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Clinical Trial
. 2016 Mar 8;86(10):890-7.
doi: 10.1212/WNL.0000000000002445. Epub 2016 Feb 10.

Results From a Phase 1 Study of Nusinersen (ISIS-SMN(Rx)) in Children With Spinal Muscular Atrophy

Free PMC article
Clinical Trial

Results From a Phase 1 Study of Nusinersen (ISIS-SMN(Rx)) in Children With Spinal Muscular Atrophy

Claudia A Chiriboga et al. Neurology. .
Free PMC article


Objective: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA).

Methods: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory.

Results: A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study.

Conclusions: Results from this study support continued development of nusinersen for treatment of SMA.

Classification of evidence: This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.


Figure 1
Figure 1. Mechanism of action of nusinersen
Nusinersen is a 2′-O-(2-methoxyethyl) modified ASO drug designed to target an hnRNP-A1/A2–dependent splicing silencer, ISS-N1, in intron 7 of the SMN pre-mRNA. Nusinersen displaces hnRNP proteins from the ISS-N1 site on the SMN2 pre-mRNA, facilitating accurate splicing of SMN2 transcripts (e.g., increasing the synthesis of transcripts containing exon 7) and resulting in increased production of full-length SMN protein. ASO = antisense oligonucleotide; hnRNP = heterogenous nuclear ribonucleoprotein; ISS = intronic splicing silencer; mRNA = messenger RNA; SMA = spinal muscular atrophy; SMN = survival of motor neuron.
Figure 2
Figure 2. CSF and plasma concentrations of nusinersen
Measured nusinersen concentrations for each dose group are shown. (A) CSF at 7 days postdose. (B) Plasma over 24 hours (all groups) or 7 days (6- and 9-mg groups) postdose (mean ± SEM). As anticipated, plasma levels were below the limit of detection of the assay at day 8 postdose.
Figure 3
Figure 3. Changes in Hammersmith Functional Motor Scale Expanded (HFMSE) scores by treatment assignment
(A) Individual change in HFMSE score from baseline for all participants. (B) Mean change in HFMSE score from baseline in participants followed through 9–14 months postdose. Bars represent mean ± SEM for each dose group. BL = baseline.

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