1 Introduction
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is characterized by progressive and often severe muscular atrophy and weakness [
1]. The disorder is one of the leading causes of infant mortality and is estimated to occur in 8.5–10.3 per 100,000 live births [
2‐
5]. SMA is caused by homozygous deletion or mutation in the survival motor neuron 1 (
SMN1) gene, resulting in decreased levels of SMN protein expression and degeneration of motor neurons in the anterior horn cells of the spinal cord and brain stem [
1,
6]. The homologous
SMN2 gene also codes for the SMN protein but fails to fully compensate for
SMN1 gene loss due to aberrant splicing, resulting in insufficient amounts of SMN protein [
1].
SMA has been broadly classified into four main phenotypes [
1]. In SMA type I, symptoms first appear at or before 6 months of age and can include severe generalized hypotonia, weakness of limbs and neck, areflexia, tongue fasciculations, abdominal paradoxical breathing, and respiratory failure [
1,
7]. Affected individuals never sit independently, require more intensive and supportive care than those with less severe forms of SMA, and generally have a lifespan of < 2 years if not treated [
1,
7]. Those with symptom onset after 6 months of age but before adulthood are considered to have later-onset SMA and are most likely to develop SMA type II or III, depending on the age of symptom onset and highest motor function achieved [
1,
7]. Children with SMA type II begin displaying symptoms at 7–18 months of age; these can include mild to moderate hypotonia, weakness, areflexia, and hand tremor. Children with SMA type II develop the ability to sit independently and may stand with support, but they are never able to walk independently and often develop significant restrictive lung disease [
1,
7,
8]. SMA type III symptoms emerge at > 18 months of age and are heterogeneous. Individuals with type III typically reach independent walking, but some require wheelchair assistance for mobility in childhood [
1,
7,
8]. The legs are often more severely affected than the arms [
1]. Type IV develops in adulthood and is the least severe form of SMA [
1]. Management of SMA, particularly the more severe forms, requires a multidisciplinary approach due to the nature of the symptoms. Most importantly, pulmonary support is frequently necessary in patients with type I and II SMA, as respiratory failure is the most common cause of mortality. Due to respiratory muscle weakness, patients are often unable to maintain a clear airway, require ventilatory support, and are at risk of pneumonia and other respiratory tract infections and respiratory distress [
1,
9,
10].
The historical SMA classifications described above are rapidly evolving with the advent of effective SMA treatment options. Nusinersen is an antisense oligonucleotide (ASO) that modifies the splicing of
SMN2 pre–messenger RNA, resulting in increased levels of full-length SMN protein [
11]. Treatment with nusinersen has demonstrated significant and clinically meaningful benefits on motor function in infants and children with SMA [
12‐
16]. The objective of this safety analysis is to characterize the safety of nusinersen across the clinical trial program in symptomatic infants and children with SMA.
4 Discussion
This safety analysis of data from seven clinical trials of nusinersen in more than 300 infants and children with symptomatic SMA showed that the rates and types of AEs reported in those treated with nusinersen were consistent with symptoms of SMA or the lumbar puncture procedure [
23‐
25,
27]. Incidences of respiratory illness were generally higher in the infantile-onset SMA groups (nusinersen-treated and control), who had more severe disease (SMA type I) than older children (later-onset; SMA type II or III). The relatively high rate of respiratory events was consistent with the natural history of SMA, as pulmonary disease represents the major cause of morbidity and mortality in individuals with SMA types I and II [
23]. In the ENDEAR study, respiratory-related events accounted for the majority of hospitalizations in both the nusinersen-treated and sham procedure–treated groups [
26]. All events that led to death occurred in the infantile-onset SMA group, but the overall incidence of such events was higher in control-treated infants compared with nusinersen-treated infants. Upon medical review by the site investigator and sponsor, the types of events leading to death were considered consistent with direct or indirect causes of death observed in the context of infantile-onset SMA. Participants in all studies received consistent standards of care including airway clearance and coughing assistance, respiratory support, and management of nutritional needs [
23]; specifically, greater utilization of pulmonary, gastrointestinal, and orthopedic consultants and dieticians may have occurred in this study than in routine clinical care. Additionally, vaccination rates may have been higher among participants from the included studies than in other SMA populations due to the standard of care guidelines. Thus, SMA disease-related events may be even further decreased in both the nusinersen and control arms compared with the general SMA community, where clinical care may be more varied than in the studies included in this analysis [
28‐
30].
PLPS-associated events, including headache, back pain, and vomiting, were more common in older participants (later-onset SMA) than in infants. This could be because the younger participants with infantile-onset SMA were not yet verbal and thus could not report these lumbar puncture–related symptoms. Incidences of events associated with PLPS have been shown to be more common in children ≥ 10 years old compared with those < 10 years old and are less common in children than adults [
24]. The overall rates of post-lumbar events when analyzed on a per-procedure basis (13% and 21% after 24 and 168 h, respectively) were comparable to rates of 16–27% for headache and 40% for back pain reported elsewhere in children who undergo lumbar puncture procedures [
24,
31]. None of the headaches reported in these patients were identified by the site investigator as an indication of increased intracranial pressure or hydrocephalus.
Mean weight for age percentile remained stable in nusinersen-treated infants from baseline to the day 394 assessment, while an increase in mean weight for age percentile over this time period was observed in control infants. The larger weight increase in control infants over the course of the study could be related to differences in caloric demands and motor function between groups. For instance, control infants may have reduced caloric demands with progressive weakness, compared with increasing caloric demands and motor function in those treated with nusinersen. Another explanation for the differences observed could be the challenge in estimating caloric requirements for both groups of infants. A larger percentage of control versus nusinersen-treated infants underwent gastrointestinal tube placement during the course of the study (41% vs. 30%). A gastrointestinal tube allows additional calories to be provided, even if not necessary. Mean length/height for age percentile decreased in nusinersen-treated infants and increased in control infants from baseline to the day 394 assessment. The mechanisms by which nusinersen could affect weight and height are not known. However, the differences in height between nusinersen-treated and control infants are most likely due to measurement challenges (e.g., hyptonia, contractures) or measurement errors. Infants with poor muscle tone would measure longer than those with more muscle tone whose limbs would not be fully extended during the measurement. Weight is closely linked to height, and overweight children are taller on average than non-overweight children [
32], indicating that the increased incidence of gastrointestinal tube placement to facilitate nutrition and feeding in the control group could also have led to the increased length gain in that group.
A range of toxicities associated with ASOs have been reported in human clinical trials and include increased aminotransferase levels (e.g., ALT and AST), proteinuria, and thrombocytopenia [
20,
33]. Although often referred to as class effects, these toxicities are only seen with a minority of ASOs tested in humans [
34‐
36]; they appear to result from the chemical structure of the ASOs and the individual nucleic acid sequence, are related to dose (i.e., systemic exposure), and are usually self-limiting after dosing is stopped [
20,
33,
37,
38]. In some cases they may represent a unique interaction between drug and disease [
37], and in other cases they may relate to the targeted pathway rather than to the ASO itself [
39,
40]. Renal and liver injury most likely occur due to accumulation with repeated doses [
38], because subcutaneously or intravenously administered ASOs bind to plasma proteins that are filtered at the glomerulus and then reabsorbed in the proximal tubule [
38,
41]. Proteinuria may be a sign of either glomerular or tubular toxicity [
38]. Although ASO-associated glomerulonephritis is uncommon, the presence of high molecular weight proteins or large increases of proteins in the urine may be indicative of glomerulonephritis [
38]. While thrombocytopenia has been one of the major concerns in the development of some ASO-based therapies, the underlying mechanism is still under investigation and may differ by severity and species [
38,
42‐
44].
In the current integrated safety analysis, there was no systemic evidence of the types of toxicities that have been reported with some ASOs, including thrombocytopenia and hepatic and renal impairment [
18‐
20]. This may be in part because nusinersen differs from other ASOs in its route of administration (intrathecal vs. subcutaneous or intravenous), dose, and dosing frequency; therefore, a lower level of systemic exposure is expected. No cases of severe, sustained thrombocytopenia were reported in nusinersen-treated participants. The US prescribing information recommends monitoring of urine protein concentration, platelet count, and coagulation at baseline and prior to each administration of nusinersen, and monitoring platelet counts and coagulation as clinically needed [
45]. Repeat testing and further evaluation is recommended for urine protein concentrations > 0.2 g/L. No imbalance in the incidence of AEs signifying possible liver dysfunction was noted between nusinersen-treated participants and those who received sham procedure, and none of these AEs were reported as serious; all events resolved. Median laboratory values of direct bilirubin, indirect bilirubin, alkaline phosphatase, ALT, and AST were similar between groups and remained stable over time. There were no reports of renal failure, glomerulonephritis, nephrotic syndrome, or other relevant renal toxicity in participants receiving nusinersen. The results reported here for shift to positive urinary protein are semi-quantitative and based on the definition of a result of ≥ 1 + on urine dipstick, which is approximately equivalent to levels of 0.3 g/L [
46]. The occurrence of proteinuria is similar to or lower than that reported previously [
45] and is not suggestive of renal toxicity, given the relative stability of blood urea nitrogen, creatinine, and cystatin C levels.
Preliminary safety data on nusinersen use in real-world clinical practice have been reported by several groups [
47‐
50]. In one report based on the experience from seven centers in Germany in children with infantile-onset SMA, SAEs were reported in 54.7% of treated children, severe AEs in 45.3%, and PLPS in 4.9% [
48]. The most frequently observed AEs across the reports were respiratory events, fever, headache, nausea, and vomiting [
47‐
50]. With the exception of a transient decrease in platelet count in one patient with mild thrombocytopenia at treatment initiation, there were no relevant changes in clinical laboratory values in 28 adults with SMA Type II or III treated with nusinersen [
49]. Although collection and reporting of safety parameters varied in the real-world reports, the safety profile of nusinersen observed in real-world clinical practice is consistent with that observed in the current integrated analysis of clinical study data.
There are limitations to this safety analysis. For data from ENDEAR and CHERISH, due to early study termination after positive interim analyses showing a benefit:risk profile favoring nusinersen [
12,
14], not all children were assessed up to the final visit date. Therefore, participants at final assessment may not be representative of the whole cohort. Some AEs requiring verbalization from the participant (e.g., back pain, headache) may not have been captured in children who were not yet able to speak (i.e., those with infantile-onset SMA). This analysis only covers safety data from clinical trials and does not address potential findings from the post-market setting. Finally, due to small population sizes, rare AEs may not have been captured. Infants and children included in this safety analysis had the option to enroll in SHINE, which is collecting long-term safety data in these SMA populations.
Compliance with Ethical Standards
Conflict of interest
Basil T. Darras has served on advisory boards for AveXis, Biogen, Cytokinetics, Dynacure, Genentech, PTC, Roche, and Sarepta; served on a speakers bureau for Biogen; received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, the SMA Foundation, and the Working on Walking Fund; received grants from Biogen, CureSMA, and Ionis Pharmaceuticals, Inc. during ENDEAR, CHERISH, CS2, CS11, and CS12; received grants from Cytokinetics, FibroGen, PTC, Roche, Santhera, Sarepta, and Summit; and has no personal financial interests in these companies. Michelle A. Farrar has received scientific advisory board honoraria from Biogen and Roche; is a principal investigator for ongoing AveXis and Biogen clinical trials; and has received funding from Motor Neuron Diseases Research Institute of Australia. Eugenio Mercuri has served on advisory boards for SMA studies for AveXis, Biogen, Ionis Pharmaceuticals, Inc., Novartis, and Roche; is a principal investigator for ongoing Ionis Pharmaceuticals, Inc./Biogen and Roche clinical trials; and has received funding from Famiglie SMA Italy, Italian Telethon, and SMA Europe. Richard S. Finkel has received grants and advisor fees from Biogen and Ionis Pharmaceuticals, Inc. during ENDEAR and CHERISH; received grants from AveXis, Cytokinetics, and Roche; served as an advisor to AveXis, Novartis, and Roche outside the submitted work; served in an advisory capacity to nonprofit organizations CureSMA, SMA Europe, the SMA Foundation, and SMA Reach (UK); and served on a data safety monitoring board for the AveXis AVXS-101 phase 1 gene transfer study and the Roche Moonfish phase 1b study; received fees for presentations at CME activities sponsored by AveXis and Biogen; and has received licensing fees from the Children’s Hospital of Philadelphia for co-creating the CHOP INTEND motor scale for SMA. Richard Foster is an employee of and stockholder in Biogen. Steven G. Hughes was an employee of and holds stock/stock options in Ionis Pharmaceuticals, Inc. He now consults for Ionis Pharmaceuticals, Inc. Ishir Bhan is an employee of and stockholder in Biogen. Wildon Farwell is an employee of and stockholder in Biogen. Sarah Gheuens is an employee of and stockholder in Biogen.