HDBuzz

uniQure is a company specializing in gene therapy, and they have been working on an experimental drug for Huntington’s disease (HD), called AMT-130, that is delivered via brain surgery. This is an unprecedented genetic approach to treating HD, and safety is the top priority for the first human trials. A press release and public presentation on Thursday June 23rd announced 12-month data on safety and huntingtin-lowering, from the first cohort (group) of 10 people with HD to undergo the surgery. HDBuzz also had the opportunity to speak with Dr. Ricardo Dolmetsch, President of Research and Development at uniQure, to get some additional clarity on what was shared. Overall, the drug and surgery were well tolerated, with no major safety issues arising so far. It can be difficult to interpret huntingtin-lowering data from such a small group, but what’s there so far looks like it could be promising – let’s explore what it means and what’s next for this study.

The first gene therapy for HD

Let’s begin with a refresher on the basics of this trial. Gene therapy is a technique that aims to permanently modify the core instructions from which living things are built. There are different targets and different methods for transporting such drugs to parts of the body and brain, but the key point is that gene therapy aims for permanence, a one-and-done delivery, to treat a genetic disease at its roots. Most HD gene therapies are focused on a technique called huntingtin-lowering, which targets the huntingtin gene or its genetic message molecule, RNA. The aim is to switch off the gene and decrease the amount of harmful huntingtin protein that is madebuilds up in the brain, with the goal of slowing the worsening symptoms of HD.

uniQure is developing an HD gene therapy called AMT-130. They are using an approach where a piece of man-made genetic material is packaged inside a harmless virus and delivered directly to the part of the brain that is most affected by HD, the striatum. This requires a single surgical procedure in which minuscule holes are made in the skull and tiny needles are used to inject the virus into six different locations deep in the brain. The drug spreads into many brain cells and sets up little factories for producing a type of genetic micro-message that tells the cell to make less huntingtin protein.

The state of uniQure’s HD clinical trials

uniQure spent several years testing their drug in different lab models and animals, including pigs that have the HD gene. Then, when it looked like they could safely achieve huntingtin-lowering in a large animal brain, they embarked in 2020 on the first trial in people, known as HD-Gene-TRX1. So far, 36 people are enrolled in different cohorts (groups) of this trial in the USA and Europe, some receiving a low dose of AMT-130, some receiving a high dose, and some receiving an imitation surgery, in which no needles are used and no drug given but the tiny holes are made.

Last week’s press release and an investor-focused presentation from uniQure shared some data, from just the first cohort of 10 participants with HD. 6 of these individuals received the low dose of AMT-130, and 4 were in the “control” group that had imitation surgery. In addition to showing that the drug and procedure were safe and well-tolerated, uniQure was able to share huntingtin-lowering data from 7 of the participants, 4 in AMT-130 group and 3 in the control group.

The very small numbers of people mean that the data is variable and should be interpreted with caution. That said, there may be reason for excitement, even with such a small group.

What was shared in the press release?

The June 23rd press release shared basic data on the side effects of the surgical procedure, levels of huntingtin after 1 year, and a protein called NfL that can act as an indicator of brain health. Essentially, what they shared addresses safety first and foremost, followed by a “biomarker” of how brain cells might be reacting to the treatment, and a measure of whether the drug is acting biologically in the way it’s meant to – this is known as “target engagement.”

Safety & Tolerability

This is the simplest piece to interpret and is solidly good news. The 10 participants were followed closely over the course of 1 year, and the main side effects they experienced were related to the surgery, which was overall very well tolerated. The surgery can take most of a day, and one person had a blood clot from being immobile for many hours, which resolved soon afterwards. Another person experienced delirium after the surgery, a period of serious confusion that happens sometimes after anesthesia, and this also resolved quickly. Those were the most serious side effects; other examples of minor ones were headaches after the surgery, and pain or dizziness after lumbar punctures to take samples of spinal fluid.

Measurements in spinal fluid

The 10 participants in the first cohort had lumbar punctures before having the surgery (“baseline”) and then 1, 3, 6, 9 and 12 months later. This was to allow uniQure to measure changes in levels of huntingtin as well as other biomarkers, like NfL, that can help to give a picture of brain health.

* Biomarkers: Temporary increase in NfL

A biomarker is something in the body that can be measured to give us a picture of an aspect of a person’s health. For a neurodegenerative disease like HD, an ideal biomarker changes reliably as things worsen, and reverts with treatment. NfL, which is released by sick brain cells, tends to increase as HD progresses, so it is increasingly being measured as part of human clinical trials. However, a short-lived increase in NfL can also indicate different types of stress on brain cells, such as that caused temporarily by an invasive brain surgery. As expected, the HD-Gene-TRX1 participants who received the drug had an increase in NfL that went up right after the surgery and slowly returned to baseline levels. For those who had sham surgery and no needles or drug, NfL levels stayed around the same over that time period.

* Target engagement: decreased huntingtin levels

The goal of uniQure’s therapy, from a biological standpoint, is to target the genetic “message” created by the huntingtin gene, so that less huntingtin protein is made in brain cells. So for AMT-130, “target engagement” means lower levels of huntingtin. They were only able to make accurate before-and-after measurements in a subset of participants, but despite this roadblock, it already looks like AMT-130 may be lowering huntingtin protein. For people who received the drug, they found that huntingtin levels dropped over time, and by 12 months they were about 50% lower on average. The people in the sham surgery group had lots of variability in the levels of huntingtin in their spinal fluid but looked fairly steady. Again, the numbers are way too small to talk about statistical significance, but overall it looks like the drug is doing what it is designed to do.

The trials and tribulations of measuring huntingtin

Ideally we would have a clever way to look directly in the brain at huntingtin levels before and after treatment, and scientists are working on tracers which would allow us to do just that, but these are not ready to use in drug trials just yet. Instead, scientists measure the very small amounts of huntingtin protein found in spinal fluid as a proxy, and these measurements are a technical challenge for the entire field of HD research. Of the 10 people in this part of the uniQure study, the researchers were only able to get reliable huntingtin-lowering data from 7; 4 people who received the drug and 3 who received the sham treatment. This means we are looking at data from a very small number of people so, whilst things look to be going in the right direction, we should still be cautious.

Another consideration is that uniQure’s drug lowers both healthy and harmful huntingtin, based on this data, by around 50% in people who received the low dose of AMT-130. Questions came up in the public presentation around whether longer exposure or higher doses could lead to “too much” lowering of huntingtin, but this seems unlikely for several reasons.

The work that uniQure have published in animal models shows that higher doses of the drug are safe and well tolerated over the course of several years. In people, the data so far show the levels of huntingtin getting lower and lower over time, but uniQure expects the lowering to level off after 12 months, as they have seen in their animal model experiments. They also show that higher doses of the drug don’t lower huntingtin levels much more than low doses; instead, the drug is able to spread to more parts of the brain, so the same level of lowering is seen in more areas, which they think will be beneficial.

Finally, there are several trial participants in the USA and Europe who have already received high doses of AMT-130, and none of them have had major dangerous side effects thus far.

So what’s next for AMT-130?

Although this early data is encouraging that AMT-130 is doing what scientists hoped – lowering huntingtin levels – there is still a long way to go before this could be a drug to treat HD. A number of scenarios are possible, all of which hinge on the outcome of the results uniQure is due to publish in the second quarter of 2023.

In the best case and probably unlikely scenario (but we can hope!), the next data release will have extremely positive findings, which could prompt uniQure to pursue accelerated approval of the drug to start treating people with HD as soon as possible. What is more likely, but still wishful thinking at this stage, is that the next data update holds up the tentative conclusions we have drawn so far – the drug appears safe, engages the target by lowering huntingtin and, perhaps, might show some indications of improving symptoms or slowing down the progression of HD. In such a scenario, uniQure would likely launch a much larger phase 3 study with over 100 patients enrolled and divided into control and treatment groups, to determine in a larger population whether the drug is really doing what the scientists hope – slowing or halting the progression of HD.

However, we must prepare for the possibility that the results in 2023 are not what we hope. One possibility is that the drug continues to be safe, but that huntingtin levels are not lowered. This may not be as bad as it seems, it could be that it takes some time to see a measurable effect of AMT-130, we just don’t know what to expect at this stage. The worst case scenario is that signs of HD in people who receive the treatment could appear to progress faster – similar to the results of the tominersen trial. In that case, uniQure would need to go back to the drawing board.

All that speculation aside, uniQure are taking concrete steps to improve upon the surgery, as well as planning for access to AMT-130, should the results of this trial prove favourable. One drawback for this “one-shot” therapy is that the procedure itself takes all day. In a third cohort of patients, uniQure are planning to test a much shorter version of the surgery which would only take half a day to complete.

All in all, uniQure’s preliminary safety and huntingtin-lowering results are encouraging. We are grateful for the brave participants in this unprecedented gene therapy trial, and eagerly await the next data release.

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.