Amping Up the Work in Rare Disease
Optimizing research and treatment for families dealing with HD.
Terry Jo Bichell, PhD, worked as a nurse midwife for a decade. She also had five children, the last of whom has Angelman syndrome, inspiring her to go back to school in middle age and earn her doctorate in Huntington’s disease neuroscience, so she could try to help her son and others with rare diseases.
In 2019, she founded COMBINEDBrain, a group that works on advocacy for treatment and cure for over 60 rare genetic diseases. This work positions her to offer wisdom on how the HD community can better garner the FDA’s attention towards treatment of early HD symptoms, and the potential to slow symptom onset and development. Getting on the FDA’s radar and partnering with them in the domain of early treatment, may also be key to incentivizing companies pursuing a cure.
My son, Lou, has Angelman’s syndrome, a neurodevelopmental disease that causes cognitive and physical impairments and severe communication disabilities. Lou has taught me patience and persistence — and the ability to take delight in small things. He is also responsible for pushing me deeply into molecular neuroscience. Because of Lou, I have a determination to understand what is needed to optimize research and treatment for families dealing with a rare neurological disease.
A huge part of moving treatments to patients is learning how the FDA “thinks” and how to make a case in a way that gets their attention and aligns with their approval processes.
The Huntington’s disease world is evolving. Medications for symptom control are improving, and in-vitro fertilization is offering HD gene avoidance for a growing number of people. Pre-motor psychiatric symptoms are better recognized as part of the disease. The time is ripe to plan to treat HD before symptoms appear. It will be crucial to find ways to partner with the FDA to address early symptoms in juvenile, early-onset disease and in those who develop HD as adults, prior to motor manifestations.
A Conceptual Model
I believe constructing a conceptual model of disease for pre-manifest HD is critical to fostering this FDA partnership. For about five to 10 years now, the FDA has been using conceptual models — a qualitative interview-based study of the lived experience of patients and their families — to understand what matters to patients. They want input from patients, but they want it in a very scientific way, of course.
To develop this, you ask families who are at high risk of HD, but are not yet grappling with motor symptoms, some very open-ended interview questions: What is your life like? What do you worry about, what do you think about at night? What’s changed in the last five years in your family? What you’re asking for is not only the patient’s feelings, but those of all the people around them.
When you do that without asking anything specific about motor symptoms, for example, you really get a much better feel for how somebody’s life is affected and what really matters to them.
These interviews are analyzed quantitatively to build that conceptual model, and that can form the basis of outcome measures and clinical trial design.
Bending the FDA’s Ear
After constructing a conceptual model of pre-manifest HD, the community should formally request a Patient Listening Session (PSL) or a Critical Path Innovation Meeting (CPIM) with the FDA. A meeting like that can highlight the conceptual model and all the other data on the non-motor aspects of HD, as well as the pre-motor aspects of HD. Patients and families can talk to the FDA about all these other aspects that can affect quality of life and function at least as much as the motor aspects do.
This puts into perspective for the FDA the fact that Huntington’s disease is not just a motor disorder — it’s much broader than that — and that those other domains of disease are worth industry’s effort to target with treatments. In other words, it’s helping the FDA make decisions in favor of these drugs, and it’s also incentivizing pharma to take risks that come along with new drug development, because they have a better chance of these trials being supported and approved.
The key is to demonstrate that in the natural history timeline, treating someone before those symptoms are already present and already affecting quality of life and functionality, actually reduces the risk to benefit ratio that the FDA and industry have to consider when they’re thinking about approving a new drug.
BJ Viau and Seth Rotberg, as well as Katie Jackson and several HD moms, have ventured into bringing data and stories from families directly to the FDA. This bold and much-needed kind of effort could only be strengthened by developing a conceptual model of disease for pre-manifest HD.
I can think of several examples of how the FDA has gotten a nudge from hearing about the experience of disease through the families’ lens. Epilepsy is one. A reduction in seizures was always the outcome that was the easiest to measure for any epilepsy trial, and health care professionals and the FDA always just assumed that reducing seizures would really be the best way to improve quality of life in kids with epilepsy. But the truth is that even though each seizure may be awful and scary, reducing the number from 10 a day to five a day doesn’t necessarily change the quality of life. The epilepsy community worked to explain to the FDA that you still have to take the same precautions, face the same potential dangers and anxieties each day, and that they should look at treatment goals differently.
The Power of the Family Story
Family stories are almost always the best source of truth. Clinicians may see an at-risk child only once a year, sitting in an unfamiliar clinical setting, presenting a snapshot of their behavior. The the clinician might say, “No improvement”, or “Wow, that kid looks tons better!”. However, they don’t know how the child is performing in everyday life unless they dig into the family’s story — is the child doing better, and how is the child doing better? If you have families talking about how much the non-motor aspects of HD impact their lives, then it’s evident that HD is already impacting them way before the motor symptoms start.
Such non-motor symptoms may seem mild to the outsider, but I guarantee they don’t seem mild to the family. For example, when the person is becoming aggressive or depressed, or taking risks or experiencing insomnia — all those other things that happen before the motor symptoms ever hit — the prospect of taking a little greater risk and treating the person with a disease-modifying drug becomes not so scary. (See panel sidebar)
Plus, once motor symptoms start, things are already going downhill. The basal ganglia has already started to degenerate quite a lot prior to their onset. So, if you can treat those non-motor symptoms way in advance with a disease-modifying drug, you could make a huge impact on the whole trajectory of the disease.
It is important to demonstrate to the FDA that the risk of a drug is worth it for the long term as well, that treating all of those other symptoms does improve quality of life. You want to also show that all of those other domains, or some of those other domains, are as impactful as the motor domains.
Most people say the worst of HD is not the chorea but the impact of their symptoms on their families. In fact, some people say they don’t care if they live longer, they just want to live better. “It’s more important to me that I have a good life, that I’m good to my family, that my family is not harmed by what I do or say.”
That message needs to be heard.
Building on the Foundation
The families’ stories are the foundation, but these stories have to funnel into specific outcome measures. You have to put numbers and degrees on things. The stories show the existence of these changes and the impact of the disease on the family, but backing that with clinical measurements of those changes in symptoms like aggression, apathy, and depression is the harder science that closes the loop.
It is best to try to use standardized validated measures of the non-motor aspects. Let’s say you do the conceptual model of HD, and you find out that poor judgment and risk-taking are the most worrisome symptoms to families. Is there a measure that’s already in use for some different disease, such as, perhaps, addictive personality disorder?
If there’s already a measurement of change in those symptoms, that measure will need to be studied to see if it can detect changes in HD. Results should be published, which is another important way to communicate with FDA.
I should mention that some symptoms aren’t always moving in a directly downward trajectory. In HD, my understanding is that certain symptoms may improve as others get worse. Part of that might be because of certain medicines, but part of it might be because as the disease progresses, and the neurons start to degenerate, volition might change as motor symptoms progress, so a patient’s trajectories may be uneven and nuanced. This complication needs to be factored into the model.
Putting it Together for the FDA
Then come the listening sessions or CPIM meetings with the FDA to show them what was found in your conceptual model and talk about the non-motor aspects. The pitch might look like this:
“Qualitative interviews showed us that increased risk-taking is a major concern for families. We borrowed a measure of risk-taking from the addiction field. Using that measure, we’re finding that we can detect when people progress and get worse in their ability to use good judgment about risks over time, and so it could possibly be an endpoint.”
If there is no such measure for an impactful symptom, there are grants that the FDA offers to develop new measures.
Adding to this some powerful survey data answering important questions like “Are you willing to take this much mortality risk for a potential benefit?” is important.
The Need for a Biomarker
In the future, adding a biomarker that tracks early disease will be a huge help in supporting measures of improvement in symptoms.
In early psychiatric symptoms, there is the need to distinguish between symptoms in people with HD and without HD, who have the same type of mental illness. Are the drugs we use for the latter group as good for patients with HD as they could be? How do we describe the psychiatric aspects of HD compared with each of those symptoms in a person without HD?
If there is a change in a protein or gene expression that tracks with changes in symptoms, it might be possible to show that treatment is disease-modifying even before symptoms progress. Or it might be possible to show that a symptom is improving because the HD progression is halted, not because of a standard medication such as an antidepressant, but because of an impact on HD itself.
Expanding Standard of Care to Include Mental Illness
Expanding the standard of care, as well, to include pre-manifest and very early HD is also important to prepare for trials, so that everyone is getting the same treatments. Otherwise, is could be hard to figure out why some patients are doing better than others from the get-go.
If you have a standard of care, where the experts agree on the best medication for depression in people at risk for HD, for example, and also agree on the second-line medication if the first one isn’t effective, there would be consistency. Plus, if there is a disease-modifying therapy, and it reduces depression, there is a better chance of being able to show that is what drove the improvement.
A uniform standard of care not only helps improve clinical trials, but it also helps primary care practitioners around the world. Huntington’s disease is so rare, that they may never have seen a case, but with an agreed-upon standard of care, they no longer have to make treatment decisions in a vacuum.
Universal Newborn Sequencing
A huge factor in expanding the study groups and informing standard of care is the fact that in the future, more people will be diagnosed with expanded CAG repeats long before they ever have a symptom. Universal newborn sequencing is around the corner. San Diego, California, Memphis, Tennessee and New York City each have medical centers that do this now.
With newborn sequencing, it will be possible to develop a standard of care from infancy to the onset of symptoms in HD.
This might include encouraging athletics because it has been shown already that exercise delays the onset of HD. Exercise increases BDNF [brain-derived neurotrophic factor), which increases the number of neurons over time. So, if parents knew that their child was going to develop HD later in life, they would probably encourage them to play a sport, like soccer, basketball, or swimming. Mouse models show that a stimulating environment delays onset, too.
Newborn genetic sequencing would also lead to more parents getting tested, making their own earlier treatment possible, and potentially avoiding some of the dysfunctional impacts of early HD on the whole family.
People still describe the idea that knowing about an HD mutation will affect life negatively. But that notion was built on the idea that there were no treatments. There is still no gene therapy that works, but there are treatments that can help, including exercise, as I mentioned. Also, recognizing bipolar disorder or depression, apathy, risk-taking or ADHD, and treating these symptoms aggressively may improve quality of life.
Plus, maybe, just maybe, by the time a person is an adult, there will be a cure, and because they were treated early, some of the worst of the symptoms will have been delayed or avoided.
There is also the other 50 percent to think about — those who come from an at-risk family but are actually negative for the mutation. How much better might their lives be and how many mental health disorders might be prevented by their knowing they will not develop HD? There are concerns about a higher depression and suicide risk among young people who find out early they have HD, but there was a study that brought into question whether this risk came from knowing or from the psychiatric impact of the disease itself.
Early Treatment is Compassionate
Having a genetic diagnosis which explains what may appear to be erratic behavior is in itself a worthy reason to learn about the diagnosis early on, rather than having others think that someone is just acting out, or is aggressive because they’re a “bad” person. It is compassionate to provide early treatments. The individual might avoid multiple brushes with the law, or possibly causing a terrible accident or committing a serious crime.
To me, knowledge is always power, and you can always use the knowledge to good effect. Having the mindset that knowledge is just going to make your life worse may need to be revised in light of all we know about how life can fall apart for people who don’t know about a diagnosis of HD, and aren’t treated for destructive behaviors.
Uniting the HD Community
One of the things I’ve found from working in the rare disease world is that it almost always divides into factions who don’t get along. I don’t understand why that happens, but it happens over and over again.
As long as the groups coordinate, it isn’t always a bad thing. It’s when everybody splits up and tries to do some of the same things repetitively, separately, and competitively, that the community stops moving forward. When constructing a conceptual model, or developing a standard of care, it is important to work with as many of the foundations and as many of the populations as possible, but with each playing to their own strengths.
Most importantly, though, remember that the FDA wants more patient input. Many clinical trials fail in part because they were being led by doctors, not patients. Every step in this process, every committee, every steering group, needs to have a patient representative and patient input at every step, to speak up with firsthand knowledge about what would make a difference in their quality of life. They also need to be people who know their constituency, and should connect with their fellow HD families, not just represent their own families.
This is the roadmap I have seen to be most successful in rare disease advocacy. Setting up the model and process for garnering the FDA’s investment in early HD treatment is one of the most promising paths to a cure. I’m encouraged as I see the evolution of various areas of knowledge and new initiatives within the HD community that can accelerate the progress.
