but eventually 48 participants were recruited from Germany, Austria, and France, and about half received the placebo treatment. All data were collected in January of this year and analysis is ongoing. Today we will hear some of the preliminary findings.

For both groups in the trial, those treated with the deep brain stimulation and those who received placebo, some people improved but others got worse. So it doesn’t seem that this treatment is especially promising for folks with HD. Some patients did improve in the trial but its not clear why this might have been and there were no significant differences between those who received the treatment or placebo. Despite the disappointing outcome, researchers developed and refined surgical techniques in this trial that could be applied to future studies in HD and other diseases.

Now we are onto the development of oral huntingtin-lowering drugs! Two companies are working on these treatments for HD. Presenting first is Brian Beers, from PTC Therapeutics. He will be telling us about PTC518, a huntingtin lowering drug which can be taken by mouth.

PTC518 – Update!

In mouse models of HD, PTC518 has been shown to effectively lower the levels of total huntingtin and preclinical data looked very promising. PTC tested their drug in healthy volunteers and showed the drug was having the desired genetic effect of messing with the huntingtin recipe, known as RNA splicing. They were also able to determine a safe and tolerable dose of PTC-518. The scientists also looked at what happened when they stopped treating with the drug and showed that the effects could be rapidly reversed. This is great news if the data suggests dosing of the participants need to be stopped for any reason.

They are sharing the new study design, which will involve two groups of participants who will get either a low or a high dose for 12 weeks. 162 patients will be recruited in this trial which they aim to begin in the first quarter of 2022. PIVOT-HD will be the new phase II clinical trial, which aims to demonstrate that PTC518 works to reduce huntingtin levels in people with HD and they will track important biomarkers to see how the drug is working. PTC will look at the safety of the drug as well as changes to the levels of huntingtin protein, the biomarker NfL, different clinical measurements of HD signs, and symptoms.

The trial is about to get going in the US, UK, France, Germany and Australia. Hopefully we will be hearing updates from PTC soon!

Branaplam – an oral HTT lowering molecule

The final talk of the conference will be from Dr Beth Borowsky, from Novartis Pharmaceuticals. We will hear some updates about the VIBRANT-HD, a phase 2b trial investigating the huntingtin lowering drug, branaplam.

Dr Borowsky explains how taking a drug by mouth has a lot of benefits for patients compared to other therapies delivered by more taxing routes, such as spinal injections or brain surgery. A pill can also work on the whole body, rather than just the brain, and the effects can be reversed!

Branaplam was originally developed for a fatal childhood disorder called SMA, but in an amazing twist of science was found to also lower huntingtin, so Novartis redirected their efforts towards HD. Branaplam targets machinery which processes genetic messages, called splicing machinery. Changing how messages are spliced can affect how much protein is made from the message, so drugs that modify splicing can change the levels of proteins in the cell.

In a phase I study, the drug was tested for the first time in adults to figure out a safe amount and frequency of dosing. This was important because branaplam was developed to treat SMA in children. VIBRANT-HD is a phase IIb study which will test branaplam for the first time in adults with HD to work out what dose of the drug needs to be administered to lower huntingtin.

Branaplam is given as an oral liquid that patients drink once per week. Different patients will be given different doses so Novartis can work out what dose will work best for a second phase of the trial.

Lots of clinical measurements will be collected from participants in the trial, including levels of various biomarkers, like huntingtin and NfL. Recruitment for this trial is underway and hopefully we’ll hear updates on how the trial is proceeding soon!

That’s all folks! Thanks so much for following along. You can read our daily reports for the CHDI conference at https://hdbuzz.net