Breaking Down Hurdles in SMA Treatment

Access to timely and appropriate treatment remains a significant challenge for individuals with spinal muscular atrophy (SMA), particularly as they age. Key barriers to early diagnosis, challenges with treatment frequency, and the unmet need for therapies in older individuals with SMA are explored in this Q&A from The American Journal of Managed Care^® (AJMC^®) featuring John Brandsema, MD, a pediatric neurologist at Children's Hospital of Philadelphia. During this interview, Brandsema also highlighted the impact of insurance coverage gaps on access to care and the burden they place on patients and families.

John Brandsema, MD

AJMC: What do you believe accounts for delays in the diagnosis of SMA, and why is this detrimental for patients?

Brandsema: As mentioned in the prior question, some people are not aware of the exceptions to newborn screening and assume that if somebody's had newborn screening in the time period where SMA was included, that it's fully ruled out, and so that leads to a delay in diagnosis for those who are not with homozygous deletion of their SMN1 gene in the context of more subtle presentations, where the person may not have a lot of bulbar involvement with speech, swallowing, and breathing, because that's really seen in the more severe forms. It's not often the first thing that comes to mind for a provider seeing the patient, certainly not for a pediatrician, a primary care provider, or an internal medicine specialist. If it's an adult presenting with the more rare, milder forms of SMA, they are going to be doing things like referring to orthopedics about the gait differences, having a physical therapist involved, and seeing whether the person responds, which can lead to further delays of these different assessments and trials of therapy before getting to a neurologist.

For a neuromuscular specialist or a neurologist, we often think of other disorders like muscular dystrophy as being perhaps more likely in those older age groups. And so it really takes doing testing like electromyography with nerve conduction studies to show that something is, in fact, neurogenic in the person rather than myopathic. A creatine kinase or CK level might be only very slightly elevated or normal, which would not be typical of muscular dystrophy. These tests and differential diagnoses do lead to delays. Sending that genetic test for SMN1, whether it's deleted or whether it is mutated, is so sensitive and specific for this disease that it's very important to do early in any diagnostic workup for somebody who is presenting with weakness. Nowadays, it's important not to miss this disease because treatment is so critical.

Now, why is this detrimental for patients? We need to get people onto the standard of care as soon as possible and to be vigilant for some of the complications of this disorder that can be life-threatening in the context of respiratory failure or bulbar insufficiency, especially in the youngest patients, but also orthopedic issues like scoliosis, joint contracture, and bone health. All of these things need to be addressed in standard of care. And then, of course, we have disease-modulating therapies that need to be initiated as soon as possible when somebody has an established diagnosis of SMA to prevent irreversible motor neuron loss.

AJMC: Many therapies for SMA are chronic in nature and require frequent dosing. How can less frequent dosing benefit patients and their families?

Brandsema: It depends a lot on the preference of the family and the individual with SMA, if they're mature enough to contribute to the decision-making relative to what might be the best option for disease-modulating therapy and medical considerations that may arise relative to each of the different options that weigh into the decision-making. Less frequent dosing can make treatment more convenient. It is easier for families to be compliant with that, which is a concern when it comes to motor neuron health. If you are not receiving the intended frequency of a therapy and you're no longer giving back SMN protein through 1 of the disease-modulating treatments, then you're going to start losing your motor neurons again because you're SMN deficient, and we don't have any way to get those back.

Some considerations for some families are deciding whether it would be a better option to be receiving a treatment that providers like us are trying to give them. Because then, we know what the patient’s getting treated with instead of wondering whether they’re being treated with something that may require the family to administer more frequent doses at home on their own. Many families manage this without difficulty, but some have more challenges with that, such as a barrier to getting into a routine of doing it every day.

This is a special issue in teenage populations where families start to trust individuals to take medication on their own. But some teenagers don't understand the importance of staying on their treatment and may present with worsened symptoms because they're not taking their treatment as the family thought they were. So there's that aspect, and then also with therapies that have potential side effects to them. Dosing less frequently puts them at less risk of having one of those issues. For example, a therapy that's delivered intrathecally through lumbar puncture has an issue, sometimes with post-procedure headaches like post-lumbar puncture headaches. The risk of that is reduced if you're able to do less frequent dosing.

AJMC: Why is it essential to develop new therapies for patients who are 2 years and older?

Brandsema: There's been such excitement around the concepts of prenatal and newborn screening and early intervention in this disease. But we can't forget the population that was symptomatic before access to disease-modifying treatments was available. There's a large population of older children and adults living with SMA who had established disease for sometimes decades before our first disease-modifying treatment was introduced to the clinic in late 2016. These individuals still need support for their motor neuron health, for motor neuron function, and for optimal standards of care and medical status with their SMA.

The other group that is emerging are those who are identified through newborn screening and have appropriate intervention early but still don't do as well, and these are usually people who have a lower SMN2 copy number. They may have a copy number of 2, and they are just not thriving the same way with their acquisition of motor milestones and may have some bulbar impairment. Could we further improve the status of those individuals by treating them later, after noting that they don't have the same response to the initial therapy that's offered? That's a very active area of inquiry.

Finally, we know that we don't have a perfect cure with any of the interventions that are implemented in the early period, and while some are almost indistinguishable from normal in our clinics, subtle signs and symptoms are there, and some have more profound symptoms that we are still helping them to manage and cope with as best as possible. It's not fully understood yet what an entire life after receiving SMN-targeted treatments would look like. And perhaps adults who start losing their motor neurons—as all humans lose their motor neurons as they age as part of senescence—will see a more profound impact of that motor neuron loss if those motor neurons are highly reinnervated and are doing the work of many motor neurons because the person's been living with SMA and had a stabilization of their disease on treatment. But the motor neurons themselves are not fully healthy, and these people are prone to having more disability or symptoms of weakness and functional impairment arise as they get older.

To address all of those populations, we continue to study various approaches that are meant to either work in tandem as genetically targeted approaches or look at the health of the lower motor neuron in general, and it's usually either the neuromuscular junction or the muscle itself that's being targeted in a way to try to make it as functional as possible and give further benefits to quality of life for people living with SMA.

AJMC: How does a lack of insurance coverage for certain medications for SMA create a cost burden on families and caregivers?

Brandsema: It can be so frustrating to have 2 people living with SMA who are quite similar to each other in terms of their overall medical status, and yet one has access to something due to insurance coverage and the other does not. We try our best to advocate that everybody living with SMA has equitable access to what could benefit them, but the reality is that's not always successful.

We see the impact of this in real-world care. It's tragic when you see somebody losing motor neurons. We should be able to offer them a treatment that stabilizes their motor neurons and gives them a better overall trajectory in their life. With SMA, the progression of the disease is relentless and degenerative, and that is something that we had many perspectives on how to best manage that experience for patients over time.

Ultimately it was supportive care, giving the best possible function and quality of life to somebody who was losing function over time. It is not possible around the world to give access to every available treatment to every person, and that's understandable because there are economic and other realities that need to be acknowledged relative to high-resource therapies and access to treatment. This disease is so heterogeneous that it doesn't mean the same thing for every person living with SMA. They are very different in their trajectories in which symptoms tend to arise relative to many factors, but especially their SMN2 copy number when patients are first diagnosed.

At the end of the day, we see the burden of not having treatment in increased need for supportive devices and increased dysfunction in terms of motor status for those who are walking but may be more prone to fall, have injuries, or need assistive devices for getting around. Patients affected earlier in life or who eventually lose ambulation and become full-time wheelchair users are sometimes never able to get to the point of walking and need more of that supportive help throughout their lives.

Then, if there's bulbar involvement, we have the needs for pressure support for respiration initially when sleeping and sometimes, during the day, for some individuals, even to the point of a tracheostomy, and the swallowing impairment leading to the need for a gastrostomy tube and formula feedings. There is a whole range of high-resource interventions that are required for some people living with SMA, and these can be either avoided or delayed if we are able to have access to disease-modifying therapy early and consistently.