Assessing Higher Dose Nusinersen in Patients With SMA

Basil Darras, MD

In September 2021, Biogen announced plans to conduct a phase 3b trial of nusinersen (Spinraza) in individuals with spinal muscular atrophy (SMA) who had exposure to another approved therapy, risdiplam (Evrysdi; PTC Therapeutics). The trial, called ASCEND (NCT05067790) is currently enrolling patients.

Originally approved in December 2016, nusinersen became the first FDA-approved therapy to treat SMA types 1, 2, and 3, and has since had several trials initiated to further study the safety and efficacy of the treatment. ASCEND is one of these trials, this time planning to evaluate a higher dose of the SMN2 splicing therapy in patients with SMA.

To find out more, NeurologyLive® spoke with investigator Basil Darras, MD, associate neurologist-in-chief, Boston Children’s Hospital, as well as the chief of its Division of Clinical Neurology and the director of its Neuromuscular Center and Spinal Muscular Atrophy Program.

NeurologyLive®: Could you offer an overview of the ASCEND study of nusinersen and the motivations for it?

Basil Darras, MD: The ASCEND study is an open-label study of a higher dose of nusinersen in patients with SMA, who had been treated previously with risdiplam. Risdiplam is another of what we call an SMN2 gene splicing modifier. But it's taken by mouth, and it was approved by FDA in August 2020. At the same time, we have picked many patients who are being treated with nusinersen at the standard dose of 12 mg, the one that was approved by the FDA. It was approved at 12 mg every 4 months, given by lumbar puncture, because that was the highest dose we used during the clinical trials. And although nusinersen at this dose was found to be effective and safe, we were always wondering whether a higher dose might be even more effective.

That triggered a study by the name of DEVOTE (NCT04089566), which is currently ongoing, and is trying to test the efficacy and safety of a higher dose nusinersen—for example, 50 mg twice is the loading dose, followed by 28 mg every 4 months. And again, it is given by lumbar puncture, intrathecally, as we say. DEVOTE is ongoing, and we don't have any results yet outside of general knowledge about safety, but we'll know about the efficacy of higher doses in the near future, I hope. ASCEND, as I said, is trying to test the safety and efficacy of higher doses nusinersen—to be more specific, the 28 mg every 4 months—this time, in patients who received risdiplam before.

What has been seen thus far with these two therapies in SMA treatment?

Risidplam, again, is drug that increases the production of SMN protein from the SMN2 gene, which is sort of the defective version of SMN1. It has the same mechanism of action as nusinersen and was studied in a number of trials that involved infants under the age of 7 months, known as the FIREFISH study, but also a study in patients with later-onset SMA between the ages of 2 years and 25 years who received different doses of nusinersen. This study, known as SUNFISH (NCT02908685), for later-onset SMA, did meet each end point. And in fact, risdiplam was approved by the FDA, the EMA, and other regulatory agencies around the world, and it seems to be effective. It was found to be effective, more effective in younger participants with SMA type 2 or 3 between the ages of 2 and 5 years. But the efficacy was somewhat lower in participants who are between the ages of 6 and 25 years. So, the hypothesis here—and again, this is hypothetical—is that the reason the efficacy was not as good in older patients is in the SUNFISH study could be related to the fact that there is a maximum dose of 5 mg in patients who are older in the age of 2 years and have a weight of more than 20 kg. So, it's possible that diminished efficacy may be related to the fact that these older patients have advanced disease with significant motor neuron loss over time. It could be that there is a lot of disease progression in some of these patients. But, again, it could be the fact that there's a cap of the 5-mg dose in patients heavier than 20 kg and older than 2 years.

Is that the goal of ASCEND?

ASCEND is trying to do to find out. It's an important study because when we see our patients and families, they ask us which medication is more effective. We have a hard time answering that question because these clinical trials, say the SUNFISH study for risdiplam and the CHERISH study (NCT02292537) for nusinersen, are not actually comparable because they had different inclusion criteria. It's important for the SMA community, for patients, families, and clinicians, to have more information about the efficacy of these drugs and how they compare to each other. This is, to some extent, what ASCEND is trying to discover.

It's going to enroll patients who have later-onset SMA, meaning they have either SMA type 2 or type 3, who are not ambulatory, who had symptom onset after the age of 6 months, and who were previously treated with risdiplam (which is supposed to be stopped before the enrollment). This study is going to continue for about 2 years with visits every 4 months. It is going to be a global study with about 145 participants at 40 sites. The end points of the study will include an outcome measure which is has been designed specifically to assess motor function in the upper extremities, known as the Revised Upper Limb Module or RULM. I think this is a good outcome given that the population has type 2 or type 3 SMA and is not ambulatory. But also safety will be assessed as well as other clinical parameters.

Transcript edited for clarity.