Overview
For more background information on the GENERATION HD1 study, click here. In the past few years, the Generation HD1 study has been of great importance to the Huntington’s Disease (HD) community. This was a clinical study using human subjects. It aimed to investigate the effects of a drug called tominersen, which had previously demonstrated an ability to lower concentrations of the huntingtin protein. Unfortunately, this study was recently paused in March of 2021, leaving many individuals in the HD community with unanswered questions. This review will attempt to explain the original HD1 study, the reasons for its premature conclusion, and future directions for tominersen and the HD community.
Background on HD1 study
To concisely summarize, the study was a Phase III clinical trial conducted by Ionis Pharmaceuticals and Roche. Previous Phase I and II trials had demonstrated the ability of the drug tomineresen to decrease mutant huntingtin protein (HTT) levels. This protein is commonly overexpressed in HD, and it is thought to contribute to HD symptoms . These first two trials showed promising effects, and the doses were well tolerated by participants. The Phase III trial aimed to validate tominersen in a larger cohort of individuals, while focusing more strongly on whether tomineresen improved cognitive and motor symptoms in those with HD.
The study separated participants into three groups: two experimental groups and a control group. The control group received a placebo treatment, which is a harmless, non-efficacious alternative to the drug. This allowed the researchers to compare the effects of tominersen in the experimental group with the non-treatment control group and see if tomineresen provides any true benefit. The two experimental groups had two dosing regimens, with one group receiving the drug every 8 weeks, and the other every 16 weeks. The study was originally slated to finish in June 2022, however, the dosing was cut short in March 2021. Participants are still being followed, and will be until March/April of 2022.
Findings and Conclusion of the HD1 Phase III trial
First and foremost, why was the HD1 study halted? Periodically, data from the study was reviewed by a third party known as an independent data monitoring community (iDMC). This group examined the data during the course of the study, looking at tominersens efficacy and safety. In March 2021, the iDMC ruled that the 8-week tomineresen dosing regimen seemed unfavorable as compared to the placebo, and suggested treatment be stopped to ensure participants safety. The data for the 16-week treatment group was inconclusive at the time.
The researchers then performed further post-hoc analyses, which are analyses taken after collecting and reviewing the data. In doing so, they hoped to discover a specific subgroup of their sample that may still benefit from tominersen. They investigated two variables in looking for this subgroup, both age and CAP score. CAP score refers to the number of CAG repeats an individual has on their huntingtin gene, and is a common marker used to classify the progression and/or intensity of HD. This gave the researchers two strong markers to categorize their sample by, and look for a group that may still receive benefits from tominersen.
First, the researchers looked at composite Unified Huntington Disease Rating Scale scores, or cUHDRs. This is a scale used to measure HD progression in regards to cognition and motor ability, and is a widely used rating method. Looking across their subgroups, they first noted that no specific group showed improvement in the 8-week treatment cohort. However, in the 16-week treatment cohort, they found low age (<48 years) and low CAP score individuals showed favorable cUHDRs upon the trial’s conclusion. This finding was also reflected when measuring total functional capacity (TFC), which is a measure of cognitive capacity. Finally, the researchers noted that the low age, low CAP subgroup reported fewer adverse events (i.e side effects) when compared to both the placebo group and the other experimental subgroups. These findings suggest that younger individuals with lower disease burden may still benefit from a 16-week dosing of tominersen.
Future directions for Roche
While the decision to prematurely discontinue the Generation HD1 study was greatly disappointing to the HD community, the data presented above still offers great insight into HD and avenues for future treatments. Currently, Roche reported they are in the early stages of planning a Phase II tominersen trial, focusing on a group of younger individuals with low disease burden. Roche still feels confident about the safety and efficacy of the drug in this cohort, and data from these individuals could be valuable in generating a future, early-disease treatment.
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Five Days Left by Julie Lawson Timmer
Five Days Left follows the two stories of Mara and Scott, seemingly unrelated yet deeply intertwined individuals. Mara is a lawyer, wife and mother, whose entire life has been upturned by a Huntington’s Disease (HD) diagnosis. Scott is an English teacher fostering a young boy, who is set to reunite with his birth mother in a few short days. Our insight into the intersection of Mara and Scott’s lives demonstrates the wealth of human experience, its deepest valleys to its highest peaks. And while their lives could not be more different, each of their stories exalts with the common hardship and passion of life. Five Days Left is a spectacular, heart-wrenching novel that can resonate with all readers, and stresses us to appreciate all of life’s facets.
Summary
This novel alternates between Mara and Scott, telling their stories in alternating chapters. The two characters never meet in the novel, yet are linked by their membership to an online forum for nontraditional families: Mara’s daughter is adopted, while Scott is currently a foster parent. While their life stories could not be more different, the forum provides an interesting connection between Mara and Scott that again reinforces their shared human experiences.
Mara’s story begins with a promise, an ultimatum she gave herself upon receiving her HD diagnosis–once she felt the disease had reached an unlivable point, she would take her own life. After an incident in the supermarket, Mara decides that she has reached this point and will take her life on her birthday, five days from now. The remainder of the novel is a beautiful, melancholic reflection on Mara’s life. We learn about her studious college days that led her to a prestigious law career, unfortunately cut short by her HD progression. We meet her husband Tom and adopted daughter Laks, as Mara reflects on her memories and immense love for them. We also deeply understand Mara as the days progress. For a high-powered working mother such as herself, HD has challenged Mara’s nature. She desperately avoids asking for help with things like driving or walking, struggling to maintain as much autonomy as possible, until she is forced into corners. HD unfortunately places Mara in several embarrassing public situations as well, such as having to buy adult diapers and collapsing in her daughter’s classroom. For her–someone with incredibly high self esteem and achievement–these events are devastating. However, we see Mara become more content and accepting as her days tick on. She generates a relationship with her taxi driver, Harry, as she loses the ability to drive herself. He drives Mara to watch Laks on the playground, convinces her to allow his help walking to the curb, and eventually shares with her his own complex story. Together, they share moments that showcase life’s little wonders, and ultimately make Mara question her ultimatum. At the end of the novel, Mara is conflicted having spent the last five days noting every blessing, every loved one, and every aspect of her life worth sticking around for. In the end, it is unclear whether she commits to her plan, as we are only left with two harrowingly beautiful suicide notes to Tom and Laks, reflecting on Mara’s love and hope for their future without her.
While Scott’s story is less connected to HD, it is nonetheless just as insightful into familial hardship and perseverance. Scott and his wife Laurie are currently fostering a boy named Curtis, whose mother, LaDania, is in jail for drug abuse. As the story begins, we learn that LaDania will be released in five days’ time, and is returning to claim ownership of Curtis. Quite quickly we see that Scott has developed a strong relationship with Curtis, and dreads the upcoming separation. Over the next few days, we see him struggle to reconcile his love for the boy, while also attempting (and failing) to be as emotional about his own baby on the way. Quite similar to Mara, Scott soaks in every moment of his last days with Curtis, reminiscing on playing driveway basketball, struggling through math homework, and reading Stuart Little before bed. We also learn of Curtis’ rough past with his birth mother, and the living situation Curtis will be returning to shortly, much to Scott’s frustration and disappointment. These feelings are only exacerbated by LaDania’s early release, and her taking Curtis back into custody two days early. During this time, Scott feels lost, while his wife attempts to cheer him up through nursery shopping and date nights. The situation only escalates when LaDania then overdoses the next day, leaving Curtis distraught and parentless. Scott immediately asks Laurie to adopt Curtis, only to be met by fierce anger and chastisement over his disinterest in their own baby. Eventually, however, Laurie agrees, acknowledging that it would have pained her to see both Scott and Curtis lost for the rest of their lives, knowing that her answer would have changed things.
Five Days Left is a celebration of life, in both its darkest and purest forms. It urges each of us to reflect on what it is we are thankful for, and to truly appreciate our loved ones. Most importantly, it demonstrates the universal struggle of livelihood, and encourages perseverance even when life seems to be at rock bottom. Whether it be through an HD diagnosis or losing a foster son, this novel capitalizes on the entirety of the human experience, and is well worth the read.
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Overview
Huntington’s Disease (HD) is an extremely multifaceted disease, and receiving treatment and care for HD can come in many different forms. Those who receive an HD diagnosis are often overwhelmed by their treatment options, and specifically, the costs associated with each option. This article attempts to provide an overview of the major cost drivers implicant of HD, as well as their frequency of use and individual costs.
Cost Drivers
As mentioned above, an HD diagnosis can leave an individual with many questions, especially regarding their treatment options and expenses. To better analyze this topic, it is useful to build our discussion of HD costs upon the general progression of HD. Medical terminology would typically divides HD into 5 stages of progressing severity; however, for the sake of clarity, we will divide HD into three distinct progression stages.
Our first stage–the early stage–of HD begins directly after diagnosis. This stage is the least expensive of the three in an HD patient’s progression. Here, the most important cost drivers include screening tests and medication. As motor and cognitive symptoms increase, HD moves into the middle stage. Currently, there exists no cure for HD, and all treatments available today are therapeutic in nature. These therapies can compromise the majority of a patient’s expense in the middle stages of HD progression. Finally, in the late stages of HD, symptoms may prevent an individual from living alone or caring for themselves. The majority of costs in the late stage, then, are long-term care, home assistance, and/or nursing home fees.
Early Stage
When discussing the early stages of HD and its costs, the first noteworthy expense is genetic screening tests. These are used to determine if someone has a genetic predisposition for HD, as well as if they have the DAG repeats of the huntingtin protein that are an indicator of HD. These tests can range anywhere from 100-2000 US dollars. A more precise and scrutinizing test usually incurs a greater cost.
The second most common cost for an individual in the early stage of HD is medication. Many patients who are diagnosed with HD are encouraged to take medication that improves symptoms, or slows the progression of symptoms. With a prescription, many of these medications (such as Xenazine, for HD chorea) are largely covered by insurance. Copays are likely around 25 US dollars. Without insurance or a prescription, however, prices for a medication such as Xenazine can range anywhere from 400 to 4000 US dollars for 30 tablets. It is important to discuss with your insurance the provided coverage for any medication prior to use.
Middle Stages
In the middle stages of HD, therapy costs can become more of an expense as managing symptoms becomes integral to treatment. Various different forms of therapy for HD exist, but the three most prevalent forms are physical therapy, speech therapy, and occupational therapy.
Physical therapy (PT) is the most common therapy utilized by HD patients. PT usage varies greatly patient to patient, but it incurs a cost regardless of frequency. Typical ranges for a single PT appointment range from 75-150 US dollars, with this dropping to 25-50 US dollars if covered by insurance. As HD progresses, symptoms may become more severe, and the need for PT or a similar therapy may increase–this is important to keep in mind when analyzing the incumbent cost on an HD patient.
Speech therapy is another common form of treatment for individuals with HD. It is very similar to PT in that while insurance greatly reduces the cost to the patient, it is never fully covered. The national average cost of a speech therapy appointment is 218 US dollars.
Finally, occupational therapy (OT) is the last, most common form of therapy among HD individuals. OT helps HD patients to complete everyday tasks and have more autonomy throughout their daily life. OT usually incurs an initial visit fee of ~200 US dollars, with subsequent visits ranging from 40-200 US dollars. OT, like PT and speech therapy, can be partially covered by insurance, depending on the type of plan.
Late Stage
When an individual reaches the late stage of an HD diagnosis, they are likely unable to continue living alone due to their symptoms. Thus, the major cost associated with a late stage HD patient is the usage of long-term care (LTC) facilities, or home assistance. The average cost of a nursing home is 198 US dollars per day, while a home aide is 21 US dollars per day. These figures are also in 2011 dollars, so likely, the cost is greater today. Prices can also vary by locale, so keep this in mind when exploring LTC options.
The above figures are obviously very expensive, and as a result, LTC insurance is important in affording these options. The first notable part of LTC insurance is that Medicare does NOT cover LTC. LTC insurance plans must be purchased separately. These plans typically cost around 2,200 US dollars per year and can help cover both nursing home and home aide costs, depending on the specifics of the plan. For more information on LTC and insurance see here (link to Maria’s insurance article).
Disclaimers
This article is not meant to provide any diagnoses on treatment, or assume that all HD cases progress through the same stages at the same rate. HD varies greatly from patient to patient, and each case will carry with it its own needs and treatment. Additionally, the costs outlined above are estimates. Actual expenses will likely vary by region and by insurance plan. The figures above are meant to offer clarity into what costs are associated with an HD diagnosis, but not define it.
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Overview
Researchers in China recently conducted a study that provided new insights into signaling pathways in the brain, and how these pathways can affect the concentration of huntingtin protein in the brain. Huntingtin protein is an important biological agent for many facets of our bodies, including cell signaling and the transport of materials; however, literature supports that the mutation of this protein also causes the majority of symptoms in Huntington’s Disease (HD). Current treatments for HD are only able to slow, not prevent, the aggregation of mutated huntingtin proteins (mHTT). A cure for HD may require these proteins to be completely destroyed or degraded.
This new study proposes a method wherein the levels of huntingtin protein can be decreased. The researchers targeted a specific signaling pathway in the brain called GPR52, which is a type of G-protein receptor (more on this in the next section). By blocking this path, the researchers observed significant decreases in mutant proteins. The findings and their implications are described in detail below.
What is a G-protein receptor pathway?
As noted, the researchers targeted a specific G-protein pathway called GPR52. At a basic level, these pathways are the major avenues by which our cells talk to each other. A great number of these paths exist in our bodies, and all have many different functions. However, they all function in similar manners. First, a specific molecule attaches to a receptor on the outside of the cell. Then, the receptor is activated, and sends a signal into the cell. This signal then has a specific effect, ranging from bodily functions to chemical reactions.
The GPR52 pathway works just like the system described above. It is activated by a certain molecule, and this molecule is able to send a signal into the cell through a receptor and trigger a response. The response, in this case, relates to the huntingtin protein. When this pathway is activated, the cell responds by moving huntingtin protein to a specific compartment of the cell. In this new compartment, the huntingtin proteins can escape the typical cell machinery that would degrade them. This is inconsequential for the healthy huntingtin proteins; they are able to be processed further and do not pose any harm to the individual in this new compartment. MHTTs, however, aggregate here with no outlet for removal. Therefore, in an HD individual, these mutant proteins are allowed to avoid processes that normally would break them down, and accumulate. These protein aggregates then cause the onset of HD symptoms.
Study Design
These researchers recognized that the GPR52 pathway may contribute to HD symptoms, and explored ways to utilize this pathway to treat HD. Since the activation of this pathway causes negative effects, they decided to block it using an antagonist, a type of molecule that sits in the pathway’s receptor, but has no effect. Essentially, it blocks other molecules from activating the pathway and causing the unwanted effects. They named the antagonist used in this study Comp-43.
The study was performed on mice with the HD mutation. The researchers administered Comp-43–their blocking agent–to one group of mice, while the other mice did not receive the treatment. They then measured several aspects of the mice to determine whether the compound had a significant effect on HD. These aspects include mHTT levels, total neuron levels, and brain inflammation, all of which studies have shown to be indicators of HD severity.
Findings
The researchers produced several noteworthy findings. The first factor they measured was mHTT levels, which is a major cause of HD symptoms. The group that received the experimental agent Comp-43 saw over a 20% reduction in their mHTT levels. This reduction, the researchers noted, was enough to restore normal function to HD mice. However, Comp-43 also targeted the healthy form of huntingtin protein, which is necessary for normal bodily functions. The researchers maintained that this reduction was within a safe level; in fact, previous studies have shown that a 50% reduction in total huntingtin protein levels is manageable.
They also measured total neuron concentrations in the striatum, the area of the brain most affected by HD. The mutant huntingtin protein mHTT typically targets this area, destroying neurons or decreasing their functioning. Besides decreasing mHTT levels, many novel therapies target the striatum to help restore functioning in HD individuals. For this study, the researchers found that the administration of the experimental Comp-43, neuronal loss and neuron death was prevented. This allowed the mice to regain motor function and greatly improved their HD symptoms, indicating a strong effect.
Implications
These preliminary findings demonstrate great promise for GPR52 treatments and compounds like Comp-43. The most encouraging part of their research is that blockage of this pathway seems to reduce mHTT levels. Many therapies are incapable of doing so, only slowing the progression of mHTT accumulation. Similarly, many treatments are minimally effective or fail completely to protect against neuron loss. Both of these aspects set this treatment apart, and show great efficacy.
There are a few considerations, however, when discussing this research. For one, it is important to remember that this was a mouse model. Expanding this treatment into humans will take time and much more research, and Comp-43 is not yet a viable drug for HD individuals. Its effects must also be studied more closely. As noted above, the GPR52 pathway is integral in much more than just regulating the huntingtin protein. It also has major effects on the neurotransmitter dopamine, which can control both movement and mood. While the researchers did not observe any erratic behavior in their study, more research is necessary to ensure any future drugs targeting GPR52 do not have unwanted effects on brain chemistry.
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