Current Series: Advances in the Treatment of Spinal Muscular Atrophy

Crystal Proud, MD: Because nusinersen has been approved for longer and has a wider age range to which it applies, there have been many patients who have been treated over time, and we, it turns out, may have another medication to add to our list in addition to Zolgensma [onasemnogene abeparvovec-xioi] and Spinraza [nusinersen]. We may be soon adding risdiplam. This is a medication that has been submitted but not yet approved by the FDA for treatment of spinal muscular atrophy [SMA]. It's unique in that it's an oral agent, and it acts on the SMN2 gene, impacting the gene’s ability to produce full-length protein. 
I'd like to review some of the studies here as well. John, the FIREFISH clinical trial evaluated risdiplam in patients with type 1 SMA. Six out of 14 infants were able to sit, including 3 who achieved unassisted sitting after 8 months of treatment. Fifty seven percent achieved a score of 40 or above on the CHOP INTEND [Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders] at their 8-month visit. Can you review the significance of a score of greater than 40 on the CHOP INTEND for this population and why that might be meaningful? 
John Brandsema, MD: The original natural history studies done in type 1 SMA, as Nancy mentioned earlier, the natural history is relentless loss that’s quite rapid in the most severe onset form, so it's been taken as gospel in the community that, generally in the natural history, people with type 1 or infantile onset SMA do not go above 40 with their CHOP INTEND score. There are very rare exceptions to that when you first meet the patient, but certainly in the natural history, they would very rapidly drop below that score.  
These studies tend to show that 40 cutoff as a landmark above which, if you're seeing gains to higher scores, you're clearly having a therapeutic impact compared to the natural history of SMA. The challenge with the FIREFISH study is that it is a newer study; it’s still ongoing, and every time we hear data, it's been longer on treatment. Some things to remember about this cohort are that they were, in general, a bit more symptomatic with SMA than some of the other studies that were done. 
Their mean age at first dose was 6.7 months in the original cohort, so some of these patients had been living with symptomatic SMA as infants for a good few months before they started treatment. To see these gains still in that cohort is remarkable. The other challenge is that these are all open-label data. There is no placebo control group, so when you're starting to look at the adverse events, some of them are quite commonly reported in the cohort. There's about half with fever; diarrhea and vomiting about a third.  
They look like they have a high prevalence of adverse events, but those who do SMA research understand that the symptomatic infants have a high incidence of adverse events in general. We need that placebo-controlled data to be able to be more clear about how different an intervention is to the natural history of the disease. 
Another encouraging thing besides the motor function aspect in these patients is that no patient in the original cohort of 21 proceeded to needing permanent ventilation, and there was no loss of swallowing ability in any of the patients. They remained able to feed at least partially orally, and at the time of the last data presentation, 18 out of the 21 were still living. This is encouraging that, even with over a year and a half of follow-up after initiation of treatment in quite symptomatic infants, they're alive, not needing permanent ventilation, swallowing, and making motor gains.