HDBuzz

In recent years, HD research headlines have trended toward huntingtin lowering: experimental therapies that target the root genetic cause of HD. But there are also several drugs in development to treat HD that do not aim to lower huntingtin. Some of these are aimed at managing individual symptoms of HD, like managing involuntary movements, or improving cognition. Others take more preventative approaches, like preserving the health of brain cells or slowing down the expansion of CAG repeats in the huntingtin gene.

Beyond huntingtin lowering

HD is caused by an expansion in one section of the huntingtin gene, so cells produce an extra-long form of the huntingtin protein. Expanded huntingtin proteins are believed to be toxic, especially to the brain cells responsible for control of mood, movement, and memory. Naturally, this has made lowering the amount of expanded huntingtin in the brain and body a major priority of efforts to treat HD.

Despite trial failures that have rocked the HD community in recent years, huntingtin-lowering remains a viable approach to treat HD, and dozens of companies and academic labs are working to make this an accessible reality. However, all of our metaphorical HD research eggs are not just in this one basket.

As novel science weaves a broader understanding of HD biology, potential new avenues of treating the disease are coming into focus, and there are dozens of companies and academic labs working to develop these strategies into accessible realities, too. In this article, we’ll explore some of these approaches to treating HD.

Targeting cholesterol

Cholesterol is a type of fat molecule found throughout the body. You’re probably familiar with its roles in heart health or hormone production, but you may not know it is especially important for the health of connections between cells in the brain. Maintaining optimal levels of cholesterol in the brain is tricky; cholesterol molecules are large, and it is difficult for them to pass freely between the brain and the blood that circulates through the rest of the body. A special enzyme, CYP46A1, helps eliminate excess amounts of cholesterol in the brain, but it can stop working properly in Huntington’s disease.

Asklepios BioPharmaceutical (AskBio) is developing an experimental gene therapy that targets this enzyme. AskBio’s drug, AB-1001, is delivered directly to brain tissues in a single dose on each side of the brain with an MRI-guided brain surgery. AB-1001 tells the body to produce more CYP46A1 to help restore a better balance of cholesterol in the brain.

AskBio hopes that repairing this cholesterol pathway will support the overall health of neurons, and could also help the brain lower its own levels of mutant huntingtin protein without affecting levels of healthy huntingtin. Currently, this drug is being studied in a small group of people with HD in a Phase I/II trial in France that began at the end of 2022. While there is no news yet as to the drug’s safety or efficacy, the results of this safety study will determine whether a larger trial will take place.

Preserving connections between brain cells

Synapses are the connections between brain cells that allow them to communicate. Sometimes these connections stop working as well as they should, and a part of the immune system, called complement, gets rid of them. This process, called synaptic pruning, is especially important in early phases of brain development, but occurs throughout a person’s life.

It’s a bit like trimming back an overgrowing shrub in a garden that might block sunlight or monopolize nutrients from surrounding plants. A complement protein called C1q attaches itself to declining synapses, causing them to be cleared, to make sure healthy synapses can continue to do their job effectively.

In HD, C1q proteins become overactive and can tell the rest of the complement system to begin breaking down healthy brain cells instead of damaged ones. If C1q protein levels could be managed, it might help preserve healthy synapses for longer to support the brain’s resiliency against the onset of HD. The company Annexon has been developing an experimental therapy to block C1q and calm over-activity in the complement system.

ANX-005 is an antibody therapy that is delivered with an IV; in 2022, a Phase II trial was completed to check its safety and efficacy in people with HD. The study didn’t have a placebo group to compare the effects of ANX-005 to the natural progression of HD, so the results are a bit difficult to interpret. However, the findings indicate that HD symptoms were stabilized in some participants, particularly those who started out with a more active complement system. Annexon is planning for a larger, placebo-controlled Phase II/III study to begin in 2024.

Slowing somatic expansion

DNA is constantly being pulled apart and put back together again to be used as a blueprint to make message molecules, called RNA, which in turn encode proteins. Our cells perform these tasks nearly 2 trillion times per day—they literally have it down to a science. This also means that there are plenty of opportunities for mistakes. Our bodies plan for this, and have machinery to detect and fix errors: DNA mismatch repair proteins.

Certain stretches of DNA pose an extra challenge for these auto-correct proteins. In people with HD, DNA mismatch repair proteins are more prone to slip on the extra CAG repeats in the huntingtin gene, like a needle might get caught on a scratch in a record. Sometimes this results in even more CAG repeats– especially in the cells of the striatum, the part of the brain that controls movement and mood.

This tendency for the expanded stretch of the huntingtin gene to grow over time is called somatic instability. While some cells are more prone to CAG repeat expansion over time, like in the brain or liver, this phenomenon is less likely to occur in other types of cells, like those in our blood. This means that the results of a person’s genetic blood test wouldn’t be changed over time by somatic instability.

Some scientists think that as CAG repeats in huntingtin gene grow longer, the resulting huntingtin proteins become even more dysfunctional and toxic. Scientists are still understanding what this means, but it is believed that somatic expansion contributes to the death of brain cells in HD, making it a key therapeutic target to treat the disease.

LoQus23 and Pfizer are researching drugs to slow or stop somatic expansion in the mutated stretch of the huntingtin gene with the goal of slowing or stopping the progression of HD. While still in early stages of development, they are targeting some of the proteins involved in DNA mismatch repair to accomplish these aims, and many more companies and academic researchers have an interest in pursuing HD treatments related to somatic instability.

Managing movements

A major goal of HD research is to find options to slow or stop the disease in its tracks. Another important objective is to help people with HD maintain independence and quality of life for longer by managing symptoms of the disease. One approach to this is reducing the involuntary movements that are common in people with HD, chorea. These movements may not be bothersome for some, but others may find chorea disruptive to day-to-day activities or safety.

There are currently three drugs available for treating HD chorea. Each is taken by mouth and employs similar drug chemistry to manage involuntary movements. Xenazine (tetrabenazine), Austedo (deutetrabenazine), and INGREZZA (valbenazine) all limit the activity of VMAT2 proteins. These proteins act as transport vehicles for the chemical messages that are passed between brain cells, especially dopamine. Dopamine plays a role in movement, and managing its levels in the brain can help minimize chorea.

While these three drugs are similar, and there are additional drugs that doctors may prescribe for movements alongside other HD symptoms, having options to manage chorea is a good thing. One drug may be preferable over others for a variety of reasons, including cost, dosage, and frequency. HDBuzz recently wrote about the FDA approval of INGREZZA in the United States in August 2023, as well as the other chorea-management medications currently available for people with HD. You can read more about that here.

Improving function

Early signs of HD often include slight disruptions in someone’s ability to perform day-to-day activities, such as handling their finances, remembering directions, and managing household chores. HD clinicians often use a rating scale to measure “Total Functional Capacity” (TFC), which encompasses many aspects of someone’s capacity to live and function independently. Maintaining TFC for longer could improve quality of life for people by preserving their independence.

Prilenia has been testing a drug to support total functional capacity in people with HD. Pridopidine, which is taken by mouth, has been studied in humans for more than a decade, but no large trial has met its goals of slowing the progression of HD. Pridopidine activates a protein called the sigma-1-receptor, which helps brain cells survive under stress.

The latest study of pridopidine, PROOF-HD, wrapped earlier this year, but the results are somewhat unclear. Pridopidine has a good safety profile, but was not found to effectively improve total functional capacity or movement symptoms in people with HD. The drug may have been helpful for the first year in some participants, those who were not taking certain medications that alter dopamine. Prilenia is continuing to analyze the data, and to conduct additional research to interpret these results.

Improving cognition

NDMA receptors are critical for tasks like combining and linking memories, multitasking, and effective decision making—functions that all fall under the umbrella of cognition. Sage Therapeutics is also hoping that their drug will improve early changes in these thinking abilities for people with HD. Their drug, SAGE-718, is designed to increase activity of NMDA receptors to preserve cognition in people with HD.

A small, early clinical trial showed some promising results in people with HD. Sage is now studying the drug’s safety, efficacy, and effects on cognitive performance in a series of Phase II trials called the PERSPECTIVE program. Two of these trials are currently recruiting participants in North America; while similar, they have different goals.

The DIMENSION study investigates the safety and efficacy of SAGE-718. The SURVEYOR study also assesses safety and efficacy, and evaluates the drug’s effects on tasks of daily living. The study protocol includes virtual reality simulations of things like cooking a meal, using transportation, shopping, or managing money, as well as an optional driving simulation.

Looking forward

Huntingtin-lowering therapies have dominated the HD-research landscape, but this is one among many approaches to treating HD. New paths to treat HD are being uncovered and explored all the time. This is one reason why observational research studies like Enroll-HD are so important; the greater our understanding of HD biology, the better our understanding of how to treat it, and the more drug targets are revealed to fight the disease and manage its symptoms.

While all cases of HD result from a single gene, this doesn’t mean that every person’s symptoms will progress in the same way. In an ideal world, there would be multiple strategies available to treat and slow HD that could be attuned to an individual’s symptoms and genetics. More tools in the toolbox is a good thing, and the treatment strategies described in this article are only a handful of the possibilities currently in the HD research pipeline from a few of many companies working to bring options to HD families.

Researchers studied a fragment of the Huntington’s disease (HD) protein in plants and found a new way to stop it from forming toxic clumps. A special plant protein that the team identified can prevent harmful buildup in plants as well as in some HD model systems, showing potential for this approach as a possible way to treat HD.

Why study HD in plants?

Plants are stuck in their environment, literally rooted to the ground, which means they cannot move if they start to experience challenging conditions such as too much sun, freezing cold or pesky predators. To help deal with the environmental troubles they can experience, plants have evolved all kinds of nifty ways to cope, which can make them very resilient to stress. Many plants can also live an extremely long time, so some scientists believe they might hold the key for studying and finding new medicines for human diseases of ageing.

HD is caused by an expansion of the number of CAGs within the huntingtin gene, which means that an expanded form of the huntingtin protein is made. The expanded huntingtin protein can form clumps, and scientists think these may cause all kinds of stresses in our cells, contributing to the signs and symptoms of HD. In this study, a group of researchers from Cologne, Germany wanted to investigate whether the resiliency of plants could be extended to dealing with stress caused by toxic clumps of the HD protein.

Plants making the HD protein grow normally

First, the research team made specially modified plants which artificially make a fragment of the HD protein. They grew some plants that had a very long CAG repeat which might be found in a person with juvenile HD (69). They also grew plants to compare them to, which had approximately the longest CAG repeat number that exists in any plant protein, but would not be likely to cause HD in humans (28).

Under normal conditions, they found that these modified plants making the HD protein grew almost exactly the same as plants without the HD protein, and that no protein clumps formed in the plant cells. They also checked that making the HD proteins did not trigger any of the stress response systems in the plants. However, if they subjected these plants to additional stress, such as high heat conditions, then they saw toxic clumps form for both forms of the HD protein.

HD proteins communicate with the cell’s cleanup system within chloroplasts

Unlike human cells, plant cells have special compartments called chloroplasts which are responsible for capturing light so the plants can make food and grow. Contained within the chloroplasts are lots of specialist bits of cell machinery, that keep protein levels in balance and clean up damaged or toxic proteins, so that energy and growth stay on track.

The scientists found that these clean-up machinery assemblies had a lot of contact with expanded HD proteins, and they could see this contact happening both in chloroplasts as well as other parts of the plant cells.. In particular, there was contact between the HD protein and an enzyme called SPP which chops up other proteins during the clean up process.

Using microscopes, the team looked at the location of the HD protein within the plant cells. They could see lots of the HD protein surrounding the chloroplasts, suggesting that these special structures may help the plant to deal with the stress of making the HD protein.

Messing with the chloroplast’s job makes HD protein clumps pile up

The research team then looked at how chloroplasts process the HD protein. In their studies, they saw that chloroplasts were able to take up the HD protein when it was floating nearby, and then remove it.

They then wanted to see what would happen if they stopped the chloroplasts from cleaning up proteins or from shuttling molecules in and out. They used different chemicals to disable the chloroplasts in these ways, and In both cases, the plants showed a buildup of HD protein and potentially harmful clumps. This provided even more evidence that the chloroplasts were very important in dealing with the HD protein.

A new way to decrease HD protein clumping

The SPP molecule can help with protein cleanup in plants, and it was found in contact with the HD protein. So could SPP help deal with HD protein clumps in other contexts – like in cells grown in dishes, or in an animal model of HD?

In the final part of the study, the scientists added the SPP gene in different models of HD to see what would happen to the HD protein. They first looked in human cells in a dish, and found that SPP stopped the build up of HD protein clumps.

Finally, they engineered microscopic worms to make the HD protein, with or without SPP as well. The worms with SPP had a lot less HD protein clumps and could move around better than those without it.

What does this all mean and what’s next?

It’s likely to be a long road before folks with HD are being dosed with SPP to treat symptoms. However, the research team behind this study believe that by researching plants, which can endure harsh conditions causing protein clumping, they might find even more valuable insights for treating human diseases.

This innovative, and slightly wacky, plant-based approach could hold promise for advancing possible new treatments for diseases like HD.

A recent paper from a group at UMass Chan Medical School, spearheaded by Dr. Daniel O’Reilly and led by Dr. Anastasia Khvorova, used genetic strategies to lower a protein other than huntingtin. This time the researchers went after a gene called MSH3. This is a gene that’s been getting a lot of attention in Huntington’s disease research as of late. So what’s all the hype about? And does this mean we’ve abandoned huntingtin lowering?

CAG stutter

One of the most interesting findings in HD research in the past several years has been something called “somatic instability,” which is also sometimes called “somatic expansion.” It refers to the perpetual expansion of the CAG repeat in “somatic” cells, or cells of the body. You can think of it like a molecular stutter of the CAGs in the huntingtin gene.

This ongoing expansion doesn’t happen in all cells though. The CAG repeats appear to be quite stable in certain cells and tissues, like blood. So that means if someone has a genetic test on their blood at the age of 18, the number of CAG repeats will very likely be the same when they’re 50, and remain unchanged throughout life. However, certain cells appear to gain CAG repeats throughout one’s life. Those cells tend to be the exact ones that are most vulnerable in HD – brain cells.

In 2003, Dr. Peggy Shelbourne carried out ground-breaking work using brain samples generously donated by people who had died from HD. Her work showed that specific areas of the brain have massive CAG expansions – up to 1000 CAG repeats! Those people certainly weren’t born with CAG repeats that big, which means that they were acquired over their lifetimes.

Interestingly, the brain region that had those massive CAG repeat expansions was also the most vulnerable to HD – an area called the striatum. For many years after this discovery, it wasn’t clear how these CAG expansions were happening or what it meant for HD progression.

What controls age of onset?

Then, in 2015, another ground-breaking paper was published, this time by the Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. This was a huge study that looked at the entire genetic makeup of over 4,000 people with HD. This gave the researchers lots and lots of data, the richest sample of genetic information that the world had ever had from individuals with the gene for HD.

The GeM-HD Consortium was interested in trying to find small genetic changes that may contribute to how early or late someone started to get symptoms of HD – genes we call “genetic modifiers.” Identifying variants that modify the age of symptom onset could uncover targets for therapeutics.

What the Gem-HD Consortium found knocked everyone’s socks off. The modifier genes that changed the age of symptom onset were almost all involved in a single biological process! Finding modifiers that clustered together like this was completely unexpected, but was also incredibly telling. The genes were involved in a process called DNA repair.

Molecular proofreaders

Proteins are the molecular machines that run our cells, and they are made using genetic messengers, RNA, which in turn are created from our DNA. Every time a new protein needs to be produced or refreshed, there’s an opportunity for mistakes in the process. DNA repair molecules are the proofreaders that check for mistakes. To ensure that there are no mistakes in that translation process from DNA to protein, these molecular proofreaders (aka DNA repair molecules) check that message.

Sometimes there are small genetic changes in DNA repair genes that cause them to function better or worse. Really great DNA repair genes do an excellent job proofreading the huntingtin gene, so no mistakes are made when the protein is made, and CAG repeat sizes remain stable. But DNA repair genes that are prone to making mistakes while proofreading may lose track of how many CAGs should be translated. This can mean that errors slip through, increasing the CAG repeat length over time.

The GeM-HD Consortium study showed that some people had tiny genetic differences that likely made their DNA repair genes better proofreaders, leading to later symptom onset. This finding finally added some perspective to Dr. Peggy Shelbourne’s work, linking DNA repair genes to the somatic expansion observed in the brains of people who had died from HD. Researchers remain very excited by this because it suggests that if we can control expansion of the CAG repeat, we may be able to delay HD symptom onset.

Targeting MSH3 controls CAG stutters

Scientists are now targeting DNA repair genes in various animals that model HD. One gene of interest is called MSH3. HDBuzz recently wrote about MSH3, its molecular partners, and their involvement in CAG expansion, which you can read about here. MSH3 proofreads the type of genetic structure that is created by CAG repeats. Scientists have been successful in blocking CAG repeat expansion by lowering levels of MSH3. They’ve used genetic methods similar to those used for lowering huntingtin.

Work led by Dr. Khvorova in a recent publication has now taken the next step, seeing if silencing MSH3 with a drug in mice that model HD has the same effect as genetic manipulation. Their drug delivers a small piece of genetic material that targets and silences MSH3 in the brain. Excitingly, they find that a single dose of their MSH3-targeting drug delivered to the brain can block CAG repeat expansion for up to 4 months in various models of HD mice!

While the potential for a drug that blocks somatic expansion is exciting, the authors acknowledge the need for more safety studies before their drugs targeting MSH3 can move into people. This new study shows that their drug only targets the MSH3 messenger molecule, sparing other genes. However, additional studies are needed to determine if other DNA repair genes are affected at the protein level. They also note the importance of long term safety studies to ensure their drugs aren’t having damaging effects on brain cells. Follow up experiments will also be needed to determine if reducing somatic instability improves HD-like symptoms in mice.

Expanding our targets

While other targets, like MSH3, are welcome in our conquest against HD, it doesn’t mean that huntingtin is being abandoned as a target. We, without doubt, know the single cause of HD lies with the huntingtin gene. So it still makes sense to design drugs that go after the root cause of the disease. In that vein, trials by Roche, Wave Life Sciences, and Vico Therapeutics testing their huntingtin-lowering drugs march on.

If experiments in mice that target MSH3 are successful though, having combinatorial therapies that go after the root cause while also blocking CAG repeat expansion could be the one-two punch needed for HD. We’ll no doubt be hearing lots more about DNA repair genes (molecular proofreaders) in HD research, and will likely see trials in the near future that target CAG expansions.

Genetic modifiers can influence when HD symptoms begin. Some of these genes encode for different types of molecular machines whose normal job is to repair our DNA when it is broken or damaged. A recently published study from scientists at Thomas Jefferson University uncovers details of how these molecular machines help repair damaged DNA structures that can occur in HD, revealing a complicated balancing act.

In this article, we explore what the scientists found, how this can help us understand how different modifiers work to alter the path of HD, and ways these new insights might guide development of new therapies.

Genetic modifiers of HD change the age at which symptoms appear

Every case of HD is caused by the same genetic change, the extension of a long stretch of the letters “CAG” in the Huntingtin gene. An intriguing mystery in HD research has been the fact that folks with the exact same CAG number can often start to get symptoms at very different ages.

To better understand why this is the case, in a number of studies now, scientists looked at DNA samples from thousands of people with HD and looked to see what small letter changes in their DNA code tallied with symptoms starting earlier or later in life.

The genes they identified in these studies are called genetic modifiers as they modify the course of HD, from what we might expect based on the CAG number alone. Interestingly, many of the genes identified in these modifier studies encode molecular machines (proteins) whose normal role in the cell is to repair DNA when it is broken or damaged.

Two such modifiers are FAN1 and MSH3, which are the focus of this research study. However, MSH3 doesn’t work on its own, it has to be together with another molecule called MSH2. One way to think about this is to consider how we make bread; yeast on its own is not enough to make the bread rise, it needs to be together with water and flour to be active and work properly. Similarly, MSH3 needs MSH2 to work, and the assembly they form together is called MutS Beta which is what Pluciennek and colleagues studied in their experiments.

DNA repair is a double-edged sword

The huntingtin gene contains a long string of “C-A-G” DNA letters repeating over and over. In people without HD this CAG number is usually less than 35, but in people with HD, the CAG number is more than 35.

Long strings of the CAG letters in DNA code can make strange shapes and structures with mismatches in the DNA helix, some of which are called extrusions. DNA damage repair machines recognise and work on these mismatches and extrusions, to try and restore them back to regular looking DNA strands. If cells fail to repair their DNA correctly, a number of bad things can happen, including the development of cancer.

Sometimes, these molecular machines are rather sloppy and can actually make things worse, adding in more CAGs into the huntingtin gene, a process called somatic expansion. In particular, MutS Beta has been shown to jump onto CAG extrusions and can make long CAG repeats even longer over time. On the other hand, FAN1 does a much better job of chopping out the damaged bits of DNA and ensuring the DNA code is faithfully maintained with no additional CAGs.

The battle of the molecular machines!

In this new study, Pluciennek and colleagues investigated how different molecular machines, FAN1 and MutS Beta, get recruited to these CAG extrusions and how they repair them.

First, the team showed that FAN1 can work on the CAG extrusions, but not on its own; other DNA repair proteins need to be present too and the chemical conditions have to be just right. One of the most important partners for FAN1 is a cool looking star-shaped protein called PCNA which clamps onto the DNA strand and helps other proteins, like FAN1, climb on too.

Next, the scientists showed that MutS Beta can push FAN1 off the DNA extrusions and stop it from working properly. Interestingly, the team found that the precise balance of MutS Beta and FAN1 was very important as to which molecular machine got to work on the extrusions. If there is more FAN1 than MutS Beta, the FAN1 wins and can get to work to start repairing damage on the DNA.

But what does this mean for HD research?

While understanding the precise minutia of how these molecular machines work may seem a million miles away from finding a cure for HD, the impact of this type of science can be very important for drug discovery.

The identification of genetic modifiers of HD gives scientists some of the best clues for how to make new medicines. These gene lists provide crucial insight about which proteins could be switched on or off, in the hope of delaying HD symptoms.

It’s because of thousands of HD patients and their families that donated DNA to research efforts that scientists were able to discover that both FAN1 and MutS Beta can influence the age of onset of HD. This new paper by Pluciennek and colleagues shines a light on some of the cool details of two of these modifiers, and the delicate balancing act between FAN1 and MutS Beta during repair of CAG extrusions.

Studies like this will in turn help drug hunters focused on these pathways to conduct better experiments as they attempt to refine and develop new drugs for HD.

The vast majority of people with Huntington’s disease experience movement symptoms known as chorea. Valbenazine, also known as INGREZZA, has recently been approved by the United States Food and Drug Administration (FDA), allowing doctors in the USA to prescribe this medicine for Huntington’s disease (HD) chorea. In this article we go through the key points of this announcement and what it means for HD family members.

Background on valbenazine

INGREZZA is the trade name of valbenazine, a drug developed by the company Neurocrine Biosciences. It works similarly to tetrabenazine and deutetrabenazine (Austedo), drugs commonly prescribed to help control the involuntary twitching or jerking movements that people with HD experience.

Treatment with these drugs blocks a protein called VMAT2 that is responsible for packaging certain types of chemicals that brain cells use to communicate. VMAT2 helps to put the chemical messenger dopamine (among others) into bubbles that cross from cell to cell. Dopamine plays a role in the movement circuits of our brain, and it’s thought that blocking VMAT2 can quiet down the cross-talk. Exactly why this improves irregular and involuntary movements is not clear, but these drugs work for many people with HD chorea.

Valbenazine has been approved in the USA since 2017 for the treatment of tardive dyskinesia (TD), involuntary movements that stem from use of medications known as neuroleptics or antipsychotics. Antipsychotics are taken by many people worldwide to treat the psychiatric and behavioral symptoms of bipolar disorder, schizophrenia, and other diseases (including HD). After using these medications for a long time, some people develop TD, which often involves twitches in the muscles of the mouth and face. Valbenazine (INGREZZA) can be helpful to control those involuntary movements, so Neurocrine began studying whether it could also be effective for chorea caused by Huntington’s disease.

Testing and approval of valbenazine for people with HD

Because valbenazine had been tested in people with TD and prescribed for several years, we already knew that it was safe in humans. However, a clinical trial was still needed to understand if it could effectively treat Huntington’s disease chorea. In collaboration with the Huntington Study Group, Neurocrine ran a Phase 3 clinical trial called KINECT-HD, beginning in 2020. 128 people participated; half were given once-a-day capsules of valbenazine for 12 weeks, and half took a placebo (a pill with no drug). Participants were invited to continue in a longer, ongoing trial called KINECT-HD2, in which everyone receives valbenazine.

KINECT-HD was a success, reaching its primary endpoint, meaning that valbenazine decreased the severity of HD chorea compared to the placebo. It improved the Total Maximal Chorea (TMC) score, a metric clinicians use to monitor chorea symptoms. That “top-line” result was made public in 2021, and since then Neurocrine has continued its studies, analyzing, presenting, and preparing the data from the two HD trials of valbenazine. They presented it to the FDA in December of 2022, and on August 18th 2023, Neurocrine announced that INGREZZA had been FDA approved, meaning that it can now be officially prescribed to people in the USA to treat HD chorea.

It can take some time for drugs to go from approval to launch to common prescription, especially for a rare disease. Once they get the green light, companies can devote more energy to educating medical professionals and the community about a new therapy. By the end of September, awareness among US doctors is likely to have ramped up, but there are already resources for family members to learn more.

What else do we know about valbenazine?

It is important to note that INGREZZA does not slow or halt the progression of HD. However, taking medication to improve involuntary movements and other HD symptoms can have a major impact on quality of life. For some people with HD and their loved ones, chorea isn’t bothersome, but for others, it can interfere with day-to-day activities and even safety, and treatment can make a big difference.

INGREZZA is taken as a single capsule which is swallowed once a day. This is a positive feature of this medication, as for many people with HD, remembering to take a complex array of tablets throughout the course of the day can be difficult. Similar to valbenazine’s “chemical cousins,” there may be ways to modify delivery for people who have swallowing issues or use a feeding tube.
The dose can also be altered over time depending on how well someone responds to the drug and any side effects they might experience. Neurocrine hopes that this means side effects will be more manageable for a larger number of people taking this medication compared to other VMAT2 targeting drugs.

Balancing side effects, cost, and other factors

Like all drugs, valbenazine has some downsides. VMAT2 inhibitors have common side effects, like sleepiness. They can also have very serious side effects which include depression as well as suicidal thoughts or actions. Therefore, it is very important that people with HD who are considering INGREZZA accurately relay their past medical history to their healthcare provider and alert them as soon as possible if they experience any side effects.

In addition to VMAT2 inhibitors, there are a variety of drugs that doctors prescribe to treat chorea alongside other symptoms. For example, some antipsychotics used for mental health and behavior in HD can also have the effect of calming movements. There are also considerations around cost, especially in countries like the US, where insurance coverage can differ or be absent entirely due to a lack of universal healthcare. Companies like Neurocrine with new drugs on the market aim to alleviate this issue through different channels including assistance programs.

It should be noted that a once-daily version of deutetrabenazine (Austedo XR) was introduced by Teva in the USA this May, which is likely not a coincidence – companies with drugs that treat the same disorder will often tailor their research strategies around public knowledge, like another company’s impending FDA approval. The reasons for prescribing or taking one medication over another diverge from doctor to doctor and patient to patient. Everyone responds to drugs differently, and coverage and approvals vary wildly from place to place.

Take home message

While we wait for treatments that can slow disease progression, drugs like INGREZZA can improve quality of life, and it is a welcome addition to our arsenal of tools to battle HD. The approval of valbenazine in the USA is good news for the HD community. It raises public awareness of Huntington’s disease, and creates healthy competition to keep costs low. Most importantly, the availability of multiple treatments for chorea increases choice for HD family members in their healthcare decisions.

That said, outside of the USA, only study participants of KINECT-HD trials will be able to get access to this drug, and Neurocrine has not yet confirmed their commitment to seeking regulatory approval in other countries. They do plan to address the community directly in the near future via a public webinar aimed at HD family members. HDBuzz hopes that all companies developing HD therapies will work towards global access to drugs that can improve quality of life for people with HD.