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

Table 1. Characteristics of the Included Studies
Spinal Muscular Atrophy (SMA) is an autosomal recessive disease that causes degeneration of motor Author Location Study Sample Population Age Symptom Age 1st Therapy Intervention Regimen (Dose) Diagnostic Quality
neurons in the spinal cord and brainstem. SMA occurs in every population with a prevalence of about and Year Design Characteristic [Median (Range)] [Median (Range)] Criteria Assesment
Aragon-
one in every 6,000 to 10,000 births. SMA's cause is a deletion on chromosome 5q11.2-5q13.3 that Gawinska
USA Cohort
Patients older than 7
months with SMA 33(15)
Mean (range) Mean (range)
Nusinersen N/A
Genetic
6/9
et al., 4 (1.5-6) 21.3 (8.3-113.1) Testing
causes the loss of SMN1 exon 7 (Claborn et al., 2018). SMA patients do not have SMN 1, but some may 2018
type 1

have several SMN 2 that act similarly to SMN 1, yet SMA 2 has a lower performance. SMA is Wurster
Case
1.0 (10.5-48.0) 34.0 (11.0-60.0) Nusinersen Intrathecal(N/A)
Case SMA patients at the 25(11) Genetic
classified into five types based on the number of SMN2 gene copies and related with the age of et al.,
2019
Germany
Control MND - NET Control
N/A 36.0 (18.0-65.0) N/A Control
Testing
6/9
25(N/A)
symptoms, one type with prenatal onset (SMA 0), three types with pediatric-onset (SMA I–III) and one Pechmann
Children with SMA Mean (range) Mean (range) Intrathecal Genetic
adult-type have been identified (SMA IV). Treatment for SMA is limited, while at the same time, SMA et al., Germany Cohort
type 1 within the EAP
61 (30)
2.78 (0-6) 21.08 (1-93)
Nusinersen
(12 mg) Testing
7/9
2018
is a severe disease that can cause the sufferer to be unable to walk, hypotonia, facial diplegia, areflexia,
L
Case 1 Intrathecal
Patiens aged between Nusinersen
Finkel et RCT 4(1) Mean (range) Mean (range) (6mg, 12mg) Genetic
and respiratory failure (Darras, 2015). Nusinersen is a modified antisense oligonucleotide that binds to al., 2016
USA
(Blinded)
3 weeks and 7 months
Case 2 2 (0.7-5.1) 4.7 (1.2-7) Intrathecal Testing
4/5
old Nusinersen
SMN2. Nusinersen showed a high enough potency clinical trials phase targeted to increase evaluated 9(7) (12mg)
Case Mean (range) Mean (range) Intrathecal
measures like efficacy, safety, and pharmacokinetics, so it has the potential to result in a positive result Finkel et USA,
RCT
Patients at 6 months 80(43) 2 (0.5 - 4.5) 5.4 (1.7 - 8.0)
Nusinersen
(12mg) Genetic
(Double 3/5
for SMA treatment (Finkel et al., 2017). This study aims to prove the efficacy, safety, and pharmacokinetics al., 2017 Canada
Blinded)
of age or younger Control
41(24)
Mean (range)
9.6 (1-20)
Mean (range)
181 (30 - 262)
SHAM
Procedure
N/A
Testing

of nusinersen for spinal muscular atrophy treatment, especially for children. Case
7.0 (0 – 60)
Mean
Nusinersen
Intrathecal
Darras et Case 100(51) 41.1 (9mg, 12mg) Genetic
USA General Population 7/9
al., 2019 Control Control Mean Testing
6.0 (0 – 20) Control N/A
100(24) 26.4

US,
Pera et type III SMA Intrathecal Genetic
Italy, Cohort 77(N/A) 9.50 (5.50–13.43) N/A Nusinersen 7/9

MATERIALS AND METHODS

al., 2021 patients (N/A) Testing
UK

Case Intrathecal
5.5 (2.0 - 11.0) 10.0 (6.9 - 15.0) Nusinersen
Literature research based on digital data conducted Acsadi et Infantile and later
14(5) (12mg)
Genetic
in PubMed, ScienceDirect, and Cochrane using Systematic review based on PRISMA Statement al., 2021
USA RCT
onset SMA patients Control
SHAM Control,
Testing
3/5
5.1 (1.8 - 11.0) 5.5 (2.0 - 11.0) Procedure, Intrathecal
7(5)
Nusinersen (12mg)
keyword ("spinal muscular atrophy") AND Case 1 Mean ± SD Mean ± SD Intrathecal
Nusinersen
("nusinersen" OR "Spinraza") AND ("child" OR Finkel et USA,
Cohort
Patients ages between 4(1) 1.6 ± 0.63 4.8 ± 2.2 (6mg, 12mg) Genetic
6/9
al., 2021 Canada 3 weeks and 6 months Case 2 Mean ± SD Mean ± SD Intrathecal Testing
"infant" OR "pediatric") AND ("treatment"). For 16(7) 2.16 ± 1.25 4.6 ± 1.9
Nusinersen
(12mg)
Screening literature based on inclusion
quality assessment, we use Newcastle-Ottawa and exclusion criteria Mercuri RCT SMA patients who
Case
84(46)
10.0 (6 - 20) 18.0 (0 − 48) Nusinersen
Intrathecal
(12mg) Genetic
et al., England (Double had symptom onset 3/5
Scale (NOS) for cohort with case control and 2018 Blinded) after 6 months of age.
Control
11.0 (6 - 20) 18.0 (0 − 48)
SHAM
Control
Testing
42(21) Procedure
Jadad Scale for RCT (Randomized Clinical Trials). Chiriboga Patients with type 2 Current Age Intrathecal
Genetic
The inclusion and exclusion criteria are: et al.,
2016
USA Cohort
and type 3 SMA aged
2-14 years
28(17) [Mean(min-max)]
6.1 (2 - 14)
N/A Nusinersen (5ml)
Testing
8/9

1. Inclusion Criteria : Find and collect all required data SMA patients in
Szabó et Hungary between Mean (min - max) Intrathecal Genetic
Nusinersen treatment for Spinal al., 2020
Hungary Cohort
April 2018 and
54(20) N/A
75.6 (4.8 - 214.8)
Nusinersen
(N/A) Testing
6/9
December 2019
Muscular Atrophy (SMA)
RCT, Randomized Clinical Trials; EAP, Employee Assistance Program; SMA, Spinal Muscular Atrophy
Efficacy, safety or pharmacokinetic
of nusinersen Quality assessment based on The characteristics of twelve included studies Author and Outcomes
Newcastle-Ottawa Scale (NOS) & Jadad Scale Year Case Type Results
2. Exclusion Criteria : were demonstrated in. Table 1. There were Aragon- Nusinersen CHOP-INTEND score increase from 31.5 to 35 (p=0.0001)
clinical trials and observational studies in this Gawinska et al., HINE-2 score increase from 1 to 3.5 (p=0.000)
No full text available
systematic review, and all of the studies yielded 2018
Not written in English 804 samples in total (589 for intervention and
Pechmann et Nusinersen (12 mg) CHOP-INTEND score improves 9.0±8.0 points (p=0.0006)
al., 2018 HINE-2 score increase 1,4±2 points (p=0.015)
Age > 18 years Total sample in 12 included studies : 804 215 for control). Nusinersen has to reach the Finkel et al., Nusinersen (6mg, 12mg) CHOP-INTEND score improves 11.5 points in 2/4 patients (p=0.008)
Irrelevant study or outcomes (589Figure 1. Conceptual
for intervention Framework
and 215 for control) motor neurons within the spinal cord to work 2016 HINE-2 score improves in ¼ patients (p=0.0002)
Peroneal CMAP increase 742% or 1.56mV (p<0.0001)
Review, case report, letter to editor optimally. The spinal cord and brain make up Ulnar CMAP increase 377% or 0.62mV (p=0.0103)
the central nervous system (CNS), but 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)
nusinersen will not cross the blood-brain barrier Peroneal CMAP increase 742% or 1.56Mv (p<0.0001)
if injected intravenously or subcutaneously. The 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)
only way nusinersen can reach the CNS is to 2017 Improvement of HINE-2 score 1.29 points in 51% patients (p=0.005)
use an intrathecal injection directly into the Improvement of Peroneal CMAP 0.371 mV
Improvement of Ulnar CMAP 0.226 mV
Identification of studies via databases and registers cerebrospinal fluid (CSF) using a lumbar SHAM Procedure Improvement of CHOP-INTEND score 28.43 points in 3% patients (p=0.004)
puncture procedure. A series of loading doses HINE-2 response in 0% patients (p=0.005)
are administered to get the level of the drug to Improvement of Peroneal CMAP 0.317mV
Improvement of Ulnar CMAP 0.225mV
an effective concentration for the patient Pera et al., 2021 Nusinersen HFMSE Increase 1.18 points in 104/144 patients (p=0.0004)
Records removed before (Mercuri et al., 2018). Nusinersen cleared from Acsadi et al., Nusinersen (6mg, 12mg) HINE-2 improves (Mean±SD) 7.6 ± 5.4 in 79% patients
Identification

Records identified from: screening: the CSF into the systemic circulation with
2021 Control HINE-2 improves (Mean±SD) 5.9 ± 4.5 in 29% patients
Nusinersen (12mg) HINE-2 improves (Mean±SD) 6.7 ± 5.0 in 29% patients
Database (n = 677) : Records marked as ineligible dose-dependent mean peak plasma Mercuri et al., Nusinersen HFMSE Increase 4.0 (2.9-5.1) (p<0.001)
Pubmed (n = 230) by automation tools (n = 306) 2018 Control HFMSE Change –1.9 (–3.8-0) (p<0.001)
concentrations observed about one hour Szabó et al., Nusinersen Improvement of CHOP-INTEND score 14.9±5.1 points (p=0.016)
Science Direct (n = 418) Duplicate records removed
after dosing and declining over 24 hours. 2020 Improvement of HFMSE score 7.2±5.0 (p<0.001)
Cochrane Library (n= 29) (n = 51) CHOP-INTEND, Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders; HINE-2, Hammersmith Infant
Nusinersen confirmed localization in neurons, Neurological Examination; HFMSE, Hammersmith Functional Motor Scale-Expanded; CMAP, Compound Muscle Action
vascular endothelial cells, and glial cells Potentials; SMA, Spinal Muscular Atrophy.

throughout the CNS through the immunohis- Figure 3. Efficacy of Nusinersen in SMA children patients
tochemical staining method. After intrathecal
dosing, nusinersen plasma concentrations AE (Adverse Event) Summary [n (%)] SAE
(Serious
Records excluded declined slowly for 20 hours, followed by a
Author Adverse
Records screened slower period of decline over the next seven n Respiratory
Irrelevant Title (n = 159) and Year Pyrexia Vomiting Pneumonia Cough Event)
(n = 320) days, which concentrations in the 6-mg Infection
Summary
Irrelevant Abstract (n = 50)
cohort had decreased to below 1 ng/mL and [n (%)]
Chiriboga
to 1% of the 20 hour post-dose concentration 28 11 (5) 14 (4) 11 (3) N/A N/A 0 (0)
in the 9-mg cohort. At the 9- to 14- month et al., 2016
post-dose evaluation, CSF nusinersen Darras et
240 90 (38) 114 (48) 58 (24) 40 (17) 43 (18) N/A
Reports sought for retrieval Reports not retrieved concentrations were still measurable al., 2019
(n = 111) No Full-Text Available (n = 24) (Chiriboga et al., 2016). In pharmacodynamics,
Screening

Finkel et
infants exposed to nusinersen had an 20 14 (70) 14 (70) 8 (40) 7 (35) 6 (30) 16 (80)
al., 2021
apparent growth in SMN protein staining in
Mercuri et
thoracic cord motor neurons, with 50–69% 84 25 (30) 36 (43) 24 (29) 2 (2) 21 (25) 14 (17)
of the SMN2 transcripts containing exon al., 2018
Reports assessed for eligibility Reports excluded: seven were found, which resulted in a 2.6 Pechmann
Not Using English (n=2) 61 31 (58.5) N/A N/A N/A N/A 29 (54.7)
(n = 87) times increase in full-length SMN2 transcripts et al., 2018
Age > 18 Years Old (n=8) compared with untreated infants with spinal
No Outcome of Interest (n=41) Figure 4. Safety of Nusinersen in SMA children patients
muscular atrophy (Finkel et al., 2016).
Review (n=16)
Case Report (n=6) As seen in Figure 3, based on five studies that analyzed CHOP-INTEND and HFMSE scores in their studies, all of the
Letter to Editor (n=2) studies showed an increase in CHOP-INTEND and HFMSE scores for treatment by Nusinersen in SMA children patients.
Finkel, et al. 2017 showed a significantly higher percentage of infants in the nusinersen group who had
CHOP-INTEND response than in the control group. A Higher CHOP-INTEND and 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
Studies included in review
Included

neurological function originally developed for normal infants, and in included studies that discuss HINE-2 score, showed
(n = 12) that HINE-2 score will increase after treatment by Nusinersen for SMA patients. Mean HINE-2 score after six months
Reports of included studies
of treatment was 2.5 ± 3.3 with a mean improvement of 1.4 ± 2.1 points (Pechmann et al., 2018). CMAP is
(n = 12)
Electrophysiological testing of the ulnar or peroneal nerve as indicators of motor neuron health (Swoboda KJ, et al.
2005). The increase in the CHOP INTEND score and the CMAP amplitude among infants who received nusinersen
confirms that nusinersen improves neuromuscular function (Finkel et al., 2017). Other than that, Nusinersen was
Figure 2. PRISMA Diagram Flowchart
approved by 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).

CONCLUSION 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
Nusinersen injection showed improvement in motor function, motor milestones, and motor neuron
only 59 from 193 patients (30.57%) that suffer SAE. Moreover, Chiriboga, et al. 2016 mentioned that there were no
health for spinal muscular atrophy children but Nusinersen caused some AEs. The most common AE
serious AEs during the study and nopatient experienced an AE causing discontinuation.
found is respiratory infection, especially in the upper respiratory tract. However, with the
considerable table of study, Nusinersen is good in pharmacokinetics. This study is the first systematic review that discusses the efficacy, safety, and pharmacokinetics of nusinersen for
Spinal Muscular Atrophy children in sufficient sample size and Nusinersen was approved for use in all SMA ptients,
across the different types. However, the limitation of this study is that nusinersen hasn’t spread all over the world
and repeated intrathecal delivery is required, thought to be very invasive and challenging, especially in young
and fragile infants but the trials show that this is well tolerated.

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