Analysis of Nusinersen Shows Favorable Safety Profile in Adults With SMA

Data on nusinersen’s safety profile in adult patients are more limited than in infant and adolescent patients, but a recent study showed positive results based on cerebrospinal fluid and blood sample parameters.

Nusinersen was the first drug approved to treat spinal muscular atrophy (SMA), but the majority of systematic data on laboratory parameters for patients treated with nusinersen are from studies in infants and children. A recent analysis of data from adult patients with SMA aimed to assess the therapy’s safety based on cerebrospinal fluid (CSF) and blood sample parameters in this subgroup.

SMA is a rare, inherited disorder caused by deletion or mutations in the survival motor neuron (SMN) 1 gene (SMN1). Patients with SMA lack sufficient SMN protein levels, which causes progressive muscle weakness and atrophy. SMA phenotypes are largely based on motor function milestones and age of onset — SMA type 1 presents in infants who do not have the ability to sit independently, SMA type 2 patients cannot walk, and SMA type 3 patients are typically classified as walkers. Two additional phenotypes, type 0 and type 4, refer to very severe prenatal onset and adult onset, respectively.

Nusinersen is an antisense oligonucleotide (ASO) that can increase SMN protein levels and has been shown to improve motor function in SMA patients, particularly infants and children. It is administered via intrathecal injection in 4 loading doses followed by maintenance doses every 4 months.

While nusinersen has proven effective, authors of a study published in The Journal of Neurology highlighted a lack of systematic data on laboratory parameters for adult patients undergoing treatment with nusinersen. With some ASOs, organ toxicities such as thrombocytopenia, renal and liver impairment, or coagulation abnormalities have been reported; the aim of the current analysis was to assess the safety of nusinersen in adults with SMA.

“In particular, thrombocytopenia, including acute severe thrombocytopenia, and nephrotoxicity are major concerns and are often considered class effects,” the authors wrote, noting that these adverse effects do not seem to occur with all ASOs.

Researchers retrospectively analyzed data from 50 patients treated with nusinersen in the Department of Neurology at the Essen University Hospital in Germany. A total of 14 patients with SMA type 2 and 36 with type 3 were included in the analysis. CSF samples were drawn ahead of intrathecal nusinersen injections, and blood was drawn before the first loading dose and at each maintenance dose.

In total, 404 samples of CSF were drawn and 362 were further analyzed. The parameters evaluated were CSF white blood cell (CSF-WBC) count, glucose, lactate, and total protein.

“Analysis of CSF parameters can detect various pathologies, such as infectious or noninfectious CNS inflammation, intrathecal hemorrhage, changes in CSF flow, or blood-brain barrier dysfunction,” the authors wrote “Changes in CSF parameters under therapy with nusinersen are of particular interest since the drug has to be administered by repeated lumbar punctures.”

At baseline, the mean CSF values analyzed were all within normal levels, although the mean CSF-WBC count increased during the first 3 loading phase injections. Other studies have found similar rises in CSF-WBC in this phase of treatment, with the cause likely being repeated lumbar injections over a shorter timeline. There were no persistent increases in CSF-WBC.

While not significant, total CSF protein was also elevated in 11 patients with SMA type 3 and 1 patient with type 2. The difference between type 3 and type 2 patients is likely due to the fact that total CSF protein levels are a measure that increases with age, but the gap was only 5.5 years in the study cohort and 2 patients had sustained levels during nusinersen treatment. This suggests possible alteration of CSF flow or blood-brain barrier dysfunction. These findings align with other research on adults patients undergoing nusinersen treatment. However, it is not known whether these effects stem from nusinersen or from intrathecal administration.

Rare cases of thrombocytopenia with platelet counts< 25/nL have been reported in clinical trials of some ASOs, and few data are available on platelet counts in adults treated with nusinersen. With regard to blood samples, 327 were available for white blood cell and platelet counts. Usable samples for the following parameters were also obtained:

  • 322 for urea nitrogen and 323 for creatinine, both kidney values
  • 321 each for the liver values alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase
  • C-reactive protein (liver measure)
  • 180 for activated partial thromboplastin time, a coagulation parameter
  • 181 for international normalized ratio, a coagulation parameter

In the study cohort, only 1 patient experienced sporadic thrombocytopenia and had a platelet count of 101/nL, which meets criteria for a grade 1 adverse event. This result was significant given the findings in other ASOs.

“Based on our results, there is currently no evidence of an increased risk of severe thrombocytopenia in adult patients treated with nusinersen,” the authors wrote. No significant and persistent changes in liver or kidney parameters were seen apart from individual cases.

One study limitation included the small cohort size, which may not allow for rare side effects to be identified. Coagulation parameters were not typically assessed during therapy for outpatients, so a large proportion of samples were from more severely affected patients. For those undergoing outpatient therapy, there was also a time gap between blood sample collection at first loading dose and collection at maintenance doses, meaning transient changes during loading doses could have been missed.

Overall, the data are positive regarding the safety of nusinersen in adults.

“Our data demonstrate a favorable safety profile of nusinersen therapy in adult SMA patients under longer-term ‘real-world’ conditions, regardless of SMA type,” the authors concluded. “In particular, we found no evidence of clinically relevant platelet declines, coagulopathies, or renal or hepatic organ toxicities, which are common concerns with the use of ASOs.”


Stolte B, Nonnemacher M, Kizina K, et al. Nusinersen treatment in adult patients with spinal muscular atrophy: a safety analysis of laboratory parameters. J Neurol. Published online April 25, 2021. doi:10.1007/s00415-021-10569-8