Dr John Brandsema Highlights Progress in SMA Treatment and Improved Outcomes for Patients

Prior to 2016, the only options available to patients diagnosed with spinal muscular atrophy (SMA) was best supportive care. However, the introduction of 3 FDA-approved therapies—nusinersen in 2016, onasemnogene abeparvovec in 2019, and risdiplam in 2020—has changed the treatment paradigm.

Now, patients are being identified/screened earlier, diagnosed sooner, and treated faster to alter the disease trajectory, keep patients stable, and improve outcomes for patients with SMA, explained John Brandsema, MD, Neuromuscular Section Head, Children’s Hospital of Philadelphia.

During an interview with The American Journal of Managed Care® (AJMC®), Brandsema reviewed the treatment landscape, the importance of diagnosing SMA early, and discussions with families and patients when considering the 3 therapies.

AJMC®:What is spinal muscular atrophy and what causes it? And who might be affected by SMA?

Brandsema: Spinal muscular atrophy is an inherited neuromuscular condition. Prior to having targeted treatments, it was the most common cause of infant death that was genetic. It is caused by a homozygous mutation of the SMN1 gene leading to a deficiency of survival motor neuron protein. And in most people, it's a deletion of both copies of SMN1 that causes the pathology, but in a small percentage, about 4% or 5%, it's a point mutation or another genetic mutation that causes the SMN1 gene to be nonfunctional.

People present with their symptoms at varying ages, depending on how deficient they are in SMN. The most common form, unfortunately, is the infantile-onset form, where people do not achieve the milestone of sitting in the natural history—that's about 60% of the patients. And then another 30% or so will be sitters, but not able to walk. And the remainder are able to walk at some point of their life but usually will lose that ability if they start with symptoms in childhood.

There's a very rare form that affects adults and is diagnosed after the age of 18 years called SMA type four in the natural history, but that's less than 2% of the patients.

AJMC®:The majority of SMA treatment is focused on pediatric patients, as you alluded to. What are some dosing considerations to take into account with this patient population?

Brandsema: In general, considerations in a pediatric-onset disease are that we want to identify patients as early as possible in a neurodegenerative condition. Once we lose ground, we can't gain that ground back. And so, we want to be sure to start treatment that's targeted as soon as possible after establishing a diagnosis. And depending on the age of the patient, the options for treatment are different.

AJMC®:Ninety-five percent of newborn babies in the United States are now screened for SMA. How does early screening and diagnosis impact treatment and care for positive individuals? And what might be some limitations, if any, to newborn screening in SMA?

Brandsema: That number is changing month to month. It feels like at this point we're actually even higher now I believe, because a couple other states have gotten going. It's the shortest timeline to the broadest screening that's ever happened in the recommended screening panel history, which speaks to, I think, the understanding of the urgency of making this diagnosis as soon as possible by the stakeholders. The advantage to identifying somebody and getting them on treatment is related to the fact that we have our motor neurons for life at birth, and there's no way to make more of them. This disease is characterized by loss of motor neurons over time. Once we've lost those motor neurons, we can't get them back. And so, starting treatment as early as possible helps to stabilize the motor neurons that you have and allow them to reinnervate and hopefully, have a much different course of the disease over the lifespan, avoiding the progression that's seen in the natural history.

The newborn screening process does not identify those individuals who don't have a deletion as the cause of their SMN1 gene being dysfunctional. And so, as I mentioned earlier, about 96% of people do have a homozygous deletion as the cause of why they have SMA, but those other 4% or 5% are going to continue to present symptomatically even in the context of universal screening being in place, because of that genetic underpinning.

The other process that's really gaining traction in many areas of the country is prenatal screening because parents can be identified as carriers of this recessive disease. And so, many parents are being tested for whether they're SMA carriers as part of standard panels that are being done by obstetricians. This is an advantage in that you can be identified as a carrier and—if your partner is also tested—you would know that you have a 1 in 4 chance of having an affected baby and then couples can decide about whether they have their fetus tested for whether they're affected by SMA. In that context, there can be a discussion about therapeutic options if the person is born with SMA, and also the relative risk of how severe their disease is going to be based on 1 prognostic biomarker that we have, which is the number of copies of a related gene called SMN2 that the person has. In general, the more copies of SMN2 you have, the milder your experience of the disease. And so, those who have a higher copy number would tend to have later onset of symptoms that are more slowly progressive.

But this all changes completely in the context of having targeted treatments in terms of the experience of the disease. So, families need to understand that and have appropriate discussion with a neurologist who is familiar with SMA and also familiar with the outcomes on treatment after having been identified as having SMA. Whether that's in the prenatal phase, as a newborn screening diagnosis, or if they present symptomatically.

AJMC®: The treatment landscape for SMA began to shift about 5 years ago. Can you discuss the evolution of some of these novel disease-modifying therapies for SMA, including nusinersen, onasemnogene abeparvovec, and risdiplam?

Brandsema: In the past, what we had to offer after making this diagnosis was best supportive care. So, we would work with many different specialties to optimize quality of life, but the pulmonary manifestations, the nutrition aspects of losing the ability to swallow and needing support for that, the orthopedic issues related to spinal curvature and joint contracture were all progressive and in the most severe forms of the disease life limiting for individuals. And so, we were dealing with loss in the clinic and that all changed in very late 2016 with the approval of nusinersen as the first targeted therapy for this disease. In 2019, we had gene transfer with onasemnogene abeparvovec approved. And then in 2020, risdiplam, which is an oral or G-tube administered small molecule, which also works on splicing the SMN2 gene similar to nusinersen, was approved.

So now if somebody is less than 2 years of age and is confirmed to have SMA, we have 3 therapeutic options to talk through with families about what we can do in terms of targeted treatment. This is a complete 180-degree shift from where we were at prior to 2016, where supportive care was what we had to offer. And it's a tremendous opportunity to have these in the clinic. But it's also complicated because each of those treatments has their own nuances in terms of how they're delivered, what kind of a commitment it is over the lifespan, what we can expect as a response to treatment, depending on when we're initiating it relative to the disease, and potential toxicities and things that we might need to watch for in terms of side effects. So, it's a very complicated conversation to navigate with families—or individuals themselves, if they're older with SMA—that are making these decisions. In this country, after 2 years of age, the conversation narrows to nusinersen versus risdiplam, because we no longer have access to the gene transfer option at this time. Although there is work being done on intrathecal delivery with a lower dose of gene transfer for older and heavier individuals, it’s felt that there's a dose-limiting toxicity to a high weight relative to the viral vector delivery that's required for the gene transfer, that limits dosing above age 2 in this country, or in other countries such as those in the European Union, a certain weight.

And so, each individual has their own preferences in terms of what might be the best option for them when presented with these various options. And our care team's responsibility is to go through the data that we have, relative to all of them and our own real-world experience with the medications and come to a consensus about what we think might be the best option relative to the circumstance of when we're meeting the patient and how affected they are by their SMA.

The option of treating “pre-symptomatically,” which is in somebody who's been identified via genetic screening, whether it be prenatal or newborn, and coming to the clinic with no detectable symptoms of SMA on exam, is a tremendous opportunity to get ahead of the disease and treat before we see any manifestations. But we know from preclinical models—and also work in other genetic forms of motor neuron disease, like amyotrophic lateral sclerosis or ALS—that you can lose a significant population of motor neurons before there's any detectable sign in the person. Up to 50% of the motor neurons can be lost before we're able to detect anything clinically. This is frustrating for those of us trying to change the outcomes for patients with treatment, because if we don't get in early enough, we can have lost significant ground with these motor neurons that never comes back.

So, the recommendation from the consensus panel that met after these therapies were approved is that we treat early in virtually every patient that's identified. With some ambiguity still around those who have a very high copy number of SMN2—greater than 4 copies of SMN2—because those individuals are likely to present later with milder symptoms and may not need immediate intervention, although that's not universally agreed upon. If you have 1, 2, 3, or 4 copies of SMN2, and you're confirmed to have SMA by missing your SMN1 gene, then we need to start treatment as soon as possible.

AJMC®: Can you go into more detail about the considerations, such as logistical requirements for administration, cost, or limitation of evidence, that you might talk through with a patient?

Brandsema: We're always balancing efficacy or what we can expect from treatment with tolerability and safety in our discussions with families. And the challenge in a rare disease like this is that the research trials are all very strong in terms of their data, but are done in small numbers of individuals, relatively, who are somewhat heterogeneous in terms of their experience of SMA at baseline. So when you try to compare across treatment modalities, those differences in the baseline population and also in how they were measured over time in the various trials, start to make things more challenging, in terms of making clear delineations between the treatment options regarding superiority. And this is where continued real-world evidence and phase 4 work is so critical in this space. Because we need to understand better what the differences are in individuals treated with these various approaches, in terms of their response to treatment and what is a realistic outcome to talk about with our patients when we're discussing therapy.

The challenges in terms of side effects are unique compared to the option. Nusinersen requires intrathecal delivery, and so, the logistics of delivering things to the spinal fluid via lumbar puncture can be challenging in some patients who have spinal anatomy that's different, whether it's from scoliosis or from prior intervention for their spinal disease. Also, the logistics: in the loading phase [nusinersen is given as] 4 doses over 2 months, but then in the maintenance phase it is 3 doses a year of this medication. It is cumulatively an exposure to procedural support, and many patients require sedation or anesthesia for delivery of their medication, which also has to be taken into consideration because this is a lifelong treatment.

Risdiplam, thus far, has been quite well tolerated. I should mention that risdiplam is a daily medication that needs to be taken orally or via G-tube. There's been some concern around [gastrointestinal] upset or some skin changes in some individuals, but most stayed on treatment and were able to tolerate those. The main concern that's still open at this time is related to impact on fertility in males [and their] sperm count, [there is] also potential effect on the seminiferous tubules in terms of remodeling. Whereas in women, taking the medication, it teratogenic early in pregnancy, and so, the recommendation is to not take risdiplam if you become pregnant and you have SMA.

The gene transfer option with onasemnogene abeparvovec is a single treatment as opposed to both risdiplam and nusinersen, which are lifelong. Once you are dosed intravenously with gene transfer, the hope is that there's going to be durable expression for life of what you are able to transduce, in terms of the motor neurons. But we know from preclinical models that we don't transduce all motor neurons with that infusion, it's probably about two-thirds, roughly, depending on the person and how robust the immune response is to the gene transfer therapy and other factors. And in terms of tolerability, there's also more significant side effects that are seen in a small number of people. We need to give steroids with the treatment to avoid liver inflammation and other short-term complications. But in a very small number of patients worldwide, there's been quite significant complement activation to the point of causing something called thrombotic microangiopathy. Which is a form of hemolytic uremic syndrome, which has led to renal failure requiring dialysis, and a small number of cases, I think less than 10 still around the world reported thus far, has led to death of individuals treated with gene transfer. And because of this, there are more significant safety-related conversations that we need to have with families. But in the early diagnosed individuals, there is a strong shift towards using gene transfer because of that one-time treatment option.

I think in all of the individuals who are making this decision and families, it's important to be aware that these are all disease-modifying treatments, but not curative treatments. And so, somebody's still living with SMA and needs appropriate standard of care from a dedicated care team for life once they've been diagnosed with SMA. The other thing that we need to be aware of as a community when we're making these decisions with families is the cost of the medications, which is significant in all 3 of the cases. And that is very important to think about on a societal level, in terms of how much of an impact we are going to have with the decision that we make relative to the experience of the disease. This is a very severe neurodegenerative disease that has high morbidity in the most severe forms, where people are in and out of hospital a lot in the natural history, related to pulmonary complications, primarily, but also, sometimes nutrition issues and orthopedic issues that can be quite costly and also significantly impacting the individual’s ability to function optimally in terms of their life in society.

This disease does not affect the brain whatsoever, and so there's cognitive potential in everybody with SMA. It's about maximizing their functional status to ensure that they reach the potential of what they're hoping to contribute. And these disease-modifying treatments significantly alter that, but the trajectory for a life of that alteration is not yet known, because these are all very new. We've been using them for 5 years maximum with the first option in the real-world setting—longer with the research trials and more experience in the extension phases of those trials to base it on. But we need to learn a lot more about what happens over decades to somebody being treated with these modalities to be able to make more nuanced and precise decisions about optimal timing of initiation and potential for using therapies in combination.

AJMC®: Do you think there's a role for potentially using some of these treatments sequentially or in combination?

Brandsema: What we want as providers is pretty similar, I believe, to what the families living with SMA also want, which is a life as free of the disease as possible. And if we could do that with no cost in terms of potential side effect burden or tolerability, and also a realistic societal cost in terms of the resources needed to do that, then of course, everybody would be on board with doing as much as possible. The first question that most of the families that I treat with one of these options has, is: “I'm seeing the impact of this, but what about more? Let's do something different and add it together.” We need to learn a lot more as a community about the realities of what that decision means in terms of efficacy and in terms of tolerability before we can be certain.

There is work being done on the research trial level to understand this. We have the RESPOND study from Biogen looking at being treated with nusinersen after you've received onasemnogene abeparvovecopen label. And there's also the JEWELFISH study, which looked at transitions, either adding risdiplam after having received gene transfer with onasemnogene or switching from nusinersen to risdiplam or other targeted therapies for SMA that had been studied previously to risdiplam. And we have some early data from those trials that is being shared, but it's all very new. We also have real-world experience of people who, practically, have received these treatments in the clinic, because it was commercially done. As we learn more and more about this as a community, more and more cases are being reported to try and understand if that trajectory is different than what we would've expected with a single therapy.

But this comes back to the challenge I was talking about earlier of this being a heterogeneous disease in the first place, and also, real-life issues coming up and making things much harder to interpret. You can imagine that for example, risdiplam was introduced into a very significantly altered world in terms of the pandemic, and so, one thing that was different was that people weren't getting exposed to as many respiratory infections. And so the data related to that was different. But also, people weren't receiving their usual hands on therapies as much in terms of physical and occupational therapy, for example, which clearly led to disuse, atrophy, and all sorts of changes in some of the functional scales that we use to measure this disease in patients that have been very stable on treatment for years, up until that point. So, to evaluate the difference in these medications in the real-world setting relative to everything that's been going on has been very challenging. I think that we're all open to the concept of trying to use things in combination, but the other thing that needs to be accounted for is additive toxicity, or whether we're having a cost in terms of side effect burden.

There is some preclinical work that suggests that having high levels of survival motor neuron or SMN protein expression in the context of, for example, having received gene transfer and then adding an SMN2 modulator on top of that, like nusinersen, may have toxicities, cumulatively, over time on the sensory motor circuit that goes on in the lower motor neuron. Those are animal models. We don't know that that happens in the human, and we haven't seen any data to suggest that in humans yet. But we have to take those kinds of messages with the appropriate weight, when we're thinking about the concept of doing this in the real-world setting in a person without any basis from a research trial or controlled setting to guide us.

AJMC®: In closing, can you provide any thoughts on disease management considerations for SMA that you find noteworthy to share with colleagues?

Brandsema: There are a few concepts that really need to be highlighted around SMA care relative to this new world that we've been in for the past 5 years, since the first targeted treatment was approved. The first is how critical it is to establish the diagnosis as soon as possible in somebody who's affected. There's been tremendous efforts to educate the frontline community in terms of pediatricians and physical therapists and others who are first interfacing with these people, to ensure that they're thinking about SMA, and that there's also widely available testing, genetically, to confirm the diagnosis. The deletion assay that we do at first is highly sensitive and specific, and then if we don't see something on the deletion assay, we'll sequence the SMN1 gene looking for that 4% or 5% that have a different change. So, establishing the diagnosis is critical so that we can get them on targeted treatment as soon as possible.

But the treatment is not curative, as I said earlier in the conversation too. And so the second really important point that we always talk about with the people involved with the person with SMA—whether it's their family or themselves, if they're older—is that having SMA is a lifelong condition and you need an SMA care team for your life that is focused on optimizing your health. There are nuances to all of the aspects of managing this disease that take expertise from the various specialties involved to make sure that we're making the right decisions together to truly have the most functional life possible with SMA.

And I think that the really key point at the end of the day is that care for this disease is completely different now that we have these treatments available. We've gone from mourning loss with our patients in terms of things that are harder to do and trying to figure out how to still maintain quality of life in the context of more and more challenges and barriers, to visits where we're able to celebrate the things that are new that somebody's able to do. Or the fact that somebody's stayed stable compared to what we would've expected, which is that they would've had more challenges over time. Or even that those challenges aren't progressing at the same pace as they used to is still something to celebrate as a therapeutic effect. So, these clinic visits are much more optimistic, they're a lot of fun to be part of as a team because we're watching videos of what people have done at home or seeing them proudly show the new skills that they have on an examination, for example, and it's made the conversations about realistic expectations with this disease in terms of outcomes to be very different than what they were in the past.

We still can't improve everybody. If you've already experienced quite a significant progression of your SMA before you're able to go on treatment, it's harder to make a big impact on that, but we can stabilize it. And we're still doing more research to try and understand how to do even better. Whether it be other genetically targeted approaches, optimizing what we have with different dosing schedules or different approaches. I mentioned intrathecal gene transfer earlier in the conversation, for example. Or supporting other aspects of how the disease affects the body, like maybe we can use something that augments muscle function or something that augments the communication between nerves and muscles to further improve the outcomes of people with SMA.

We certainly don't think we're done now that we have these 3 options, but we're in a very different place than where we used to be. We want to keep striving to just make a life with SMA as functional as possible.