Clinical Trials for Risdiplam for SMA

Crystal Proud, MD: The SUNFISH clinical trial is a double-blind, placebo-controlled trial in children and young adults aged 2 to 25 with types 2 and 3 SMA [spinal muscular atrophy], and this demonstrated improved SMN protein measurements in the blood as well 70% of patients demonstrating any degree of improvement in motor function from baseline. Nancy, what promise do you think this drug holds if FDA approved?

Nancy L. Kuntz, MD: This drug has an advantage in that it is orally administered. With the older patients with spinal muscular atrophy who are already symptomatic, one of the medical problems that is encountered over time in a significant number of patients is scoliosis. As many of us who've been involved in treating some of the spinal muscular atrophy patients who have scoliosis have discovered, that can make it more complex and require either video perioscopy or interventional radiology to assist with the intrathecal administration of the medication when intrathecal medication was the only option.

Having an oral medication with a similar mechanism of action gives us an option that makes it much simpler, particularly for those people who have scoliosis and therefore a complex approach toward intrathecal medication. The other advantage to this medication is that it is systemically available because of the oral administration. We haven't talked much, but people have primarily thought about spinal muscular atrophy as being something that affects the anterior horn cells or the motor system.

We realized when we looked at individuals with severe spinal muscular atrophy or a long course of spinal muscular atrophy that many people can identify other sensory or autonomic involvement. One of the things that is frequently seen clinically, for example, is GI [gastrointestinal] dysmotility. Beyond usual constipation, almost like pseudo-obstruction, the degree of GI dysmotility is an example of the kind of autonomic problem you can have.

We don't know, but the question is whether systemic administration might be helpful in addressing those kinds of symptoms that aren’t just in the anterior horn cells, therefore accessed by the administration of the medication into the spinal fluid. We haven't talked about this overtly, but with these medications, having options is very important. For example, it's a small fraction of newborns who have appeared to have any antibodies against the AAV9 [adeno-associated virus type 9] viral vector that allows the onasemnogene abeparvovec-xioi to be administered.

There are some ongoing clinical trials, and it appears that to some limited extent, the number of individuals who have antibodies that would prevent use of that agent does increase to a small degree. If you are the 1 person who might have those antibodies, it's a very important issue. Then you’ve got to rely on other treatments. Then nusinersen and risdiplam become more important because they are the ones that would be available to someone who was not able to be treated with the gene replacement because of antibodies preventing that.

Crystal Proud, MD: We've talked about the utility of risdiplam with regard to infantile SMA and then some of our younger patient population. JEWELFISH is a study evaluating patients receiving risdiplam aged 6 months to 60 years old, so quite broad. Recent data presented demonstrated no drug-related safety findings leading to withdrawal, with data from 45 patients who received the medication for up to 29 months.