The Success of Risdiplam and Importance of Screening Infants for SMA


The professor of neurology and pediatrics at Columbia University Irving Medical Center spoke about the success of the small molecule in older infants with SMA, and about what she’s looking forward to in the future of SMA treatment.

Dr Claudia Chiriboga

Claudia A. Chiriboga-Klein, MD, MPH, a professor of neurology and pediatrics at Columbia University Irving Medical Center

Claudia A. Chiriboga-Klein, MD, MPH

Patients with spinal muscular atrophy (SMA) and the physicians treating it are currently faced with major challenges, as the condition lacks an adequate number of treatment options, with only 1 FDA approved for use.

Although, risdiplam, an orally active small molecule treatment is making its way, successfully, through the pipeline in clinical trials. Claudia A. Chiriboga-Klein, MD, MPH, a professor of neurology and pediatrics at Columbia University Irving Medical Center, has been involved in a number of those trials. Thus far, positive data were presented at both the Cure SMA1 and the World Muscle Society2 2018 annual meetings.

Most notably, data has shown that in older infants (mean age, 6.7 months) the therapy was exceptionally successful compared to what’s been seen with other treatments. To find out more about the treatment’s success so far and what the former interim director of the Division of Child Neurology within the Departments of Neurology and Pediatrics at the College of Physicians and Surgeons of Columbia University is looking forward to in the treatment of SMA, NeurologyLive spoke with Chiriboga in an interview.

NeurologyLive: Is Risdiplam’s success in older patients a potential positive caveat to its use?

Claudia A. Chiriboga-Klein, MD, MPH: I think that’s exactly what that means. In the SUNFISH data, which had older individuals, shows improvements as well. These are individuals who have minimal requirements for entry in the study, whereas in some of the other studies, the later onset studies with nusinersen, patients were much younger, were less severe, they couldn’t have scoliosis to a certain degree, and these are not individuals in the SUNFISH study. But what was presented are individuals who are much more advanced, who have more scoliosis, and who are further along in their disease. If you look at the rates of scoliosis in the older population—they’re treating adults, unlike the others that are only treating pediatric populations—and those older populations have significant scoliosis, and despite that, they’re finding improvement. It’s milder, of course, as you would expect, but there is an improvement in the group as a whole. Despite the fact that they’re very advanced, these are adults with type 2 SMA who have had their disease for many, many years before seeing improvement. That’s very encouraging for symptomatic patients, that they can have improvement even though they’ve had chronic disease and suffered from the changes of that chronic disease.

Have any of the findings to date been surprising or unexpected in any way?

I don’t know if I could call it surprising. It just speaks to the fact that having a medication every day, and unlike some of the others that are episodic where you get a peak or it might wane until the next dose, this is steady dose. Once we saw the pharmacodynamics, meaning when you look at the SMN protein that they measure in blood and they see that it increases 2-fold, 4-fold, up to 6-fold in the infant studies, and it’s sustained over time after 4 weeks—that was very encouraging. That seems to correlate, as well, with the response that’s being seen in these older individuals, so I think it just speaks to the fact that daily and systemic distribution that may play a role in the benefit you see this late in the disease.

I was very surprised, mostly with the infant data, that they did as well as the gene replacement babies even though they were much older. We’ve seen a lot of infants in all the studies, earlier studies with the antisense oligonucleotide, and they didn’t have such a robust response as this one did with regards to not needing additional nutritional support.

What’re you excited about in SMA treatment going forward?

What we’re looking forward to, and we’re already enrolling babies, is that, increasingly, states have embraced newborn screenings where they’re identifying babies with newborn screenings shortly after birth, on every child that’s been born in a specific state. They’re identifying SMA, and we’re receiving referrals for babies with SMA who are not yet symptomatic, and those are the studies that are currently underway. That’s very exciting, to prevent disease before it initially starts. Newborn screening affords us that opportunity.

For those sites that don’t have newborn screening, there is a delay in diagnosing SMA and now that we have treatment, it’s a matter of helping change the mindset that if someone is hypotonic, that we should wait for them to improve. They should be referred early on to a neurologist, or if you think it’s more specific, to a neuromuscular specialist and a geneticist to check for SMA before anything else. Time is motor neuron, and if you wait it may be a bit late for that child.

It’s already the case that early treatment is being done with the commercially available medication. We also have the 2 other treatments that are available to us out of research, and the hope is in the near future there’ll be options, and that will have SMN-modifying treatments, like the small molecule risdiplam. Then, there may be additional adjuvant treatments that still, I don’t think, would be stand alones. For example, the myostatin inhibitors that increase muscle size and potential in strength and the muscle calcium inhibitors that increase contractility of the muscle might be useful to use together with another medication.

More exciting than that, I’m very excited of the possibility of combination therapy. Meaning you’ve treated someone with, let’s say, a gene replacement therapy and they’re not doing quite as well as you would like. You could add something, like an oral medication, on top of that to supplement SMN protein being made by the human SMN gene that the replacement therapy gave, plus the SMN2 splicing modifier risdiplam, so you’re increasing SMN2 through 2 methods that might supplement each other very nicely.


1. PTC Therapeutics Announces Risdiplam (RG7916) is Well Tolerated at All Dose Levels With No Drug-Related Safety Findings [press release]. Dallas, TX: Cure SMA; Published June 19, 2018. Accessed February 19, 2019.

2. Baranello G, Servais L, Day J, et al. FIREFISH Part 1: early clinical results following a significant increase of SMN protein in SMA type 1 babies treated with RG7916. Presented at: 23rd Annual Congress of the World Muscle Society; October 2 to 6, 2018; Medoza, Argentina. Poster #258.

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