Disease-modifying agents play a significant role in treatment strategies for patients with SMA.
Julie Parsons, MD: This is an amazingly exciting time for treatment of spinal muscular atrophy [SMA]. We’re blessed to have 3 FDA-approved therapies for patients with spinal muscular atrophy. We always have to remember that the cornerstone of treatment is following care considerations with the multidisciplinary team. Because even prior to having disease-modifying therapies, just the institution and widespread acceptance and use of the clinical care guidelines extended life for patients with SMA.
We can’t forget that aspect of things.
In the United States, we have 3 FDA-approved therapies. The first drug approved was nusinersen, or Spinraza, which is given via spinal tap. After a loading dose of 4 doses within 2 months, patients are treated quarterly for life. This medication is indicated for all patients with 5qSMA, little babies as well as adults. The next disease-modifying therapy that was approved was onasemnogene abeparvovec, or Zolgensma. This medication involves a gene transfer agent. Patients with SMA are missing an SMN1 gene, and this gene transfer product reintroduces the SMN1 gene. This is indicated only for patients under the age of 2 years in the United States. In Europe, the indication is a little different, and it’s weight based.
There are ongoing trials looking at intrathecal possibilities of treatment with gene transfer therapy, but this agent isn’t approved for intrathecal use. Patients treated with onasemnogene, or Zolgensma, need to be monitored very carefully. It’s a great medication and outcomes can be wonderful, but there are also significant adverse events that need to be monitored, including some types of liver failure, liver injury, and kidney problems that can occur, so patients need to be monitored quite carefully.
The third agent, and most recently approved, is risdiplam, or Evrysdi. This is an oral agent that’s given on a daily basis. In the past 6 months, this medication was approved for infants as well, so newborns can be treated with risdiplam through adulthood. We also monitor this agent with some laboratory testing and physical exams. There are potentially some issues around male fertility issues and fetal injury, so we have to be careful during reproductive years with this medication.
Those are the 3 medications that we have available. There are other agents in the pipeline being investigated that we may be able to use as adjunctive therapies, but we have 3 therapies that we’re able to use now. In all the clinical trials that have been done, we’ve shown that if patients are treated early when they have fewer symptoms, they have better outcomes. We’re very aggressive in our newborn screening programs about getting patients in to treat them with one of these agents as quickly as possible.
John Brandsema, MD: One advantage that we have in SMA is that the underlying genetic problem is the same for everybody, with missing that SMN1 gene and having an SMN2 gene—at least 1 copy of it—present in their body that can be modified through either risdiplam or nusinersen. This led to the broad approvals of the therapies, although there are nuances with the gene transfer, as Dr Parsons mentioned, in terms of how feasible it is to give a dose for an older individual who’s heavier, because there’s dose-limiting toxicity when delivering it intravenously.
The differences between the therapies are mostly related to their method of administration, with the intrathecal delivery of the repetitive lumbar punctures for nusinersen vs a daily oral suspension for the risdiplam and a single IV dose of the gene transfer treatment. Looking at efficacy vs safety, with efficacy, 1 significant factor is how far a patient is into their disease experience before you’re able to intervene. When we’re born, we have our population of motor neurons for life, and we can’t make new motor neurons once they’re lost. This is what’s so critical about the ability to intervene with strategies such as prenatal or newborn screening. Hopefully we can get people into the clinic before they experience any significant symptoms of SMA, stabilize those motor neurons to keep them healthier for longer, and not lose ground before we’re able to intervene.
If you’ve been symptomatic, we still see an effect of these therapies in terms of benefit, at minimum through slower loss of decline but usually stabilization of a person, where they stay the same, when the natural history would have been to lose. The hope is to see some gain in function, which we see in the majority of the patients when they’re starting these treatments. The critical thing is to intervene as soon as possible because we have a limitation with what we’re able to do with the motor neurons with these genetically targeted treatments. This is why looking at other approaches outside that genetic motor neuron story has such an interest from the research community. Could we boost muscle function, neuromuscular junction function, and other aspects that we know aren’t functioning optimally in SMA to give them the best possible quality of life?
Julie Parsons, MD: I’d like to add that although we’re very aggressive about treating newborns, as Dr Brandsema said, we have a prevalent population of patients, young adults and older adults, with spinal muscular atrophy. In trials that have been done and in real-world evidence and data that we’ve collected, these patients also benefit from treatment with the disease-modifying therapies. The disease-modifying therapies aren’t only for babies and young children. They’re also for older patients with spinal muscular atrophy who may be seated.
It’s a little harder. As Dr Brandsema said, it takes longer to see the stabilization of strength or sometimes benefit, so patients will say, “I’m able to take notes in my college class without fatiguing. I’m able to take my dishes to the table. I can open a door myself. I can drop something, and I can bend down, pick it up, and get my trunk back up instead of staying bent over because I didn’t have the strength to lift my head and shoulders into a seated position.” There’s clearly benefit for adults as well, but it takes longer for us to assess and measure this over time. The goal of treatment isn’t necessarily continued improvement. It’s stabilization of strength, as Dr Brandsema said. Sometimes we’re happy when we have some gain of skills as well.
Transcript edited for clarity.