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Professor of Pediatrics and Neurology
Northwestern University Feinberg School of Medicine
Mazza Foundation Neuromuscular Disorders Program
Ann & Robert H. Lurie Children's Hospital of Chicago
Nancy L. Kuntz, MD, has disclosed that she has received consulting fees from AveXis, Biogen, Cytokinetics, and Genentech.
It is exciting to practice neuromuscular medicine in recent years because of the translational science that is bringing new treatments into clinical trials and practice for neuromuscular disorders. In 2020, we now have 3 FDA-approved drugs for treating spinal muscular atrophy (SMA).
It is important to be knowledgeable about all of these agents to educate families and assist them in decision-making about treatment.
We Now Have 3 Approved Treatments for SMA
Between clinical trials and commercial use, there is most experience with intrathecal nusinersen therapy, which has been estimated to have been used in more than 10,000 individuals. The number of individuals treated with onasemnogene abeparvovec gene replacement is lower—likely in the many hundreds of individuals. Risdiplam, as it was most recently approved for commercial use, has the least cumulative human experience.
The first drug to be approved by the FDA for treatment of SMA (in individuals of all ages) was nusinersen, which was approved in 2016. Nusinersen is an antisense oligonucleotide agent that causes exon skipping in a manner that promotes inclusion of exon 7 into the mRNA produced by reading the SMN2 backup gene, thereby allowing production of stable SMN protein.
This agent does not cross the blood–brain barrier and requires administration by lumbar puncture. There are 4 loading doses over 2 months, followed by maintenance intrathecal dosing every 4 months indefinitely. Some individuals require sedation or brief general anesthesia for the lumbar puncture, and individuals with severe scoliosis may require interventional radiology assistance to accomplish the lumbar puncture.
Adverse events have been minimal and primarily are infrequent low pressure headaches or back pain post lumbar puncture.
The second drug for SMA was approved by the FDA in 2019. Onasemnogene abeparvovec is a synthetic SMN transgene administered within capsids of adeno-associated virus type 9 (AAV9). This has been approved by the FDA for use in children younger than 24 months of age with confirmed SMA.
This is a one-time IV infusion of a weight-based dose (1.1 x 1014 vector genomes/kg) of the transgene surrounded by otherwise empty AAV9 capsids. This requires administration of daily oral corticosteroids beginning 24 hours before the infusion and continuing with a gradual taper of the corticosteroids over 6-8 weeks depending on individual response.
Adverse events have included transient thrombocytopenia and elevation of hepatic enzymes. A trial of a lower dosage/kg intrathecal dose of the transgene in older/larger individuals with SMA is on hold.
The drug most recently approved by the FDA for individuals older than 2 months of age is risdiplam, which was approved in August 2020. This is an oral small molecule that crosses the blood–brain barrier and induces exon skipping to promote inclusion of exon 7 into the mRNA produced by SMN2, which promotes stable SMN protein production. This small molecule is not as specifically targeted to exon 7 inclusion, and animal studies have demonstrated some off-target responses including retinal changes and germ cell lines.
Human clinical trials to date have demonstrated mild and usually transient gastrointestinal upset while initiating the drug (although no one in the clinical trials stopped therapy for this reason). The package insert states that it is not known whether risdiplam affects human fertility.
Can You Combine Treatments?
There is some encouraging anecdotal evidence suggesting that we might combine therapies in individuals with severe weakness and/or later onset of treatment, primarily when the second drug was added as part of a clinical trial. These results are too preliminary to draw conclusions, but they warrant further study.
Newborn screening for SMA will clearly change our treatment approach. At present, clinical trials of risdiplam have not been completed (nor FDA approval sought) for use in presymptomatic newborns or infants younger than 2 months of age. Options for treating infants younger than 2 months of age newly diagnosed with SMA, therefore, include gene replacement with onasemnogene abeparvovec or initiation of intrathecal nusinersen.
Presence of significant titers of AAV9 antibodies is a contraindication for use of onasemnogene abeparvovec. The frequency of AAV9 antibodies in neonates has been low (primarily passive transfer from mothers which is transient). However, the frequency of AAV9 antibodies increases with age.
Deciding Treatments With Patients and Their Families
Treatment of newly diagnosed individuals with SMA older than 2 months of age but younger than 2 years of age includes a choice among all 3 FDA-approved drugs. Clinical studies and observation suggests that efficacy appears reasonably equivalent. Therefore, it is likely the differences in adverse event profiles and family burden of treatment that will help families decide among treatments, depending on what factors are most important to them.
With onasemnogene abeparvovec, the convenience of one-time treatment with a single IV infusion done in an outpatient setting may be a factor. However, the potential adverse events—including lowering of platelet count and liver dysfunction—require oral corticosteroid therapy for several months and frequent blood tests and clinical monitoring (typically once weekly for the first month, every 2 weeks during the second month and monthly for several more months, although this varies).
With intrathecal nusinersen, the drug is administered multiple times a year via lumbar puncture, with the outpatient procedure and observation period usually lasting half a day. It also requires demonstration of normal clotting blood studies and absence of significant urine protein before each dose.
Oral administration of risdiplam once daily is clearly simpler for families, but this must be weighed against the need for ongoing treatment. However, initial gastrointestinal symptoms demand attention in some fraction of the patients, and safety labs (blood and urine) are required intermittently.
Cost is another factor to consider. At present, drug costs over 4-5 years of cumulative dosing is equivalent for the 3 drugs. However, the different drugs accumulate differing amounts of cost for administration.
Children Younger Than 2 Years
Onasemnogene abeparvovec is approved for treatment of SMA in individuals younger than 2 years of age only. So, for treatment of patients older than 2 years, the treatment decision is between intrathecal nusinersen and oral risdiplam.
To me, a major advantage of intrathecal nusinersen is that we understand its safety profile based on its more extensive dosing experience. By contrast, there is less experience with oral risdiplam, which gives us less data about potential adverse events. However, a major advantage of risdiplam is its ease of oral administration (avoiding repeated lumbar punctures).
Finally, the landscape of treatment for SMA is in a state of evolution as additional experience with existing agents is accrued, potential future agents are introduced, and combination therapies are tried.
How have you discussed treatment decisions with families of patients on the 3 available treatments for SMA? Please share your experiences and thoughts in the comments box.