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Introduction Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease in which patients with SMN1 gene (motor neuron survival gene 1) are either pure or absent or mutated, resulting in insufficient SMN protein production, which in turn causes precordial spinal cord syndrome.
Angular α-motor neurons degenerate and die, and progressive muscle weakness and atrophy occur
.
Nosinasan is an antisense oligonucleotide (ASO) drug that can target and promote the retention of exon 7 of SMN2 gene mRNA, thereby increasing the production of full-length functional SMN protein for the treatment of SMA
.
Nosinaxen, the world's first disease-modifying drug for SMA, was approved by the U.
S.
Food and Drug Administration (FDA) in 2016 and was approved for marketing in China in February 2019
.
In recent years, an increasing number of papers have reported real-world data on the application of nocinarsen in different cohorts of SMA patients
.
A recent meta-analysis1 published in the "Orphanet journal of Rare Diseases" entitled "Motor function in type 2 and 3 SMA patients treated with Nusinersen: a critical review and meta-analysis" critically reviewed and analyzed the Real-world motor function data of patients with type 2 and type 3 SMA treated with noxinarsen, the results were subdivided according to SMA type (type 2, type 3), age (children, adults) and different assessment indicators, and the results were analyzed.
Meta-analyses with results
.
Available data collected in untreated patients using the same method are also reported
.
This meta-analysis showed that treatment with spinaxine improved motor function in both type 2 and type 3 SMA patients over an observation period of 10-14 months
.
Although no direct comparison with study data in untreated patients was possible, longitudinal changes in the treated group (which were always positive) were different from those observed in the untreated group (which was always negative)
.
This difference could be observed in the overall cohort or in subgroups broken down by age, type or functional status
.
Research overview To screen articles related to motor function in the treatment of SMA with nosinasane, Giorgia Coratti et al.
applied the search terms in pubmed, mediline and other databases: "spinal muscular atrophy", "SMA", combined with the keywords "nusinersen", "Spinraza", meanwhile, searches for "SMA" or "Spinal Muscular Atrophy" in combination with "Motor Function", "Prognostic Indicators", "Natural History" to identify changes in untreated patients
.
A total of 14,627 articles were initially selected according to their titles.
After a series of full-text review and screening, a total of 19 articles (including 13 for adults, 4 for children, and 2 for both) were finally included, reporting on the treatment of nosinathan.
and 12 papers reporting on untreated cohort studies
.
See Figure 1
.
Figure 1 The data in the above papers were analyzed using the PRISMA framework search and selection process to observe the changes and standard deviations of individual motor prognostic indicators in different treatment groups, and grouped by age (children, adults), motor function (walking, unable to walk) And SMA classification (type 2, type 3) for subdivision
.
The motor function of SMA patients was assessed by various indicators including Hammersmith Motor Function Scale Extended (HFMSE), Revised Upper Limb Module (RULM), and Mean 6-Minute Walk Test (6MWT)
.
RESULTS: In the vast majority of studies, regardless of SMA patient type, age, or the use of motor function assessment tools, treatment with nocinarsen resulted in significant improvements in all patient scores
.
01HFMSE score analysis results HFMSE score scale is one of the most commonly used scales for SMA motor function assessment
.
In this meta-analysis, 13 papers reporting nasinasane treatment and 5 papers reporting on untreated cohort studies were included
.
Three of the papers provided individual data on HFMSE
.
RESULTS: HFMSE scores increased in all spinaxine-treated patients (pooled mean change, 2.
27; 95% CI, 1.
41 to 3.
13); whereas HFMSE scores were significantly decreased from baseline in untreated patients (pooled mean change -1.
00; 95% CI, -1.
33 to -0.
67); the pooled mean change between treated and untreated patients was statistically different (p<0.
0001)
.
Multiple regression analysis found that the difference in HFMSE score was related to whether or not to receive noxinarsen treatment (coefficient (standard error (SE)): 3.
30 (0.
51), p<0.
0001), and was related to SMA type (p=0.
437), patient age (p=0.
981) There was no significant correlation, and the results were consistent at 10/12/14/24 months of follow-up
.
See Figure 2
.
Figure 2 HFMSE score results 02RULM score analysis results In this meta-analysis, a total of 13 papers reporting noxinarsen treatment and 5 papers reporting untreated cohort studies were included
.
RESULTS: All but one report on spinaxine treatment showed an increase in RULM score, and the overall benefit of spinaxine treatment was statistically significant (pooled mean change, 1.
11; 95% CI, 0.
53-1.
69)
.
Multiple regression analysis found that the change in RULM score in patients with type 3 SMA was lower than that in patients with type 2 (coefficient (SE): −1.
00 (0.
37), p=0.
007), and the change in RULM score in adults with SMA was lower than that in children (coefficient (SE) : −1.
28 (0.
40), p=0.
002), possibly due to a ceiling effect; when adjusted for SMA type and age, the change in RULM score was significantly higher in the treated group than in the untreated group (coefficient (SE): 1.
0 (0.
45), p=0.
025), and the results were consistent at 10/12/14/24 months of follow-up
.
Results of the 036MWT analysis Eight papers reporting noxinarsen treatment and one paper reporting an untreated cohort study were included in this meta-analysis
.
RESULTS: All reports of spinaxine treatment showed an increase in 6MWT distance, and the overall benefit of spinaxine treatment was statistically significant (pooled mean change, 19.
80; 95% CI, 6.
70-32.
89); For treated patients, the pooled mean change was −8.
29 (95% CI, -19.
10 to 2.
52); the pooled mean change was statistically different between treated and untreated patients (p<0.
0001)
.
Multiple regression analysis found that, when adjusted for age and whether or not to receive nosinathan treatment, the increase in 6MWT distance was associated with nosinathan treatment (coefficient (SE): 27.
81 (10.
43), p=0.
008), but not with patient age.
Significant correlation (p=0.
977)
.
04 Results of other scale analyses In addition, reports included in this review included other rating scales, including: Medical Research Council (MRC) Strength Rating Scale, Children's Hospital of Philadelphia Assessment Scale for Adults with Neuromuscular Disorders (CHOP ATEND), Measurement of Motor Function (MFM), Children's Hospital of Philadelphia Inventory for Infant Assessment of Neuromuscular Disorders (CHOP INTEND), and Hammersmith Assessment of Infant Nervous System (HINE) Part II - Motor Milestones,
etc.
The results of its research are not repeated
.
The results of this meta-analysis showed that both type 2 and type 3 SMA patients treated with spinaxine had improved motor function over an observation period of 10-14 months
.
Although no direct comparison with study data in untreated patients was possible, longitudinal changes in the treated group (which were always positive) were different from those observed in the untreated group (which was always negative)
.
This difference could be observed in the overall cohort or in subgroups broken down by age, type or functional status
.
Implications of the study Previously reported papers in infants with type 1 SMA treated with noxinaxan consistently demonstrated improved survival, motor function, and motor milestones 2-4
.
These findings differ from the known natural history of untreated infants with type 1 SMA, which have a poor survival rate and have never shown any functional improvement 5-9
.
Improvements in motor function have also been reported in children/adult SMA types 2 and 3, but interpretation of the data and comparisons between different datasets are complicated by differences in study cohorts and differences in the tools used to establish efficacy
.
Interpretation of the results is further complicated by the relative lack of age-specific reference data in untreated patients, especially in the adult cohort
.
This review reviewed and analyzed data from real-world studies on motor function improvement in patients with type 2 and 3 SMA treated with spinaxine, as well as the natural history of untreated patients to determine the potential for data collected using the same methods in untreated patients.
differences exist
.
RESULTS: Regardless of cohort age and SMA type, positive HFMSE changes were reported in all studies receiving spinaxine; RULM also showed positive changes, with smaller magnitudes of changes than HFMSE, likely due to ceiling effects ; Similar findings were found when analyzing assessments such as MFM, MRC, and 6MWT, showing positive changes in every assessment in all patients treated
.
CONCLUSIONS: In the vast majority of studies, motor function was significantly improved in all SMA patients treated with spinaxine, regardless of SMA patient type and age, compared with patients who did not receive spinaxine
.
This study is the first meta-analysis of real-world studies on the treatment of nosinaxan, which answers the question of the benefits of treatment in patients of different ages in the clinic to a certain extent, and is also consistent with the results observed in previous pivotal clinical studies.
Clinical practice provides further guiding evidence
.
References: 1.
Giorgia Coratti, et al.
Orphanet J Rare Dis.
(2021) 16:430.
2.
Pane M, et al.
Ann Neurol.
2019;86(3):443–51.
3.
Aragon-Gawinska K, et al.
Neurology.
2018;91(14):e1312–8.
4.
Pechmann A, et al.
J Neuromuscul Dis.
2020;7(1):41–6.
5.
Finkel RS, et al.
Neurology.
2014;83(9 ):810–7.
6.
Mercuri E, et al.
Orphanet J Rare Dis.
2020;15(1):84.
7.
Kolb SJ, et al.
Ann Neurol.
2017;82(6):883–91.
8.
De Sanctis R, et al.
Neuromuscul Disord.
.
2016;26(11):754–9.
9.
De Sanctis R, et al.
Neuromuscul Disord.
2018;28(1):24–8.
Angular α-motor neurons degenerate and die, and progressive muscle weakness and atrophy occur
.
Nosinasan is an antisense oligonucleotide (ASO) drug that can target and promote the retention of exon 7 of SMN2 gene mRNA, thereby increasing the production of full-length functional SMN protein for the treatment of SMA
.
Nosinaxen, the world's first disease-modifying drug for SMA, was approved by the U.
S.
Food and Drug Administration (FDA) in 2016 and was approved for marketing in China in February 2019
.
In recent years, an increasing number of papers have reported real-world data on the application of nocinarsen in different cohorts of SMA patients
.
A recent meta-analysis1 published in the "Orphanet journal of Rare Diseases" entitled "Motor function in type 2 and 3 SMA patients treated with Nusinersen: a critical review and meta-analysis" critically reviewed and analyzed the Real-world motor function data of patients with type 2 and type 3 SMA treated with noxinarsen, the results were subdivided according to SMA type (type 2, type 3), age (children, adults) and different assessment indicators, and the results were analyzed.
Meta-analyses with results
.
Available data collected in untreated patients using the same method are also reported
.
This meta-analysis showed that treatment with spinaxine improved motor function in both type 2 and type 3 SMA patients over an observation period of 10-14 months
.
Although no direct comparison with study data in untreated patients was possible, longitudinal changes in the treated group (which were always positive) were different from those observed in the untreated group (which was always negative)
.
This difference could be observed in the overall cohort or in subgroups broken down by age, type or functional status
.
Research overview To screen articles related to motor function in the treatment of SMA with nosinasane, Giorgia Coratti et al.
applied the search terms in pubmed, mediline and other databases: "spinal muscular atrophy", "SMA", combined with the keywords "nusinersen", "Spinraza", meanwhile, searches for "SMA" or "Spinal Muscular Atrophy" in combination with "Motor Function", "Prognostic Indicators", "Natural History" to identify changes in untreated patients
.
A total of 14,627 articles were initially selected according to their titles.
After a series of full-text review and screening, a total of 19 articles (including 13 for adults, 4 for children, and 2 for both) were finally included, reporting on the treatment of nosinathan.
and 12 papers reporting on untreated cohort studies
.
See Figure 1
.
Figure 1 The data in the above papers were analyzed using the PRISMA framework search and selection process to observe the changes and standard deviations of individual motor prognostic indicators in different treatment groups, and grouped by age (children, adults), motor function (walking, unable to walk) And SMA classification (type 2, type 3) for subdivision
.
The motor function of SMA patients was assessed by various indicators including Hammersmith Motor Function Scale Extended (HFMSE), Revised Upper Limb Module (RULM), and Mean 6-Minute Walk Test (6MWT)
.
RESULTS: In the vast majority of studies, regardless of SMA patient type, age, or the use of motor function assessment tools, treatment with nocinarsen resulted in significant improvements in all patient scores
.
01HFMSE score analysis results HFMSE score scale is one of the most commonly used scales for SMA motor function assessment
.
In this meta-analysis, 13 papers reporting nasinasane treatment and 5 papers reporting on untreated cohort studies were included
.
Three of the papers provided individual data on HFMSE
.
RESULTS: HFMSE scores increased in all spinaxine-treated patients (pooled mean change, 2.
27; 95% CI, 1.
41 to 3.
13); whereas HFMSE scores were significantly decreased from baseline in untreated patients (pooled mean change -1.
00; 95% CI, -1.
33 to -0.
67); the pooled mean change between treated and untreated patients was statistically different (p<0.
0001)
.
Multiple regression analysis found that the difference in HFMSE score was related to whether or not to receive noxinarsen treatment (coefficient (standard error (SE)): 3.
30 (0.
51), p<0.
0001), and was related to SMA type (p=0.
437), patient age (p=0.
981) There was no significant correlation, and the results were consistent at 10/12/14/24 months of follow-up
.
See Figure 2
.
Figure 2 HFMSE score results 02RULM score analysis results In this meta-analysis, a total of 13 papers reporting noxinarsen treatment and 5 papers reporting untreated cohort studies were included
.
RESULTS: All but one report on spinaxine treatment showed an increase in RULM score, and the overall benefit of spinaxine treatment was statistically significant (pooled mean change, 1.
11; 95% CI, 0.
53-1.
69)
.
Multiple regression analysis found that the change in RULM score in patients with type 3 SMA was lower than that in patients with type 2 (coefficient (SE): −1.
00 (0.
37), p=0.
007), and the change in RULM score in adults with SMA was lower than that in children (coefficient (SE) : −1.
28 (0.
40), p=0.
002), possibly due to a ceiling effect; when adjusted for SMA type and age, the change in RULM score was significantly higher in the treated group than in the untreated group (coefficient (SE): 1.
0 (0.
45), p=0.
025), and the results were consistent at 10/12/14/24 months of follow-up
.
Results of the 036MWT analysis Eight papers reporting noxinarsen treatment and one paper reporting an untreated cohort study were included in this meta-analysis
.
RESULTS: All reports of spinaxine treatment showed an increase in 6MWT distance, and the overall benefit of spinaxine treatment was statistically significant (pooled mean change, 19.
80; 95% CI, 6.
70-32.
89); For treated patients, the pooled mean change was −8.
29 (95% CI, -19.
10 to 2.
52); the pooled mean change was statistically different between treated and untreated patients (p<0.
0001)
.
Multiple regression analysis found that, when adjusted for age and whether or not to receive nosinathan treatment, the increase in 6MWT distance was associated with nosinathan treatment (coefficient (SE): 27.
81 (10.
43), p=0.
008), but not with patient age.
Significant correlation (p=0.
977)
.
04 Results of other scale analyses In addition, reports included in this review included other rating scales, including: Medical Research Council (MRC) Strength Rating Scale, Children's Hospital of Philadelphia Assessment Scale for Adults with Neuromuscular Disorders (CHOP ATEND), Measurement of Motor Function (MFM), Children's Hospital of Philadelphia Inventory for Infant Assessment of Neuromuscular Disorders (CHOP INTEND), and Hammersmith Assessment of Infant Nervous System (HINE) Part II - Motor Milestones,
etc.
The results of its research are not repeated
.
The results of this meta-analysis showed that both type 2 and type 3 SMA patients treated with spinaxine had improved motor function over an observation period of 10-14 months
.
Although no direct comparison with study data in untreated patients was possible, longitudinal changes in the treated group (which were always positive) were different from those observed in the untreated group (which was always negative)
.
This difference could be observed in the overall cohort or in subgroups broken down by age, type or functional status
.
Implications of the study Previously reported papers in infants with type 1 SMA treated with noxinaxan consistently demonstrated improved survival, motor function, and motor milestones 2-4
.
These findings differ from the known natural history of untreated infants with type 1 SMA, which have a poor survival rate and have never shown any functional improvement 5-9
.
Improvements in motor function have also been reported in children/adult SMA types 2 and 3, but interpretation of the data and comparisons between different datasets are complicated by differences in study cohorts and differences in the tools used to establish efficacy
.
Interpretation of the results is further complicated by the relative lack of age-specific reference data in untreated patients, especially in the adult cohort
.
This review reviewed and analyzed data from real-world studies on motor function improvement in patients with type 2 and 3 SMA treated with spinaxine, as well as the natural history of untreated patients to determine the potential for data collected using the same methods in untreated patients.
differences exist
.
RESULTS: Regardless of cohort age and SMA type, positive HFMSE changes were reported in all studies receiving spinaxine; RULM also showed positive changes, with smaller magnitudes of changes than HFMSE, likely due to ceiling effects ; Similar findings were found when analyzing assessments such as MFM, MRC, and 6MWT, showing positive changes in every assessment in all patients treated
.
CONCLUSIONS: In the vast majority of studies, motor function was significantly improved in all SMA patients treated with spinaxine, regardless of SMA patient type and age, compared with patients who did not receive spinaxine
.
This study is the first meta-analysis of real-world studies on the treatment of nosinaxan, which answers the question of the benefits of treatment in patients of different ages in the clinic to a certain extent, and is also consistent with the results observed in previous pivotal clinical studies.
Clinical practice provides further guiding evidence
.
References: 1.
Giorgia Coratti, et al.
Orphanet J Rare Dis.
(2021) 16:430.
2.
Pane M, et al.
Ann Neurol.
2019;86(3):443–51.
3.
Aragon-Gawinska K, et al.
Neurology.
2018;91(14):e1312–8.
4.
Pechmann A, et al.
J Neuromuscul Dis.
2020;7(1):41–6.
5.
Finkel RS, et al.
Neurology.
2014;83(9 ):810–7.
6.
Mercuri E, et al.
Orphanet J Rare Dis.
2020;15(1):84.
7.
Kolb SJ, et al.
Ann Neurol.
2017;82(6):883–91.
8.
De Sanctis R, et al.
Neuromuscul Disord.
.
2016;26(11):754–9.
9.
De Sanctis R, et al.
Neuromuscul Disord.
2018;28(1):24–8.