Highlighting Rare Disease: Spinal Muscular Atrophy (SMA) Management Considerations - Episode 5

Optimizing Treatment of SMA With Disease-Modifying Agents

Disease-modifying treatments are highlighted as key contributors to the optimization of SMA management.

John Brandsema, M.D.: There are a few scenarios in which it’s very clear that there needs to be a change or that something isn’t working, and there are other things that are more subtle and nuanced. If somebody chooses onasemnogene abeparvovec, the gene transfer, that’s an irreversible decision. We can’t take that back. It’s very important to talk about that with the family, that it’s like transplanting something or doing an irreversible surgery. We need to contract that we’re making that decision in an irreversible way.

The other two options, nusinersen and risdiplam, are modifiable. When you come off of them, they’ll leave your system and won’t be effective any longer. That comes into play when you see an adverse effect. You might want to change because of adverse effects. That’s often a very early decision if it’s something severe that’s particular to the medicine. But both nusinersen and risdiplam generally have been quite well tolerated by most of our patients, so it’s unusual to get into that situation. Sometimes for the repetitive lumbar puncture, it’s the procedure itself that’s an issue for patients, whether it’s getting in — if they have a lot of spinal pathology and it’s challenging to access their intrathecal space, and we’re talking about methods that may have complications as a way to get in there — or post-procedure issues, such as post-lumbar-puncture headache. If that’s recurring and becoming more severe, we obviously prefer not to have that affect the quality of life of the person, and we may consider a switch in that situation.

Seeing an effect of the treatment depends on where in the course of the disease you’re starting the intervention. If somebody presents to you normal through newborn screening, you do an intervention, and they come back to clinic looking normal, you’ve probably adequately treated them because they aren’t behaving the way that you’d expect in the natural history of SMA, which is progressively symptomatic.

If somebody already has SMA symptoms and they’re treated, the impact of the therapy depends on how severe those symptoms were and where in the body they were being experienced. For people who have been living with the disease longer, that’s more subtle over time. Even in the infantile-onset form, which is very severe, if you’ve lost most of your function by the time you start the intervention, you’re going to have had a natural history of very subtle change over time, even in the severely affected patients once they’ve reached that nadir or the floor effect of things that we can measure in terms of their respiratory, motor, and nutrition function.

Those who are more subtly affected with their SMA — whether they were initially sitters or walkers with the disease — are sometimes progressing in a more gradual fashion in the natural history. Seeing an impact of the intervention may take a significant interval of time — on the order of a year or two — to show the significant difference of what you’re seeing with the follow-up on treatment compared with what would have happened in the natural history.

The other complicating factor that we run into frequently in the clinic in that situation is that real life happens to people and they aren’t in a little box where the only thing changing is the medicine. Other things can come up. They might need a spinal surgery, fracture their leg, or have a significant respiratory failure exacerbation and be bedridden for a period when they would’ve normally been more mobile. These things will also significantly affect someone’s baseline and make it more challenging to interpret what the effect of the medication has been because other factors came into their life. That’s why we need pooled experience among many people living with the disease to see the effects of these treatments in some, but it makes focusing in on the individual more challenging in terms of establishing that effect. I believe that I haven’t seen a nonresponder to treatments. They have an impact on every person in whom they’ve been started in my clinic. I’m a pediatric neurologist, so most of my patients who started an intervention were children. But the magnitude of the effect is variable depending on how affected they were at the start of the treatment.

In terms of when we might consider changing, there’s a difference between truly switching from one medicine to another, such as from nusinersen to risdiplam, versus combinations, such as adding something like an SMN2 modulator — such as nusinersen or risdiplam — on top of the SMN1 replacement with the gene transfer. Because with it being irreversible, all you can do is add on at that point if you feel somebody may benefit from an additional treatment.

Transcript edited for clarity.