Welcome to Day 2 of the Hereditary Disease Foundation (HDF) conference! The morning was spent listening to an interview between a neurologist and their patient living with HD. All HDF meetings begin this way, to better connect scientists with the people who matter most, those living with HD.

Different flavors of HTT

Up first is Tony Reiner, who studies the structure of the brain and how it changes in HD. Interestingly, HD doesn’t affect the whole brain equally. There are certain parts that are more vulnerable – specifically, a region called the striatum, which is found almost exactly in the center of the brain.

Cells found within the striatum tend to get sick and die in HD, causing this part of the brain to get smaller as the disease progresses. The outer wrinkly bit of the brain, called the cortex, also shrinks in HD.

The gene that causes HD produces a protein (huntingtin, HTT) that is quite sticky, and clumps up in the brain. Tony’s work examines brains generously donated from HD families to track where these sticky clumps are found throughout the brain.

Tony’s lab has studied donated brains to measure the loss of different brain regions at different stages of disease, to ask whether the most vulnerable regions are those with the most HTT protein. Surprisingly, this is not always the case.

In fact, certain cells within the brain that aren’t very vulnerable to HD produce lots more HTT protein than very vulnerable cells in the striatum. Quite surprising!

If not the mere presence of the HTT protein, then what causes cells in the striatum to be so vulnerable? To answer this question, Tony is meticulously tracking different forms of the sticky HTT protein throughout the brain.

Like chocolate can come in different forms (hot chocolate, bar, chips), proteins can come in different forms too. These different protein forms can perform different functions, good or bad, perhaps making some forms of the sticky HTT protein toxic.

Knowing which form of the protein is found in which areas of the brain will help researchers understand if certain types of HTT are more toxic than others, which could help with understanding the details of how HD affects the brain.

It’s not all about neurons

Up next is Osama Al Dalahmah, who is another brain pathologist – someone who studies the structure and function of the brain. He’ll be talking to us about his research on a star-shaped cell in the brain called astrocytes.

Neurons get a lot of attention in HD – and rightfully so! Neurons are the cell type that send electrical signals to help us think, move, and feel. And they’re the cell type most affected by HD. But neurons aren’t the only cells that make up the brain.

Astrocytes connect to neurons to help maintain the environment of the brain to keep neurons happy and healthy. We’ve previously written about astrocytes and the role they play in HD.

Osama’s group is asking how astrocytes in people with HD may be different and if astrocytes may even be protective against the disease! Using donated brain samples and cutting-edge technology, they can study minute differences in each astrocyte cell within a brain sample.

In particular, they are looking to see which genes get turned on/off in the astrocytes found in the brains of people with HD. There seem to be some patterns that make up a “molecular signature” for astrocytes in HD. Interestingly, it seems that cells with some of these molecular signatures are actually adapted to work to help protect the brain during HD.

Osama likens neurons to crowd surfers being carried by the crowd, in this case, supporting astrocytes. Some astrocytes in people with HD support crowd surfing neurons, but others, without the right signature, allow for stage dive fails. No fun for crowd surfing neurons!

The cellular trash bin

Up next is Joan Steffan who is going to be talking to us about her research looking at what the HD protein does normally. We know the HD protein, HTT, doesn’t work well in disease. But the HTT protein has lots of important jobs to do in healthy cells and Joan, and the other speakers of this session, are interested in investigating these functions.

Joan is studying the role of the HTT protein in cleaning up components of the cell that are no longer needed. This process, called autophagy, is very important to keeping cells healthy. Joan found that HTT works with lots of protein friends in the cell to take out the cell’s trash.

Many proteins involved in autophagy bind to the cell trash via a molecular tag. So Joan’s team asked if the HTT protein could also bind this tag. Turns out it can in a test tube!

The HTT protein is huge, one of the largest that our bodies make. Joan and her team have mapped the exact part of HTT which binds onto this tag. The tag-binding region is right on the edge of the donut structure of this massive molecule.

Looking closer, Joan asked what cellular trash might be bound by the HTT protein. She found that lots of these were proteins whose job is normally to bind genetic message molecules, called RNA. Joan has lots of ideas about what this might mean for HD biology.

She also found that the expanded form of HTT, which causes HD, interacted more tightly with the trash tag. This gives us more clues about the normal role of HTT and what might be going wrong in HD.

Huntingtin’s BFF – HAP40

Next up is HDBuzz’s very own Rachel Harding! She’ll be telling us about cool new tools she’s using to better understand the structure of our favorite protein.

Rachel reminds us of how very big the HTT protein is. She’s very interested in its shape: one half looks like a donut, which is connected to the other half through a bridge. These two halves are held together by another protein called HAP40.

Rachel’s lab is very good at producing the HTT protein in a test tube. This is used by labs all over the world to understand what the HTT protein does.

An important part of understanding what a protein does is knowing what other proteins it interacts with. One of the tools used to discover these interactions is antibodies. So it’s very important that the HTT antibodies are of good quality. The good news is, we have some great antibodies. The bad news is, some of the antibodies regularly used by HD research labs are not so great.

To make sure we’re using the best tools possible, Rachel is developing an alternative to antibodies called macrocycles. These are small molecules that bind to HTT very tightly and can be attached to other things like fluorescent tags that will make the HTT protein glow. Very cool!

Using several fancy technologies, Rachel’s group is figuring out exactly where each macrocycle is binding on the HTT-HAP40 structure.

Macrocycles can be used for much more than just studying HTT in a test tube. They can also track HTT in cells, which will be pivotal in helping researchers understand the function of HTT and what might be going wrong in HD.

They may also be used to find “pockets” in the HTT protein that would make good drug targets.

Picking up speed

Next up is Bob Handsaker who will talk to us about somatic expansion in HD – the idea that in some cells, the CAG repeat can get longer over time. HD scientists are trying to figure out how this might contribute to the path of disease progression, a very exciting area of research.

Bob and the team he works with at Harvard have built a model of how they think somatic expansion happens in cells, first in a slow and then in a rapid phase. They have collected evidence from brain tissues analyzed from people who have passed from HD that they believe supports this model.

Next, Bob tells us about changes to genes being switched on and off and how this correlates with somatic expansion of the CAG tract. Interestingly, they don’t see much difference until the expansion becomes very large, around 150 CAGs.

After the cells reach this very long CAG repeat length (which takes decades), they start to see accelerated changes in genes that are turned on and off, leading to toxicity in the cell, and eventually death of those cells.

The model Bob is proposing is somewhat in contrast to data published by other scientists, many of whom are in the room – but this is what conferences are for, to discuss these hot topics and see how the collective evidence shakes out, to move the science forward.

Interestingly, when they dig into the data to see which genes are turned off in neurons from the striatum (the very center of the brain) they’re genes associated with “cell identity”. This means the cells, in a way, lose their ability to tell what kind of cell they are.

Bob and the team also looked at the protein clumps that they see in the brain and how these change over time. Their modelling and analysis suggest that this is a late feature of HD, happening in just a subset of cells in the brain.

Overall, the model Bob proposes suggests why HD might take decades to develop and they hope it can be used to develop better therapeutics for HD, or to track how new drugs might slow or halt HD.

Different disease, similar effects

Up next is Harry Orr, who works on a different CAG repeat disease called spinocerebellar ataxia 1 (SCA1). While there are similarities with HD, there are also differences. SCA1 typically has adult onset, causes movement changes, and problems with thinking. Also like HD, there is no treatment.

One major difference is the primary cell type affected. While HD primarily affects neurons of the striatum, SCA1 primarily affects a different type of brain cell called a Purkinje cell in an area of the brain called the cerebellum.

Harry’s lab has been working on developing mouse models of SCA1 to better understand this disease. They are using these models to look at somatic expansion in different parts of the brain

It seems ongoing CAG expansion isn’t unique to HD, but may be a common feature in several diseases, including SCA1. As we’ve heard already at this meeting, a rising tide lifts all ships – finding treatments for one brain disease could have implications for others, including HD.

Location, location, location

Our last talk of day 2 is from Longzhi Tan whose talk is titled, “3D genome architecture across the lifespan and in HD” – sounds like it will be high tech!

Each of our cells carries the entire genome – all of our DNA – in its nucleus. Tan analyses the shape of this DNA at the single cell level. Measuring the shape of DNA is incredibly difficult. This is because DNA shape differs cell to cell, so shapes within 2 cells aren’t the same.

Tan developed his own technique to solve these challenges and define the shape of DNA across many cells. Combining computers with microscopes gives a high-tech solution, allowing him to back calculate DNA shapes within the nucleus.

He’s showing the crowd super cool videos that have caused audible murmuring throughout the audience. There’s very cool science being done in the HD space!

Each cell uses different genes to do its job. Tan is explaining how the genes used by one cell type move toward each other in the nucleus. For HD we’re of course interested in brain cells. Tan can tell the difference between diverse brain cell types simply by looking at the position of their genes. Wow!

Tan is using his cool technology to study HD by asking if the disease affects the position of DNA within a cell and if that may alter which genes are on or off. He is currently working on these questions in mice that model HD. They have found that the biggest differences in the DNA’s 3D shape happen in the very cells that are vulnerable in HD!

Tan is also looking at how DNA shape changes when he turns off a gene associated with somatic instability, called MSH3. Turning off MSH3 rearranges the DNA location so that it more closely matches cells without HD.

Overall, Tan’s work is a super cool debut of new technology that can be used to analyze HD in very fine detail.

That’s all from us for day 2 of the conference! We’ll be back for day 3 to share updates about cells other than neurons, somatic instability, and DNA repair. Stay tuned!

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 20 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 International 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 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 40-50% 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 the placebo group. 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.

On June 20, 2024, we received an update from PTC Therapeutics about their ongoing trial, PIVOT-HD. PIVOT is testing PTC-518, a small molecule drug, taken as a pill, that lowers huntingtin (HTT) in people with Huntington’s disease (HD). Their most recent update shared data from people who had been on the drug for 12 months. Read on to learn what their new results tell us!

HTT lowering

Before we get into the juicy details of the data release, let’s cover some basics about why PTC is interested in lowering HTT and what they hope it will do.

We know that the genetic cause of HD is an expansion of the genetic code within the HTT gene. There’s an extra bit of genetic message that repeats the letters C, A, and G more times than it should. When someone has 40 or more CAG repeats in their HTT gene, they’ll go on to develop HD, unless researchers can find some way to intervene.

With such a conclusive test for determining if someone will develop HD, researchers have narrowed in on the HTT gene itself to develop potential treatments. We now have the technology to target HTT and reduce the amount of protein that’s produced. The thought is, with less of this nefarious player, progression of the disease itself would be slowed, or possibly stopped. Lowering HTT in the lab in animal models of HD has had success, and it’s now being tested in people.

PTC’s approach for lowering HTT

There are several companies testing HTT lowering in trials, and many of them are taking different approaches. We’ve covered ongoing HTT lowering trials from Roche, uniQure, and Wave Therapeutics. Currently, PTC Therapeutics is one of two companies testing a pill that can lower HTT in clinical trials. (The other is Skyhawk Therapeutics, who are advancing their HTT lowering small molecule SKY-0515.) PTC’s drug, PTC-518, works by rearranging the HTT message molecule.

Like stories, all genetic messages have a beginning, a middle, and an end. The end is the part of the code that tells molecules that the genetic story is over, like the last page in a storybook that reads, “The End”. PTC-518 works placing “The End” into the middle of the message. So rather than a logical story, the message is interrupted by “The End”. The cell realizes that the message doesn’t make any sense, and doesn’t bother making that protein.

After encouraging results in animal studies, PTC Therapeutics moved their drug into clinical trials. PIVOT-HD is a Phase 2 trial primarily designed to test the safety and tolerability of PTC-518. It tests 2 doses (5 mg and 10 mg) over the course of 12 months in people in Stage 2 and early Stage 3 of HD according to the HD-ISS.These are people who have begun to show clinical signs of HD and have just started showing difficulties with daily functioning. After the 12 months, all participants can continue taking the drug in an open label extension.

PIVOT-HD is a very small and relatively short trial, with just 32 people enrolled for the 12 month study – we don’t want to give too many folks the drug for too long until we know for sure it is safe. Although safety is one of the key goals of the study, lots of other measurements are taken to see how the drug might be working. These provide exciting hints but we really need a Phase 3 trial, which would test the drug in a lot more people for a longer timeframe, to see whether PTC-518 actually slows or halts HD.

What we learned a year ago

The last update we received about PTC-518 was exactly a year ago. That update released 12 week data from people with HD taking PTC-518. In the summer of 2023 we learned that PTC-518 did seem to lower HTT levels in blood. This may seem like an obvious point, but checking that the drug working as expected is important so that we know things are on the right track.

We also learned that PTC-518 was well tolerated overall, it got to the brain, and biomarker levels seemed to remain stable over the 12 week timeframe. The specific biomarker that was measured was neurofilament light (NfL), which measures the breakdown of brain cells, and is used as a measure of overall brain health. NfL steadily increases in people with HD as the disease progresses. NfL is becoming one of the field’s most reliable biomarkers to track HD progression. Last year’s data release suggested that PTC-518 seemed to be on the right path, so the study continued.

12 months later – biomarkers moving in the right direction!

People in the PIVOT-HD trial have now been taking PTC-518 for 12 months. The key objectives for the 12 month time point are to: 1) show that the drug is still getting to the brain and lowering HTT, 2) examine disease biomarkers, and 3) measure any changes in participant functionality. Cutting to the chase – things look positive for all of their 12 month objectives!

To determine if PTC-518 is lowering HTT in the brain, they take a sample of the cerebrospinal fluid (CSF) that bathes the brain. Since they can’t directly sample brain cells, this is the next best option to measure what’s going on with HTT levels in the brain. PTC reported that 5 mg of PTC-518 lowers HTT in the CSF by ~20%, and 10 mg by ~40%. Similar decreases were also seen in blood samples taken.

At 12 months, one of the biomarkers that they examined was NfL levels in blood. Natural history studies, like Enroll-HD, have shown us that NfL levels in blood typically increase by about 10-12% per year in people with Stage 2 HD.

In people taking PTC-518 for 12 months, the increase seemed to slow down and was 3% on 5 mg of PTC-518 and 4% in people taking 10 mg. These results show that taking PTC-518 does not seem to cause the brain any harm, and in fact, may even slow the damage to brain cells that occurs in HD.

12 months later – improved clinical scores!

For clinical metrics to determine how PTC-518 affects functionality of people with HD, they examined Total Motor Score (TMS), the Composite Unified Huntington’s Disease Rating Scale (cUHDRS), and Total Functional Capacity (TFC). What a mouthful! Let’s break down what they found.

The TMS scale measures movement symptoms in people with HD. For people taking PTC-518, there was a reduced progression on the TMS by over 70%! In the webcast update, PTC Therapeutics noted that the TMS is one of the most reliable metrics for determining disease progression in people with Stage 2 HD. So reducing progression of TMS is very encouraging as it suggests there might be a slowing of disease progression.

The cUHDRS is one of the most comprehensive clinical measures for assessing HD progression. It looks at changes in movement, thinking, behavior, and functioning. Typically, people with HD progress by 1 point on this scale per year. In people taking PTC-518, this progression seems to be cut in about half.

TFC measures the ability of a person to function on day-to-day tasks and looks at the ability of someone to hold a job, do their own finances, and carry out activities of daily living. In people taking PTC-518, this also looks to have moved in a positive direction. Together, these improvements in clinical scores suggest that taking PTC-518 could have a chance at slowing the progression of HD – very big news!

FDA hold lifted

While the most exciting updates were related to biomarkers and clinical scores (understandably!), PTC also looked at safety. At the end of the day, this Phase 2 trial is ultimately designed to test the safety and tolerability of PTC-518. Thankfully, all safety metrics suggest that PTC-518 is also checking this box. The most common symptoms reported were headache, falls, and flu-like symptoms, which were also reported in the placebo group.

Another important note, especially for the very astute readers, is that the FDA has lifted their hold on PTC-518. We previously reported that the FDA was pausing the PTC-518 clinical trial in the U.S. This wasn’t related to the safety of the drug, but rather the amount of data that had been produced to that point and shared with the FDA. The regulatory agency likes to see animal data extending past the time point being tested in the trial in people, and PTC only had data out to 3 months at that point. Excitingly, the new 12 month data has convinced the FDA to lift their previous hold in the U.S.

What’s next for PTC-518?

Overall, this is GOOD news! And we realize the HD community is very thirsty for a tall glass of good news at this point. However, we do need to temper expectations on all this excitement a bit. While these results are encouraging, they can’t be used to conclusively say if PTC-518 will be effective in modifying disease course of HD.

The ultimate goal of this Phase 2 trial is to work out if PTC-518 is safe enough to move into a larger Phase 3 study. The number of people in the trial is very small, at a total of 32 participants, so any conclusions drawn about the biomarker and clinical data need to be taken with a pinch of salt.

To conclusively determine if PTC-518 is effective in treating HD, a Phase 3 trial will need to be performed. Thankfully, PTC announced in their update that they’re in the midst of planning that Phase 3 trial. This trial will specifically be designed to test how well PTC-518 works in slowing or stopping progression of HD. They hope that this trial will serve to land them close to regulatory approval in what would be the first ever disease modifying treatment for HD, a drug for which we’re all eagerly waiting!