Guide
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease in which patients suffer from insufficient PRODUCTION of SMN protein due to the purity and deletion or mutation of the SMN1 gene (motor neuron survival gene 1), which in turn causes degeneration and death of α-motor neurons in the anterior horn of the spinal cord, and progressive muscle weakness and atrophy occur. Northinalsan is an antisense oligonucleotide (ASO) drug that targets exon mRNA 7 in the SMN2 gene, thereby increasing the production of full-length functional SMN proteins for the treatment of SMAs. Northinalson, the world's first SMA disease modification treatment, was approved by the U.S. Food and Drug Administration (FDA) in 2016 and approved for marketing in China in February 2019.
In recent years, a growing number of papers have reported real-world data applied by Northinalsen in different cohorts of SMA patients. Recently, a paper published in the Orphanet journal of Rare Diseases titled "Motor function in type 2 and 3 SMA patients treated with Nusinersen: a critical review and meta-analysis" Meta-analyses1 critically reviewed and analyzed real-world motor function data from patients with type 2 and type 3 SMA who received Norcinsen, subdivided the results according to SMA classification (type 2, type 3), age (children, adults) and different assessment indicators, and meta-analysed the available results. Available data collected in untreated patients using the same approach were also reported.
This meta-analysis showed that during the observation period of 10-14 months, northinalsen therapy had an improving effect on motor function in patients with type 2 and type 3 SMA. Although it is not possible to directly compare with the study data of untreated patients, the longitudinal changes in the treatment group (always positive) differ from the changes observed in the untreated group (always negative). This difference can be observed in the overall cohort or in subgroups segmented by age, typing, or functional status.
Overview of the study
In order to screen articles related to motor function in the treatment of SMA in Northinalson, Giorgia Coratti et al. applied search terms in pubmed, mediline and other databases: "spinal muscular atrophy", "SMA", and combined with the keywords "nusinersen", "Spinraza", and at the same time, combined "SMA" or "spinal muscular atrophy" with "motor function", "prognostic indicators", "natural history", to determine the changes in the untreated patient. A preliminary selection of 14,627 articles based on the title was followed by a series of full-text reviews and screenings to include 19 papers (13 of which were adults, 4 of whom were children, and 2 of which included both) reporting treatment with Nocinachon and 12 papers covering untreated cohort studies. See Figure 1.
Figure 1 Search and selection process using the PRISMA framework
The data in the above paper were analyzed, the changes and standard deviations of individual exercise prognosis indicators in different treatment groups were observed, and subdivided by age (children, adults), motor function (able to walk, unable to walk) and SMA classification (type 2, type 3). The Hammersmith Motor Function Scale Extended Edition (HFMSE), revised Upper Limb Module (RULM), and Average 6-Minute Walking Test (6MWT) were used to assess motor function in patients with SMA. The results showed that in the vast majority of studies, regardless of the typing, age or use of motor function assessment tools in patients with SMA, patient scores improved significantly after treatment with Northinalsen.
01 HFMSE scoring analysis results
The HFMSE scale is one of the most commonly used scales for SMA motor function assessments. In this meta-analysis, a total of 13 papers reporting treatment with Nocinazine and five papers covering untreated cohort studies were included. Three of the papers provided individual data on HFMSEs.
Results Showed that all patients treated with Nocinasin increased HFMSE scores (pooled mean change of 2.27; 95% CI, 1.41 to 3.13), while for untreated patients, HFMSE scores were significantly lower than baseline (pooled mean change of −1.00; 95% CI, -1.33 to -0.67); there was a statistically significant difference in combined mean change between treated and untreated patients (p<0.0001).
Multiple regression analysis found that the difference in HFMSE score was related to whether or not to receive noncinnasine (coefficient (SR)): 3.30 (0.51), p<0.0001), and there was no significant correlation with the classification of SMA (p=0.437) and the age of patients (p=0.981), and the results were consistent at 10/12/14/24 months of follow-up. See Figure 2.
Figure 2 HFMSE scoring results
02 RULM scoring analysis results
In this meta-analysis, a total of 13 papers reporting treatment with Nocinazine and five papers covering untreated cohort studies were included. Results showed that all but one report reported an increase in RULM score and a statistically significant overall benefit of noncinasine treatment (combined mean change of 1.11; 95% CI, 0.53 to 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 adult SMA patients was lower than that in children (coefficient (SE): −1.28 (0.40), p=0.002), which may be due to the emergence of a ceiling effect; when adjusted by SMA typing and age, The change in RULM score was significantly higher in the treatment 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.
03 6MWT analysis results
In this meta-analysis, a total of eight papers reporting treatment with Nosinassen and one paper covering untreated cohort studies were included. The results showed that all reports of treatment with noncinsan showed an increase in the distance of 6MWT, and the overall benefit of noncinasine treatment was statistically significant (the mean change in pooling was 19.80; 95% CI, 6.70 to 32.89), while the mean change after pooling was −8.29 (95% CI, -19.10 to 2.52) for untreated patients, and the mean change in pooling was statistically different in treated and untreated patients (p<0.0001).
Multiple regression analysis found that the increase in 6MWT distance was associated with noncinnassine treatment (coefficient (SE): 27.81 (10.43), p=0.008) when adjusted for age and whether or not to receive nocinnassine therapy, and no significant correlation with patient age (p=0.977).
04 Other scale analysis results
In addition, other scales of scoring were included in the review, including the Medical Research Council (MRC) Muscle Strength Assessment Scale, the Philadelphia Children's Hospital Neuromuscular Disease Adult Assessment Scale (CHOP ATEND), Motor Function Measurement (MFM), the Philadelphia Children's Hospital Neurological Disorder Infant Assessment Scale (CHOP INTEND), and hammersmith Infant Neurological Assessment (HINE) Part II - Exercise Milestones. The results of the study are not repeated.
The results of this meta-analysis showed that motor function improved in both patients with type 2 and type 3 SMA treated with Northinasin during the observation period of 10-14 months. Although it is not possible to directly compare with the study data of untreated patients, the longitudinal changes in the treatment group (always positive) differ from the changes observed in the untreated group (always negative). This difference can be observed in the overall cohort or in subgroups segmented by age, typing, or functional status.
Research implications
Previously reported papers in infants treated with Type 1 SMA treated with Northinason consistently showed improvements in survival, motor function, and motor milestones2-4. These findings differ from the known natural history of untreated infants with low survival rates in infants with type 1 SMA and never showing any functional improvement 5-9. Improvement in motor function in children with type 2 and type 3/adult SMA has also been reported, but the interpretation of the data and comparisons between different data sets are complicated by differences in the study cohort and the tools used to establish efficacy. The interpretation of the results is further complicated by the relative lack of age-specific reference data in untreated patients, particularly in the adult cohort.
The review reviewed and analysed data from real-world studies of motor function improvement in patients treated with type 2 and type 3 SMA treated with Northinasin, as well as the natural course of the disease in untreated patients to identify possible differences in data from untreated patients collected using the same method. The results showed that all studies receiving nocinnassan reported positive changes in HFMSE, regardless of age and SMA typing of the study cohort; RULM also showed positive changes, with smaller variations than HFMSE, possibly due to ceiling effects; and similar findings were made in the analysis of assessments such as MFM, MRC, and 6MWT, with each assessment indicator showing positive changes in all patients treated. It can be seen that in the vast majority of studies, the motor function of all SMA patients receiving noncinnasine was significantly improved, regardless of the type and age of SMA patients, regardless of the type and age of patients treated with noncinnasine.
The study is the first real-world study meta-analysis of treatment in Northinalsen, which answers the question of treatment benefits in patients of different ages in the clinic to some extent, while also aligning with the results observed in previous key clinical studies, providing further guiding evidence for clinical practice.
bibliography:
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.