|Year : 2020 | Volume
| Issue : 3 | Page : 165-169
Nusinersen in spinal muscular atrophy: Respiratory outcomes at tertiary care centers
Fahad Alsohime1, Mohamad-Hani Temsah1, Muneera Al-Jelaify1, Hind Ali Bafaqih2, Kamal El Masri3, Ahmed Abusibah4, Ayman Al-Eyadhy1, Gamal Hasan5, Ali Alhaboob1, Majed Alabdulhafid1, Mohammed Abdulrahman Almazyad1, Abdulaziz Alghamdi6, Fahad A Bashiri7
1 Department of Pediatric, College of Medicine, King Saud University; Department of Pediatric, Pediatric Intensive Care Unit, King Saud University Medical City, Riyadh, Saudi Arabia
2 Department of Pediatrics, Division of Pediatric Intensive Care, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
3 Department of Pediatric, Pediatric Intensive Care Unit, King Fahad Specialist Hospital, Dammam, Saudi Arabia
4 Department of Pediatric, Pediatric Intensive Care Unit, Arryan Hospital, Dr. Suliman Al Habib Medical Group, Riyadh, Saudi Arabia
5 Department of Pediatric, Pediatric Intensive Care Unit, King Saud University Medical City, Riyadh, Saudi Arabia; Department of Pediatrics, Faculty of Medicine, Assiut University, Asyut, Egypt
6 Department of Pediatrics, Division of Pediatric Neurology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
7 Department of Pediatric, College of Medicine, King Saud University; Department of Pediatric, Division of Neurology, King Saud University Medical City, Riyadh, Saudi Arabia
|Date of Submission||15-Dec-2019|
|Date of Decision||04-Jan-2020|
|Date of Acceptance||18-Jan-2020|
|Date of Web Publication||02-Jul-2020|
Department of Pediatrics, College of Medicine, King Saud University, P. O. 14135, Riyadh 11424
Source of Support: None, Conflict of Interest: None
Objectives: The objective of the study wasto describe the effect of nusinersen therapy and its 1st-year associated outcomes, weaning of ventilator support, and length of stay in pediatric intensive care among ventilator-dependent spinal muscular atrophy (SMA) patients. Methods: This is a multicenter, retrospective case series study that was conducted in four tertiary care centers in Saudi Arabia. We report all the genetically diagnosed SMA ventilator-dependent patients who were admitted to the pediatric intensive care unit (PICU) and received a course of nusinersen therapy from (January 2017 to March 2018). The study endpoints were success to wean or extubate the patient and discharge from the PICU. Results: Five patients from four tertiary PICUs were included in this report. All five patients received a minimum of four doses of nusinersen intrathecally as per the manufacturer. At 12 months postinitiation of therapy, only one patient showed clinical improvement, while the other four patients did not experience improvement in their respiratory status following the administration of nusinersen. These four patients are still admitted in the PICU due to the inability to wean them from respiratory support. The remaining patient was discharged to home successfully and neither require any home ventilatory support nor oxygen therapy. Conclusion: In conclusion, our clinical experience and data suggest that the response to nusinersen therapy is very likely but mostly dependent on the time of initiation of nusinersen therapy and the cumulative number of doses among other variables related to disease severity. However, further studies targeting a larger group of patients with better standardized respiratory care are needed to investigate the effect of nusinersen on particularly the long-term outcomes.
Keywords: Nusinersen, pediatric intensive care, spinal muscular atrophy, ventilator dependent
|How to cite this article:|
Alsohime F, Temsah MH, Al-Jelaify M, Bafaqih HA, Masri KE, Abusibah A, Al-Eyadhy A, Hasan G, Alhaboob A, Alabdulhafid M, Almazyad MA, Alghamdi A, Bashiri FA. Nusinersen in spinal muscular atrophy: Respiratory outcomes at tertiary care centers. J Nat Sci Med 2020;3:165-9
|How to cite this URL:|
Alsohime F, Temsah MH, Al-Jelaify M, Bafaqih HA, Masri KE, Abusibah A, Al-Eyadhy A, Hasan G, Alhaboob A, Alabdulhafid M, Almazyad MA, Alghamdi A, Bashiri FA. Nusinersen in spinal muscular atrophy: Respiratory outcomes at tertiary care centers. J Nat Sci Med [serial online] 2020 [cited 2020 Sep 24];3:165-9. Available from: http://www.jnsmonline.org/text.asp?2020/3/3/165/283211
| Introduction|| |
Spinal muscular atrophy (SMA) is a congenital, autosomal recessive disease characterized by mutation of the survival motor neuron (SMN) gene, SMN1, located on 5q13.
The SMN1 gene is critical for the survival and function of motor neurons., Symptom onset occurs within the first few months of life, and it is characterized by increasing muscle weakness, hypotonia leading to lung underdevelopment, hypoventilation, and inability to clear airway secretions. The primary cause of mortality in these patients is respiratory insufficiency. According to the international consensus statement for standard of care in SMA patients, a wide spectrum of treatment options can be offered to those patients, ranging from no ventilatory support to complete mechanical ventilatory support.
There was no approved pharmacological therapy for the management of spinal muscular atrophy until December
In 2016 when the Food and Drug Administration approved nusinersen, it was the only available medication for this life-limiting condition. Nusinersen is a synthetic antisense oligonucleotide that promotes the inclusion of exon 7, which helps promote the production of SMN proteins. Previous clinical trials have demonstrated the safety and tolerability of multiple intrathecal doses of nusinersen.,, In addition, there is evidence that nusinersen has the potential to improve motor function as well as mechanical functional outcomes and ventilator-free survival.
Following the approval of nusinersen by the Food and Drug Administration, several countries, including Saudi Arabia approved the drug for SMA
Saudi Arabia approved the drug for SMA. However, the high cost of nusinersen and complex logistics related to its administration are restricting patient access to therapy.
This report aims to describe the effect of nusinersen and its associated outcomes in terms of ventilator support and length of stay in pediatric intensive care among the subcategories of SMA patients who are ventilator dependent.
| Methods|| |
This is a multicenter retrospective case series study that was conducted in four tertiary centers in Saudi Arabia: King Saud University Medical City, Prince Sultan Armed Forces Hospital, Sulaiman Al Habib Hospital, and King Fahad Specialist Hospital in Dammam.
We included all the five SMA patients who were admitted to the pediatric intensive care unit (PICU) in the aforementioned institutes with a genetic documentation of homozygous deletion or mutation in the SMN1 gene, known to be ventilator dependent, and they received the course of nusinersen therapy as recommended by the manufacturer (January 2017–March 2018). All patients received a minimum of four intrathecal injections (12 mg/injection) at days 0, 15, 29, and 64, as loading then one dose every 4 months as maintenance.
Treatment outcomes were assessed for all patients and were defined based on the ability to wean and/or extubate their ventilatory support and their length of PICU stay at 12 months of initiation therapy with nusinersen.
As these were individual case reports that were retrospectively reported anonymously, the Institutional Review Board of King Saud University reviewed the study and waived the need for approval.
| Results|| |
The study included a total of five patients who were fulfilling the inclusion criteria. A summary of their demographic and clinical characteristics is shown below.
This is a 22-month-old boy who had onset of his symptoms at the age of 4 months, and the diagnosis of SMA type I was confirmed genetically at the age of 9 months. He had multiple PICU admissions due to recurrent respiratory tract infections complicated by respiratory insufficiency, which justified the need for intermittent ventilatory support. He was admitted on five different occasions to the PICU, with an average duration of ventilatory support of 8 days during each hospital stay.
Nusinersen was administered to the patient at the age of 13 months, and he received by the time of data collection (which is the appropriate time window for response assessment based on the clinical studies, 6–12 months posttreatment) a total of five doses as per protocol. The patient was subsequently admitted four times after the 6 months therapy with nusinersen. During each admission, the patient had a similar presentation characterized by respiratory insufficiency due to a respiratory tract infection. Noninvasive ventilatory support was required for 6 days on average during each PICU admission. The patient was discharged after the last episode and is currently 26-month old baby; he is at home without ventilator support nor oxygen therapy.
The patient is a 23-month-old girl who was diagnosed as SMA Type I at the age of 7 months and has been ventilator dependent since the age of 13 months. Nusinersen was offered to the patient at the age of 17 months and she received a total of four doses at the time of data collection. The patient is still hospitalized at the PICU and could not be weaned from mechanical ventilation.
This is a 22-month-old girl who had a confirmed diagnosis of SMA Type II since the age of 6 months. Upon her admission to the PICU, she had severe hypotonia and respiratory failure. Since presenting to the hospital, she has been hospitalized at the PICU due to the inability to wean her from respiratory support. Nusinersen was administered to the patient at the age of 15 months, and by the time of assessment, she has received a total of four doses. The patient is still hospitalized in the PICU and could not be weaned from mechanical ventilation.
This is a 3-year-old boy who was symptomatic since the age of 3 months; he had hypotonia with frequent respiratory infections and was diagnosed as SMA Type II at the age of 14 months. He was admitted to the PICU at the age of 12 months. Since that time, he has been hospitalized at the PICU and has been dependent on mechanical ventilation. Nusinersen was administered to the patient at the age of 2 years and 7 months, in a total of four doses. The patient is still hospitalized at the PICU and could not be weaned from mechanical ventilation.
This is a 20-month-old boy with a confirmed diagnosis of SMA Type I at the age of 4 months. He was admitted to the PICU for respiratory failure and has been dependent on mechanical ventilation since admission. He received his first dose of nusinersen at the age of 14 months followed by four doses as recommended. The patient is still admitted to the PICU and could not be weaned from mechanical ventilation.
There were no safety concerns identified in association with receiving the nusinersen therapy for the five cases.
[Table 1] summarizes the demographic, clinical, and outcome measures for the studied patients.
|Table 1: Summary of the patients' characteristics and outcomes following nusinersen administration|
Click here to view
| Discussion|| |
The efficiency of nusinersen in SMA has showed in several reports.,, However, a major breakthrough was achieved in a randomized, double-blind, sham-controlled Phase III clinical study “ENDEAR,” which was terminated early as an interim analysis showed significantly favorable results in the nusinersen group. All the patients in the control group were subsequently switched to the treatment group. In another clinical trial conducted among SMA patients aged 2–12 years with SMA symptom onset at age >6 months, investigators found statistically and clinically significant improvements in motor function in the nusinersen group versus sham-treated children.
This case series report represents the first report that shows the clinical characteristics and outcomes measures for a subcategory of SMA patients who are ventilator dependent, admitted to the PICU, and received nusinersen therapy as a newly approved and introduced therapy for such patients in Saudi Arabia. This treatment was given to these patients with off label indication, based on the treating team recommendations for the families' desperate need for a therapeutic trial.
In this case review, the majority of the studied patients did not experience an improvement in their respiratory status following the administration of nusinersen except for case no. 1. In his case, he was successfully weaned of noninvasive mechanical ventilation and ultimately discharged home without the need for ventilatory support. The improvement in his symptoms may be attributed to the use of nusinersen, as this patient's course did not follow the expected progression of this disease where they become dependent on mechanical ventilatory support. The other four patients did not manifest significant improvement in their respiratory status and failed to be weaned from mechanical ventilation and remained admitted in the PICU.
The failure of nusinersen therapy to improve outcomes in the other four cases might be due to multiple reasons. Reason one is the possibility that the therapeutic window was missed due to the late administration of nusinersen to these patients, who had been dependent on mechanical ventilation and were exposed to its consequences, including ventilator-induced respiratory muscle atrophy that might make an unfavorable response to nusinersen therapy. Our patients were started nusinersen therapy at variable ages (earliest therapy started at the age of 13 months and the eldest at the age of 31 months) and variable time interval from the onset of symptoms to the initiation of nusinersen therapy ranging between 9 and 28 months.
This is why some researchers recommended initiating treatment before the potentially irreversible neuronal loss or motor neuron damage, or within the 1st month, and if possible, during the early neonatal period.
Data fromin vivo studies conducted in rodents and larger animals suggest that when therapy is being administered in the early course of SMA, this might correlate with better motor performance, prolonged survival, and infrequently recovery of the pathological phenotype. In addition, recent clinical trials on pediatric patients with SMA Type 1 have demonstrated more rapid attainment of motor milestones and decreased disease severity due to early administration of treatment at an early age and during the presymptomatic stage.,
According to one report, while the therapeutic window is narrow, children with severe SMA Type I can benefit from treatment. Data from autopsy series and neurophysiological studies suggest that treatment might have an effect on the disease phenotype within the first 3 months. Conversely, the effect is mediocre when the treatment is administered between 3 and 6 months.,,
Reason two: the four patients in our case series were diagnosed to have SMA at variable ages, with the earliest by the age of 4 months and the eldest by the age of 14 months with an average age at diagnosis of 10 months. Such relatively late diagnosis could have an impact on the expected outcome after nusinersen therapy due to the possible consequences of chronic ventilation on the status of respiratory muscles and the possible occurrence of atrophy.
This case series population differs from that described in the ENDEAR study which involved SMA Type I patients only and all patients had the onset of symptoms at the age of fewer than 6 months. They also received nusinersen therapy at the median time of 13.1 weeks after the onset of symptoms. Importantly, the ENDEAR results suggested that the early initiation of therapy (within 13.1 weeks of symptoms onset) was most beneficial and that a minimum treatment window (not clearly defined) may be necessary to observe the full benefit of the nusinersen therapy.
These findings raise a series of concerns, including whether more evidence-based data are needed to determine the ability of nusinersen to produce the desired result and improved respiratory status in specific patient subgroups. Furthermore, due to the lack of research data, there might be a need to standardize respiratory care in these patients to achieve better outcomes. Although the cases in this report were managed in a tertiary care setting, variations of intensivists' therapeutic attitude toward SMA patients and variable awareness of the international consensus for the standard of care in SMA patients may have resulted in the lack of standardization of care. A recent study revealed that about half of 169 physicians treating SMA patients is Saudi Arabia were uncertain about nursinersen treatment protocol for SMA-diagnosed patients, while the other half were hesitant about its outcomes. Our current findings reinforce the need for strict selection criteria for SMA patients who are more likely to benefit from this novel treatment rather than prolongation of their mechanical ventilation and hospitalization without significant, meaningful clinical results.
Prolongation of hospitalization for our reported patients is another consideration. Cost-effectiveness of nusinersen in the treatment of patients with infantile-onset SMA is a major consideration for these children. A recent study from Sweden found that although nusinersen resulted in overall survival and quality-adjusted life-year benefits, this was associated with incremental costs above €2 million per patient's lifespan.
Although previous reports have demonstrated the efficacy of nusinersen for the management of SMA,,, outcomes remain undefined among ventilator-dependent SMA patients who are hospitalized at the PICU. In the ENDEAR study, 26% of the patients in the nusinersen treatment group had ventilatory support, but the investigators did not specify to what degree the patients were dependent. Three months into the study, the investigators reported that 15% of the patients in the nusinersen treatment group needed permanent ventilatory support. The number of patients requiring mechanical support increased to 31% at 13 months of the study in the nusinersen treatment group compared to 8% in the control group who needed permanent ventilatory support at 3 months and 48% at 13 months.
However, due to the limited sample size, further studies targeting a larger group of patients with better standardized respiratory care are needed to investigate the effect of nusinersen on this subcategory of ventilator-dependent SMA patients, particularly regarding the long-term outcomes.
| Conclusion|| |
In conclusion, our clinical experience and data suggest that the response to nusinersen therapy is very likely but mostly dependent on the time of initiation of nusinersen therapy and the cumulative number of doses among other variables related to disease severity.
However, further studies targeting a larger group of patients with better standardized respiratory care are needed to investigate the effect of nusinersen on particularly the long-term outcomes.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
The authors would like to thank the Deanship of scientific research for funding and supporting this research project.
Financial support and sponsorship
This project was supported by the College of Medicine Research Centre, Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia. The funder had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest
There are no conflicts of interest.
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