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

Abstract

BackgroundTreatment with nusinersen has demonstrated significant and clinically meaningful benefits in clinical trials in infants and children with spinal muscular atrophy (SMA).ObjectiveThe objective of this analysis was to characterize the safety of nusinersen across the clinical trial program in infants and children with symptomatic SMA.MethodsAn 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.ResultsData 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.ConclusionsNusinersen 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.RegistrationNCT01494701, NCT01703988, NCT01839656, NCT02193074, NCT02292537, NCT01780246, NCT02052791.Electronic supplementary materialThe online version of this article (10.1007/s40263-019-00656-w) contains supplementary material, which is available to authorized users.

Targeting Alternative Splicing as a Potential Therapy for Episodic Ataxia Type 2

“…Following these results, nusinersen, a 2 -O-methyl-modified ribose AON with a full-length phosphorothioate backbone (2 OMePS), which increases the inclusion of exon 7 in the SMN2 mRNA, has been delivered in patients using intrathecal injections. These clinical trials indicated that the drug is generally well tolerated and effective in alleviating SMA symptoms and improving motor functions [95][96][97][98][99]. In addition, investigations of neuronal tissue in treated deceased patients have revealed a two-to six-fold increase in SMN2 transcripts containing exon 7, as well as an increase in SMN protein, as compared to untreated patients [100].…”

Delivery of oligonucleotides to bone marrow to modulate ferrochelatase splicing in a mouse model of Erythropoietic Protoporphyria

“…We scanned regions on the FECH pre-mRNA close to the c.315-48 polymorphism (Fig 2a; sequences in Supplementary Information) for splice-switching activity by using a set of sequence-overlapping 19nt MOE-PS oligonucleotides. We elected to use MOE-PS SSOs because of their successful use in clinical programs (www.ionispharma.com) (33), their excellent safety record (33,34), their efficient distribution in vivo (16), the ease with which they can be elaborated with targeting groups or stereopure linkages (29). We employed a mini-gene assay transiently expressing the FECH-C variant in COS-7 cells, which we have described previously (21).…”

Nusinersen w leczeniu rdzeniowego zaniku mięśni

“…Analizowane dane, z wyłączeniem badań NURTURE i EMBRA-CE, pochodzą od 323 pacjentów, włączając 240 leczonych nusinersenem (100 pacjentów z postacią niemowlęcą -typ I i 140 pacjentów z postacią późniejszą, głównie typ II), jak również 83 pacjentów z grupy leczenia pozorowanego, którzy po zamknięciu randomizowanych, zaślepionych badań przeszli do otwartego przedłużonego badania SHINE i rozpoczęli aktywne leczenie. Mediana ekspozycji na lek wyniosła 449 (zakres 6-1538) dni [26]. Pacjenci z badania NURTURE (n=25) z obiecującymi pierwszymi wynikami analiz częściowych dotyczących przeżycia, braku wymogu włączenia przewlekłej wentylacji i rozwoju ruchowego, wciąż kontynuują badanie i nie są jeszcze dostępne pełnotekstowe analizy badania [14].…”

“…Kryteriami włączenia do badania było wystąpienie pierwszych objawów choroby pomiędzy trzecim tygodniem a szóstym miesiącem życia, w wieku do siódmego miesiąca życia w momencie włączenia do badania. Pacjenci w badaniu CS3A (n=20) otrzymywali trzy dawki po 6mg a następnie dziewięć dawek (n=4) po 12 mg lub dwanaście dawek po 12 mg (n=16), a okres obserwacji wynosił 1352 dni [23,26]. Większość pacjentów analizowanych w badaniu CS3A z grupy 12 mg uzyskała zadowalające wyniki w obszarze przeżycia i braku konieczności stosowania stałej wentylacji (p=0.0014), w zakresie uzyskania nowych kamieni milowych rozwoju ruchowego w oparciu o skalę HINE (p<0.0001) i oceny funkcji ruchowych według skali CHOP INTEND (p=0.0013).…”

“…Najczęstszym działaniem niepożądanym w grupie leczonej nusinersenem była tachykardia na poziomie 6% (15/240). W grupie kontrolnej tachykardia raportowana była łącznie u 8% (7/83) pacjentów [26].…”