Risdiplam: An Oral Treatment for Spinal Muscular Atrophy

Nancy L. Kuntz, MD: This idea of promoting development, or production, of SMN2, SMN protein, particularly with the antisense oligonucleotide, has been approached with this particular science and the intrathecal administration, but there have been attempts in studies that have done this with oral approaches as well. Maybe you can share your experience with that, Claudia.

Claudia A. Chiriboga, MD, MPH: We’re talking about small molecules, and the 1 that’s more advanced is risdiplam. And it’s an oral medication given once a day that works in a very similar fashion as nusinersen does, in that it increases alternative slicing of the SMN2 gene so that more SMN, a protein, is produced. I think a difference, other than that it’s administered orally, is that it also penetrates systemically. Goes uniformly into the central nervous system with a 1-to-1 penetration, at least in many species, including monkeys, so that blood levels are thought to reflect concentrations in the brain. And so SMN protein has been monitored and found to increase several-fold with treatment.

There are several studies, and they’re referred to FISH studies; don’t ask me why they’re called FISH. FIREFISH is the infant study, and that’s a very exciting study, and we just heard about the results of the phase 1 study, which is the dose-finding component. There’s now a pivotal trial under way, which is an open-label treatment. After what we learned with the controlled babies that did not do so well, and we missed that window, I think the studies going forward have not included a sham control or a control study.

And what they found is that even though these infants were older than the children or the infants that we included on the ENDEAR study, or even in the AVXS-101, they did very well. A significant proportion of them improved at least 3 points on their CHOP INTEND [Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders test], where if they didn’t have swallowing difficulties, they didn’t develop swallowing difficulties and they didn’t reach end point.

And similar to the ENDEAR study, in which the outcome with survival included an end point of survival or permanent ventilation—defined as 16 hours on a ventilator, or a tracheostomy—if they didn’t have these issues, they did not develop them, which was very striking given that they were a bit older. And it was safe and well tolerated and no child or infant had to be withdrawn from the study. And they were able to find that, I think, 40-something percent of them who had reached the age sitting were able to sit. And there’s actually 1 child who’s standing. We saw that presented at the AAN [American Academy of Neurology Annual] Meeting.

Very exciting, and also the SMN protein in blood increased several-fold, between 2- and 6-fold, which is quite dramatic in the increase. There’s also SUNFISH, which is a study with older children. It’s later-onset SMA, and it includes adults. And they have ages 2 to 12 and greater than 12 to 24. And compared with the other studies, including the older-onset CHERISH study that you alluded to, who were children, this study includes adults with type 2 SMA and those who have scoliosis and more advanced disease. Their response hasn’t been as robust as what we saw with CHERISH, in that they had maybe 2.5 points. I think 2.6 points, on the MFM. They used the MFM, which is the Motor Function Measure, which differs from what we’ve used here in the United States, which is the Hammersmith Functional Motor Scale Expanded, on which 3 points is meaningful change. And the MFM is thought to be a little a more sensitive and to include items that would address upper-limb mobility. But they also have a Hammersmith. So those are very exciting studies. And they’re going to be submitting soon to the FDA for approval. Hopefully soon, if it’s approved, we’ll have an alternative.

There’s another study that they have called JEWELFISH, which is for children who have been on a modifying agent and that includes nusinersen, and they are advancing it to include AVXS-101 as well,