• Many parents of children with spinal muscular atrophy (SMA) have questions about combination therapy — treating SMA with two or more approved medications.
• The long-term safety and effectiveness of combination therapy is still unknown.
• Decisions about treatment combinations are made by parents in partnership with the child’s neurologist.
• It may be difficult to get health insurance to cover a second SMA treatment unless it is administered as part of a clinical trial.

Before 2016, there was no treatment to change the course of spinal muscular atrophy. Now, three therapies have been approved by the U.S. Food and Drug Administration (FDA) to treat the condition:

• Zolgensma (onasemnogene abeparvovec-xioi), a gene therapy that must be administered by IV infusion before age 2
• Spinraza (nusinersen), which is injected intrathecally (into the spinal canal) once every four months and is approved for both children and adults
• Evrysdi (risdiplam), an oral medication for those 2 months and older

With multiple treatments available, parents of children with SMA have questions about whether combinations of these therapies might provide even better outcomes, and whether they are safe. An early report about risdiplam after gene therapy has shown promising results, but long-term research is needed to better understand the safety and effectiveness of this approach or any other treatment combination. To date, no research has been published comparing the results of different combinations of SMA therapies.

Many questions remain about combination therapy for children with SMA. To gain a better understanding of this topic, mySMAteam talked with Dr. Jonathan Strober. Dr. Strober is a specialist in childhood disorders of the nerves and muscles. He directs the Neuromuscular Clinic at the UCSF Benioff Children’s Hospital.

Can you explain the strategy behind combination therapy in SMA?

In SMA, you have two copies of this gene, the SMN (survival motor neuron) gene. This SMN gene copy one is abnormal in people who have all types of SMA. And then we have the second copy of the gene that sometimes works and sometimes doesn’t work. Spinraza and Evrysdi work on that second copy, and gene therapy is giving you the first copy. So if you give somebody that first copy, but at the same time you increase the amount of protein being made with the second copy so that you have more full-length SMN protein, it makes sense that patients may do better.

I can’t say definitely, because there’s no data to prove any of that. But people are studying combinations to see whether we can start a newborn on both and then either taper the continuing treatment off over time or continue with it.

There’s a clinical trial in which babies who have gotten Zolgensma are getting Spinraza. And I know that there are patients who have gotten Evrysdi after getting Zolgensma. Those combinations make sense in my mind because either Spinraza or Evrysdi works in a different way from Zolgensma.

Which SMA treatment do you most frequently recommend as an initial treatment for infants diagnosed with SMA, and why?

It’s very important to talk to your child’s health care providers and find out what all the pros and cons of all the different medications are before making a decision. Right now, my preference is to try and start with Zolgensma, the gene therapy, with newborns or very young babies. The nice thing about Zolgensma is that it’s a one-time treatment. It’s given with steroids to prevent the possibility of complications from gene therapy, and steroids may cause some temporary side effects. It’s not a no-risk treatment, but it’s low-risk.

Since Zolgensma is a gene therapy, it’s also a viral product — that is how we give gene therapies, through a virus. Some babies may have antibodies to that virus through breastfeeding, and then you can’t treat with Zolgensma right away. Typically what we do is check for antibodies when we’re confirming a diagnosis from a newborn screening. If there are antibodies, we might wait for two months to see whether the antibodies go away so we can give Zolgensma, or we might start with Spinraza instead since Evrysdi cannot currently be started before 2 months of age.

How and when do you decide whether to recommend a second treatment? Is there a waiting period before a second treatment?

We follow the patient and then decide if we want to add a second-line treatment. With SMA, we say, “Time is neurons.” If we wait, we might be losing neurons. So if our kids are not doing as well as we hope after getting Zolgensma, we see about adding on Evrysdi or Spinraza. A lot of that is up to the families, which route they want to go to at that point.

Which treatment do you most frequently recommend as a second treatment, and why?

There’s not a lot of data out there, so we’re trying to piece it together from all the different trials. But the trials are not all done the same way, and that’s why it’s hard. Nobody’s going to necessarily do a head-to-head comparison trial of these combinations.

If a child is younger than 2 months, and we want to start something right away, then we’ll start with Spinraza. So that’s why Spinraza might be a better treatment for the earlier diagnosis, just because we can’t start with Evrysdi until 2 months of age.

Can you speak to the safety of combining SMA therapies?

We don’t really know for sure about safety because there haven’t been a lot of studies out to know if there’s safety in combinations, but I feel like it should be safe since both Spinraza and Evrysdi work differently from Zolgensma, and both are fairly safe molecules. I haven’t seen too many people on combination therapies. But those people I know who’ve been getting both, as far as I can tell you, they seem safe. There’s not a lot of significant risk for severe side effects associated with Evrysdi or Spinraza.

Do your patients ever take all three treatments for SMA?

I don’t see a time when you would want to do Evrysdi and Spinraza together at the same time, because they’re basically doing the same thing. And we don’t know if they would interact with each other and prevent each other from working, that’s a whole other story. I would never do all three.

What should parents know about health insurance coverage for a second treatment?

It’s been mostly the kids in the Spinraza clinical trial who got Zolgensma and are able to continue getting Spinraza through the trial. That’s how a lot of combination therapy has been possible. Insurance companies won’t approve both, for the most part. When you’re paying $2 million for gene therapy, then to pay another $375,000 a year for Spinraza, for example — insurance companies just really don’t want to go down that path if they don’t have to. So a lot of them won’t approve it.

If a patient has gotten Zolgensma, but they’re not doing well, especially if they’re losing function, then they might be able to push insurance companies to approve a second therapy.

What is most important for parents of children with SMA to keep in mind as they face treatment decisions?

Get as much information as you can from your neurologist, Cure SMA, and the FDA, and feel like you’re well-informed. You have to base the decision on what information is available to you and go with your gut. And if it doesn’t work out as well as you’d hoped, there’s the possibility of switching things around. Five years ago, we didn’t have any options whatsoever. Being able to discuss two or three different medications and which one you want to go on is a much better experience.

You have to go with what you feel is right, and if the kids aren’t doing well, you can consider switching courses. That’s why it’s so important to follow up with your neurologist.