Dr John Day, PhDJohn W. Day, MD, PhD
After displaying success in treating older infants with spinal muscular atrophy (SMA), risdiplam, an orally active small molecule treatment is now being explored in adult patients in the ongoing SUNFISH trial (NCT02908685).

John W. Day, MD, PhD, a professor of neurology, pediatrics, and pathology at the Stanford University Medical Center, has been involved in the clinical development of risdiplam and other investigational therapies for SMA, and has been impressed with the data that the treatment has returned thus far. Additionally, he pointed to its oral administration as a major advantage.

In a conversation with  NeurologyLive, Day spoke about the treatment and provided further insight into the goals of the SUNFISH trial, and why it’s being conducted in adult patients with SMA.

NeurologyLive: What’s your experience been with risdiplam?

John Day, MD, PhD: It’s a very simple compound to use. That’s one of its advantages, that it’s an orally administered compound that is directed specifically at the splicing of the SMN2 gene. We are hoping—and the evidence to date is—that it improves SMN protein production, and thus it can really resolve the effects of SMA. So far to date, this has been evidently effective in the published data and the presented data, and it’s been really very well tolerated.

Is there anything that makes risdiplam a unique therapy?

It’s definitely easier to use than the only commercially available product, which at this point is nusinursen (Spinraza, Biogen) which would have to be administered intravitally. So that’s one of its advantages. The second potential advantage is that, because it’s orally administered, it’s a systematic administration. What we really still don’t know is what aspects of SMA might be related to the loss of SMN protein production in cells other than the central nervous system.

We know that SMN protein production is ubiquitous naturally, and we know that infants born with SMA have a very small amount of SMN protein production due to their naturally occurring SMN2 genes. What we don’t know is whether or not the small amount of SMN protein production from their intrinsic SMN2 genes is sufficient in tissues other than the central nervous system and motor neurons. We know that it is totally insufficient for the motor neurons and increasing the amount of SMN protein production in the motor neurons has been game-changing, but that is true for nusinursen, that is true for AVXS-101 (Zolgensma, Novartis), it’s true for the gene therapy product, and it’s true for risdiplam. The difference with risdiplam is that it’s systemically delivered, and basically, it must be affecting tissues other than the central nervous system. What we don’t know is what the advantage is clinically in doing that.

Can you speak to the trial design of SUNFISH and why these criteria were chosen?

The situation in SMA is that it’s always clearest to see the benefits of treatment in treatment-naïve infants. That’s just obvious. You start with infants that are minimally affected and you know that because of their disease, they’re going to die within a year or so, and consequently, it makes it very easy to see whether or not you’re having an impact on them.

The goals of SUNFISH are to extend those findings to a larger population, and that’s always a challenge. In the nusinursen data, that’s the difference between the ENDEAR study, which was with infants, and the CHERISH study, which was with older children. If you look, it shows that there’s clinical and statistical significance in treating the older children, but the difference is, nonetheless, more modest than it is between infants that would die and those that are now living and getting stronger. When you go into these older populations, inevitably, the population is more heterogeneous in terms of their level of function when they enter the trial and their rate of progression. That’s where it gets to be challenging and that’s why you need to expand the number of patients in order to see those differences. I think we’re all optimistic that we’re going to see differences. The data to date has supported that, but I think that’s why we get into this situation of needing to expand the population.

How long are the treatment periods?

It’s a 2:1 randomization of treated to control subjects for the first 12 months, and then after 12 months all patients will be in the treatment group and there will be another 12 months of study amongst both groups where everyone will be treated for another 12 months. After that, everybody enters an open-label extension. The 12 months will be coming up later this year, and then everyone will be on treatment, so it’s another year to a year plus. It’ll be in 2020 that we’ll finalize the 24-month data.

What makes SUNFISH exciting as a trial?

The point of this trial is to extend the age range of the patients, and so in the initial trial—the FIREFISH trial—we were looking at patients that were infants, and now we’re getting patients up to 25 years of age. That’s entering a new population. We had some experience with early studies with nusinursen with older patients and they were very small numbers, and then we had experience in commercialized use of nusinursen in much older patients, a much wider range of patients. But there’s been very little evidence from control trials of what it’s like to treat SMA in adults.

Here, we are at least getting into young adults in this controlled trial. That’s a value to the field, irrespective of what means of treatment you’re talking about. Having more data showing the response of that age range in a controlled trial format is very valuable. This has not been done in a controlled trial format. We have data from for nusinursen for adult populations that are now coming out, but it’s all commercially available, so you can’t do that in a controlled trial.

What has risdiplam shown which suggests it will achieve FDA approval?

Well because the data in the infants is quite strong, we’re confident that there are children that have been treated that are following a course that is enormously different than the natural history of the disease. So that is unquestionable now, just with the data that’s been presented with FIREFISH.

What everybody wants to know is: does it work as well as nusinursen or does it work as well as AVXS-101? Those questions just can’t be answered because they haven’t been addressed in a controlled trial. There are enough differences between trials and between patients that you can’t answer that. But what you can say is that risdiplam is clearly working, clearly showing benefit in the patients with SMA, and that it’s a much easier treatment to take. It’s something that basically anyone can take, as opposed to a treatment that requires intrathecal administration. Those are the slam dunk kind of elements in the attempt to get this available for the general population.

Anything to add?

The important point is this extension into the adult population. It’s problematic that nusinursen was approved for all patients with SMA irrespective of age, SMA type, or degree of severity. I’m not arguing that—I thought that was an appropriate response to the FDA with the data they were presented. But it did leave us with little to argue with insurance companies about whether or not it was appropriate to treat adult patients. I think that argument persists, and a lot of adults are having trouble being treated because there was scant data available to substantiate the value. If we can show in the SUNFISH trial that modification of SMN protein improves the function of adults in SMA, that’s going to be really useful across the board for SMA patients.