Redefining Functional Measures in SMA: Insights From Clinical Research

Tina Duong, PhD, MPT

The evolution of functional assessments for spinal muscular atrophy (SMA), the challenges of applying pediatric scales to adults, and the need for modified evaluations to better reflect patient function were key topics discussed by Tina Duong, PhD, MPT, senior research scientist of neurology at Stanford Medicine, during an interview with The American Journal of Managed Care® (AJMC®).

In part 1 of the interview, she also highlighted how understanding the natural history of SMA has guided clinical trial design and the development of assessments used across different age groups.

AJMC: What is your role as a physical therapist and clinical researcher in the management of patients living with SMA?

Duong: My involvement in SMA prior to treatment really was working on phenotyping or characterizing the natural history of SMA. So basically, looking at the progression of the different SMA types, because that's really important whenever you're comparing treatments—to not have a typical control group that is particularly important in real-world data not represented in clinical trials.

Historical understanding of clinical outcome tools guides clinical trial design, and treatments are based on some of that knowledge as a physical therapist. A lot of what we do has to do with the primary end points that are used to prove efficacy, particularly in phase 3 trials, and that includes some kind of functional measure. So, in SMA, because of the progressive weakness and the variability depending on the type. We have evaluations for infants all the way up to teenagers, and with [better] treatment availability, we realized we needed more assessments that are geared towards adults.

And so, we helped design some of these functional evaluations and now teach them as ways to measure treatment effectiveness so that clinicians out in the field who were not in those clinical trials know how to perform the evaluations that were used in the trial. This allows them better manage clinical care.

A lot of these outcomes were really developed in the pediatric cohort. So, the CHOP INTEND scale was developed for weak infants with SMA.1 And then the RULM [Revised Upper Limb Module] and the Hammersmith [Functional Motor Scale Expanded] are used to measure kids to adults. Multiple versions of these scales exist as we learn what works best in the untreated SMA population. We learned more and looked at the psychometric testing of these assessments, resulting in the need to modify and validate them. A lot of these tests require patients to get out of the wheelchair to do these assessments. It's a little bit easier to do on smaller individuals or children, but when evaluating adults, they typically don't get out of their chair due to contractures and difficulty and safety related to transferring out of their wheelchair.

However, because of the end points used in clinical trials, payers require these assessments for approval of these treatments. For example, an adult who's really weak [may be] required to perform in the CHOP INTEND [study], and the CHOP INTEND was designed for really weak infants. There's no way we can do that assessment in adults. And so, we tried to modify it, and it just didn't work well because parts of the test require us to pick up the infants. We ended up modifying this into what we call the CHOPATEND, which took out the lifting parts, and then eventually we designed the ATEND, a scale that's designed to only assess weaker individuals in the wheelchair. It wasn't used in clinical trials, but now is used in clinical practice, based on the need after the broader label approval for treatment availability.

AJMC: What are the clinical features of SMA, and how is this diagnosed?

Duong: It depends on what you're talking about. So, before treatment, it was a little bit simpler in some ways. As I mentioned before, there are different types. There's type 1, 2, 3, and 4. And it really is based on the highest level of function that the person achieves. For example, SMA type 1 is the most severe type and most prevalent, and so [these patients] never achieve sitting up. And the normal natural history, even without respiratory treatment, was a year to a year and a half or so with respiratory treatment that delayed [the condition] to maybe 2 years or so after disease-modifying treatment. Depending on when you get treated—presymptomatically or [after symptoms present], there's a different phenotype, and as we're learning more about the phenotype, we're seeing clear differences between the previous untreated phenotype and a treated phenotype, and they definitely look different.

The presymptomatic babies look normal [according to] the typical norm reference test, but we don't know what they would look like further on if there's some kind of weakness that develops as they age. As a community, we're really trying to find other ways to measure them to better assess possible changes. And then, because we're managing the muscle phenotype, we are seeing other organ systems that are impacted that we may not have been aware of before treatment. Now, the focus [is more on] how we can better assess bulbar function in early infants as well as those with chronic SMA.

Moving on to SMA type 2. Typically, that's when they're able to sit up. And so anyone who's able to achieve the highest motor function of sitting up, they're labeled as [having] SMA type 2. Type 3 is when they're able to walk. And within those subtypes are 3a and 3b. The adult subtype is diagnosed later, and severity is based on onset of weakness and SMN2 copy number. So that kind of categorizes some of these patients. As you can imagine, with this changing phenotype, that highest level of muscle function becomes really ambiguous, because if a patient is treated, how do we know if they're type 1 because they're treated? Now they've achieved the role of sitting. Do we change [the diagnosis] from SMA type 1 to SMA type 2? And so, the community really is needing language that can better characterize these patients so we have a common language.

AJMC: How can SMA subtypes be differentiated from each other, and what are the prognoses for each type?

Duong: With type 1, [patients are] much weaker, and there's more respiratory involvement. So, a lot of the focus usually is on tolerating being able to sit upright. Newborn screening is now available throughout the US. And so hopefully, we don't see this severe phenotype anymore. This is the most prevalent type. They are really hypotonic. Example: If you pick up a baby with SMA type 1 or 2, they’re hypotonic. One [common thing] is that they just slip right through your hands when you try to pull them up. They just have their heads hanging back because of the severe weakness, severe head lag.

Part of the severity of the types is also based on the number of copies of the SMN2 gene. So, it's like a paralog of SMN1, but it produces a limited functional protein, and some of the treatment availability is based on [whether] they have more copies of the SMN2 gene. Their phenotype is less severe, and as the patients are getting treated, we are also seeing that correlation with SMN2 copy number with severity of disease.

AJMC: How does the progression of this disease differ in children, teens, and adults compared with infants?

Duong: Teens and adults have a more “chronic SMA,” and so it really varies because, again, when their symptoms arise and number of SMN2 copies. So, if they get treated, what we really see is not a dramatic improvement in motor skills, like in infants. Instead, we see maintained motor abilities with possible but more minor improvements compared with the treated infants.

The adult literature out there is based on real-world literature. So, it's not controlled studies. So we actually really don't know for sure the expected improvements but rather seeing maintenance of functional level. At Stanford we see a lot of the adults, and our adults tend to be weaker. Even looking at 4 or 5 years of treatment, they are pretty much maintaining their motor function, which is different from what we know of the natural history, which is slower yet progressive decline. One complication you have in the teenage years is growth. So, at a certain level, they get treated, but then they still develop orthopedic difficulties.

The most prevalent one that we talk about trying to learn how to treat better is scoliosis. So, they still are getting scoliosis—just a different type of scoliosis. So, the infants are getting more of a kyphotic scoliosis, and we're trying to figure out the cause of the kyphotic development and whether we need to provide more support as they gain skills such as sitting while there is still trunk weakness. As parents and clinicians, we really want them to attain sitting, and so they're sitting, but they don't have the trunk control to be able to sit fully upright. And so they sit with a more kyphotic posture and head stacking that may contribute to it. We don't know.

The more we learn, the more we can change our care management. It is possible that we may need to provide more supports for the trunk as they get older. As they become teenagers, you still see the development of scoliosis, and then the question is, do we brace? Do we suggest spinal fusion or rods? These are the things that we actually do not know but—what we've seen from a clinical practice—those who are treated and get spinal surgery actually recover better than [when they were] pretreated.

These surgeries will impact their function because it may take away their ability to compensate with their spine. For example, getting their hand to their mouth. When they get their spine fused, they can't flex their neck to help get their hand to their mouth. And so, they actually may lose some function, but with treatment, they have a better capacity to regain function than before treatment availability.

Reference

1. Goedecker NL, Rogers A, Fisher M. Outcomes of early-treated infants with spinal muscular atrophy: a multicenter, retrospective cohort study. Muscle Nerve. 2024;70(6):1247-1256. doi:10.1002/mus.28267