Nusinersen treatment in adult patients with spinal muscular atrophy: a safety analysis of laboratory parameters

Abstract

Background Nusinersen is an intrathecally administered antisense oligonucleotide (ASO) that improves motor function in patients with spinal muscular atrophy (SMA). In addition to efficacy, the safety of a therapy is the decisive factor for the success of the treatment. For some ASOs, various organ toxicities have been described, such as thrombocytopenia, renal and liver impairment, or coagulation abnormalities. However, systematic data on laboratory parameters under treatment with nusinersen are mainly available from studies in infants and children. Therefore, our aim was to assess the safety of nusinersen therapy in adult SMA patients. Methods Laboratory data from 404 nusinersen injections performed in 50 adult patients with SMA type 2 and type 3 were retrospectively analyzed. Results The total observation period was 76.9 patient-years, and patients received up to 12 injections. Our data provides no new safety concerns. In cerebrospinal fluid (CSF), the mean white blood cell count and lactate remained stable over time. Total CSF protein increased by 2.9 mg/dL. No change in mean platelet count was observed under therapy. Only one patient showed sporadic mild thrombocytopenia. Coagulation parameters and inflammatory markers were stable. The mean creatinine level decreased by 0.09 mg/dL. Analysis of mean liver enzyme levels revealed no relevant changes during treatment. Conclusion Our data demonstrate a favorable safety profile of nusinersen therapy in adult SMA patients under longer-term “real-world” conditions. 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.

Stability of serial platelet and urine protein measurements in patients receiving nusinersen for spinal muscular atrophy

“…It is unclear why a small positive effect was seen on platelet count in adults. Regardless, this work is consistent with recent studies showing mean platelet count does not decrease with therapy, and that instances of relative thrombocytopenia in patients receiving nusinersen have been transient 9,10 …”

“…Regardless, this work is consistent with recent studies showing mean platelet count does not decrease with therapy, and that instances of relative thrombocytopenia in patients receiving nusinersen have been transient. 9 In adult and pediatric patients, the degree of proteinuria did not increase with nusinersen treatment, supporting previous work that suggests nusinersen for SMA does not cause structural or glomerular damage that was seen in treatment of other diseases with other ASOs. 5 Because adverse effects are variable based on specific backbone chemistry of the drug, broad statements of renal toxicity cannot be made purely based on the ASO drug class, or even for a generation of ASOs.…”

Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy

“…We therefore hypothesize that CHIT1 dynamics under nusinersen treatment may occur as a response of nusinersen-exposed circulating monocytes in the CSF. In addition, we found a mild increase of Qalb and total protein during therapy (fitting to [32,33,49]), which underline the occurrence of a low unspecific inflammatory reaction following treatment initiation.…”

Nusinersen: A Review in 5q Spinal Muscular Atrophy

“…In nusinersen recipients, there were no cases of severe, sustained thrombocytopenia, no reports of glomerulonephritis, nephrotic syndrome or renal failure, and median alkaline phosphatase, ALT, AST, and direct and indirect bilirubin levels were stable over time [ 37 ]. According to a recent retrospective analysis of laboratory parameter data from 50 adults with 5q SMA type 2 or 3 receiving nusinersen, there was no evidence of clinically relevant thrombocytopenia, coagulopathies, or renal or hepatic toxicities [ 40 ].…”