One of the first questions that arises when talking about adults living with SMA [spinal muscular atrophy] is that most people have a concept of this disease as being pediatric onset. This is true in the vast majority of cases. Most people will already be experiencing symptoms of their SMA from the beginning of life if they have the most severe form, or at the latest in late childhood or teenager-hood in the least severe form of pediatric-onset SMA.

There is a very rare form in less than 2% of SMA patients that presents exclusively in adulthood, classified as type 4, in which patients will have been entirely healthy until after their 18th birthday. At that point they may experience symptoms of progressive weakness.

The point is that the disease, while it can be quite rapid at the beginning for the most severely affected patients, by the time people reach the age of adulthood, they are much more slowly progressive in their relentless loss of strength with this disease. Rather than noticing a difference week to week or even month to month, it sometimes takes years before a significant difference in function is appreciable by the patient.

When we’re talking to an adult living with SMA in the clinic, we often ask, “Is anything different from your last visit 6 months or a year ago?” They’ll often say, “No.” So it really has to be a reflection on 5 years ago or 10 years ago with regard to the things that the patient was able to do then that they can’t do now. Most people can then reflect and bring those things forward. That slow rate of change does make trying to understand a therapeutic response to a new treatment in SMA much more challenging because the effect of the disease itself is slow in its change. Unless the treatment had a very big impact on someone’s baseline level of function, and they noticed it right away, understanding that there’s a difference from the natural history of progressive loss takes much more time.

Another important point to consider when dealing with adults with SMA is that they should have a genetic confirmation of their disease. By far, the majority of patients with SMA have a double deletion of the 

 gene. About 3% or 4% will have a sequence change or some other genetic mutation in 

 that is leading to it being unfunctional on 1 of the alleles.

If your patient does not have classically defined 5q SMA through genetic testing, it is not appropriate to offer them targeted therapies that are now available for SMA. They should really have further testing such as EMG [electromyogram] and possibly other broader genetic panels to try to understand why they have the symptoms of weakness that they do.

Identifying Adult Patients with Spinal Muscular Atrophy

When discussing the impact of SMA [spinal muscular atrophy] on a patient’s overall quality of life, you have to consider the huge variability in how this disease affects people depending on their genotypes. This means looking at their copy number of 

 and how many copies of the backup gene they have making the SMN protein that their body is lacking. When they first presented with symptoms, was it the most severe early onset as an infant? Did they start having symptoms much later in life? We can then start to think of categories of functions.

In the natural history, we used to describe types of SMA defined by the maximal motor function that someone would achieve, such as sitting or walking. Nowadays, because targeted treatments sometimes blur these lines a bit, we’re starting to think of 3 broad categories of SMA function. We have nonsitters: those who are unable to sit independently. We have sitters who can sit but cannot take independent steps by themselves. We also have walkers with SMA.

Those groups are different in terms of the overall experience of their symptoms because those who are more mildly affected don’t tend to have some of the bulbar effects that we see in the more severe forms that can affect things like speaking, swallowing, needing supplemental nutrition, and sometimes alternative feeding through things like the G-tube [gastrostomy tube]. They also don’t tend to have as much breathing involvement with the need for BiPAP [bilevel positive airway pressure] support at nighttime or sometimes even daytime respiratory support, as well as the vulnerability to respiratory infections that can come from chronic respiratory failure. The orthopedic implications of milder SMA are also not present, whereas in the more severe forms, things like scoliosis, limb contracture, hip dislocation, and all these other orthopedic sequelae that we see with this progressive weakness are much more of a consideration for patients.

You could imagine that a 19-year-old living with SMA could be somebody who had infantile onset of their disease with a very rapid loss of strength and is now barely able to move their fingers just a flicker, living entirely on tracheostomy support for their breathing and needing full feeding via a G-tube in terms of their nutrition. It could also be somebody who’s just starting to experience weakness and is having a type 4 onset of their disease but is otherwise entirely normal. They may just have some subtle difficulty with exercise tolerance or a bit of difficulty with stairs.

As you can see, both of those people have SMA, but they are very different in terms of the impact on their quality of life. What I will say in general is that this is a neurodegenerative disease, so regardless of when you have onset of symptoms, what you will notice over time is that your strength is worse and that you’re dealing with more symptoms and more burden. This can be very impactful for the overall quality of life for the patients themselves, such as having limitations to their function, living in fear of catching a respiratory infection and ending up in the hospital with extra need for respiratory support, and having chronic pain and other things related to positioning and orthopedic considerations.

It also has a significant impact on all the caregivers involved in that person’s life: their family members, their loved ones, people with whom they are romantically involved, or people who are nursing or caregiving for them. All these people are touched by the person living with SMA’s symptoms and their friends and some social contacts as well.

It’s a disease that really affects every aspect of somebody’s quality of life, and it’s very clear that quality of life is impacting in this disease. However, when we do objective measures of it, people living with weakness find ways to cope and can have quite a high-quality life in terms of their perceptions of their own health and well-being.

In general, it’s important to keep in mind that things like anxiety and depression are more common when living with a chronic illness, so we need to be vigilant for that in our long-term follow-up with these patients.

Impact of Spinal Muscular Atrophy on Quality of Life

When thinking about the ways that people living with SMA [spinal muscular atrophy] interact with the health care system as adults, it depends on the severity of their disease, but we hope that all patients with SMA have at least a neuromuscular care center as a medical home. This is a complex disease that affects multiple systems, so it needs good interdisciplinary management to optimize quality of life and outcomes.

We don’t just need to diagnose the disease. We also need to manage all the potential complications: the impact on function with things like physical and occupational therapy input and rehabilitation as well as assistance devices for maximal interaction with the world such as ambulation or power wheelchairs for those who aren’t able to ambulate independently. We must also be thinking about respiratory support and be proactive rather than reactive in terms of potential complication, and we must ensure that people have extra respiratory support if they need it while they’re sleeping. We must stay ahead of the respiratory failure through techniques such as cough assist, chest physiotherapy, and other techniques that can help with pulmonary hygiene.

We must also be thinking about the orthopedic complications and trying our best to avoid development of contracture and scoliosis as much as possible through bracing and stretching, physical therapy, and all the other techniques, which can help in maintaining joint integrity and spine integrity to optimize the quality of life of the patient. If somebody is relatively mildly affected with SMA, they may only need a once-a-year visit with this care team to still be doing well, generally, in terms of their function.

More severely affected adults often need much more frequent interaction with our health care system where they’re sometimes coming to clinic as infants if they’re rapidly progressing up to monthly or every couple of months, which may be related to some of the feeding concerns and other things that we’re trying to stay on top of as much as possible. Eventually, most get to a fairly stable place, so we may feel comfortable seeing them twice a year or once a year in terms of their care.

There is then the whole concept of emergent care needs as well, which is a huge issue for this disease. Many patients have frequent respiratory exacerbations, with have acute or chronic respiratory failure requiring extra medical attention in the emergency department, which often includes admission to an intensive care unit setting many times for a long period before they’re able to recover and go back to an outpatient care experience.

We sometimes have patients in the hospital for months on end with their respiratory concerns. This can be a significant burden on the person themselves, their caregivers, and the health care system in terms of optimizing outcomes with this disease.

Spinal Muscular Atrophy and Healthcare Resource Utilization

Once somebody knows that they have SMA [spinal muscular atrophy], then they should establish care with an SMA care center as soon as possible. This is really evolving in 2020, when I’m speaking to you, because newborn screening is coming into play across the United States. Many babies are being identified as being genetically affected with SMA before they have any symptoms with the disease, which means that this is a very exciting time.

We also have the ability to diagnose a fetus with SMA if their parents are also carrier tested during the pregnancy. If both parents test positive as carriers of an 

 mutation, which is usually a deletion, we can test the fetus and determine that they are in fact affected by SMA before they’re even born.

The concept is to get to care as soon as possible because we know that, even without any other considerations of treatment, optimizing interdisciplinary support for these patients improves outcomes. When you look at the life expectancy for people living with infantile onset SMA in the 1980s and 1990s vs new advances in things like pulmonary support and nutrition support, we have extended the life span of patients living in the natural history with SMA by decades in some cases with good quality of life because of this augmentation in their supportive care.

Since 2016, we have had a major shift in our SMA care with the emergence of targeted therapies. We now have 3 FDA-approved therapies for this disease in the context of nusinersen, risdiplam, and onasemnogene abeparvovec or gene transfer for SMA. All 3 of these treatments work to correct the genetic deficiency in SMA by increasing the amount of survival motor neuron, or SMN protein, that a patient has when they’re deficient due to their genetic issue.

The challenge in this disease in terms of treatment is that it’s not like epilepsy, where if you put somebody on antiseizure medication, then they stop having seizures and you have a good outcome. What’s happening in this disease is that motor neurons are dying. Once a motor neuron is gone, it does not come back. We don’t have the ability to make more motor neurons with our body. We have the population that we’re going to have for life when we’re born.

Stabilizing motor neurons with these interventions, whether it’s any of the 3 available treatments, SMA treatment needs to be done as soon as possible for anybody living with SMA. They need to get these motor neurons healthy and stabilized so that they’re not lost, because once a motor neuron disappears, all the body can do is reinnervate from the motor neurons that are left. If those motor neurons are also sick, all you’re going to see is worse and worse weakness over time and a poor outcome.

If we get somebody on treatment, then we’re able to stabilize their motor neurons and keep them either the same for long periods of time, or if you catch them early in development, sometimes even normal development can improve a patient at first in terms of their function before they start to plateau and stay stable for a longer period of time.

Even if we’re able to slow down the rate at which things are getting worse in this disease, by just having the trajectory being less steep in terms of the loss, that is a therapeutic effect that warrants treatment in a disease that is as severe and impactful as SMA is in terms of neurodegeneration. The basic message is time is motor neuron, just as time is brain and stroke. We need to get people on treatment as soon as possible once they’re identified with this genetic disease.

Importance of Establishing Care Early in SMA Diagnosis         

When we’re thinking about treatment options for SMA [spinal muscle atrophy], it depends on the age of the patient and their severity in terms of what you might be considering based on the FDA label. We have nusinersen available for all people with SMA regardless of their age, risdiplam is available for anybody over 2 months of age, and gene transfer is available for anybody under 2 years of age based on the FDA labeling for those 3 medications. If you have somebody under age 2 but above 2 months of age, then you have 3 options to use. But if your patient is above 2 years of age, and you’re considering treatment for their SMA, then you’re deciding between nusinersen, risdiplam, or nothing.

The challenges in terms of implementing these therapies are protean for our teams and the families involved. These are not straightforward in terms of treatments. Nusinersen requires serial lumbar punctures for delivery, which is a big ask for somebody who is living with weakness because they’re often not comfortable being positioned for the procedure itself. If they have any degree of scoliosis or especially if they have spinal hardware, it is difficult to get access to the intrathecal space with the medication nusinersen sometimes. We’ve sorted this out for our patients in 2016 with the availability: anybody who wanted access to nusinersen at our center [Children’s Hospital of Philadelphia] was able to start treatment successfully with some creative approaches to intrathecal injection.

In terms of gene transfer, 1 of the practical barriers is simply age based on the label. If you’re above 2 years of age, then it’s not currently available to you. There is ongoing research that is looking at dosing older patients. The challenge there is that the intravenous delivery of gene therapy that is approved becomes unsafe at a certain point because of the sheer burden of viral vector that you’re giving as the patient gets bigger, and it starts to become toxic to other tissues.

The thought is that there’s a point at which you need to start thinking about giving the therapy directly intrathecally the way that we do for nusinersen through lumbar puncture. In that situation, the medication gets just to the motor neuron itself, which is the target where most of the pathology of this disease is going on.

However, the question remains: how much does the SMN deficiency affect the rest of the body in terms of what’s going on in other tissues that are deficient in SMN. Both nusinersen and gene-transfer therapy may get somewhat to the systemic circulation, but the option that does that most effectively is risdiplam, which is the small molecule that can be given orally for this disease or through a G-tube [gastrostomy tube] if the patient cannot swallow. That small-molecule therapy, however, is unique because it needs to be given every day. It’s a daily medication with a short half-life.

You can imagine the compliance issues that we’re considering now that this has been was approved in mid-2020 in the United States. If a patient goes on a trip and forgets their medication at home, if they are vomiting and can’t tolerate po [by mouth], or if the patient is a teenager and thinks that they’re too cool for medication and doesn’t tell their parents that they’ve stopped taking it, what is the amount of time that the motor neurons still have resilience in someone who’s been taking treatment before the motor neurons start to irreversibly die?

It’s the same issue in epilepsy. If somebody comes into the emergency department having a seizure, then you know they’ve not been taking their medication. If their level is low, then you can say, “You really need to take your medication” and get them started again. Hopefully there’s not a bad outcome for that person, but if there’s no forgiveness, if you’re not taking your medication, then your motor neurons are going to die, and we can’t get them back.

This is a huge concern regarding compliance with daily treatment. At least with nusinersen, we know when people are coming for their doses and when they’re overdue, and we can start interacting with families or patients about that. With risdiplam, there’s a lot of trust involved, and it’s a little nerve-racking for the provider. We want to keep a close relationship with people and ensure that they’re getting the treatment they need.

Treatment Challenges in Spinal Muscular Atrophy Patients

When we’re considering the response to treatment when using these 3 targeted treatments we have approved for SMA [spinal muscular atrophy], there are many factors that need to be taken into account.

The first is simply tolerability: Are there any safety factors associated with these treatments? There are some things that we have to monitor for all the treatments related to their safety, but honestly, they’ve very new, and some are still actively in research trial as well. We’re still learning about them, and we’ll likely have other things that we will start to realize as both short-term and long-term concerns in terms of safety that we need to monitor.

In terms of efficacy, this again depends on where you’re starting relative to the trajectory of the disease that the person is experiencing. You can imagine that, in people who have a milder form of SMA, they may start to have symptoms superimposed on normal childhood development. There are clearly issues, but they’re making progress based on any child’s ability to get better at movement as they age.

There has been a point where they plateau because there is no ability for development to keep happening naturally because the disease had gotten to such a severe point. There is then the decline phase. In the most severe form in babies, this is very rapid; there is almost no gain. There’s a quick plateau, but it’s mostly a steep decline where you reach a very minimal level of function quickly in the severe form. In the milder forms, it can be months to years of slow improvement with some symptoms, a very long period of plateau, and then a very slow decline in function. Even in those more severe patients, once they’ve reached a certain level of function, it starts to plateau again and gets much slower in terms of change over time.

When we’re trying to look at the therapeutic response to an intervention, this is a challenge in the clinic. What we’ve seen with nusinersen is that even people who are far into their disease trajectory, who have very minimal function, have meaningful and measurable differences in their function after starting treatment. Whether or not it is stabilization of motor neurons, many of us in the field also believe that there’s a role for SMN protein in nerve signaling, neuromuscular junction integrity, and other aspects of how the lower motor neuron functions.

Whatever is happening, you can see an improvement in some patients. Even if they don’t improve, if they stay the same for a longer period of time than what we could have expected in the natural history based on our understanding of SMA for decades, then that is a therapeutic response because they’re not getting worse the way that you would have expected them to.

An even harder concept to prove to an individual is that, yes, they’re getting a bit worse, but the amount that they got worse is not as much as they would have been if they weren’t taking medication. This is very difficult to prove in a 1-person, n=1 kind of thing. As we look at aggregates of data among the research trials with many dozens or sometimes hundreds of patients with SMA being studied in some of these research trials, we start to understand the difference from what we understand is the natural history.

The key point as you’re trying to use these medications is that it’s not just giving the medication and your SMA is cured, so you can just go home and never have to access the medical system again. These are not cures: These are treatments that make SMA less severe. The patient still needs to stay linked up with an SMA care team who will then carefully evaluate their overall function from many different perspectives: pulmonary function, orthopedic function, nutrition, and all the different aspects of function in addition to the motor function that somebody is displaying. We can measure these things with various skills, but at the end of the day, quality of life is important too. What the patient and their family, their loved ones, and their caregivers are telling them and are telling us is different about them is really important to listen to in terms of whether a treatment is having an effect for the individual and whether it should be continued.

Spinal Muscular Atrophy Treatment Goals and Considerations

From the perspective of somebody who doesn’t have a clinical background, it’s pretty intuitive to understand what living with weakness might mean for you. You can imagine, if your body doesn’t move the way you expect it to, what kind of impact that would have on your day-to-day function and how many ways it impacts you.

It’s what we all take for granted. When I finish speaking here, I’m going to get up from my chair and walk out the door, and I wouldn’t think twice about being able to do that. If somebody is living with weakness, then they have to think about everything they intend to do in their lives and whether they need help to do that. Some people are dependent on machines and other people to accomplish almost anything

Other people can do quite a few things for themselves with SMA [spinal muscular atrophy] and can be creative about some of the things that they’re challenged by. I’m constantly inspired by how much quality of life many of my patients have. Some of them honestly make me feel like a bit of a slacker because all I managed to do was to get to work that day, and here they are doing all these amazing things with their lives that I haven’t had the bandwidth to be able to think about doing.

The concept is that, if you’re looking at a therapeutic response, yes we can measure it with our scales. But what’s happening in that person’s day-to-day life is the bottom line in terms of how they’re experiencing their disease, including having less fatigue so they are more able to sustain activities. I have a patient who is dependent on switches for schools, and when they started having difficulty with that in their natural history, it essentially locked them in in terms of being able to learn because they had no way to communicate what they were thinking. When they went on to treatment, they were able to use the switches with more sustained strength again, they could attend longer sessions of school and be able to do more test work and again start to achieve things. He’s now in post–high school studies.

This was a huge change in the quality of life for that patient that isn’t easily measured on any of our functional skills, but it meant something significant in that person’s ability to interact with society and achieve things. You can get into practical aspects of this too. You can think that, if somebody’s respiratory function is more preserved, they can get a cold without that being an ICU [intensive care unit] experience for them. So interacting with the outside world is much more safe and straightforward.

In 2020 of course, for all of us, this is bit loaded with the pandemic going on. But being able to interact and have as high as possible an interaction in a school setting, in a work setting for adults living with SMA, or in social and community settings is really important for minimizing the impact of the disease that’s chronic and degenerative like SMA for the people living with it.

Quantifying and Measuring Treatment Success in SMA

We’re fortunate as an SMA [spinal muscular atrophy] community. This is a rare disease, and there are very passionate but also very specialized people who are taking care of it. In terms of people who are truly focused on SMA and have it as their primary focus of their practice, the community is small around the world. We have international care consensus guidelines for this disease, but there’s not a version that includes the new therapies available. This is being worked on, and it should be available soon.

In terms of the targeted treatments that we have to offer, all of them have been studied in research trials, but the challenge is that the research trial is set up intentionally to be able to detect a therapeutic response with the best possible benefit of the investment of doing the trial in the first place. There is a subpopulation chosen for participation in the research that has the potential for maximal benefit to be able to see that benefit. All these trials have strict inclusion-exclusion criteria that kept the patients relatively pure in terms of only being affected by SMA and no other medical concerns. Their SMA-associated medical concerns were at a point where they were not end stage in terms of needing constant respiratory support, having full nutrition by tube feeding, or being unable to achieve a certain score on our functional scales in terms of a floor effect.

When we bring these therapies into the clinic, the challenge we have sitting with the patient in front of us is this: It is probably the least common situation that they’re going to be exactly like the research trial data. Most likely, they have other things going on, and they’re in a different stage of their disease from the people who were studying the research. This is particularly true with adults living with SMA because none of the research trials has included older adults. We now have 1 trial, the SUNFISH study from Roche, that at least enrolled patients up to 25 years of age. There are some adult data associated with sitters with SMA or walkers with SMA treated with risdiplam.

When we start looking at bringing these therapies into the clinic, we have to think about the patient who is sitting in front of us and whether they’re like the patients who were studied in the research trials or whether they’re having different experiences with their SMA related to other medical comorbidities or where they’re at in their experience of SMA-related symptoms and morbidity.

Real-world data become critical in this space because we need to understand how this impacts the patient’s everyday life as well as the outcomes, safety, and tolerability in people who have experiences with the disease that are different from those in the research trial. This is particularly true in adults living with SMA.

I am always encouraged when we see real-world data emerging in the literature, and we have had some recent publications in 2020. There was a large German collaborative that published its experience with nusinersen as well as the natural history in SMA. I know that there are multiple initiatives in the United States that have been multicenter collaboratives to try to gain better experience of both cross-sectional and longitudinal data in adult SMA, both the natural history and on treatment, and how we can frame realistic treatment expectations and outcomes for people living with SMA when they’re making decisions between different treatment options and what might be available to them.

It’s an exciting time in SMA because we’re trying to think about the new phenotype that we’ve created through targeted treatment, in which people are having their survival motor neuron protein deficiency corrected through these targeted therapies. They’re having an entirely different experience with the disease from what would have been expected in the natural history.

How do we better think about the different implications of this from an orthopedic perspective and from a pulmonary perspective as well as nutrition-wise, function-wise, and rehabilitation-wise? What do we do with contractures? What do we do with scoliosis? What do we do with hips? What do we do with diet? What do we do with pulmonary support? All of these are open questions that we need to better understand to optimize in people on therapy.

This is going to be a huge area of focus for many years for our international community focused on the treatment of SMA. It’s exciting to be in a space where 3 different approaches have come into the clinic so rapidly for such a rare disease. It’s an exciting time, and all of us are thrilled to be a part of it. We’re looking forward to collaborating more to better understand how to make life for a person with SMA as functional and independent as possible.

Utilizing Real-World Data to Drive Evidence-Based SMA Treatment

Challenges and Considerations in Treatment of Adult Spinal Muscular Atrophy

Key opinion leader discusses considerations for adult patients with spinal muscular atrophy (SMA) including disease burden, treatment evaluation, and the use of real-world evidence.

Challenges and Considerations in Treatment of Adult Spinal Muscular Atrophy

EP 1: Identifying Adult Patients with Spinal Muscular Atrophy

EP 2: Impact of Spinal Muscular Atrophy on Quality of Life

EP 3: Spinal Muscular Atrophy and Healthcare Resource Utilization

EP 4: Importance of Establishing Care Early in SMA Diagnosis

EP 5: Treatment Challenges in Spinal Muscular Atrophy Patients

EP 6: Spinal Muscular Atrophy Treatment Goals and Considerations

EP 7: Quantifying and Measuring Treatment Success in SMA

EP 8: Utilizing Real-World Data to Drive Evidence-Based SMA Treatment