Nusinersen Treatment for SMA

James Wymer, MD, FAAN: Nusinersen came out in December 2016. That was a huge event for SMA [spinal muscular atrophy] patients because it was the first medication that would actually treat the underlying disease cause. When we talk about the disease, we talk about SMN1 and SMN2. One percent of SMN2 is abnormal, compared with the normal SMN1. Nusinersen can change the way the protein is produced in SMN2, so it becomes more like SMN1. It doesn’t replace SMN1, but it helps make it function more like SMN1. When you can increase that amount of functional SMN1, you provide the body with the tools it needs to fight this disease.

The introduction of a medication in 2016 that allowed us to directly go in and correct the genetic abnormality was huge. We’ve never had an opportunity like that in neurology. In the clinical trials that got it FDA approved, kids who typically wouldn’t have been able to walk had dramatic improvement with this introduction. It’s been approved across all stages of SMA and in all ages because of its benefit.

Nusinersen has been FDA approved across all stages of SMA, in types 1, 2, 3, and 4. We know from the data that the earlier you get it in the disease course, the more the benefit, but that is still being analyzed. That is still being looked at. 

It is given through an intrathecal injection. That is a spinal fluid injection, so you need a lumbar puncture to do it. There’s a set program that they have in place for how frequently it has to be done. For the most part, it is very well tolerated, except for the obvious complications that can happen from doing any sort of spinal tap. The other potential risks are glomerulonephritis and thrombocytopenia. Prior to any injections, you have to check the liver and blood counts, as well as the renal function to look for any proteinuria. 

Tim Hagenacker, MD: The approval of nusinersen includes all types of 5q SMA, independent of disease severity and patient’s age. When you have a confirmed 5q SMA, you can start treatment with nusinersen.

The mechanism of action is that nusinersen is an antisense oligonucleotide. It involves single-strand genetic information binding to the RNA [ribonucleic acid]. Therefore, it includes exon 7 within the transcript. This is the problem you have with the SMN2 copy number, which codes for a truncated protein with a defect, in contrast to the SMN1 gene. With nusinersen, you make an intact SMN gene out of the defective SMN2 gene. This is the mode of action of nusinersen, and it has to be administered via intrathecal injection, or a lumbar puncture, because it cannot cross the blood-brain barrier. It has to be administered 6 times within the first year of treatment. Four injections are within the first 2 months during a loading phase. Then you have a maintenance phase with repeated injections every 4 months. Independent of SMA type and age, each injection includes 12 mg of nusinersen.