Rare Neurological Diseases: Spinal Muscular Atrophy and Huntington's Disease - Episode 14

Approval of Nusinersen for SMA

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Peter L. Salgo, MD: We have been teasing our viewers because we’ve been talking about novel therapies, something in the pipeline, something good…One of the new drugs is nusinersen.

John Brandsema, MD: Yeah, nusinersen has been available since December of 2016 with a label for SMA [spinal muscular atrophy]. This is again an antisense oligonucleotide. It’s intrathecally delivered, so it requires lumbar puncture with both a loading phase and then a maintenance phase of dosing. The intent of this antisense oligonucleotide is it targets that SMN2 gene that all patients with SMA still have. The SMN2 gene normally doesn’t make the SMN protein very well because of that nucleotide change compared with SMN1. But with nusinersen on board, it alters the premessenger RNA to actually include an exon that’s normally not part of the transcript, so that the SMN2 gene can make the SMN protein more efficiently, and you get higher SMN protein levels in the patients.

Peter L. Salgo, MD: OK, so that was a genetic word salad.

John Brandsema, MD: Yes.

Peter L. Salgo, MD: I was following it. If you give this drug, you get more good stuff because the gene is made to work differently and better.

John Brandsema, MD: Yes.

Peter L. Salgo, MD: I got that.

John Brandsema, MD: Yeah, you corrected your SMN deficiency.

Peter L. Salgo, MD: That’s simply amazing. How did people come up with this?

John Brandsema, MD: Again, it’s a genetically targeted treatment. SMA is a highly appropriate target because these are these 2 genes that are so similar to each other. It’s a very unusual situation, genetically, in humans. We have this backup or homolog gene that is present in all patients who are affected that we can target. It really was a unique target for an intervention such as this to come forward.

Peter L. Salgo, MD: If there’s such a thing as luck in this disease, having a backup gene is that. It’s lucky. It’s simply there, and it just happens. But in order to know this, we had to do gene sequencing. We had to be able to do all that. We had to understand what was going on with the mechanism of this disease and why these people got these symptoms. That’s a lot of heavy lifting.

John Brandsema, MD: The pace is truly breathtaking. We just understood the genetics of this in the mid-1990s, and then we were already in preclinical trials in the early 2000s with this technique. We had the in-the-clinic trials starting in the 2010s, and we had an approved therapy in 2016.

Peter L. Salgo, MD: That’s breathtaking.

John Brandsema, MD: That’s lightning fast in the context of drug development, in my opinion.

Peter L. Salgo, MD: I’ll put it to you this way: it’s lightning fast, period.

John Brandsema, MD: Yes.

Peter L. Salgo, MD: The complexity of this is appalling, and the fact that some of the gene sequencing is automated, I suspect, helps. But still, somebody had to think about this and do this. Now that this drug is out there, what is your personal experience with it?

John Brandsema, MD: We have quite a large SMA center at Children’s Hospital of Philadelphia [CHOP], where we have the majority of our patients on nusinersen therapy at the current time because it’s the only clinically available medication—although there are research trial alternatives that have been going on for a period of time now. Our earliest patient was dosed a couple of months after the approval, actually the next month after approval at CHOP in January of 2017.

Peter L. Salgo, MD: What took you so long?

John Brandsema, MD: It was within a week. We were also part of the original research trials for nusinersen, so we had patients on therapy for years before that in the research context. We have experience across the severity types of SMA—from a newborn baby to an adult who’s been living with SMA for decade—receiving this treatment. We also have lots of real-world data that we’re starting to accumulate as a community and share in terms of what’s happening in our patients with this treatment.

Peter L. Salgo, MD: And what are you sharing? What are you seeing?

John Brandsema, MD: What we’re seeing are remarkable improvements in various age groups for various types of SMA. Certainly, the peer-reviewed research publications about this—the pivotal trial, the ENDEAR study in the infantile onset, and also the CHERISH study in type 2 SMA—were both published in the New England Journal of Medicine and showed striking efficacy with high tolerability and remarkably minimal safety implications in terms of the medication.