Risdiplam for the Treatment of SMA


Expert pediatric neurologist Carolina Tesi Rocha, MD gives insight into the mechanism of action of risdiplam and comments on the need for further monitoring of its potential adverse effects.

Crystal Proud, MD: We have talked a little bit about nusinersen and onasemnogene abeparvovec. Now, I would like to talk about our most recently FDA-approved medication, risdiplam. Carolina, I’m looking to you to talk to us a bit about the mechanism of action and indication of risdiplam.

Carolina Tesi Rocha, MD: Sure. As you said, risdiplam was approved in August of last year [2020] to treat patients 2 months of age and older with all forms of SMA [spinal muscular atrophy]. It is the first drug for this disease that can be taken orally, so that was a big thing. This provides an important treatment option for patients with SMA, particularly for those, as someone mentioned earlier today, for whom intrathecal administration becomes more challenging. This medication contains survival motor neuron 2 [SMN2] that is directed to the RNA splicing modifier. The way this works is that this is a difference of the antisense oligonucleotides.

It’s a small molecule, but it does modify the SMN2 precursor mRNA [messenger RNA] splicing. As a consequence, it allows the inclusion as opposed to the natural exclusion of exon 7 during the splicing of the pre-RNA for the molecule. Patients with SMA universally, as you know, lack SMN1 expression and then depend solely on the SMN2 gene. By including exon 7, they can produce a more functional protein. This is exactly what risdiplam does. The medication has shown—I know that we are going to talk in detail about these studies—good bioavailability into the central nervous system and peripheral tissues when administered orally. I know that was a big question initially. Doses are calculated based on age, but also weight. For patients who are 2 months to 2 years old, the dose is 0.2 mg per kg per day. For patients who are over 2 years of age, the medication is divided based upon if the patient is 20 kg or less. If the patient is above 20 kg, they take is 5 mg daily. That is consistent for all ages above that kilogram margin. 

The medication is well tolerated. It’s very new. We have done the clinical trials; many of the speakers here today have participated in the clinical trials, so we have experience over more years, but it is still very new. Often, when drugs go into the commercial space, we might start seeing some other adverse effects. But thus far, it is tolerated, and the most common adverse reactions in patients were fever, diarrhea, or rash. There were many concerns about the potential of ophthalmological adverse effects based on drugs that were similar to ours, but neither during or after the study were those seen. Still, that continues to be an area we are monitoring closely. There is also some information about the preclinical models and whether fertility could be involved as well, but again, that was not checked during this study. It is up to us to see, when the future comes, if that will be, indeed, a concern as we are treating patients.

Crystal Proud, MD: Excellent. Thank you for that summary. Thank you for watching this NeurologyLive® Peer Exchange. If you enjoyed the content, please subscribe to our e-newsletters to receive upcoming Peer Exchanges and other great content right in your inbox.

Transcript Edited for Clarity

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