<p>Recent advances in spinal muscular atrophy (SMA) treatment have improved patient survival and motor function, but unmet needs remain. Data are emerging on the combination or sequential use of US Food and Drug Administration (FDA)–approved disease-modifying therapies (DMTs) and adjunctive therapy with novel agents that target muscle and may improve function in patients with SMA.</p>

The reason we can consider combination or sequential therapy is because we now have several different therapies that are FDA approved for SMA. In terms of rational considerations for combination treatment, we have SMN-directed DMTs and non–SMN-directed therapy, which may be available soon. It would make rational sense to use 2 DMTs (ie, 1 targeting SMN1 and 1 targeting SMN2) if we are not seeing a response in a treated patient. However, this is challenging because some therapies may work better for one patient than for another depending on the individual’s SMN2 copy numbers, physiologic response, age, and functional motor activity at the time of treatment.

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Currently, gene transfer therapy with onasemnogene abeparvovec is FDA indicated for children with SMA under the age of 2. However, it can take time to receive insurance authorization for gene therapy, and, unfortunately, some newborns, infants, and toddlers have antibodies against the AAV9 vector, so we cannot treat them with onasemnogene abeparvovec until those titers drop. As a result, for families who desire gene transfer therapy, a bridging therapy can be used, where infants can be treated with either nusinersen or risdiplam before onasemnogene abeparvovec.

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For older patients with SMA who were not able to benefit from early treatment with DMTs, and who have more advanced disease, the goal is always to maintain function. These patients may not benefit as much from additional therapies, and we may want to switch medications if they start losing function because one therapy may provide that patient with a little bit more benefit than another.

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For patients with SMA who are still walking, we typically do not want to look at adding another DMT if they are doing well. There are not great data on combining nusinersen and risdiplam. As providers, we need to be careful about how and why we are making the decision to either change therapies or add a therapy for a patient who is already being treated.

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I am excited about the possibility of adjunctive treatment with antimyostatin therapies that target the muscle. The concept is that if we could increase muscle size, that might increase force, which could potentially increase function and, hopefully, decrease fatigue. Various clinical studies, including the TOPAZ, SAPPHIRE, ONYX, RESILIENT, and MANATEE trials, are investigating adjunctive therapies. If there is a possibility of achieving an improvement in motor function, which we have seen in some of the data, that would be great. So, I think that this is an exciting area to look at, and having solid data demonstrating clear evidence of benefit and reporting safety will be important to rationally consider using combination and sequential therapy, but we have a long way to go in collecting this information.