Risdiplam Shows Potential for Older Infants With Spinal Muscular Atrophy


The professor of neurology and pediatrics at Columbia University Irving Medical Center spoke about the treatment’s success thus far and its potential to treat infants with more severe disease.

Dr Claudia Chiriboga-Klein

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

Claudia A. Chiriboga-Klein, MD, MPH

Risdiplam is a highly potent, selective, and orally active small molecule investigational treatment being developed to treat spinal muscular atrophy (SMA), and thus far, has shown success in the first part of its phase 2/3 trial, FIREFISH (NCT02913482).

That success has been notable due to the fact that the patients who have shown improvement are older than those who have been included in previous clinical studies, suggesting an effect that could help patients with more severe disease. Additionally, the treatment is being explored in other trials, notably the SUNFISH (NCT02908685) and the JEWELFISH (NCT03032172) studies.

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 these studies. While there are a couple of options for patients with SMA in the pipeline, there are limited options available to patients, marking risdiplam’s success thus far as a major positive.

To find out more about the treatment and the data to this point, NeurologyLive spoke with Chiriboga-Klein, 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.

NeurologyLive: What do clinicians need to know about risdiplam? What sets it apart from other agents developed for SMA?

Claudia A. Chiriboga-Klein, MD, MPH: Well, risdiplam is a novel SMN2 modifying treatment. There are 3 SMN modifying treatments that are out there, 1 is the known antisense oligonucleotide nusinersen (Spinraza, Biogen), another is the gene replacement therapy AVXS-101 (Zolgensma, Novartis), and then there’s risdiplam (formerly RG7916, Roche). Risdiplam, unlike the other 2 medications, is a small molecule that’s given orally once a day and it penetrates into all tissues. So, it has systemic effects that the other 2 medications don’t have, and that’s an important advantage of risdiplam.

Going back to the presentations from the Cure SMA1 and the World Muscle Society,2 the data on the infants was very impressive because if you look at it, there were gains in motor milestones in infants that were much older than some of the other infants in trials. They were 6.7 months mean age, which is an age where you don’t have as much of a response with the other agents as we found with this agent. Most of them gained milestones and were able to sit, did not require trichotomy, and did not require G-tubes, so it looked very positive. If I’m remembering correctly, there was a 16-point difference at the end of this, after 12 months that they were followed, more or less—and this was the dose-finding component of the study. There’s FIREFISH part 1, which is the dose-finding study, which is open-label and dose-escalating, so not all of the babies received, all of the time, the dose that is now being used for the pivotal trial, which is part 2, their phase 3. We are waiting for its completion and those data to be announced and analyzed. But in this preliminary data that they analyzed, it looked very strong, very powerful, and if you stratified that by age, for those that were under 5 months it was almost 18 points that they gained. It’s quite substantial, and over 90% of them had 4 points on the CHOP-INTEND.

Overall, for babies that are of this age, that is a striking response, which to me raises the issue that perhaps there are systemic requirements of SMN that aren’t really being addressed with some of the other medications. SMN is ubiquitous, you need it everywhere. It’s much more noticeable in the neurological deficits, of course, if the nervous system presents first it shows the SMN deficit first, but other organs can be involved as well.

What is the takeaway from risdiplam’s efficacy in older patients?

If you look at all the data that’s come out with SMA—and this is not novel—based on this data, early treatment is much better. The earlier you treat, the better the response, and that was born out from the nusinersen, the antisense oligonucleotide, and they have a pre-symptomatic study going on, NURTURE, that shows that you can really prevent disease progression and even have normal outcomes developmentally and strength-wise in infants identified and treated before they develop symptoms. So, early is better and works better, but this was the opposite—these were older babies that were at the tail end of what the usual studies enroll. In contrast, let’s say if you compare it to the gene replacement therapy, the mean age of those babies was 3.5 months. They were much younger, and they had a robust response. Risdiplam had a robust response in babies who were much older and, therefore, likely had more symptoms and more severity because we know that increases with time.


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. curesma.org/news/ptc-therapeutics-update-june2018.html. 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. wms2018.com/wp-content/uploads/2018/full-congress-%20issue-final_28_9.pdf.

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