Treatment of 5q-spinal muscular atrophy with nusinersen in Southern China: A single center retrospective study

doi:10.21203/rs.3.rs-2566569/v1

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Treatment of 5q-spinal muscular atrophy with nusinersen in Southern China: A single center retrospective study

https://doi.org/10.21203/rs.3.rs-2566569/v1

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Nusinersen is the first approved disease-modifing therapy for all 5q-spinal muscular atrophy patients regardless of age or disease severity. In 2019, nusinersen treatment was approved by China Food and Drug Administration. Here, we first present the results of nusinersen treatment in Southern China. We analyzed clinical and laboratory data from 45 5q-spinal muscular atrophy patients between December 2019 and May 2022. Nine patients with 5q-spinal muscular atrophy type 1, 22 patients with type 2 and 14 patients with type 3 were enrolled. Mean age receiving therapy was 51 months. The mutational analysis revealed 3 SMN2 gene copies in the majority of patients (80.0%). Two and 4 copies were found in 4.4% and 15.6%. Total 230 nusinersen injections were performed. 98% (44/45) patients improved or remained stabilized, and 2.0% (1/45) worsened on motor scales during the follow-up. Over 60% (27/44) patients had gained a responder rate (improvement ≥ 4 points) after 4 doses injection in functional test. Nusinersen was well tolerated. But there were still 44.4% patients suffering respiratory tract infection during therapy. In conclusion, our data indicates that nusinersen treatment is safety and effective in motor function recovery for many Chinese 5q-spinal muscular atrophy pediatric patients, but the improvement of respiratory function is not obvious, which needs further assessment.

5q-spinal muscular atrophy

SMN

nusinersen

Chinese

Spinal muscular atrophy (SMA) caused by a homozygous deletion or mutation in the survival motor neuron (SMN) 1 gene on chromosome 5q13.2 is the most common childhood-onset hereditary motor neuron disease .¹ The disease is characterized by progressive muscle weakness and atrophy, including skeletal muscles of the limbs and trunk, and of the bulbar and respiratory muscle due to the degeneration of anterior horn cells.² Based on the onset age and maximum motor function achieved, SMA is classified into 4 main phenotypes. SMA type 1 which is the most severity form, have severe hypotonia and intercostal muscle weakness before 6 months of age, usually develop respiratory failure before 2 years of life. SMA type 2 are able to sit, but never able to walk independently with onset at 6–18 months. SMA type 3, with onset after 18 months of age, are able to walk and stand unassisted, but with the progressive weakness and development of joint contractures and scoliosis, may necessitate the need of a wheelchair at some point. There is no cure in the past decade.³

The antisense oligonucleotide called nusinersen, as the first pharmacologic treatment for all 5q SMA, was approved by US Food and Drug Administration (FDA) in December 2016 and by China FDA in Febeury2019. Subsequent studies confirmed the drug beneficial effects on motor and respiratory functions recovery.^4,5 However, there is little experience in China. In this study, we firstly assessed the safety and efficacy of nusinersen treatment in Chinese infantile and childhood SMA patients.

Subjects and treatment with nusinersen

Data from 45 patients with 5q-SMA type 1,2 or 3 with nusinersen therapy in the department of pediatric endocrinology and genetic metabolism at the Guangzhou Women and Children’s Medical Center, China, were retrospectively analyzed from December 2019 to May 2022. The diagnosis of 5q-SMA was confirmed by onset of clinical signs and symptoms, genetically analyses that met the guidelines published in 2007 as consensus statement for standard of care in SMA.⁶ We reviewed the charts for the type of SMA, data of nusinersen administration and results of motor function outcome testing.

SMA patients who attended to our center received medical consultation by multidisciplinary team that included a neurologist specialized in neuromuscular disorders, an endocrinologist, an anesthesiologist, a physiotherapist and a clinical pharmacist. Patients received nusinersen injection in the pediatric anesthesia care unit. To alleviate patient’s anxious, anesthesiologist treated them with intravenous or oral sedation. All patients were administrated by intrathecal injection according to the recommended schedule with routine dose of nusinersen. Eight patients had scoliosis, data of X-ray were decribed in Fig. 1. The drug injection time was controlled over 1 to 3 minutes. After drug injection, patients were sent to the ambulatory care department and remained under observation supine for 4–6 hour before going home.

Evaluation

The baseline information pre-treatment including: SMN1 mutations, SMN2 copies, sex, age of symptom onset, age at diagonisis, age of first nusinersen, body weight, respiratory support, scoliosis, feeding status and motor function were collected. All patients underwent motor function assessments by an experienced physiotherapist using the test——Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorder (CHOP INTEND) or Expanded Hammersmith Functional Motor Scale (HFMSE) test.⁷ These assessments were performed before treatment initiation and each time of application.

Statistical analysis

Data on baseline demographics and clinical characteristics were presented with descriptive statistics. GraphPad Prism (version 5.0) software was used for statitiscal analysis. Linear regression was used to study the relationship between motor function score improvement and the age at treatment start or the disease duration time.

Baseline characteristic

Forty-five SMA patients were enrolled in the study, including 9 patients were SMA type1, 22 individuals were SMA type2 and 14 were SMA type3. The mean age at disease onset, at diagnosis and treatment start of anaylzed patients were 14, 20 and 51 months respectively. All patients had an SMN1 homozygous deletion of exon 7 or 8. The majority of patients had 3 SMN2 copies, seven patients had 4 copies and two patient had 2 SMN2 copies. In the SMA type1, three patients were divided into type 1c with the onset symptoms between 3 and 6 months, which implied no head control. They received nusinersen therapy at the age of 3,6 and 10 years old respectively. The clinical characteristics, SMN2 copies, spinal muscular atrophy symptoms at baseline were summarized in Table 1.

Table 1

Demographic and clinical characteristics data
	SMA type1	SMA type2	SMA type3
Number of patients	9	22	14
Gender
Female	1	9	6
Male	8	13	8
Age at disease onset, months
Mean ± SD	5.2 ± 1.3	10.6 ± 4.6	24.5 ± 16.02
Min-Max	2–6	6–21	12–60
Age at diagnosis, months
Mean ± SD	6.6 ± 2.0	13.4 ± 4.7	38.2 ± 18.5
Min-Max	4–9	7–21	13–96
Age at treatment start, months
Mean ± SD	35.2 ± 12.6	39.4 ± 23.4	79.3 ± 53.0
Min-Max	4−120	10–108	24–204
Body weight
Mean ± SD	10.8 ± 3.0	13.4 ± 5.9	25.1 ± 15.6
Min-Max	5.6–17.0	6.3–26.0	9.9–58.6
Ventilation
Not needed	5	22	14
Respiratory support	4	0	0
Feeding difficulties	2	1	0
Scoliosis	4	2	2
SMN2 copies, n (%)
2	1(11.1%)	1(4.5%)	0
3	8(88.9%)	20(90.9%)	8(57.1%)
4	0	1(4.5%)	6(42.9%)

Follow-up

Since December 2019, 230 total injections have given in 45 patients. There have no fail injection attempts and no individuals that were delayed treatment because of COVID-19. Anesthesia was used in 73.0% injections. 98.0% (44/45) patients acquired motor improvement or remained motor function stabilized. 61.3% (27/44) patients had gained a responder rate (improvement ≥ 4 points) in functional test. Detail data on motor function assessment ,body weight follow-up and respiratory infection during treatment were summarized in Table 2. Patients with early treatment or shorter disease duration tended to improve in motor functional tests more than the rest of the patients, but this effect was non-significant (p = 0.13 and p = 0.08). About 40% patients had the first moter improvements after the administration of the first dose. Patients with longer time of nusinersen treatment had significantly higher motor score improvement than the rest of patients (p = 0.0034), which was showed in Fig. 2.

Table 2

Characteristics of enrolled SMA patients under nusinersen therapy
Case	type	CHOP INTEND		HFMSE		Respiratory tract infection	Body weight(kg)
Case	type	Base	Last	Base	Last	Respiratory tract infection	Base	Last
1	1	4	27	-	-	Y/ 2^nd and 4^th dose	5.6	10.0
2	1	23	21	-	-	Y/ 3^rd and 4^th dose	10.3	11.8
3	1	31	45	-	-	Y/ 2^nd ,3^rd and 4^th dose	10.0	11.0
4	1	33	40	-	-	Y/ 2^nd dose	13.0	13.0
5	1	24	24	-	-	N	9.0	9.3
6	1	20	22	-	-	N	17.0	16.5
7	1	37	40	-	-	N	10.0	10.1
8	1	16	17	-	-	Y/ 2^nd dose	12.0	11.4
9	1	27	31	-	-	N	10.5	11.4
10	2	-	-	11	25	Y/ 6^th dose	11.8	17.8
11	2	34	60	-	-	N	7.5	9.0
12	2	-	-	42	54	Y/ 2^nd dose	9.4	9.8
13	2	-	-	30	33	Y/ 1^st, 3^rd dose	9.6	12.0
14	2	28	52	-	-	Y/4^th dose	10.3	9.8
15	2			31	34	Y/3^rd dose	14.5	14.5
16	2	-	-	13	22	N	10.4	11.5
17	2	-	-	30	34	N	13.0	13.9
18	2	-	-	26	33	N	17.0	17.0
19	2	19	20	-	-	N	25.1	26.5
20	2	24	29	-	-	N	26.0	26.1
21	2	-	-	17	22	Y/ 1^st dose	8.0	8.7
22	2	-	-	6	12	Y/ 1^st dose	11.5	11.7
23	2	-	-	14	17	N	12.3	13.3
24	2	45	48	-	-	N	9.8	10.2
25	2	14	21	-	-	N	10.5	10.8
26	2	11	19	-	-	N	12.1	12.7
27	2	-	-	17	19	N	17.1	17.8
28	2	-	-	15	19	N	10.0	10.0
29	2	-	-	22	31	N	13.3	13.9
30	2	-	-	8	14	N	21.3	21.8
31	2	-	-	17	19	N	26.0	25.0
32	3	-	-	40	55	Y/9^th and 10^th dose	12.6	17.5
33	3	-	-	48	53	Y/ 2^nd dose	15.6	18.2
34	3	-	-	32	38	Y/ 5^th dose	9.5	11.0
35	3	-	-	38	52	Y/2^nd dose	13.0	17.9
36	3	-	-	55	60	N	35.5	38.0
37	3	-	-	47	53	Y/ 5^th dose	40.7	45.0
38	3	-	-	54	57	N	58.6	59.0
39	3	-	-	12	14	Y/3^rd dose	22.0	24.4
40	3	-	-	22	25	N	52.5	55.0
41	3	-	-	33	40	Y/2^nd,3^rd dose	25.0	26.5
42	3	-	-	43	44	N	16.0	16.0
43	3	-	-	52	53	N	19.0	19..0
44	3	-	-	37	42	N	16.8	17.0
45	3	-	-	11	33	N	14.5	15.8

Safety

Through the study period, we did not observe any major complications and side effects related to nusinersen itself. Drug administration was tolerated well. Laboratory parameters in all children including blood count, coagulation, liver and kidney values, and CSF parameters showed in normal range before and after nusinersen intervention. The adverse events observed in patients were: respiratory tract infection (20/45, 44.4%), low fever (2/45, 4.4%) and flushing of face (1/45, 2.2%). Respiratory tract infection occurs in 55.6% (5/9) type1, 36.3% (8/22) type2 and 50% (7/14) type3 SMA patients. Four type1 and one type2 patients who suffered severe pneumonia received hospitalized treatment with ventilator supported in intensive care unit during nusinersen therapy. The other patients had mild upper respiratory tract infection and received outpatient treatment. Low fever and flushing in face were slight, which were gradually disappeared no more than 12 hours after injections. No CSF leakage was observed in our study.

Since nusinersen was approval by China FDA in 2019, Chinese SMA patients successively received nusinersen therapy. However, because the drug was exorbitantly expensive in the early days, only a small group of Chinese SMA patients could receive treatment. Here, we firstly conducted a retrospective observation of evaluating maximum 30 months or at least 4 loading doses treatment with nusinersen in the largest single center in Southern China. The result of our study indicated that nusiersen treatment was safe and effective to improve motor function for most patients.

Base on the previous clinical trial for SMA type I, the shorter disease duration, earlier medical treatment starting age, SMN2 copies and higher base line CHOP INTEND score may predict better milestone gains and treatment effect.^9,10,11,12 For SMA type II, the benefit of nusinersen treatment had been reported by Audic F in 89 patients followed by 12 months, by Mercuri E in 84 patients followed by 15 months, and by Coratti G in 77 patients followed by 12 months respectively.^13,14,15 In Coratti G study, it observed that there was a higher percentage of treated patients showing an improvement, and no deterioration in motor functional scores compared to the untreated patients. For SMA type Ⅲ, the clinically meaningful improvements in motor function scores were seen in 28% adult patients at 6 months, 35% at 10 months, and 40% at 14 months during therapy¹⁸, while the untreated patients showed a 12-month decline in motor function during the natural disease course.¹⁶

In our study, we treated 45 SMA patients with nusinersen therapy, and considered treatment to be safe in all cases and satisfactory for 98% cases. The patients showed an stable or rising motor scores, and the slowly increased body weight during treatment without any serious adverse events. Over 60% (27/44) patients had gained a responder rate (improvement ≥ 4 points).⁸ Only one patient remained deterioration on motor scales during the follow-up. Further, we observed that the effect of motor function improvement was inversely correlated with the age of initial medical treatment and disease duration, but positively correlated with the times of durg injection.

It’s worth noting that the frequency of respiratory tract infection in treated patients was still high. 44.4% patient suffered upper respiratory infection or pneumonia during follow-up. Five patients (11.1%) suffered serious pneumonia and needed for ventilator support, including one SMA typeⅡand four typeⅠpatients. After infection, these patients showed few positive changes or even retrogression in motor functional evaluation. Chen et al.¹⁹ published a 2 year single center experience and highlighted that children with SMA typeⅠtreated with nusinersen continued to develop considerable respiratory comorbidities. The paper by Lavie et al offer insights that respiratory support over the first 2 years of nusinersen treatment would reduce progressive decline and death in 90% SMA typeⅠpatients, which means the nusinersen treatment on respiratory positive outcome is still questionable, and the real-world respiratory experiences for SMA is still limited.²⁰

In conclusion, our data provides evidence that it’s safe and benefit effective with earlier initiation of nusinersen to various types of Chinese SMA patients from infant to childhood. The respiratory infection still continues during medical treatment. We need an observation with longer time and larger specimen to better understand the real-world of respiratory, nutritional and motor experience of nusinersen in China.

Ethics approval and consent to participate

This study involving all participants, material and all clinical data have been performed in accordance with the Declaration of Helsinki and have been approved by the Ethics Committee of Guangzhou Women and Children’s Medical Center, Guangzhou Medical University [approval number:20201221001]. Written informed consent was obtained from the proband’s parents with the agreement to share the clinical and genetic information for research analysis.

Consent for publication

Not Applicable.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Conflict of interest statement

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Author contributions

Dr Minyan Jiang designed and wrote the manuscript. Dr Cuili Liang followed up the SMA patients. Dr Yani Zhang, Kelu Zheng, Kaishou Xu, Lu He, Jianping Tao, Weizhe Wu, Ruidan Zheng, Min rao, Wen Zhang and Li Liu are members of multidisciplinary team, who are responsible for diagnosis and treatment of SMA patient. Dr Li Liu designed and revised the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (grant number 81800789 and 81873661) and by the Guangzhou women and children’s hospital Pre-National Natural Science Foundation of China (Pre-NSFC-2019-001).

Acknowledgements

Not applicable.

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No competing interests reported.

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Treatment of 5q-spinal muscular atrophy with nusinersen in Southern China: A single center retrospective study

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Abstract

Figures

Introduction

Materials And Methods

Subjects and treatment with nusinersen

Evaluation

Statistical analysis

Result

Baseline characteristic

Follow-up

Safety

Discussion

Declarations

References

Additional Declarations

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