An Integrated Safety Analysis of Infants and Children with Symptomatic Spinal Muscular Atrophy (SMA) Treated with Nusinersen in Seven Clinical Trials

Abstract

Background: Treatment with nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA).

Objective: The objective of this analysis was to characterize the safety of nusinersen across the clinical trial program in infants and children with symptomatic SMA.

Methods: An integrated safety analysis evaluated end of study data from seven completed clinical trials that enrolled infants and children with symptomatic SMA who were treated with intrathecal nusinersen or underwent sham procedures. Two of the studies were conducted in symptomatic infants with infantile-onset SMA (most likely to develop SMA type I or II) and the remaining five in symptomatic children and adolescents with later-onset SMA (have or are most likely to develop SMA type II or III). Safety assessments included incidence of adverse events (AEs), physical and neurological examinations, vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), and electrocardiograms.

Results: Data were analyzed from 323 infants and children, including 240 treated with nusinersen (100 with infantile-onset SMA and 140 with later-onset SMA) and 83 who underwent sham procedures (41 infantile-onset, 42 later-onset). Median (range) exposure to nusinersen was 449.0 (6-1538) days (375.9 participant-years). The most common AEs with nusinersen were pyrexia, upper respiratory tract infection, nasopharyngitis, vomiting, headache, and constipation. The incidence of serious AEs was lower with nusinersen than with the sham procedure (41% vs. 61%). The overall incidence of respiratory, thoracic, and mediastinal AEs was higher in participants with symptomatic infantile-onset SMA than those with symptomatic later-onset SMA and similar in nusinersen- versus sham procedure-treated participants. Rates of post-lumbar puncture syndrome and related events were higher with nusinersen versus sham procedure in later-onset SMA participants. No abnormal patterns or trends in laboratory test results were observed.

Conclusions: Nusinersen demonstrated a favorable safety profile in children with symptomatic infantile- and later-onset SMA. Most reported AEs and serious AEs were consistent with the nature and frequency of events typically seen with SMA or in the context of lumbar puncture procedures.

Registration: NCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.

Conflict of interest statement

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.

Figures

Fig. 1

Overview of the clinical studies used for the integrated analyses. SMA spinal muscular atrophy

Fig. 2

Median, minimum, and maximum platelet counts in nusinersen-treated and control participants from a ENDEAR and b CHERISH. Study visit day 2: nusinersen, n = 80; control, n = 40. LLN lower limit of normal, ULN upper limit of normal

Fig. 3

Median, minimum, and maximum creatinine levels in nusinersen-treated and control participants from a ENDEAR and b CHERISH. Study visit day 2: nusinersen, n = 81; control, n = 40. LLN lower limit of normal, ULN upper limit of normal