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The ups and downs of huntingtin-lowering

Tominersen is a type of drug called an ASO, which aims to lower levels of the huntingtin protein, and is delivered through spinal injections. People with Huntington’s disease make an expanded form of the huntingtin protein, due to an expansion in their huntingtin gene. By reducing the amount of the expanded huntingtin protein, scientists working on these drugs hope they might slow or halt the progression of symptoms of Huntington’s. Many companies are working on huntingtin-lowering using different types of drugs, including Roche, Wave, uniQure, and PTC therapeutics.

The path of tominersen from the research lab to this most recent clinical trial has certainly been a bumpy one. A study of tominersen which concluded in 2019 was the first to show that it was possible to lower levels of the huntingtin protein. It also appeared to be safe in people for the duration of the 3-month trial. In a subsequent Phase III trial, called GENERATION HD1, more than 800 participants were enrolled to test if tominersen might improve signs and symptoms of Huntington’s. Unfortunately, GENERATION HD1 was cut short due to safety issues. We still don’t fully understand the reasons for this, but participants who received the highest and most frequent dose of the drug did worse by many measures than patients who were given the placebo, the exact opposite of what we had hoped for.

Roche scientists then spent a long time poring over all the findings from GENERATION HD1 and uncovered some trends suggesting that tominersen may have benefitted some trial participants, especially those who were younger and began the trial with less prominent symptoms of HD. This type of analysis where scientists pick back through subsets of the data is called “post hoc”. The original GENERATION HD1 study was not designed to answer the question of whether the drug is better for this category of Huntington’s patients, but there does seem to be a potentially promising pattern. To address this question properly, Roche scientists need to run another clinical trial and this is how GENERATION HD2 came about.

GENERATION HD2 – a fresh approach to questions about tominersen

This new trial will try to answer a few different questions about the possibility of using tominersen as a treatment for Huntington’s, focusing on the safety of the drug and whether it’s properly hitting its target (huntingtin).

* First, scientists will hope to answer if lower doses of tominersen are safe as a long-term treatment for this younger, less progressed subgroup of Huntington’s patients. As with previous trials, lots of different measures will be taken to check for participant safety.
* Second, they will investigate if tominersen has impacts on biomarkers of Huntington’s, things that can be measured in blood or spinal fluid to get a picture of brain health. This will include a protein called NfL, levels of which go up in people suffering symptoms of neurodegenerative diseases.
* Thirdly, they will assess how well the drug is hitting its target in this more focused patient group. This will include a measure of the huntingtin protein itself, which we expect to be lowered, as we have seen in previous tominersen studies.
* Lastly, they’ll also look at how tominersen affects peoples’ thinking, movements, and behaviour.

Everyone recruited into this trial will be randomly assigned to one of three groups, where they will either receive a low 60 mg dose of tominersen, a higher 100 mg dose of tominersen, or a placebo dose. Both doses are lower than the 120 mg tested in GENERATION HD1. As per previous tominersen trials the drug will be given by spinal tap, but in this trial, everyone will receive their dose every 4 months for a total of 16 months of treatment and monitoring. Data collected will be assessed approximately every 4 months by an independent data monitoring committee (iDMC) which will monitor the trial safety and look at the clinical and biomarker data to see how things are progressing. This is confidential, unless there are serious issues, and completely independent of Roche’s own analysis of the data which will happen when the trial ends.

Who will be enrolled into this new trial?

This new trial will last 16 months, and approximately 360 participants will be enrolled. To follow up on their post hoc analysis from GENERATION HD1, this study will be enrolling participants aged 25-50 years old who have only the very early signs of Huntington’s. You may have read the terms “prodromal” or “early manifest,” which is the science-y way doctors and researchers refer to people with Huntington’s right around the time that movement symptoms appear.

The study will take place across 4 continents with sites in 15 countries spread across North America, Europe, South America and Oceania. Precise information about the sites will become available once they are each approved and will be posted on clinical trial directories such as www.clinicaltrials.gov (global) and www.hdtrialfinder.org (North America), but sites are expected in Argentina, Austria, Australia, Canada, Denmark, France, Germany, Italy, New Zealand, Poland, Portugal, Spain, Switzerland, UK and the USA. Each site may have slightly different rules about participant recruitment i.e. how close to the site you need to live to be considered for enrollment, and not all of the sites from previous tominersen trials will participate in the GENERATION HD2 trial. Keep in mind that most clinical trials recruit through strong relationships between doctors and patients.

Those individuals who were previously in a trial testing tominersen would only be eligible for enrollment in GENERATION HD2 if they had received the placebo dose. Roche stated that their decision to exclude individuals who previously received tominersen was not made lightly, and was made “following extensive consultation with HD experts and community leaders.” This news, and the narrower age range for eligibility, may be very disappointing for some. But Roche is committed to answering important safety questions about tominersen, based on previous data. Although this trial will focus on younger people with less advanced HD symptoms, Roche emphasised that they have not forgotten the complete range of patients which comprise the HD community, nor the commitment of previous participants, and there may be other opportunities for these folks in future.

How can I learn more about GENERATION HD2?

Roche participated in an HDSA Research Webinar last week where more of the specifics of the trial were discussed, including the precise criteria for participant enrollment and members of the Huntington’s community put their own questions directly to the scientists at Roche. You can rewatch this webinar here until early April, 2023. Stay tuned on HDBuzz for more news as things progress.

Huntingtin-lowering therapies are being pursued in the clinic by many companies

Many companies are exploring huntingtin-lowering as a strategy for treating HD. HD is caused by a mutation in the huntingtin gene, which leads to the production of a faulty version of the huntingtin protein. The faulty protein causes all sorts of problems in the brain and including the death of nerve cells, which results in the symptoms of HD. Huntingtin-lowering drugs aim to reduce the levels of the faulty huntingtin protein in the brain , with a goal of slowing or stopping HD’s progression.

Huntingtin-lowering treatments are being developed using a variety of different approaches, such as anti-sense oligonucleotides (Wave Life Science and Roche) or viral gene therapies (uniQure). One problem is that the drugs these companies have developed cannot easily spread through the whole body, so they are given to patients through an infusion into the spinal fluid, or by direct injection into the brain. Giving drugs this way is expensive and demanding for patients so this type of therapy could not be trivially rolled out to the global HD community.

To overcome these problems, researchers are keen to develop “small molecule therapies” which would be cheaper to manufacture and administer. Small molecule drugs can be formulated to be taken orally as a pill or syrup, like most common medicines you may already be taking, such as pain killers or an allergy medication. Because they can hitch a ride in the bloodstream, small molecule drugs are also better at spreading to nearly all the organs of the body. Some small molecule drugs, although not all, can even make the leap from the blood into the brain – enabling treatment of the body and brain with a single drug.

Branaplam lowers huntingtin but was originally designed to treat another disease, SMA

Two different companies, Novartis and PTC Therapeutics, are both testing small molecule drugs which can lower huntingtin in HD patients. The drugs from both companies are called splice modulators because they target how our cells which edits genetic messages, a process call splicing. Each genetic message can be thought of like a story book, and when the story is over, the final part of the message reads the genetic equivalent of “the End” to tell the cell that the sequence for that message is complete. Splice modulator drugs rejig the pages of the story book so “The End” is read the ending, so the cell destroys the message and doesn’t make the associated protein at all. Just like you would toss a book that made no sense with a premature ending and read, “Once upon a time, The End”.

The splice modulator developed by Novartis is called branaplam, a drug originally developed for a completely different disease called spinal muscular atrophy (SMA), because it also changes the levels of a protein called SMN2, which underlies that disease. Very unexpectedly, scientists at Novartis discovered branaplam also changes the levels of the huntingtin protein in different models so wanted to explore if this drug might be a good treatment for people with HD in a trial called VIBRANT-HD.

Branaplam has bad side effects for some people treated with this drug

VIBRANT-HD aimed to work out if branaplam was safe and effective at lowering huntingtin levels but, before recruitment was completed, dosing for the trial was paused due to safety concerns. The decision to pause the trial was made by an independent Data Monitoring Committee, who assess data generated by the trial before the doctors, patients, or study sponsor (Novartis) know the outcomes to ensure participants are safe in case issues arise.

We have since learned in this most recent announcement that Novartis has decided to end all development of branaplam for HD due to safety concerns associated with the drug. When dosing was paused back in August, information was released indicating that there were issues in some study participants with a condition called peripheral neuropathy – damage to nerve cells outside of the brain and spinal cord. In this most recent announcement, Novartis have provided further information about safety issues seen in many, although not all, participants.

As we expected to learn, symptoms and changes in neurological examinations consistent with peripheral neuropathy were confirmed as being observed in some participants. Some participants also had increased levels of neurofilament light chain (NfL), a lab test used to assess injury or damage to nerve cells. This means that there may be damage to the nervous system after branaplam treatment. Also of concern is the observation that there was an increase in the size of a region of the brain called the ventricles. The ventricles are a fluid filled space deep in the brain and an increase in the size of this region can mean several different things, which we don’t yet have enough information to fully understand. In their letter, Novartis state that no clinical symptoms have been associated with these brain scan findings to date.

What does this mean for HD patients who received branaplam?

Novartis have stated that all study participants who received branaplam will continue to be monitored. We don’t yet know if the side effects experienced by participants in the trial are permanent or whether they will get better now that dosing with the drug is stopped, so monitoring of symptoms is important.

What can we learn from trials that end this way?

Trial failures like this can be very hard-hitting and it is very normal to feel upset about this type of news, especially for the brave and dedicated members of the HD community who participated in this trial.
Despite this sad development, there is still a lot we can learn from trials which don’t turn out as we had hoped. Tons of data is collected throughout the course of trials and more will continue to be collected in the coming months as things formally conclude. This data can give us important insights into what might have happened so that the community can learn and move on from this trial. Novartis has stated that they are committed to sharing what they learn with HD families, researchers, and other professionals in the HD community.

Do we know why branaplam didn’t work as we had hoped?

This announcement is the latest in a series of disappointing news regarding HD trials so what’s going on? It’s important to note that branaplam was not developed to treat HD. We knew unexpected side effects were possible, because as well as lowering huntingtin, branaplam also changes the levels of the SMN2 protein, as well as potentially others. Changing the levels of lots of different proteins can disrupt the intricate processes performed by nerve cells, which could explain some of the symptoms observed.

In fact, in some animal studies, Novartis note in their announcement that toxicity of the nerves was seen as a side effect of branaplam treatment, which is why they included robust safety monitoring procedures in the VIBRANT-HD trial. Interestingly, children with SMA treated with branaplam do not seem to have these symptoms, which is why there was still optimism that this would not prove to be a problem in HD patients. We will likely learn more about why this happened as more data from the trial is compiled and analysed.

What does this mean for the other splice-modulator drugs to treat HD?

Other companies are working to develop a splice modulator to treat HD, including Roche who are doing pre-clinical research in this area. Another trial, called PIVOT-HD, will be testing the splice modulator PTC-518 developed by PTC therapeutics which is very similar to branaplam. This trial is underway in Europe and Australia although recruitment is paused in the US as PTC work to provide some extra data to the US regulatory agency, the FDA. It’s important to note that PTC-518 was specifically designed for HD, and data from PTC indicates this drug spreads more efficiently into the brain than branaplam, so the hope is that the side effects observed for branaplam won’t be an issue for PTC-518; we will learn more as the trial proceeds.

When will we learn more?

Novartis have vowed to keep the community updated as their analysis of the data from the trial proceeds. HDBuzz will write another article as soon as we learn any more information about branaplam or the VIBRANT-HD trial.

It’s important to remember clinical trials are some of the biggest and most complicated experiments which we can run, with no guarantees of good outcomes, but each trial adds to our knowledge and brings us closer to finding drugs to treat HD. We are extremely grateful to the brave and selfless HD community members who participated in this trial.

What is the aim of the PIVOT-HD trial?

The PIVOT-HD trial, run by PTC Therapeutics, aims to test how the drug PTC518 might be beneficial in HD patients, by lowering levels of huntingtin protein. PTC518 can be taken in pill form, and is a type of drug called a splice modulator. This type of drug can change how genetic messages are processed which can affect the levels of the protein molecules they encode.

In the case of PTC518, the drug affects how our bodies process the genetic message made by the Huntington’s gene, resulting in lowered huntingtin protein levels. PTC518 does not discriminate between the unexpanded or the expanded forms of the huntingtin genetic message, so both the regular and toxic forms of the huntingtin protein are lowered. You can find more about this drug from a piece we wrote earlier this year about how PTC518 works.

PIVOT-HD is a Phase 2 study which will test two different doses of PTC518, with the option for a third dose depending on the results, in addition to a placebo control. The study will run for a total of 12 months, with a 3-month dose-finding period at the beginning, followed by a 9-month period in which blood, spinal fluid and other measurements will be taken of the participants, to see how they are responding to the drug.

What did the update say?

On the 18th of October, PTC released an announcement which confirmed that enrollment for the trial is active and ongoing. The announcement also confirmed that the study has approval from both European and Australian agencies to proceed as planned.

However, although enrollment for the trial had already started in the US, this has now paused. PTC reiterated in their statement that this is not due to any bad side effects seen with the drug. The reason for this pause is because the main drug regulation agency in the US, the FDA, has requested that PTC provide additional data in order for the study to continue as planned in the US.

More details on the US recruitment pause

In a November 2nd webinar hosted by the Huntington’s Disease Society of America, PTC’s Chief Operating Officer Dr. Matthew Klein elaborated on the reasons for the yellow light from the FDA. First he explained that the length of time that a drug can be tested in people usually needs to match what was tested in animals. Typically, if a company wants to test a drug for 9 months or more in humans, they must have tested the drug for at least 9 months in animals, and at doses that will match the human study.

When PTC launched the PIVOT-HD trial, they had 3 months of promising data in animals, allowing them to begin a 3 month study in humans. In the meantime, they knew they would be getting the results of their 9-month study in animals, so they could apply to extend the study up to 1-year in people. When they got the results of those longer animal studies, the safety and dosing data remained encouraging, so they applied to regulatory agencies, like the FDA in the US, and the EMA in Europe, to lengthen the study in humans.

Whereas agencies in several countries (for example, Australia, the UK, Germany, the Netherlands) approved the longer study, the FDA in the US said that they would like to see more data in animals before extending the study in people. Exactly what data has been requested is not public information at this stage. At this time, PTC is working with the FDA to move things forward in the US, while focusing their efforts on enrolling the study at active sites in other countries.

What does this mean for the PIVOT-HD clinical trial?

For the study sites outside of the US, everything will continue as planned for PIVOT-HD. As far as we know, once PTC meets the new criteria set out by the FDA, the study will also continue as planned in the US.

You may have seen that some blogs and pharma news sites have written different ideas about what this means for the future of PTC518 as a treatment for HD. Unfortunately, some of these articles are not based on facts but are instead, very speculative.

It’s important to remember that the job of the FDA is to ensure that clinical trials are safe, ethical and scientifically sound. It is not uncommon for additional data to be requested by the FDA prior to trials proceeding, their remit is to work in the best interests of the participants in the trial.

When will we know more?

The next planned update from PTC Therapeutics about this trial will be in the first half of 2023, when we will hear what they have found in the first 12 week portion of the trial. We also anticipate PTC Therapeutics will probably update the community once recruitment in the US begins again.

Whenever there is an update, HDBuzz will write again to keep the HD community informed.

Updates from Roche

First, let’s recap Roche’s work in HD research in recent years. Roche had been running a global clinical trial, GENERATION-HD1, starting in 2019, to test a drug called tominersen in people with HD. This was a Phase 3 trial, a big study designed to determine whether a drug can slow or stop the progression of HD symptoms. An earlier, shorter trial, run by Ionis Pharmaceuticals had already shown that tominersen appeared safe and that it could lower the amount of huntingtin protein in the spinal fluid of people with HD.

The 800 participants with HD in GENERATION-HD1 hailed from all over the globe, and were split into three groups, known as cohorts. One group received tominersen via spinal injection every 8 weeks, one every 16 weeks, and one received placebo (spinal injections but no drug). Their participation was planned to last for two years, with the option to continue in what’s known as an “open label” trial, in which every participant could choose to receive tominersen regularly after they completed their two year period in GENERATION-HD1.

In March of 2021, Roche stopped dosing people in the trial, because the data were starting to reveal potential safety issues. Tominersen not only had no overall benefit for people with HD, but the people in the 8 week group seemed to be doing worse, symptomatically, than those in other groups. It’s still not completely clear why this is the case, but it could have been due to the high dose of tominersen (120 mg) and frequent dosing leading to an immune reaction that was problematic over long periods of time. This would override the potential benefit of lowering huntingtin.

Wait, so why another trial?

Over the course of the past 18 months since the tough news came about GENERATION-HD1, Roche has been busy analyzing (and sharing) data from the trial, to try and understand what went wrong, and whether there might be a future for tominersen in HD. A glimmer of hope came in late 2021 when a new analysis showed that some participants in the trial might have benefitted from tominersen. Specifically, younger people who began the trial in earlier stages of HD did not seem to experience a worsening of symptoms over the course of their participation.

This finding comes with many caveats because the trial wasn’t designed to split people into smaller analysis groups, so it’s not clear how significant this finding is or if it will hold true for a larger group of people. However, Roche believed the data was hopeful enough to test tominersen again, this time in younger people with earlier signs and symptoms of HD. Taking all the data along with community and expert input into account, they have now announced what the new trial will look like. This happened in a presentation and community statement released during the recent conference of the European Huntington’s Disease Network (EHDN) in Bologna, Italy.

The new tominersen trial

This new tominersen trial will be called GENERATION-HD2, and if all goes as planned it will begin enrolling people with HD in early 2023. This is a Phase 2 study, looking at both safety and how huntingtin levels are lowered with different doses of tominersen. It will also involve three cohorts of participants, all receiving spinal injections every 4 months for 16 months. One group will get a lower dose (60 mg) of tominersen, one will get a higher dose (100 mg), and one will get placebo (injection with no drug). They aim to recruit about 360 people in 15 countries.

We’re waiting for more information on locations and exact guidelines for eligibility, but right now what we know is that the trial will recruit people aged 25 to 50, with very early subtle signs of HD or early movement symptoms. GENERATION-HD1 and the open label extension are now over, but people who previously participated in these trials of tominersen will not be eligible for GENERATION-HD2.

Just like with GENERATION-HD1, an independent data monitoring committee (iDMC) will review the data as the trial progresses. Roche scientists hope that lower, less frequent doses, and earlier treatment could help to overcome the safety issues and might reveal some of the potential benefits of huntingtin lowering with tominersen.

Updates from Wave

At nearly the same time that we got news from Roche that GENERATION-HD2 would be launching, another piece of news regarding huntingtin lowering emerged. This came from Wave Life Sciences, who are also using ASO drugs to try and improve HD symptoms.

Before we can talk about Wave’s news, we have to remind ourselves of some basic HD Biology. Every human has two copies of the HD gene – the one from mom and one from dad. In the vast majority of cases, HD patients have only one mutant (expanded) copy of the HD gene – the one they inherited from their parent with HD. Their other copy doesn’t have the genetic change required to drive the development of HD.

Wave’s approach to huntingtin lowering is a little different from that taken by Roche and Ionis. Instead of trying to use an ASO to silence both copies of the HD gene in treated patients, Wave is only targeting the expanded copy of the HD gene.

We’ve covered the ideas behind Wave’s approach before on HDbuzz, but basically the concept is that preserving the levels of the normal huntingtin protein could be important. Although researchers still don’t understand everything the HD gene does, we know it’s a very important one, and so keeping some healthy protein around might prove beneficial.

A selective approach to treat HD

What’s difficult about this selective approach is that, so far, we don’t have effective ASOs that target the actual HD mutation. So Wave has come up with a clever way to target only the expanded copy of the HD gene, by taking advantage of other tiny spelling changes in the HD gene.

While this technology theoretically lets you only reduce the mutant copy of HD, it has a limitation that a given person must have the right little spelling changes for Wave’s targeted drug to work. So not every HD patient could use any of the ASOs that Wave is currently testing in clinical trials.

An earlier version of their ASO failed in clinical trials; it wasn’t harmful, but it just didn’t lower huntingtin. Wave went back to the drawing board and made a new ASO with different chemistry which they hope will work better. Wave is now running a trial called SELECT-HD to test whether this new selective ASO drug can lower the mutant Huntingtin protein, and if that has benefit for HD patients. This is a relatively small trial – 18 participants have been enrolled to date and they expect around 36 total. Each participant is getting either placebo, or one of several doses of Wave’s selective ASO.

The goal of Wave’s study is to see if the drug is safe, and to try and figure out ahead of time what doses of the drug are effective at reducing levels of the huntingtin protein in the spinal fluid. This trial intentionally doesn’t include enough people to determine whether the drug has an impact on HD symptoms – as we saw with the GENERATION-HD1 trial, that takes many hundreds of participants. Exposing that many people to a drug at this early stage would be unethical, so Wave will dose a smaller group of volunteers with the drug to establish its safety.

Lowering of the HD protein

Last week, Wave provided us with an update from their trial. In a planned monitoring of the efficiency of the drug, Wave was able to see that treatment with 30 or 60 mg of drug led to a reduction of levels of the mutant Huntingtin protein. This is the first time that Wave’s HD ASOs have been shown to lower levels of the target protein.

The data are a little more complicated than we’re used to hearing about from Roche, because Wave has the goal of lowering the mutant HD gene, but preserving the regular one. Scientists at Wave have developed a test that they believe allows them to measure both of these things from the same sample. So, for the first time, we’re able to see what impact a treatment has on the levels of both normal and mutant huntingtin.

Wave shared data in their update which indicates that their drug was able to lower the levels of mutant huntingtin by 20-30%. This did not seem to be matched by a reduction in levels of regular Huntingtin, which stayed about the same. This is, as far as we know, the first time anyone has ever selectively lowered only one copy of a protein inside of a human body.

Increased neurofilament levels?

There was some news in the press release that gave us pause, however. While there weren’t any adverse events associated with treatment with Wave’s ASOs, some participants showed an increase in the levels of Neurofilament in their spinal fluid. We’ve discussed neurofilament before at Buzz – basically it’s a marker of brain cell damage.

In HD and other brain diseases, levels of neurofilament are increased, due to the harm caused to brain cells in these conditions. An attractive idea is to use neurofilament levels to try and see if an experimental drug lowers the levels of neurofilament as the damage to brain cells is halted or reduced.

The Wave study hasn’t run long enough to expect to see a big rescue of the neurofilament levels in HD patients. In the spinal fluid samples from some of the patients in the study, Wave saw an unexpected increase in the levels of neurofilament. No information has been provided by Wave as to why this might be happening but they plan to monitor this carefully.

Long-time readers might remember that in the early days of Roche’s development of tominersen, something similar happened. The people in the first human study of tominersen saw some increases in neurofilament as well. In the case of tominersen, those increases went away over time, for reasons that no one yet understands.

It could be that the increase in neurofilament that Wave is seeing in some of their SELECT-HD study could get back to normal, as happened in the early studies with tominersen, but we just don’t know at this stage. We need more data from longer treatments in more patients to understand what these short-term increases in neurofilament might mean.

Key takeaways

The past few years have been a tough time for people in the HD community. The pandemic years have brought a pandemic of difficult news, most recently with the halting of the VIBRANT-HD trial being run by Novartis with yet another huntingtin lowering approach.

It’s a welcome change to have some more positive news on this front, and good to see advances being made by multiple companies, with distinct approaches to huntingtin-lowering. Until we have effective drugs for HD, we won’t know which approach will be most effective, so it’s critical that we continue testing different approaches to this really tricky problem.

That said, it’s important to remember that huntingtin-lowering remains an unproven approach to treat HD in people. Even if we can safely lower the levels of total huntingtin or just the mutant huntingtin protein in people, we don’t yet know if this will help slow or halt the progression of symptoms. But that’s why we need to run these clinical trials to test out these approaches and hopefully find something which works.

We remain optimistic that at least one of the approaches currently being tested in the clinic or the lab may prove beneficial for people with HD. It’s thanks to the brave and selfless volunteers who participate in this research that we may find a treatment. Stay tuned to HDBuzz for more news on these trials as they develop.