HDBuzz

Hello and welcome from the HDBuzz team who are currently at the Hereditary Disease Foundation (@hdfcures) 2022 Milton Wexler Biennial Symposium in Boston! It’s the dawn of an exciting new era for HDBuzz. Due to our new partnership with @hdfcures, we are now able to live tweet many of the talks from this meeting which was previously closed to social media.

Huntington’s disease orientation

Two talks will kick off the meeting tonight, discussing when to treat HD and understanding treatment effects of the huntingtin-lowering drug, tominersen.

The ideal time to treat HD

The first talk of the meeting is from Sarah Tabrizi from UCL. Sarah will be talking to us about when it might be best to treat people with HD. Sarah begins her talk by reminding us that we can test for HD with a genetic test, long before we might see signs and symptoms of the disease in patients.

Thanks to many studies that HD families have participated in, like PREDICT-HD and ENROLL-HD, we know a lot about the timing of when HD begins. The HD Young Adult Study (HD-YAS) aimed to establish when biomarkers of HD first become detectable in participants who had a positive test for HD but many decades away from having symptoms. HDBuzz wrote about HD-YAS when it was first published by Dr. Tabrizi’s lab group.

Lots of different measurements were taken from all of the participants in this study including many types of brain scans and imaging. The scientists in the study looked at how these different measurements changed with participant age, CAG number, and other factors.

Many of the measurements, including thinking and psychiatric testing, showed no difference between the participants without HD and those with the HD gene expansion. Out of 8 brain regions, only a part of the brain most affected by HD (called the putamen) was slightly smaller in the group with HD compared to the controls.

Interestingly, the levels of a biomarker called NfL (neurofilament light), were significantly increased in the HD group compared to controls. However, the levels were still very low, indicating that there was probably not much neurodegeneration yet. Many other biomarkers from spinal fluid were assessed (about a dozen!), and only NfL levels indicated there was a change in people with and without HD.

Overall, this is great news. People born with the HD gene expansion have brains and biomarkers which are indistinguishable from people without HD. Even 24 years from predicted onset of symptoms, there were no obvious changes in thinking, in the size of most brain regions, and in many biomarkers.

BUT there were detectable changes in NfL levels, which means researchers do have a biomarker they can look at during the very beginning stages of HD, before obvious symptoms appear. This very subtle detectable change associated with HD may indicate the best time to treat to prevent loss of brain cells – people with HD are completely healthy by almost every measure, but there’s a biomarker (NfL) that allows researchers to determine if they could get better.

Next Dr. Tabrizi talked about using the HD Integrated Staging System (HD-ISS) to streamline recruitment for clinical trials which we wrote about a few months ago.

The HD-ISS stages people with HD from 0 to 4, much like the way the cancer field stages patients. This new system will allow HD researchers and clinicians to compare results between trials. Importantly, it is hoped that this new symptom will help HD researchers conduct clinical trials in patients at much earlier stages of the disease.

People with HD won’t need to know their stage and it won’t influence day-to-day life with HD or care. It will only be used behind the scenes for organizing clinical trials.

The scientists who came up with this new system did a large-scale systematic assessment of the different landmarks which could be measured to indicate disease stage. Over 20,000 data points were analyzed! This created a very robust, objective dataset from which the HD-ISS was created. For a person with a particular CAG number, scientists can predict how HD signs and symptoms might progress over that person’s lifetime.

Currently, trials have been done in people with later stages of HD. The HD-ISS staging system sets up a framework that can be used to recruit trials designed for people before they have symptoms of HD. While we’re not quite ready for trials in people with the earliest stages of HD, some HD patients are eager to see this happen and the HD-ISS sets up the system to allow this.

Sarah rightly highlights that this work was only made possible by HD research participants and families who contributed to the many studies which informed the design of the HD-ISS.

Update from Roche on the tominersen trial and moving forward

Next up is Peter McColgan from Roche. Peter will be talking to us about the huntingtin-lowering drug, tominersen, the trial of which was halted early last year.

Peter is going to tell us about some of the additional analyses Roche have done regarding the findings from the halted GENERATION-HD1 trial. He rightly thanks the commitment and dedication of HD families who participated in the trial. Without them, we wouldn’t have data or knowledge from one of the first HTT lowering trials.

In this Phase III trial, participants were either dosed with 120mg tominersen every 8 weeks or every 16 weeks or were given a placebo. Although the drug lowered the levels of the huntingtin protein, patients did not get better. In fact, patients who received the drug did worse than placebo.

Over the course of the treatment, levels of NfL did not change that much but alarmingly the changes in volume to a part of the brain called the ventricles were worse in participants who received the drug compared to placebo.

Now Peter will cover new data from the trial! Roche is interested in understanding the mechanism behind what happened. One question they’re interested in exploring is if they can maintain reduction of HTT while avoiding some of the negative effects they observed.

Peter shows new data from Roche which suggests there is a correlation in the amount of toinersen drug in the CSF and the lowering of HTT levels in the CSF. However, it seems that there is no correlation between the changes in CSF HTT levels and clinical measures.

Next Peter detailed data that looked at increases in CSF NfL they saw with tominersen dosing. They found there was no relationship. Remember that NfL levels go up with damage to brain cells. So if it’s not tominersen, what is driving the early spike in CSF NfL?

The scientists at Roche looked at exposure to the drug i.e. how much drug is actually in the CSF, and the levels of NfL they observed in the early spike. Highest levels of exposure to tominersen had the biggest NfL spike and the largest amount of HTT lowering.

Next they looked to see if increases in volume of the ventricles influenced the clinical outcomes. They found there was no relationship. However the scientists wanted to try and work out why this brain volume measurement changed more in patients who received the drug.

Increase in the volume of the ventricles correlates with an increase in the amount of immune cells, like white blood cells called leukocytes. Interestingly there is no change in overall brain volume, even though the ventricle volume is increasing. Peter suggests this means there is no brain atrophy in these patients.

Based on the data Roche currently have, they’re unable to tease out the effects that are coming from “on-target” and “off-target” effects of tominersen – meaning effects they want and expect from the drug vs those that they don’t. What they do know is that some of the negative changes that they see related to increased size of the ventricles is likely due to inflammation in the brain.

Now Peter moves on to the “post hoc analysis” – the analysis of the data that was done after the trial was over that split people treated with tominersen into different groups to see if the drug had a positive effect on some. It’s important to note that a post hoc analysis tries to ask questions of the data collected in the trial which it was not designed to do – so all of this is to be taken with a pinch of salt

In the younger patients in the trial with a lower CAG number, Roche believe that there is some hope for tominersen and perhaps there was some clinical benefit. Note that these findings are NOT statistically significant. Roche is using this analysis to guide the design of the new study, which they’re using to
target people with HD with symptoms that are less advanced and those that have lower CAG repeat sizes.

This new Phase 2 study will also test a lower dose of tominersen to “explore the full therapeutic range of tominersen”. Since they already have data on the effects of higher doses, this lower dose will fill in a gap in their data. They plan to only give participants the drug every 16 weeks and will be using lower doses of 100 mg and 60 mg. From the GENERATION-HD1 trial, Roche knows that dosing every 16 weeks was well tolerated in the patient sub group that they’re targeting in the new trial i.e. younger folks with less severe symptoms of HD.

Overall, Roche feels their data support further exploration of tominersen as a therapeutic for HD. While the road to get to this conclusion had disappointment, Roche believes the data suggests there is hope and supports additional trials for tominersen.

That’s a wrap for the kick-off session of the meeting. We’ll be back tomorrow morning for interesting updates on various clinical trials. Stay tuned!

To learn more about the Heredtiary Disease Foundation, visit their website. To learn more about the science discussed at #HDF2022, tune into a live webinar on September 15th at noon EST! Register here. You can also follow HDF on Facebook, Instagram, and Twitter to ensure you don’t miss future webinar updates.

Last month, we relayed positive news from uniQure’s trial testing AMT-130, a gene therapy delivered via brain surgery to lower huntingtin (HTT). Data released by uniQure in June suggested AMT-130 was safe and well tolerated in the small group of people that were treated with a low dose of the drug. Now we’re back to provide an update on findings from the group of people treated with a higher dose of AMT-130. This new set of data shows that the higher dose of the drug may be causing serious side effects. This doesn’t necessarily mean AMT-130 doesn’t work and won’t move forward, but it does mean that we need to take a pause, really look into what the data are telling us, and work out a safe plan to move forward for people being treated with the drug.

Despite setbacks, HTT lowering is still considered an attractive strategy by many researchers

One advantage researchers that study Huntington’s disease (HD) have is that we know exactly what causes HD – an expansion in the HTT gene. The expanded HTT gene produces an expanded HTT message that is then processed into an expanded form of the HTT protein that causes damage in brain cells. So, in theory, reducing the presence of that expanded HTT protein could alleviate the symptoms associated with HD because it directly targets the root cause of the disease. This means that despite recent setbacks for several clinical trials designed to lower HTT levels, HTT lowering is still considered an attractive strategy for HD therapeutics by many researchers.

There are several different ways researchers are trying to lower HTT. The first horse out of the gate in the HTT lowering race were antisense oligonucleotides (ASOs). These are short sequences that bind to a specific message which then cause it to be degraded. Without the message, no protein can be produced. So while the gene remains intact, the protein is never made. This type of HTT-lowering technology is being explored by Roche with their drug tominersen that took a step back to find the right dose and patient population. Wave Life Sciences is also using ASOs to selectively lower the expanded copy of HTT with their ongoing Phase I/II trial for WVE-003, SELECT-HD.

Another way to lower HTT that’s being tested in clinical trials is through “splice modulators”. These are drugs that change how the genetic message is edited. Like a story, every gene has a beginning, middle, and end. The end is a specific sequence that tells molecules in the cell to stop reading the code for that gene. Splice modulators work by editing the message to move that ending code up, confusing the sequence of that gene. So rather than a beginning, middle, and end, the story is just a beginning and end. The cell recognizes that this makes no sense and stops producing that protein.

HDBuzz recently wrote about the splice modulator branaplam, being tested by Novartis in the VIBRANT-HD study, for which dosing was suspended due to safety concerns. Another splice modulator, PTC-518, is being tested by PTC Therapeutics. Even though PTC-518 works in a similar way to branaplam, a head-to-head comparison of these drugs suggests they are actually quite different. So bad news for one doesn’t necessarily mean there will be bad news for the other. We’re still eagerly waiting for news about the PTC-518 trial!

AMT-130 is a one-shot gene therapy approach to lower HTT

A third way to lower HTT is through gene therapy, which is the technology being used by uniQure with AMT-130. This drug works by using a harmless virus to deliver DNA instructions that will destroy the HTT message. The HTT gene still exists in its original form, but now the cell contains a new message that will prevent the production of the HTT protein. Because the cells infected with the harmless virus contain the genetic instructions, they can make the HTT lowering message all on their own. This means AMT-130 is a one-and-done approach – deliver the therapy through a single procedure, and the cells will continue to make the instructions that allow them to lower HTT. This is both exciting and nerve-wracking. While it means only one treatment is necessary, it also means any changes are likely permanent.

To get AMT-130 directly where it’s needed most – the brain – it’s delivered using brain surgery. Because brain surgery is always risky, this trial was rolled out very slowly to be as careful as possible. After the first 2 surgeries were complete, the participants were watched to make sure there were no immediate negative effects. When everything went well, surgery for the rest of the study participants continued.

The trial testing AMT-130, HD-Gene-TRX1, is a Phase I/II designed to test safety and tolerability of the drug as well as find the right dose that will work for people with HD. Because one of the primary goals of this study was finding the right dose that will work best for people with HD, 2 groups were tested: a low dose group and a high dose group. Scientists at uniQure believe that the higher dose of the drug will not necessarily lower HTT further in each cell, but that more drug will mean that more brain cells will have their levels of HTT lowered by the same amount.

36 people in total were enrolled in uniQure’s AMT-130 study: 10 that received an imitation surgery that will act as the control group, a critical part of any study, and 26 people in the treatment group. Of the 26 in the treatment group, 12 were treated with a low dose of AMT-130 and 14 were in the group for the high dose. So far, 12 of those 14 have undergone surgery.

In June we got an update from uniQure about people that were treated with the low dose of AMT-130 12 months after their surgeries, which HDBuzz wrote about. In that group, the surgeries and drug were well tolerated with no major safety issues reported. uniQure shared that preliminary data indicating that HTT seemed to be lowered more in the group treated with AMT-130 than the control group. While this is exciting news because it means AMT-130 appears to be doing what we want it to do – lowering HTT – this was reported in a very small group of only 4 participants.

Some participants in the AMT-130 study have suffered serious side effects

In early August, uniQure made an announcement about participants from the high dose group in the AMT-130 study. Three participants (out of 14) from this arm of the study were found to have severe adverse reactions by an independent safety review committee. Two people that underwent surgery in Europe reported swelling and a third person, treated at a U.S. location, reported a severe headache and related symptoms shortly after surgery. While this is very upsetting and disappointing news, importantly, all three patients have either fully or substantially recovered and have now been released from the hospital.

What’s next for AMT-130?

There are many theories as to why these patients suffered these side effects, including some form of immune response. However, there is no clear or definitive explanations just yet and we must wait for further information before jumping to conclusions.

While the safety review committee doesn’t suspect the effects observed in the high-dose group of the trial are due to the drug itself, surgeries for the remaining 2 participants in this arm of the study have been halted for now. The low-dose arm is proceeding as planned and all trial particiants – in both the low- and high-dose groups – will continue to be followed for the duration of the trial. uniQure still expect to report data from the trial according to the originally planned schedule and we will be hearing further updates from the company about this trial in early 2023.

What does this mean for HTT lowering as an approach to treat HD?

The HD community has received disappointing news from many of the HTT lowering trials now and it is easy to feel like perhaps this is not a good strategy to keep pursuing to try and treat people with HD. It is important to keep a few things in mind though as all is not lost just yet. All of these trials have suffered very different problems and we only really have theories for why they haven’t panned out as we hoped, all of which might be unrelated to HTT lowering itself. All of these trials are also treating people with HD who are already showing symptoms and perhaps these folks are more vulnerable to potential side effects from these drugs. It’s important to note that none of these trials have given us a definitive answer as to whether HTT lowering in people with HD will improve symptoms or change the course of the disease. As the uniQure trial continues, we hope that the next data release might shed some light on this important question.

The VIBRANT-HD study began in early 2022 and was a long-awaited trial of a huntingtin-lowering drug, branaplam, that could be taken by mouth. On Monday, August 8th, we learned that dosing has been temporarily suspended at the recommendation of an independent committee that is monitoring the data from the trial. This decision was made because of signs that some of the participants taking branaplam may be experiencing new problems with their nerves, known as peripheral neuropathy. Let’s talk more about what happened and what’s next.

The HD gene and the quest to lower huntingtin

Huntington’s disease is genetic, meaning that it’s passed down in families from generation to generation. The genetic mutation that causes HD occurs in a gene called huntingtin, which produces a faulty RNA recipe, ultimately producing an extra-long huntingtin protein. This protein is believed to be harmful to brain cells, causing them to become sick and eventually disappear, and this leads to the many different symptoms of HD.

Over the past decade or so, novel approaches to treating HD have focused on a technique called huntingtin-lowering, which aims to decrease the amount of harmful huntingtin protein in the brains of HD patients. So far, the ones tested in people have been pretty invasive, requiring frequent spinal injections or brain surgery to deliver. Novartis, however, had recently begun a clinical trial of a huntingtin-lowering drug that could be taken once weekly, by mouth.

Branaplam and the promise of oral huntingtin-lowering

The story of branaplam and the VIBRANT-HD trial began with a different disease, known as SMA, which affects children. SMA is also genetic; it causes worsening muscle weakness in babies and young kids and is eventually fatal within just a few years.

Branaplam was originally developed as a genetic treatment for SMA. It is known as a splicing modulator – essentially this means that it can steer the remixing of the RNA recipe for the gene involved in SMA, and restore the function of the protein. In a fascinating twist of science, Novartis discovered that branaplam could also affect the RNA recipe for huntingtin, in this case leading to less huntingtin being produced.

In the summer of 2021, as more genetic treatment options became available for kids with SMA, Novartis made the decision to stop developing branaplam for kids with SMA, and to focus its efforts on adults with HD. This decision was supported by data in HD model animals, and very early safety trials of branaplam in healthy adults. Excitement built in the HD community around the possibility of an oral huntingtin-lowering treatment, and the Phase 2 VIBRANT-HD trial began in early 2022.

This week’s sad news

The VIBRANT-HD trial was planned to involve 75 people with early symptoms of HD, at more than 20 sites around the world. The main goals of the study are to test safety and the ability of the drug to lower huntingtin measured in spinal fluid. The plan was to test high and low doses of branaplam, each taken as a liquid once weekly for four months. Since early 2022, only the first cohort of participants had begun the trial. This was approximately 25 people, around 20 taking low dose branaplam and 5 taking placebo.

We learned today that the dosing in the trial has been stopped for safety reasons. We’ll get right to the point: branaplam was showing signs that it could be toxic to the nervous system. This was determined by an independent Data Monitoring Committee (DMC), a group of evaluators that has access to the data, long before the doctors, patients, or study sponsor (Novartis) know the outcomes. This is an important and standard practice in the vast majority of drug trials and it’s exactly for this reason – to keep participants safe in the event that problems arise.

The recommendation to suspend dosing in the study was based specifically on signs that branaplam might be causing damage to nerves outside the brain and spinal cord, known as peripheral neuropathy. Evidence from neurological exams, nerve conduction studies, and assessments of HD symptoms, as well as measurements of levels of a protein called NfL in the blood, all pointed to some concerns that some patients could be experiencing new nerve damage in their limbs.

What happens next?

In the immediate term, everyone participating in the trial will stop taking the treatment they were assigned. However, they will be asked to continue having their planned study appointments, which include blood and spinal fluid collection, and tests of nerve health. Essentially, the study will continue, but without branaplam or placebo, and participants will be monitored closely for other safety signs. This will be essential to understand as much as possible about branaplam’s effects on adults with HD.

There may also have been some people who were all set to begin participating in the VIBRANT-HD trial, at either a low or a higher dose – these folks will not begin the study. Current participants and doctors will stay “blinded” until the end of the study, meaning they still don’t know who was on drug or placebo.

What does this mean for branaplam…and huntingtin lowering?

Essentially, this trial suspension is a way to protect participants from further potential danger to their nervous systems. It also means that Novartis will need to take a step back, take the time to analyze and learn more from the data, and determine whether it would make sense to keep testing branaplam.

It might be that the drug is really not safe for people with HD, and moving forward isn’t an option. On the other hand, it might be possible to use lower or less frequent dosing, or it could be that branaplam may have affected some participants differently than others. This latter possibility is similar to how Roche will be running a new trial of the huntingtin-lowering drug tominersen in a specific group of people.

It’s a tremendous disappointment that branaplam looks much riskier than expected for adults with HD. This will of course be especially tough for the first brave trial participants in VIBRANT-HD. But the news affects everyone in the community who felt hopeful about the first oral huntingtin-lowering drug to be tested in people.

That said, this news is not reason to abandon hope in huntingtin-lowering – nor even in oral huntingtin lowering. Branaplam was originally designed to treat a different disease, and though it lowers huntingtin, there may be other reasons it is causing unforeseen issues, known as “off-target effects.” There is another oral huntingtin-lowering drug in clinical trials right now – it’s called PTC-518 and is being developed by PTC Therapeutics. Based on data published by the company, that drug may have more ideal drug properties, compared to branaplam. Importantly, PTC-518 shows more accumulation in the brain, compared to the rest of the body, and the brain is the primary treatment goal for HD. We look forward to updates from PTC after they digest the branaplam results, but we’re hopeful that their trial can continue, if experts feel it’s likely to be safe.

Gratitude and moving forward

Beyond these oral drugs, there’s a wide field of folks working on various approaches to huntingtin lowering, and ongoing clinical trials are being conducted by uniQure and Wave, with Roche’s next study in planning stages. There are also some important HD research conferences approaching this summer and fall, and there is sure to be exciting news to share from HD clinical studies and basic research laboratories worldwide.

There’s no doubt this is a tough day for the HD community, and for those of us hopeful for Huntingtin-lowering drugs to be an effective treatment for HD. But, as we often say, science is cumulative, and if we do it right, even failures in the clinic can teach us more than we knew before we started the trial.

The entire community owes the participants in the VIBRANT-HD study a huge debt. They rapidly signed up for the study, and their participation enabled us to get to this point – disappointing as it is – as quickly as possible. Their selfless contribution will enable the design of the next study to take into account the lessons learned in VIBRANT-HD, and get us closer to a day when we have effective treatments for HD.

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.