New DMTs in SMA: Onasemnogene and Risdiplam

Emma Ciafaloni, MD and Mary Schroth, MD, FAAP, FCCP discuss recent clinical trial designs and results for new disease-modifying treatments in SMA: onasemnogene and risdiplam.

Dennis Scanlon, PhD: Dr Ciafaloni, could you talk about the next treatment, onasemnogene?

Emma Ciafaloni, MD: Onasemnogene is SMN1 gene replacement, which is a very different mechanism of action. This is the first in vivo gene therapy for systemic disease. SMA [spinal muscular atrophy] is breaking ground and leading the field for gene therapy. It is a medication that has been approved for all genetically proven SMA patients, from 0 to 24 months of age. That’s what the label says. It is delivered with a 1-time IV [intravenous] infusion. The dose is based on weight. It requires parallel use of prednisone for a few weeks because the gene is delivered through an AAV9 capsid that is not able to replicate. It does not have the AAV9 DNA. The SMN1 gene very rapidly goes into the interior horn cells and sits in those nuclei as an episome and very rapidly, because of a promoter, starts producing full-length SMN protein. It’s a different mechanism of action. The only absolute medical contraindication before treatment is that the patient needs to be tested for the presence of antibody against AAV9, which would exclude them from receiving the treatment.

The pivotal trial was START, which was done in the most severe type 1 babies who were treated before 6 months of age. The trial is fully published, and the primary outcomes were reached with hitting major milestones that were defined as survival and respiratory independence, meaning breathing independently. There is a very rich program of the phase 3 in type 1. There’s 1 in Europe and 1 in the United States, and they are progressing very well. We have an ongoing trial for presymptomatic babies treated before 6 weeks if age. We also have a trial for type 2. It’s a very rich program. More trials and data are soon to come.

The other thing we need to be aware of in terms of safety is that there is potential for liver toxicity, like in an autoimmune inflammatory response, with potential for a liver failure, so there is very important monitoring that needs to be done. This is a medication that we cannot take back once it’s delivered. It’s not like the other 2 drugs where we can stop depending on adverse effects or lack of efficacy. Once it’s done, it’s there, and the patient needs to be monitored. It’s just a onetime delivery, a onetime dose, but there is more that goes into it after that is done in terms of following safety and efficacy.

Dennis Scanlon, PhD: You had mentioned the START trial. Were you referring to the STR1VE trial as well?

Emma Ciafaloni, MD: Yes. STR1VE is a larger multicenter phase 3 trial that is happening in the United States and Europe for type 1. The START is the pivotal open-label trial that only had 15 patients because there was a phase 2 dose finding, but that’s how the drug actually got approved.

Dennis Scanlon, PhD: Let’s move to another therapy available: risdiplam. Dr Schroth, you were going to talk a little about this.

Mary Schroth, MD, FAAP, FCCP: Yes. Risdiplam was approved in August 2020 for individuals over 2 months of age with all types of SMA. It is given orally or enterally, so it can be given through a feeding tube as well. It is given daily. It acts on the SMN2 premessenger RNA-splicing modification. The clinical trials for Evrysdi are in process. It was approved based on the FIREFISH trial, which is for infants 1 to 7 months of age. There were 2 components to that trial. The first part was dose finding, and the second part was based on safety and efficacy. The approval was based on part 2. What part 2 demonstrated, and we’re looking forward to updates from this clinical trial, but at the time of approval, the trial met its primary end point, which was the ability for infants diagnosed with SMA between 1 and 7 months of age to achieve sitting. Twenty-nine percent of the babies participating achieved the ability to sit. Some went on to also stand and roll over, so there were additional milestones that were achieved which then led to a significant improvement in motor function based on the CHOP INTEND [Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders] scores for this particular clinical trial. Ninety-three percent of infants were alive at 12 months; 85% of infants were also event-free at 12 months of age. Of interest, 95% of infants were able to swallow after 12 months of treatment. Almost half the infants did not require hospitalization during their first year of life. These are all milestones that are significant and very different from the natural history of SMA for those babies who have not been treated. There were no drug-related safety findings that led to any of those infants withdrawing from the FIREFISH trial.

The second trial, by which the risdiplam was approved by the FDA, was the SUNFISH trial. It was also a pivotal 2-part double-blind, placebo-controlled study with patients who are 2 to 25 years of age with SMA type 2 or 3. It showed significant change in baseline using 2 different motor function scales. The primary outcome used the MFM-32 [Motor Function Measure-32] score and was significantly greater in people who were treated. This motor function scale is most commonly used in Europe and was chosen because this was a global trial. In addition, a secondary end point, the revised upper limb module, was also significantly improved in individuals who received treatment compared with those in the placebo group. The greatest change was observed in the youngest age group, 2 to 5 years of age. In the older individuals, 18- to 25-year-olds, there was significant disease stabilization. Based on these trials, risdiplam was approved.

Transcript edited for clarity.

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