Research news

The stormy trial updates that hung over the Huntington’s disease (HD) field in 2021 have certainly parted, making way for the bright and clear forecast we’ve had so far in 2024! Close on the heels of recent positive trial news from Sage Therapeutics, PTC Therapeutics, Wave Life Sciences, and uniQure, we’ve received more encouraging results from another company, Skyhawk Therapeutics, about their drug SKY-0515. Since there are a lot of trials going on right now in the HD space testing various drugs, let’s break down how SKY-0515 works, what we’ve learned so far from this Phase 1 trial, and how it differs from other drugs being tested.

How does SKY-0515 work?

SKY-0515 is designed to lower huntingtin (HTT), the molecule that ultimately causes HD. While we all have the HTT gene, folks who go on to develop HD have an extra stretch of genetic message within their HTT gene. The good news is that since we know the exact genetic cause of the disease is within the HTT gene, it gives us a very reasonable target to go after. That’s why Skyhawk, along with many other companies, have focused on developing drugs that lower HTT.

It turns out that the extra stretch of genetic message that causes HD within the HTT gene can get bigger in some cells as people with HD age, like brain cells. This can cause biological functions to go awry, leading to toxicity in some cells, and eventually cell death. This perpetual increase of that extra bit of genetic code within the HTT gene is called somatic expansion, something frequent readers of HDBuzz have no doubt heard about.

Some people think if we can control somatic expansion, we could slow, or maybe even stop, the progression of HD. Interestingly, SKY-0515 also targets another molecule - PMS1 - which helps to control somatic expansion. So not only can SKY-0515 lower HTT, but it can also help prevent somatic expansion. Because of this, Skyhawk is hoping this drug will have a double impact against HD.

Phase 1 trial update

On July 10, 2024 we received a short update from Skyhawk Therapeutics about their ongoing Phase 1 trial testing SKY-0515. Ultimately, they hope that this drug will be able to modify the disease course of HD, but first they need to know if the drug is safe to take and if it can do what it’s supposed to do. Phase 1 trials are the first time new drugs are given to humans, so the primary goal is always safety.

This is a small trial being run in Australia with multiple parts. In the first part, SKY-0515 is being given to healthy people without the gene for HD. So far, SKY-0515 appears to be safe and well tolerated at all the doses that were tested in healthy volunteers.

Trial participants have received the drug at increasing doses so that Skyhawk can work out which dose would be best to carry forward in a larger trial. They’ve also found a dose-dependent lowering of HTT, meaning the more drug that they give, the more they’re able to lower HTT. This indicates that SKY-0515 is engaging the target and doing what they hoped it would do.

How is SKY-0515 different?

With HTT being the cause of HD, logically, lots of companies have designed drugs to target HTT and lower it. But not all HTT lowering drugs are the same and many require different delivery methods. Excitingly, SKY-0515 is a small molecule, which means it can be taken orally. This is obviously a much less invasive way to take a drug compared to those that would require a spinal injection or brain surgery.

SKY-0515 not only targets HTT, but also somatic expansion. While there are suggestions that other HTT-lowering drugs could also have this effect, that wasn’t specifically stated in the design of trials testing those drugs. We also don’t yet have data for the somatic expansion piece in people yet. Hopefully that will come with Skyhawk’s next data release.

An important aspect of drug design is potency - the ability of a drug to have an effect at a specific concentration. The more potent a drug is, the less of it needs to be taken to get the same effect. And, very often, taking less of a drug can mean there are fewer potential negative side effects. SKY-0515 appears to be very potent. At just 9mg (the high dose tested in this Phase 1 trial), the drug is able to lower HTT by ~70%! While we can’t say for sure that SKY-0515’s potency means that there will be fewer side effects, this is something we’ll be looking for in future updates.

Astute readers may notice that 70% lowering is a fair bit higher than the current target in other HTT lowering trials of around 50%. Currently, most companies have targeted the 30-50% range for HTT lowering drugs. If Skyhawk finds safety issues at the higher doses, they may chose to scale dose back and lower HTT less.

What’s next?

Now Skyhawk will begin the next part of their Phase 1 trial - testing SKY-0515 in people that have the gene for HD. A low and a high dose will be tested in people with early-stage HD, corresponding to people with stages 1, 2, and early 3 on the HD-ISS scale. These are people with early HD, prior to overt clinical onset in some cases. Recruitment for this part of the trial is underway and dosing is set to begin as early as this month.

If all goes well, Skyhawk plans to initiate a Phase 2 trial in early 2025. While the current Phase 1 is being conducted in Australia, we don’t yet have details about where the potential Phase 2 trial would take place.

While we’ve had a windfall of good news lately for HD clinical trials, it’s not all sunshine and rainbows just yet. We are hopefully optimistic about all this recent good news, but we have to temper that excitement with the knowledge that these are early trials with very few people. On the horizon are larger trials that will bring much more clarity over the next few years, hopefully making a clear path for getting a disease-modifying drug to market.

New data from uniQure, who developed a one-and-done gene therapy for Huntington’s disease (HD) called AMT-130, indicates that the drug is relatively safe and might be able to slow down signs and symptoms of HD. AMT-130 is currently under investigation in Phase I/II clinical trials in Europe and the US which are mainly focused on drug safety. These hot new data are very encouraging, so let’s dive into what it all means!

What is AMT-130?

Developed by uniQure, AMT-130 is the first gene therapy for HD. Like many of the other therapies being tested in the clinic right now, it aims to reduce the levels of the HD protein, huntingtin, in the brain. What makes it a bit different, however, is that AMT-130 is a one-and-done gene therapy; you are only given one dose of the drug ever in the course of your life.

AMT-130 is made up of a harmless virus packaged with genetic material that contains the instructions to reduce the amount of huntingtin in each cell that the virus infects in the brain. The drug is given to people with HD by a very specialised type of brain surgery which delivers it into the fluid-filled spaces of the brain, known as the ventricles.

All of this was obviously rather daunting back when AMT-130 was first developed and we didn’t know how safe the drug might be. The one-and-done nature of the drug means that effects of the drug, good or bad, can not be undone.

uniQure did a huge number of studies before they tested AMT-130 in people, which took place over years using many different types of HD animal models. Even when uniQure began testing AMT-130 in people in 2019, they did so very slowly, starting with just a few brave folks who selflessly signed up to test this innovative therapy. Only when things looked ok following these first surgeries did they begin giving the drug to more people.

HD-GeneTRX-1 and HD-GeneTRX-2 - two trials for AMT-130 on two continents

There are in fact two clinical trials testing AMT-130 in people with HD; HD-GeneTRX-1 in the US and HD-GeneTRX-2 in Europe. Together, 39 participants of the trials were given either a high dose of AMT-130, a low dose of AMT-130, or a sham surgery, which means that participants underwent surgery but no drug was given. All people in the trial are then tracked for 4 years after their surgery, where all sorts of clinical, biomarker, brain imaging, and other measurements are taken.

The key aim of both trials is to investigate whether AMT-130 is safe in people. In addition to this, lots of other data are collected along the way which might hint at how well AMT-130 is working and how it might impact signs and symptoms of HD.

Since the trials began, AMT-130 has had a bit of a bumpy road. In the first people treated, everything seemed to be going ok but in August 2022, serious side effects were reported for some people who received the high dose of AMT-130. Fortunately, things got back on track after a 3 month pause in enrollment into the trial, and uniQure shared the good news that their trial will continue as planned, with new safety measures in place.

Since the brief trial pause, uniQure has reported steady progress with signs that this drug appears safe. There were also some hints of trends in the data they collected from all of the study participants that seemed to suggest that the drug might be having an effect on some symptoms of HD, although this was just a signal and is not conclusive.

Some things to keep in mind with this latest update

It’s important to note that the two trials are not over, the most recent data is an interim update. There are still 2+ more years of data to be collected for most folks. In fact, only 12 people who received the low dose (out of 13 in this group) and 9 people who received the high dose (out of 20 in this group) are at the 24 month mark.

Given the arduous way this drug is delivered, it takes a long time for everyone to get their surgery, even after they are enrolled. This means that the numbers of people from which the data comes from in this release are very tiny, so we should be very cautious in how we interpret the findings - we don’t yet know how this will play out in a bigger pool of people over a longer period of time.

Another important thing to note is that all comparisons in this data release are against natural history data, not placebo controls. Natural history data tracks people with HD over the course of their lives to see how their symptoms, brain imaging, biomarkers, and other clinical measurements change over time. This is very different to a placebo group who undergo the same procedures as the folks receiving the drugs, the only difference being they don’t actually receive the drug. The placebo effect can be very powerful so if we are using natural history data as our baseline, we should be cautious in the direct comparisons we draw. This decision was taken as there is only complete data for people in the sham surgery group up until 12 months.

Keeping all that in mind, this update is still rather exciting, so buckle in!

What’s the latest news about AMT-130?

Safety

The good news is that AMT-130, at both the low and high dose, appears to be relatively safe. There are manageable effects which we would expect to see following brain surgery, like headaches and pain associated with the procedure. However, the important part is that no new serious side effects were reported since the trial was paused back in August 2022, which is good news.

NfL - insights to brain health

An important measurement for tracking general brain health is the biomarker neurofilament light, often called NfL. Because HD has a detrimental effect on brain health, NfL levels go up over time as HD progresses. Therefore, NfL measurements can tell us two things: Firstly, whether the therapy might be causing harm, and secondly, whether the therapy might be slowing down disease progression, and therefore slowing the rate at which NfL levels go up over time in someone with HD.

We learned in previous updates from uniQure that there’s an initial spike in NfL levels. This is to be expected for any treatment requiring brain surgery, since the surgery itself will temporarily reduce overall brain health. What’s important is that this is short-lived - the initial spike is followed by a rapid decline in NfL levels over the next 6-8 months after surgery. Looking at NfL levels after the initial spike is where the juicy details are - this is what will tell us if AMT-130 is improving brain health and slowing HD progression.

In the last data release in December of 2023, only 6 people in the low-dose group and 2 people in the high-dose group had made it to the 24 month time point. Now, there are 12 people from the low-dose group and 9 people from the high-dose group that have reached the 24 month mark. Having data from more people helps give us a clearer picture of the effect AMT-130 is having on NfL 2 years after treatment.

Excitingly, the new data show that people treated with both the low- and high-dose of AMT-130 have NfL levels significantly below what would be expected, suggesting their decline in brain health is slowed compared to folks who have not been treated with AMT-130. While this sounds incredibly exciting, this is still a very small dataset so we shouldn’t get our hopes up too high.

Clinical measures

uniQure also looked at clinical measures to get an idea of the effect that AMT-130 might have on slowing or stopping symptoms of HD. Specifically, they looked at the Composite Unified Huntington's Disease Rating Scale, or cUHDRS. This is a collection of tests that measures the ability of someone with HD to carry out daily tasks, movement control, capacity to pay attention, and memory. Overall, the cUHDRS is known to be the most sensitive way to measure clinical progression of HD.

At the end of the day, clinical measures will be the most important readout. Having a drug that is effective at slowing or stopping progression of clinical signs and symptoms of HD is what we all want. Compared to a natural history study, disease progression was slowed by around 80% in people on the high dose of AMT-130. This suggests that AMT-130 may be having an effect in slowing progression of HD as measured by cUHDRS. Again, this is only data from 9 people, so it must be interpreted with caution.

cUHDRS is actually made up of many different clinical measures including Total Function Capacity (TFC) and Total Motor Score (TMS). Looking at these individual measures, the effect of AMT-130 is less obvious although there is a suggestion of a trend of things heading in the direction of slowing HD symptom progression. Not to be a broken record, but again, the tiny number of folks whose data is being analysed at this stage means we have to be careful in drawing too strong conclusions.

Other measures uniQure didn’t report this time

Interestingly, this update included no new information about whether huntingtin protein levels are being lowered by the drug, the effect we expect this drug to have in the brain. We also didn’t learn any new information about what brain imaging might tell us about how AMT-130 is working. Hopefully, uniQure gives us updates on both of these measures the next time they share data.

What does this all mean?

Overall, this update is exciting, positive and certainly cause for very cautious optimism. That said, this does not mean that AMT-130 is a cure for HD, there is still a long road ahead. We need more data from more people over longer timeframes to be sure of the effect this drug is really having on slowing down symptoms of HD. Nonetheless, the fact that the drug appears relatively safe and there are positive signs in how it might be helping slow down symptoms is good news for the HD community.

What’s next for AMT-130?

Recently, the FDA granted AMT-130 Regenerative Medicine Advanced Therapy (RMAT) designation - the very first time this has happened for an HD therapeutic. This gives them more frequent interactions with the FDA and priority review of their data, so that if the time comes that they’re ready to file for regulatory approval, they can hit the ground running to get accelerated approval.

uniQure have disclosed that they expect to meet with the FDA in the second half of 2024 to continue their discussions about the development of AMT-130. In those conversations, they hope to define a path for getting approval of AMT-130 for HD.

Lot’s of things to be thankful for

Sometimes when it rains, it pours! We have had what feels like a deluge of positive and encouraging news about HD clinical trials lately, and certainly at HDBuzz, we are feeling thankful. It was not so long ago that the news deluge was delivering a very different and much more difficult message, that many drugs just weren’t working as we had hoped.

So, what’s changed? Well it’s important to remember that even when clinical trials don’t give us the results we had hoped for, there is still so much to be learnt from the wealth of data that is collected. All of the selfless hours in the clinic from the folks with HD who sign up for these trials count for a huge amount. The rich datasets they help generate have a huge impact in how scientists understand how different therapies might work in people, and what they can change and improve to give us the best chance of success. Their contributions have gotten us to this exciting point where we still have lots of irons in the fire and are edging closer to disease-modifying therapies.

The future of HD clinical trials is bright, thanks to the resiliency, fortitude, and sacrifice of so many people with HD who bravely stepped up to test these experimental drugs. We are forever thankful to them and are buckled in for the ride to see what comes next.

On 25th June 2024, Wave Life Sciences shared the results of their SELECT-HD clinical trial. This trial tested a therapy called WVE-003, designed to only lower the expanded, harmful form of the huntingtin (HTT) protein found in people with Huntington’s disease (HD). The data released today give positive updates on the safety of this therapy as well as how well it is working. Let’s get into it!

Allele selective lowering - what’s that about?

HTT lowering therapies are one of the leading approaches being tested in clinical trials at present, with the aim that they might slow or halt the progression of HD. As the name suggests, all of these therapies aim to reduce the amount of the harmful HTT protein that is made in people who have HD.

Since we all inherit two copies of every gene - one from Mom and one from Dad - nearly everyone who has HD would have inherited a regular copy of the HTT gene, and an expanded copy of the HTT gene, which has more than 36 “CAG” DNA letter repeats. The expanded HTT gene makes an expanded form of the HTT protein which is thought to be harmful. By reducing the amount of this harmful protein, scientists hope this might improve signs and symptoms of HD.

There are lots of different approaches scientists are taking to try and lower the levels of the HTT protein in people with HD. Many of those currently in the clinic actually target the levels of both regular and expanded HTT, so both forms of the protein are lowered. This is the case for tominersen, developed by Roche; AMT-130, developed by uniQure; and PTC-518, developed by PTC Therapeutics.

Wave are taking a different approach to these companies as their therapy only targets the expanded form of HTT. WVE-003 is an antisense oligonucleotide which exploits very specific single letter changes in the genetic code which are only found in the expanded HTT gene. The scientists at Wave think that this is important as the regular HTT protein has lots of important jobs to do in the cells of our bodies. So by maintaining the level of the regular protein, and reducing the levels only of the expanded HTT, their drug might be safer and have fewer side effects.

This approach does have some drawbacks. Everyone who is interested in participating in a trial for this drug first needs to have a genetic test. Only folks who have the specific letter changes targeted by the drug, termed SNP3, are then eligible for this therapy. This means that only a portion of people with HD might be treated with WVE-003 at present. Based on current genetic data, scientists estimate this to be about 40% of the patient population.

WVE-003 is given to people participating in the SELECT-HD trial by spinal tap. This is the same way tominersen, another antisense oligonucleotides or ASO therapy, is administered. This does pose a bit of an extra burden on people receiving this drug over say a drug in tablet form, as it must be administered by a specialist in a clinic with a particular set up.

How was SELECT-HD designed?

There were two different arms to the study: a single dose arm and a multi-dose arm. The single dose arm tested a single shot of the drug at various doses and then tracked participants over the course of almost 90 days. The multi-dose arm tested three repetitions of the lowest dose given at 8 week intervals and participants were tracked for almost 200 days. Both arms of the study had a placebo control group who received spinal taps which did not administer the drug.

The trial enrolled 45 people in the single dose arm and 23 people in the multi-dose arm. In both arms, the majority of participants are either Stage 2 or 3, with just two Stage 0 folks in the single dose arm, as defined by the HD Integrated Staging System. All folks in the trial were monitored in clinical evaluations, had MRI scans of their brains, and gave spinal fluid samples at regular intervals.

What were the findings of the trial?

Safety first

The most important thing for a Phase 1 / 2 trial like this, is to make sure that the therapy being tested is safe. In the single dose arm of the study, the side effects experienced by folks receiving drug or placebo were approximately the same, suggesting that this dosing regime is safe and the drug was well tolerated. In the multi-dose arm, more mild and moderate side effects were observed in participants who received the drug. No serious adverse events were seen at 30mg for either arm.

Another measurement the trial looked at is neurofilament light, often called NfL, a biomarker of brain health. In people with HD, NfL levels tend to rise over time, as higher levels of NfL generally indicate that the brain is getting more sick. In this trial, Wave found that folks treated with the drug largely had similar changes to their levels of NfL as those who received the placebo.

There were a few folks whose NfL levels rose above that of the placebo control group but this data was not broken down by HD stage or dosing regimen in the data presented. In such a small trial it is difficult to say exactly what this might mean, but it’s something Wave and others will be keeping an eye on as this program moves forward.

Overall, the news is largely positive with respect to safety. The data collected so far indicate that the WVE-003 is generally well tolerated with limited side effects at the doses tested.

Selective lowering of expanded HTT

The next critical thing to be assessed in this trial is whether WVE-003 does indeed selectively lower levels of the harmful, expanded HTT protein, whilst leaving the regular healthy protein intact. When looking at changes to the levels of expanded HTT in both the single and multi-dose arms of this trial, the protein levels were reduced in participants taking the drug compared to those taking placebo. In both arms, this effect was shown to be statistically significant which means we can be very confident in the changes to the levels of expanded HTT affected by this drug - good news!

In the single dose arm, whether the participant received 30, 60 or 90 mg of the drug didn’t seem to make too much difference, and they all led to a 20-30% reduction of expanded HTT compared to placebo. What is interesting to see is that this single shot of drug gave a sustained HTT lowering effect measured up to 90 days later, suggesting this drug sticks around and keeps working over a fairly long period of time. Similarly, in the multidose arm, a 44% reduction of expanded HTT levels was observed on Day 197 of the trial, a full 12 weeks after the last treatment with WVE-003. This kind of data is useful to help the scientists figure out what kind of dosing strategy they might use moving forward.

The data presented by Wave also show that levels of the normal HTT protein are largely unaffected, and possibly even increase a little bit with treatment. Again, this is good news. It shows that WVE-003 does seem to only be changing the levels of the expanded HTT protein, leaving regular HTT levels intact.

Other measures from the trial

This trial is not designed to measure whether WVE-003 impacts signs or symptoms of HD. Showing effective HTT lowering with a drug is very different from showing the drug is disease-modifying, a term used to describe a therapy which might slow or halt HD. Nonetheless, Wave conducted some exploratory studies in this trial to look at possible changes to brain structure as well as other clinical measurements.

MRI scans were taken of trial participants to measure how a region of the brain called the caudate changed over time. The caudate gets smaller over time in people with HD. People in the multidose arm of the trial seemed to maybe have slightly less change to the size of their caudate over time. Another region of the brain, called the ventricles, also tracked in size the same as people not taking the drug. Neither of these findings were statistically significant but if shown to hold true in a subsequent study, they could suggest WVE-003 is slowing down the death of cells in the brain. However, at present, the data are promising, but inconclusive.

The trial also assessed Total Motor Score (TMS), a clinical metric which assesses movement symptoms in people with HD. The higher the score, the more advanced the symptoms. Again, the data seem to point to a slight decrease in TMS for people in the trial receiving WVE-003 for just over six months, when compared to placebo. This would be good news if true, but we will need a much bigger study to figure this out for sure.

So what’s next for WVE-003?

Overall, the findings from the SELECT-HD trial are positive: the drug appears largely safe and works as intended to effectively lower just expanded HTT. This is the first time any drug has been shown to only impact the expanded harmful form of HTT, so a big milestone for the HD community. There are also some positive suggestions that the drug might be helping signs and symptoms of HD, but we need more data to be sure of that.

It should be noted that Phase 1 / 2 trials like this are, by design, very small: until we know the drug is safe, we don’t want to be testing it in lots of people. With this encouraging safety data in hand, the next step is to test this drug in a much larger cohort of people to find out whether WVE-003 might truly slow or halt the progression of HD.

Given the encouraging data, the team at Wave are thinking about a potential path for accelerated approval of WVE-003 for the treatment of HD. They have even started to draft the design of their next study which would be much larger (around 150 people) and focus on testing WVE-003 in people with stage 1 or 2 HD. We look forward to learning more from Wave in the coming months about their forthcoming study.