The Efficacy, Safety, and Pharmacokinetics of Nusinersen for Treatment

on Spinal Muscular Atrophy Children: A Systematic Review

Maxwell Salvador Surya Atmaja, Fan Maitri Aldian, Melissa Valentina Ariyanto

INTRODUCTION RESULTS AND DISCUSSIONS

Spinal Muscular Atrophy (SMA) is an autosomal recessive disease that causes degeneration of Table 1. Characteristics of the Included Studies
motor neurons in the spinal cord and brainstem. SMA occurs in every population with a preva- Author Location Study Sample Population Age Symptom Age 1st Therapy Intervention Regimen (Dose) Diagnostic Quality
and Year Design Characteristic [Median (Range)] [Median (Range)] Criteria Assesment
lence of about one in every 6,000 to 10,000 births. SMA's cause is a deletion on chromosome Aragon-
Patients older than 7
Gawinska Mean (range) Mean (range) Genetic
5q11.2-5q13.3 that causes the loss of SMN1 exon 7 (Claborn et al., 2018). SMA patients do not have et al.,
USA Cohort months with SMA 33(15)
4 (1.5-6) 21.3 (8.3-113.1)
Nusinersen N/A
Testing
6/9
type 1
SMN 1, but some may have several SMN 2 that act similarly to SMN 1, yet SMA 2 has a lower per- 2018
Case
formance. SMA is classified into five types based on the number of SMN2 gene copies and related Wurster 1.0 (10.5-48.0) 34.0 (11.0-60.0) Nusinersen Intrathecal(N/A)
Case SMA patients at the 25(11) Genetic
et al., Germany 6/9
Control MND - NET Control Testing
with the age of symptoms, one type with prenatal onset (SMA 0), three types with pediatric-onset 2019
25(N/A)
N/A 36.0 (18.0-65.0) N/A Control

(SMA I–III) and one adult-type have been identified (SMA IV). Treatment for SMA is limited, while Pechmann
Children with SMA Mean (range) Mean (range) Intrathecal Genetic
et al., Germany Cohort 61 (30) Nusinersen 7/9
type 1 within the EAP 2.78 (0-6) 21.08 (1-93) (12 mg) Testing
at the same time, SMA is a severe disease that can cause the sufferer to be unable to walk, hypoto- 2018
Case 1 Intrathecal
nia, facial diplegia, areflexia, and respiratory failure (Darras, 2015). Nusinersen is a modified antisense Finkel et RCT
Patiens aged between
4(1) Mean (range) Mean (range)
Nusinersen
(6mg, 12mg) Genetic
USA 3 weeks and 7 months 4/5
oligonucleotide that binds to SMN2. Nusinersen showed a high enough potency clinical trials phase al., 2016 (Blinded) Case 2 2 (0.7-5.1) 4.7 (1.2-7) Intrathecal Testing
old Nusinersen
9(7) (12mg)
targeted to increase evaluated measures like efficacy, safety, and pharmacokinetics, so it has the po- RCT
Case Mean (range) Mean (range)
Nusinersen
Intrathecal
Finkel et USA, Patients at 6 months 80(43) 2 (0.5 - 4.5) 5.4 (1.7 - 8.0) (12mg) Genetic
tential to result in a positive result for SMA treatment (Finkel et al., 2017). This study aims to prove al., 2017 Canada
(Double
of age or younger Control Mean (range) Mean (range) SHAM Testing
3/5
Blinded) N/A
41(24) 9.6 (1-20) 181 (30 - 262) Procedure
the efficacy, safety, and pharmacokinetics of nusinersen for spinal muscular atrophy treatment, Case Mean Intrathecal
7.0 (0 – 60) Nusinersen
especially for children. Darras et
USA
Case
General Population
100(51) 41.1 (9mg, 12mg) Genetic
7/9
al., 2019 Control Control Mean Testing
6.0 (0 – 20) Control N/A
100(24) 26.4

MATERIALS AND METHODS Pera et

al., 2021
US,
Italy,
UK
Cohort
type
patients
III SMA
77(N/A) 9.50 (5.50–13.43) N/A Nusinersen
Intrathecal
(N/A)
Genetic
Testing
7/9

Literature research based on digital data conduct- Case Intrathecal

ed in PubMed, ScienceDirect, and Cochrane using Systematic review based on PRISMA Statement 14(5)
5.5 (2.0 - 11.0) 10.0 (6.9 - 15.0) Nusinersen
(12mg)
Acsadi et Infantile and later Genetic
USA RCT SHAM Control, 3/5
keyword ("spinal muscular atrophy") AND ("nusin- al., 2021 onset SMA patients Control Testing
5.1 (1.8 - 11.0) 5.5 (2.0 - 11.0) Procedure, Intrathecal
7(5)
Nusinersen (12mg)
ersen" OR "Spinraza") AND ("child" OR "infant" Case 1 Mean ± SD Mean ± SD Intrathecal
Nusinersen
OR "pediatric") AND ("treatment"). For quality as- Finkel et USA,
Cohort
Patients ages between 4(1) 1.6 ± 0.63 4.8 ± 2.2 (6mg, 12mg) Genetic
6/9
Screening literature based on inclusion al., 2021 Canada 3 weeks and 6 months Case 2 Mean ± SD Mean ± SD Intrathecal Testing
sessment, we use Newcastle-Ottawa Scale (NOS) Nusinersen
and exclusion criteria 16(7) 2.16 ± 1.25 4.6 ± 1.9 (12mg)
Case Intrathecal
for cohort with case control and Jadad Scale for Mercuri RCT SMA patients who
84(46)
10.0 (6 - 20) 18.0 (0 − 48) Nusinersen
(12mg) Genetic
et al., England (Double had symptom onset 3/5
RCT (Randomized Clinical Trials). The inclusion Control SHAM Testing
2018 Blinded) after 6 months of age. 11.0 (6 - 20) 18.0 (0 − 48) Control
42(21) Procedure
and exclusion criteria are: Chiriboga Patients with type 2 Current Age Intrathecal
Genetic
Find and collect all required data et al., USA Cohort
and type 3 SMA aged 28(17) [Mean(min-max)] N/A Nusinersen (5ml) 8/9
1. Inclusion Criteria : Testing
2016 2-14 years 6.1 (2 - 14)
Nusinersen treatment for Spinal SMA patients in
Szabó et Hungary between Mean (min - max) Intrathecal Genetic
Muscular Atrophy (SMA) al., 2020
Hungary Cohort
April 2018 and
54(20) N/A
75.6 (4.8 - 214.8)
Nusinersen
(N/A) Testing
6/9
Efficacy, safety or pharmacokinetic December 2019
of nusinersen Quality assessment based on RCT, Randomized Clinical Trials; EAP, Employee Assistance Program; SMA, Spinal Muscular Atrophy
Newcastle-Ottawa Scale (NOS) & Jadad Scale
2. Exclusion Criteria :
No full text available The characteristics of twelve included studies were Author and Outcomes
Year Case Type Results
Not written in English demonstrated in Table 1. There were clinical trials Aragon- Nusinersen CHOP-INTEND score increase from 31.5 to 35 (p=0.0001)
Age > 18 years Total sample in 12 included studies : 804 and observational studies in this systematic review, Gawinska et al., HINE-2 score increase from 1 to 3.5 (p=0.000)
Irrelevant study or outcomes (589 for intervention and 215 for control) and all of the studies yielded 804 samples in total 2018
Pechmann et Nusinersen (12 mg) CHOP-INTEND score improves 9.0±8.0 points (p=0.0006)
Review, case report, letter to editor (589 for intervention and 215 for control). al., 2018 HINE-2 score increase 1,4±2 points (p=0.015)
Figure 1. Conceptual Framework Nusinersen has to reach the motor neurons within Finkel et al., Nusinersen (6mg, 12mg) CHOP-INTEND score improves 11.5 points in 2/4 patients (p=0.008)
2016 HINE-2 score improves in ¼ patients (p=0.0002)
the spinal cord to work optimally. The spinal cord Peroneal CMAP increase 742% or 1.56mV (p<0.0001)
and brain make up the central nervous system Ulnar CMAP increase 377% or 0.62mV (p=0.0103)
(CNS), but nusinersen will not cross the blood-brain Nusinersen (12mg) CHOP-INTEND score improves 11.5 points in 12/14 patients (p=0.008)
HINE-2 score improves in 15/15 patients (p<0.0001)
barrier if injected intravenously or subcutaneously. Peroneal CMAP increase 742% or 1.56Mv (p<0.0001)
Identification of studies via databases and registers The only way nusinersen can reach the CNS is to Ulnar CMAP increase 377% or 0.62mV (p=0.0103)
Finkel et al., Nusinersen (12 mg) Improvement of CHOP-INTEND score 26.63 points in 71% patients (p=0.004)
use an intrathecal injection directly into the cerebro- 2017 Improvement of HINE-2 score 1.29 points in 51% patients (p=0.005)
spinal fluid (CSF) using a lumbar puncture proce- Improvement of Peroneal CMAP 0.371 mV
dure. A series of loading doses are administered to Improvement of Ulnar CMAP 0.226 mV
Records removed before get the level of the drug to an effective concentra-
SHAM Procedure Improvement of CHOP-INTEND score 28.43 points in 3% patients (p=0.004)
HINE-2 response in 0% patients (p=0.005)
Identification

Records identified from: screening: tion for the patient (Mercuri et al., 2018). Nusiners- Improvement of Peroneal CMAP 0.317mV
Database (n = 677) : Records marked as ineligible en cleared from the CSF into the systemic circula- Pera et al., 2021 Nusinersen
Improvement of Ulnar CMAP 0.225mV
HFMSE Increase 1.18 points in 104/144 patients (p=0.0004)
Pubmed (n = 230) by automation tools (n = 306) tion with dose-dependent mean peak plasma con- Acsadi et al., Nusinersen (6mg, 12mg) HINE-2 improves (Mean±SD) 7.6 ± 5.4 in 79% patients
2021 Control HINE-2 improves (Mean±SD) 5.9 ± 4.5 in 29% patients
Science Direct (n = 418) Duplicate records removed centrations observed about one hour after dosing Nusinersen (12mg) HINE-2 improves (Mean±SD) 6.7 ± 5.0 in 29% patients
Cochrane Library (n= 29) (n = 51) and declining over 24 hours. Nusinersen confirmed Mercuri et al., Nusinersen HFMSE Increase 4.0 (2.9-5.1) (p<0.001)
localization in neurons, vascular endothelial cells, 2018 Control HFMSE Change –1.9 (–3.8-0) (p<0.001)
Szabó et al., Nusinersen Improvement of CHOP-INTEND score 14.9±5.1 points (p=0.016)
and glial cells throughout the CNS through the im- 2020 Improvement of HFMSE score 7.2±5.0 (p<0.001)
munohistochemical staining method. After intrathe- CHOP-INTEND, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE-2, Hammersmith Infant
Neurological Examination; HFMSE, Hammersmith Functional Motor Scale-Expanded; CMAP, Compound Muscle Action
cal dosing, nusinersen plasma concentrations de- Potentials; SMA, Spinal Muscular Atrophy.
clined slowly for 20 hours, followed by a slower
period of decline over the next seven days, which Figure 3. Efficacy of Nusinersen in SMA children patients
Records excluded concentrations in the 6-mg cohort had decreased to
Records screened
Irrelevant Title (n = 159) below 1 ng/mL and to 1% of the 20- hour AE (Adverse Event) Summary [n (%)] SAE
(n = 320) post-dose concentration in the 9-mg cohort. At the
Irrelevant Abstract (n = 50) (Serious
9- to 14- month post-dose evaluation, CSF nusin- Author Adverse
n Respiratory
and Year Pyrexia Vomiting Pneumonia Cough Event)
ersen concentrations were still measurable (Chiribo- Infection
Summary
ga et al., 2016). In pharmacodynamics, infants ex- [n (%)]
posed to nusinersen had an apparent growth in Chiriboga
SMN protein staining in thoracic cord motor neu- 28 11 (5) 14 (4) 11 (3) N/A N/A 0 (0)
Reports sought for retrieval Reports not retrieved rons, with 50–69% of the SMN2 transcripts con-
et al., 2016
(n = 111) No Full-Text Available (n = 24) Darras et
Screening

taining exon seven were found, which resulted in a 240 90 (38) 114 (48) 58 (24) 40 (17) 43 (18) N/A
2.6 times increase in full-length SMN2 transcripts al., 2019
compared with untreated infants with spinal muscu- Finkel et
20 14 (70) 14 (70) 8 (40) 7 (35) 6 (30) 16 (80)
lar atrophy (Finkel et al., 2016). al., 2021
As seen in Figure 3, based on five studies that Mercuri et
Reports assessed for eligibility Reports excluded: analyzed CHOP-INTEND and HFMSE scores in their al., 2018
84 25 (30) 36 (43) 24 (29) 2 (2) 21 (25) 14 (17)

(n = 87) Not Using English (n=2) studies, all of the studies showed an increase in Pechmann
Age > 18 Years Old (n=8) CHOP-INTEND and HFMSE scores for treatment by 61 31 (58.5) N/A N/A N/A N/A 29 (54.7)
et al., 2018
No Outcome of Interest (n=41) Nusinersen in SMA children patients. Finkel, et al.
Review (n=16) 2017 showed a significantly higher percentage of Figure 4. Safety of Nusinersen in SMA children patients
Case Report (n=6) infants in the nusinersen group who had CHOP-INTEND response than in the control group. A Higher CHOP-INTEND and
Letter to Editor (n=2) HFMSE score equal better motor function also assesses activities related to daily living (O’Hagen et al., 2007). The HINE-2
outcome marks a test of overall neurological function originally developed for normal infants, and in included studies that dis-
cuss HINE-2 score, showed that HINE-2 score will increase after treatment by Nusinersen for SMA patients. Mean HINE-2
score after six months of treatment was 2.5 ± 3.3 with a mean improvement of 1.4 ± 2.1 points (Pechmann et al., 2018).
Studies included in review
Included

CMAP is Electrophysiological testing of the ulnar or peroneal nerve as indicators of motor neuron health (Swoboda KJ, et
(n = 12) al. 2005). The increase in the CHOP INTEND score and the CMAP amplitude among infants who received nusinersen con-
Reports of included studies firms that nusinersen improves neuromuscular function (Finkel et al., 2017). Other than that, Nusinersen was approved by
(n = 12) Food and Drug Administration (FDA) for the first treatment of Spinal Muscular Atrophy (SMA) on December 23, 2016
because based on the clinical trial, patients who were treated with Nusinersen can improve their motor milestones, such as
head control, sitting, standing, walking, and kick in a supine position, while no one of the control patients did. (FDA, 2016).
Figure 2. PRISMA Diagram Flowchart
As seen in Figure 4, based on the five studies above, we conclude that most of the patients experienced AEs and a few of
them suffer SAE but only Darras, et al. (2019) didn’t mention SAE in their study. Based on the data, there are only 59 from
193 patients (30.57%) that suffer SAE. Moreover, Chiriboga, et al. 2016 mentioned that there were no serious AEs during the

CONCLUSION study and no patient experienced an AE causing discontinuation.

This study is the first systematic review that discusses the efficacy, safety, and pharmacokinetics of nusinersen for Spinal
Nusinersen injection showed improvement in motor function, motor milestones, and motor Muscular Atrophy children in sufficient sample size and Nusinersen was approved for use in all SMA patients, across the
neuron health for spinal muscular atrophy children but Nusinersen caused some AEs. The most different types. However, the limitation of this study is that nusinersen hasn’t spread all over the world and repeated in-
common AE found is respiratory infection, especially in the upper respiratory tract. However, trathecal delivery is required, thought to be very invasive and challenging, especially in young and fragile infants but
with the considerable table of study, Nusinersen is good in pharmacokinetics. the trials show that this is well tolerated.

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