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Different forms of HTT contribute to HD

The genetic cause of HD is an extra stretch of DNA in a gene called Huntingtin (HTT) that leads to an expanded form of the HTT protein. The vast majority of people with HD inherit one copy of the gene from their parent without HD, and an expanded copy from their parent with HD. This means that for a person with HD, half their HTT protein is completely regular and unexpanded, while the other half is expanded.

The expanded HTT protein is thought to be the cause of HD-related symptoms. However, there are questions about what problems are caused by the presence of expanded protein, versus what problems are caused by the absence of enough unexpanded protein.

To address questions about the balance of expanded and unexpanded HTT protein levels in HD, researchers can use a variety of genetic tricks in mice, to manipulate where, when, and how much HTT protein is made, or “expressed,” in the brain and body.

Previous research in the HD field has shown that just expressing the expanded copy of the HTT protein for short periods during development in mice is enough to cause symptoms associated with HD when the mouse is older. But what’s also interesting is that the same thing happens when the normal, unexpanded copy of HTT is removed from the mouse during development!

Dr. Humbert’s team recently set out to explore in more depth the effects of losing or gaining different forms of HTT using specialized mouse models of HD.

Communication breakdown

Brain cells communicate, in part, by sending electrical signals throughout the brain. To study brain diseases, researchers will often measure these electrical signals to see how well brain cells are talking to one another.

Dr Humbert’s group ran experiments to compare electrical signals in the developing brains of mice with or without expanded HTT. The researchers found differences in these electrical signals when mice were very young. However, the electrical signals leveled out when the mice were older and eventually matched the mice with unexpanded HTT.

This seems to suggest the brain is able to compensate for changes in brain cell communication that it experiences early on in HD. The big question is – does this compensation last long enough and do these changes contribute to HD-related symptoms experienced later in life?

Cause and effect conundrum

HD researchers have long explored this cause-and-effect conundrum, questioning whether certain symptoms associated with HD are caused by the presence of the expanded HTT protein or loss of the regular HTT copy.

Dr. Humbert’s group asked if gaining expanded HTT or losing unexpanded HTT causes the changes they see in brain cell communication in their HD mice. They used creative molecular tools to turn off expression of only the regular HTT copy in nerve cells in the brain.

Interestingly, nerve cells with lower amounts of the regular HTT protein responded in a similar way as those that express the expanded HTT protein, except their electrical signals didn’t level out over time. So it seems the brain cells without regular HTT did worse than those that have expanded HTT!

The researchers think this means that the HTT protein is necessary for communication between brain cells when mice are very young, and the presence of either form (expanded or regular) helps compensate as mice get older.

HTT affects nerve cell size and shape

Next the researchers looked at how the different forms of the HTT protein influence the shape of the nerve cells. Nerve cells are shaped like trees – with a cell body that contains many branches at the top, a long trunk, and a branched “root” system at the bottom of the cell.

They found that nerve cells from mice expressing the expanded HTT copy were less complex and had fewer branches when the mice were very young. As the mice got older though, they caught up in size and shape to match nerve cells from mice without the expanded HTT copy.

Interestingly, when they repeated the experiment that decreased the amount of regular HTT in nerve cells in mice, they had similar findings as before – they matched what was observed in the HD mice, except there was no compensation as the mice got older. This once again suggests that loss of regular HTT causes larger negative effects than expression of expanded HTT!

For this experiment they also added a drug called CX516 that increases the ability of nerve cells to send electrical signals. Using cool science, they added this drug to mouse embryos without HTT in their nerve cells before they were born. Excitingly, this drug improved the shape and size of the nerve cells. This suggests loss of the HTT protein affects the way cells communicate through electrical signals, but when that is restored, the brain can compensate!

Balance is key

The next question the researchers asked was if improving electrical communication in HD mouse brains with CX516 would affect HD “symptoms” in mice. They looked at different tests that examine mouse behavior, like how well mice can cross an open gap or how they travel through mazes. They found that CX516 improved how the HD mice performed on these tasks.

Interestingly, on all of the tests that looked at the effects of CX516 in mice without the regular HTT protein, the mice did worse. So even though CX516 increases electrical communication between brain cells, it seems that in mice without HD this does harm. These results highlight how delicate the communication circuits between cells are and show that tipping the scales too far in the other direction can also be bad.

It’s worth noting that the researchers won’t explore CX516 as a potential medicine for HD. It was previously studied as a possible treatment for Alzheimer’s disease, but it didn’t work very well. It’s more likely that they’ll look at ways to target brain cell communication in the same way CX516 does to further understand how the brain can compensate for HD-related changes.

Compensating for communication deficits

There are a few caveats to this work. The first is that CX516 was given to the HD mice before they were born. This undoubtedly leads to questions about how early we have to treat to see some of these effects.

While it might seem like this work suggests that we need to treat people that have expanded HTT almost as soon as they are born, that might not be the case. The brain is really good at compensation! There are lots of redundant pathways that ensure if something goes wrong, other mechanisms make up for it.

This is why the experiments in this paper saw a leveling off of electrical signals and changes in size and shape of nerve cells as mice got older – the brain was compensating. So treating HD when people are adults might still allow the brain time to compensate for changes related to HTT expression when people are young.

The second caveat to this work is that mice aren’t people! Seeing effects in mice is no guarantee that we’ll see the same thing in humans.

What we learned

Rather than studying HTT lowering for therapeutic gain, this new work by Dr. Humbert’s group lowered different forms of HTT as a tool – it allowed them to gain a deeper understanding of the effects caused by different forms of the HTT protein in mice that model HD. Studies like these could be very informative for therapeutics aimed at lowering HTT, giving us a more complete picture of what’s happening in HD.

This work also details some of the effects caused by the disease and the effects caused by the brain trying to compensate. Understanding that last bit – how the brain compensates – could help find balance in the brain and develop treatments for HD.

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.