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

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

Outcome and survival of asymptomatic PML in natalizumab-treated MS patients

OBJECTIVE: As of 3 September 2013, 399 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) were confirmed in multiple sclerosis (MS) patients. We evaluated outcomes of natalizumab-treated MS patients who were asymptomatic at PML diagnosis. METHODS: Analyses included data available as of 5 June 2013. Asymptomatic patients diagnosed with PML by magnetic resonance imaging (MRI) findings and JC virus DNA detection in the central nervous system were compared with patients presenting with symptoms at diagnosis. Demographics, MRI, and survival over 12 months were analyzed. Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were recorded pre-PML, at diagnosis, and at 6 and 12 months post-diagnosis. RESULTS: A total of 372 PML cases were analyzed; 30 patients were asymptomatic and 342 were symptomatic at PML diagnosis. Classifications of PML lesions on MRI in asymptomatic versus symptomatic patients were unilobar in 68% versus 37%, multilobar in 21% versus 24%, and widespread in 11% versus 40%. In both groups with unilobar lesions, frontal lobe lesions predominated. Prior to PML, mean EDSS and KPS scores were similar for asymptomatic and symptomatic patients. At diagnosis, mean EDSS score was significantly lower for asymptomatic patients (4.1; n = 11) than for symptomatic patients (5.4; n = 193; P = 0.038). Six months after PML diagnosis, asymptomatic patients had less functional disability than symptomatic patients. As of 5 June 2013, 96.7% of asymptomatic patients and 75.4% of symptomatic patients were alive. INTERPRETATION: PML patients asymptomatic at diagnosis had better survival and less functional disability than those who were symptomatic at diagnosis